Comprehensive Dermatologic Drug Therapy E-Book

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Safely and effectively treat a full range of skin disorders with Comprehensive Dermatologic Drug Therapy, 3rd Edition! This trusted dermatology reference provides concise, complete, up-to-date guidance on today's full spectrum of topical, intralesional, and systemic drugs. Dr. Steven E. Wolverton and a team of leading international experts clearly explain what drugs to use, when to use them, and what to watch out for.

  • Consult this title on your favorite e-reader with intuitive search tools and adjustable font sizes. Elsevier eBooks provide instant portable access to your entire library, no matter what device you’re using or where you’re located.
  • Prescribe with confidence thanks to quick-access summaries of indications/contraindications, dosage guidelines, drug interactions, drug monitoring guidelines, adverse effects, and treatment protocols.
  • Assess your knowledge and prepare for certification or recertification with more than 800 review questions and answers throughout.
  • Contain costs and meet patient expectations with purchase information provided for major drugs.
  • Quickly evaluate drug options for each disease discussed using a highly detailed, disease-specific index.
  • Discover the best uses for new biologic therapeutics such as ustekinumab and rituximab, as well as newly improved TNF inhibitors.
  • Offer your patients the very latest in cosmetic procedures, including chemical peels, intradermal fillers, and botulinum toxin.
  • Use the safest and most effective drugs possible with new chapters on irritants and allergens in topical therapeutic agents, plus a new, separate chapter on mycophenolate mofetil.
  • Review drugs recently taken off the market by the FDA, and use that knowledge to improve your current dermatologic drug therapy.

Subjects

Books
Savoirs
Medicine
Botox
Pediculosis pubis
Drug combination
Editorial
Vitamin D
Anthelmintic
SAFETY
Oncology
Herpes simplex
Amoebic liver abscess
Systemic lupus erythematosus
Franceschetti?Klein syndrome
Arthropod
Gingivitis
Acne
Lupus erythematosus
Ulceration
The Only Son
Histamine antagonist
Canakinumab
Patient education
Tumor necrosis factors
Mouth
Belimumab
Ustekinumab
IL-23
Bexarotene
Alitretinoin
Mycophenolate mofetil
Photopheresis
Enzyme inhibitor
Complicity
Cyproheptadine
Alpha hydroxy acid
Long-term care
Venous ulcer
Psoralen
Risedronic acid
Glycolic acid
Carcinogenesis
Octyl methoxycinnamate
Hydroxychloroquine
Adverse event
Tazarotene
Atopic dermatitis
Dermatitis
Interleukin 12
Pregnancy
Insect repellent
Mycosis fungoides
Actinic keratosis
Acitretin
Irritant
Ivermectin
Retinoid
Keratolytic
Alendronic acid
Fatty liver
Urticaria
Mupirocin
Bacitracin
Topical
Hydroxycarbamide
Medical Center
Anti-inflammatory
Pharmacodynamics
Biological agent
Light therapy
Cephalosporin
Anesthetic
Permethrin
Stroke
Ichthyosis vulgaris
Psoriatic arthritis
Itraconazole
Graft-versus-host disease
Antifungal drug
Inhibitor
Glucocorticoid
Mycophenolic acid
Protein isoform
Seborrhoeic dermatitis
B-cell chronic lymphocytic leukemia
Hair coloring
Applause
Photodynamic therapy
Sarcoptes scabiei
H1 antagonist
Cytotoxicity
Sunscreen
Generic drug
Methotrexate
Survey
Immunosuppressive drug
Tetralogy of Fallot
Complete blood count
Androgen
Tired
Demographics
Isotretinoin
Titanium dioxide
Alopecia
Pharmacist
Intravenous therapy
U.S. Patients' Bill of Rights
Local anesthetic
Alopecia areata
Randomized controlled trial
Paste
Ciclosporin
Creativity
Hirsutism
Hypertension
Acne vulgaris
Dermatology
Mucous membrane
Hematology
Crohn's disease
Allergen
Multiple sclerosis
Informed consent
Antiviral drug
Salicylic acid
Risk management
Rheumatoid arthritis
Pharmacology
Pediatrics
Penicillin
Neurology
Major depressive disorder
Chemotherapy
Caesium
Bactericide
Appendix
Ascorbic acid
Allele
Antibacterial
Anxiety
Oxiconazole
Cyclophosphamide
Fluconazole
Finastéride
Ciclosporine
Terbinafine
Doxycycline
Gene
Filler
Hydroquinone
Shampoo
Étanercept
Cholécalciférol
Rituximab
Méthotrexate
Format
Toxin
Desquamation
Cortisone
Lactation
Azathioprine
Electronic
Service
Thalidomide
Lidocaïne
Prednisone
Contact
Cytokine
Dapsone
Psoriasis
Son
Copyright

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Published 18 October 2012
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EAN13 9781455738014
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Comprehensive Dermatologic
Drug Therapy
Third Edition
Stephen E. Wolverton, MD
Theodore Arlook Professor of Clinical Dermatology,
Department of Dermatology, Indiana University School of
Medicine
Chief of Dermatology, Roudebush VA Medical Center,
Indianapolis, IN, USA
S a u n d e r sTable of Contents
Cover image
Title page
Copyright
List of contributors
Preface
Dedication
Acknowledgements
A dozen suggestions to help the reader optimally utilize this book
Part I: Introduction
Chapter 1: Basic principles of pharmacology
Introduction
Pharmacokinetics – part I (Tables 1-2 and 1-3)
Pharmacodynamics (the drug produces the desired pharmacologic effect)
Pharmacokinetics – part II
Percutaneous absorption
Chapter 2: Principles for maximizing the safety of dermatologic drug
therapy
Introduction
Anticipation
Prevention
Diagnosis
Management
Parting thoughts
Chapter 3: Polymorphisms: why individual drug responses vary
Introduction
Evaluating the patient
Factors that influence medication effects (including adverse effects)
Drug metabolism – Phase I reactions
Drug metabolism – Phase II reactions (Table 3-9)
Severe cutaneous adverse drug reactions linked to genetic polymorphisms
Tests for genetic polymorphisms and clinical significance
Conclusions and future directionsChapter 4: Adherence to drug therapy
Introduction
Measures of adherence
The magnitude of poor adherence in dermatology
Factors that influence adherence behavior
Strategies to improve adherence behavior
Conclusions
Part II: Important Drug Regulatory Issues
Chapter 5: The FDA drug approval process
Introduction
Federal legislation for drug safety and efficacy
Phase I–IV testing
FDA advisory panels
Off-label drug use
Generic drugs
Special drug approval categories
Related issues
Chapter 6: Pharmacovigilance: verifying that drugs remain safe
Introduction
Summary
Chapter 7: Drugs taken off the market: important lessons learned
Introduction
Presentation of benefit–risk in labeling
Product label ‘lifecycle’ changes
RISKS AND BENEFITS: FDA safety information
Drug withdrawal
Part III: Systemic Drugs for Infectious Diseases
Chapter 8: Systemic Antibacterial Agents
Introduction
Penicillins
Cephalosporins
β-lactam and β-lactamases inhibitor combinations
Carbapenems and monobactams
Other systemic agents affecting the bacterial cell wall
Macrolides
FluoroquinolonesTetracyclines
Rifamycins
Folate synthesis inhibitors
Lincosamides
Glycyclines
Oxazolidinones
Quinupristin and dalfopristin combination
Daptomycin
Lipoglycopeptides
Summary
Chapter 9: Systemic antifungal agents
Introduction
Conclusion
Chapter 10: Systemic antiviral agents
Introduction
Drugs for human herpes virus infections
Drugs for human immunodeficiency virus infections
Summary
Acknowledgment
Chapter 11: Systemic antiparasitic agents
Ivermectin
Albendazole
Thiabendazole
Alternative agents – doxycycline as antiparasitic agent
Part IV: Systemic Immunomodulatory and Antiproliferative Drugs
Chapter 12: Systemic corticosteroids
Systemic corticosteroids
Pharmacology (Table 12-1)
Systemic corticosteroids chapter update
Chapter 13: Methotrexate
Introduction
Pharmacology
Clinical use
Chapter 14: Azathioprine
Introduction
PharmacologyClinical use
Summary
Chapter 15: Mycophenolate mofetil and mycophenolic acid
Introduction
Pharmacology
Mechanism of action
Clinical use
Off-label dermatologic uses
Immunobullous disease
AUTOIMMUNE CONNECTIVE TISSUE DISEASE
Chapter 16: Cyclosporine
Introduction
Summary
Chapter 17: Cytotoxic agents
Introduction
Major subcategories of cytotoxic agents and the cell cycle
Patient education issues
Antimetabolites
Alkylating agents
Chapter 18: Dapsone
Introduction
Pharmacology
Clinical use
Chapter 19: Antimalarial agents
Introduction
Pharmacology
Clinical use
Monitoring guidelines70–72,107
Drug interactions
Therapeutic guidelines
Chapter 20: Systemic retinoids
Introduction and historical perspective
Pharmacology
Clinical use
Acknowldgment
Chapter 21: InterferonsIntroduction – interferon
Pharmacology
Clinical use
Acknowledgment
Part V: Drugs Used in Conjunction with Ultraviolet or Visible Light
Chapter 22: PUVA photochemotherapy and other phototherapy
modalities
Introduction and drug history
Puva photochemotherapy
Clinical use
Treatment procedure
Narrowband UVB phototherapy
UVA-1 phototherapy
Chapter 23: Extracorporeal photochemotherapy (photopheresis)
Introduction
Treatment delivery and considerations
Pharmacology
Clinical use
Chapter 24: Photodynamic therapy
Introduction
Pharmacology
Part VI: Biological Therapeutics
Chapter 25: Tumor necrosis factor (TNF) inhibitors
Introduction – psoriasis pathogenesis
Etanercept
Infliximab
Adalimumab
Chapter 26: Interleukin 12/23 inhibitors
Introduction
Monoclonal antibody treatments
Interleukin-12/23 therapy
The future: combination therapy and switching
Conclusions
Chapter 27: Rituximab and future biological therapies
Introduction
Part VII: Miscellaneous Systemic DrugsChapter 28: Antihistamines
Importance of histamine in skin diseases
Historical overview
First-generation antihistamines
Second-generation H1 antihistamines
Fexofenadine
Loratadine
Cetirizine
Desloratadine
Levocetirizine
H1 antihistamine therapy – special TOPICS
Chapter 29: Vasoactive and antiplatelet agents
Pathophysiology involving cutaneous vasculature
Calcium channel blockers
β-blockers
Aspirin
Dipyridamole
Pentoxifylline
Nitric oxide donors
Phosphodiesterase-5 inhibitors
Iloprost
Antiangiogenesis agents
Chapter 30: Antiandrogens and androgen inhibitors
Introduction
Physiologic role of androgens
Antiandrogens
Androgen inhibitors
Hormone preparations
Gonadotropin-releasing hormone analogs
Herbal remedies
Chapter 31: Psychotropic agents
Introduction
Classification of psychodermatologic disorders
The management of anxiety in dermatology
The management of depression in dermatology
The management of delusional disorders in dermatologyThe management of obsessive–compulsive disorder in dermatology
Summary
Chapter 32: Intravenous immunoglobulin therapy
Introduction
Pharmacology
Acknowledgment
Chapter 33: Systemic anticancer agents: dermatologic indications and
adverse events
Introduction
Epidermal growth factor receptor inhibitors (EGFRIs)
Multitargeted kinase inhibitors (MKI)
Alkylating agents
Topoisomerase inhibitors
Antimicrotubule AGENTS (TAXANES)
Anthracyclines
Histone deacetylase (HDAC) inhibitors
Miscellaneous
Monoclonal antibodies
Antimetabolites
Biotherapy (immunokines)
BRAF inhibitors
Summary
Chapter 34: Drugs for the skinternist
Introduction
Therapy for corticosteroid-induced osteoporosis
Bexarotene for cutaneous T-cell lymphoma – central hypothyroidism
Therapy for retinoid- OR Cyclosporine-induced hyperlipidemia
Fibric acid derivatives
Corticosteroid-associated peptic ulcer disease
Vitamin D therapy
Acknowledgment
Chapter 35: Miscellaneous systemic drugs
Introduction
Anticholinergic agents – glycopyrrolate and propantheline
Attenuated androgens – danazol and stanozolol
BiotinClofazimine
Colchicine
Fumaric acid esters
Gold
Nicotinamide
Non-steroidal anti-inflammatory drugs
Penicillamine
Potassium iodide
Thalidomide
Vitamin E
Zinc sulfate
Part VIII: Topical Drugs for Infectious Diseases
Chapter 36: Topical Antibacterial Agents
Introduction
Drugs used for wound care and minor topical bacterial infections
Drugs used for acne and rosacea
Antiseptics
Acknowledgment
Chapter 37: Topical antifungal agents
Introduction
Polyenes
Azoles
Allylamines and benzylamines
Other topical antifungals
Comparative studies
Chapter 38: Topical and intralesional antiviral agents
Introduction
Viricidal drugs
Immune-enhancing drugs
Cytodestructive drugs
Chapter 39: Topical antiparasitic agents
Introduction
Part IX: Topical Immunomodulatory and Antiproliferative Drugs
Chapter 40: Topical corticosteroids
Introduction
PharmacologyClinical use
Chapter 41: Topical retinoids
Introduction
Pharmacology
Clinical use
Acknowledgement
Chapter 42: Topical and intralesional chemotherapeutic agents
Introduction
Topical chemotherapeutic agents
Intralesional chemotherapeutic agents
Chapter 43: Topical contact allergens
Introduction
Mechanism of action in alopecia areata
Mechanism of action in warts
Diphenylcylopropenone
Squaric acid dibutyl ester
Dinitrochlorobenzene
Chapter 44: Topical calcineurin inhibitors
Introduction
Tacrolimus
Pimecrolimus
Chapter 45: Topical Vitamin D3
Introduction
Pharmacology
Vitamin D analogs
Part X: Miscellaneous Topical Drugs
Chapter 46: Sunscreens
Introduction
Sunscreen options
Clinical use
Summary
Chapter 47: Therapeutic shampoos
Introduction
Dermatoses involving the scalp
Historical perspective
PharmacologyClinical use
Therapeutic guidelines
Summary
Chapter 48: α-Hydroxy acids
Introduction
Pharmacology
Clinical use
Formulations
Adverse effects
Summary
Chapter 49: Chemical peels
Introduction
Superficial chemical peels
Medium-depth chemical peels
Deep chemical peels
Chapter 50: Products for the care of chronic wounds
Introduction
Wound healing physiology and ideal wound healing environment
General approach to a patient with chronic wounds
Venous ulcer disease
Systemic and surgical treatments
Chapter 51: Agents used for treatment of hyperkeratosis
Introduction
Chapter 52: Cosmetic therapy
Cosmetic therapy overview
Skin bleaching agents
Skin pigmenting products – dihydroxyacetone
Facial foundations and camouflage cosmetics
Skin cleansers
Moisturizers
Hair shampoos
Hair permanent waving agents
Hair-straightening agents
Hair-dyeing agents
Hair-bleaching agents
Nail polishChapter 53: Irritants and allergens: When to suspect topical therapeutic
agents
Introduction
Contact dermatitis: the concept
When to suspect contact dermatitis
Final thoughts
Chapter 54: Insect repellents
Introduction
Insect biology
Insect repellents overview
Chemical insect repellents
Biopesticide repellents
Plant-derived repellents
Efficacy of DEET versus botanical repellents
Related issues
Chapter 55: Miscellaneous topical agents
Introduction
Topical antioxidants
Topical agents for hemostasis and hyperhidrosis
Other topical agents
Part XI: Injectable and Mucosal Routes of Drug Administration
Chapter 56: Local anesthetics
Introduction
Injectable local anesthetics
Topical anesthetics
Co-injectable vasoconstrictors
Other agents with local anesthetic effects
Chapter 57: Injectable dermal and subcutaneous fillers
Introduction
Categories of dermal fillers
Fillers on the horizon
Chapter 58: Botulinum toxin injections
Introduction and history
Conclusions
Chapter 59: Oral mucosal therapeutics
IntroductionReview of common terminology
Erosive gingivostomatitis
Herpetic gingivostomatitis
Oral candidiasis
Hairy tongue
Recurrent aphthous stomatitis
Acute necrotizing ulcerative gingivostomatitis
Mucositis (stomatitis)
Xerostomia
Burning mouth syndrome
Part XII: Major Adverse Effects from Systemic Drugs
Chapter 60: Hepatotoxicity of dermatologic drug therapy
Introduction
The liver and drug metabolism
Mechanisms of drug hepatotoxicity
Risk factors for drug hepatotoxicity
Drug information dissemination issues
Classification systems (Table 60-7)
Drug etiologies
Diagnosis
Management
Looking to the future – lessons from the past
Chapter 61: Hematologic toxicity of drug therapy
Introduction
General principles
Major categories of drug-induced hematologic toxicity
Drugs Prescribed by Dermatologists – Risk of Hematologic Toxicity
Treatment of hematologic toxicities
Acknowledgments
Chapter 62: Drug-induced malignancy
Introduction
Assessment of drug causation for malignancy induction
General principles of carcinogenesis
Review of malignancy risk with organ transplantation
Review of malignancy risk with autoimmune diseases
Specific drugs used in dermatology and their potential risk for malignancyPrevention and detection of possible malignancies
The bottom line
Chapter 63: Neurologic adverse effects from dermatologic drugs
Introduction
General principles
Progressive multifocal leukoencephalopathy
Demyelinating disorders
Pseudotumor cerebri (idiopathic intracranial hypertension)
Drug-induced CNS toxicity and seizures
Peripheral neuropathy/polyneuropathy
Specific drugs
Chapter 64: Dermatologic drugs during pregnancy and lactation
Introduction
General principles
Guide for specific drug use
Summary Q64-8
Chapter 65: Drug interactions
Introduction
General principles of drug interactions
Cytochrome P-450-based drug interactions
Importance of the order of drug administration
Drug interaction risks by drug category
Genetic polymorphisms
Pharmacodynamic mechanisms of drug interactions
Do all drugs in a given class behave in a similar manner?
Summary
Chapter 66: Cutaneous drug reactions with systemic features
Introduction
Drug hypersensitivity syndrome (DHS)
Serum sickness and serum sickness-like reactions
Drug-induced lupus (DIL)
Acute generalized exanthematous pustulosis
Stevens–johnson syndrome and toxic epidermal necrolysis
Anaphylaxis
General discussion
Part XIII: Special Pharmacology and Therapeutic TopicsChapter 67: Pharmacoeconomics
Introduction
Various cost analyses
Analyzing the various cost analyses
How are pharmacoeconomic analyses used?
Pharmaceutical pricing strategies
Pharmaceutical patient assistance programs
Generic drugs and substitution
Why is pharmacoeconomics important to clinicians?
Chapter 68: Informed consent and risk management
Introduction
Historical perspective
Ethical perspective
Basic legal principles
Components of informed consent
Systemic drugs and informed consent
Optimizing patient understanding
Exceptions to the informed consent requirements
Medicolegal risk management
Dermatology malpractice
Summary
Chapter 69: Compounding in dermatology
Introduction
The ‘compounding triad’
Developing a stable compounding formula
Properly write the prescription
Monitor the patient
Summary
Chapter 70: Dermatologic drug therapy in children
Introduction
General issues
Specific medications used in children
Appendix I – Ten drugs of increasing importance to dermatology
Appendix II – Dapsone patient education and informed consent
Subject IndexCopyright
SAUNDERS is an imprint of Elsevier Inc.
© 2013, Elsevier Inc. All rights reserved.
First edition 2001
Second edition 2007
Third edition 2013
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Notices
Knowledge and best practice in this 4eld are constantly changing. As new research
and experience broaden our understanding, changes in research methods,
professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and
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ISBN: 978-1-4377-2003-7
Ebook ISBN: 978-1-4557-3801-4
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1List of contributors
David R. Adams, MD, PharmD
Associate Professor of Dermatology, Penn State Milton S.
Hershey Medical Center, Hershey, PA, USA
Stephanie S. Badalamenti, MD, PhD, LLC
Fellow, Department of Medicine, Saint Barnabas Medical
Center, West Orange, NJ, USA
Mark A. Bechtel, MD
Director of Dermatology, The Ohio State University College of
Medicine, Columbus, OH, USA
Brian Berman, MD, PhD
Voluntary Professor of Dermatology and Cutaneous Surgery,
Department of Dermatology and Cutaneous Surgery, University
of Miami Miller School of Medicine, Miami, FL; Skin and Cancer
Associates, LLP and Center for Clinical and Cosmetic Research,
Aventura, FL, USA
Tina Bhutani, MD
Clinical Fellow, Psoriasis and Skin Treatment Center,
University of California, San Francisco, CA, USA
Robert Bissonnette, MD, FRCPC
Director, Innovaderm Research, Montreal, QC, Canada
Robert T. Brodell, MD
Professor of Internal Medicine; Clinical Professor of
Dermatopathology in Pathology; Master Teacher, Northeast Ohio
Medical University, Rootstown, OH; Associate Clinical Professor
of Dermatology, Department of Dermatology, Case Western
Reserve University, Cleveland, OH; Instructor in Dermatology,
University of Rochester School of Medicine and Dentistry,
Rochester, NY, USADavid G. Brodland, MD
Private Practice; Assistant Clinical Professor, Departments of
Dermatology and Otolaryngology, University of Pittsburgh,
Pittsburgh, PA, USA
Jeffrey P. Callen, MD, FACP
Professor of Medicine in Dermatology; Chief, Division of
Dermatology, University of Louisville School of Medicine,
Louisville, KY, USA
Charles Camisa, MD, FAAD
Director of Phototherapy and Camisa Psoriasis Center,
Riverchase Dermatology, Naples and Fort Myers, FL; Affiliate
Associate Professor, Department of Dermatology and Cutaneous
Surgery, University of South Florida, Tampa, FL, USA
Caroline V. Caperton, MD, MSPH
Clinical Research Fellow, Department of Dermatology and
Cutaneous Surgery, and Internal Medicine, University of Miami,
Miller School of Medicine, FL, USA
Jaehyuk Choi, MD, PhD
Instructor in Dermatology, Yale School of Medicine, New
Haven, CT, USA
Richard A. Clark, MD
Director, Burn and Nonscar Healing Program, RCCC Armed
Forces Institute of Regenerative Medicine; Professor, Biomedical
Engineering and Dermatology, Stony Brook, NY, USA
Kevin D. Cooper, MD
Professor and Chair, Department of Dermatology; Director,
Skin Diseases Research Center, University Hospitals of Cleveland
and Case Western Reserve University, Cleveland, OH, USA
Julio C. Cruz-Ramon, MD
Dermatologist, Private Practice, Buckeye Dermatology, Dublin,
OH, USAMarc A. Darst, MD
Private Practice, Darst Dermatology; Laboratory Director,
Charlotte Dermatopathology, Charlotte, NC, USA
Loretta S. Davis, MD
Professor of Dermatology, Division of Dermatology, Georgia
Health Sciences University, Augusta, GA, USA
Cynthia M.C. DeKlotz, MD, MASt
Chief Resident in Internal Medicine/Dermatology, Division of
Dermatology and Department of Medicine, Georgetown
University Hospital; Department of Dermatology and Department
of Medicine, Washington Hospital Center, Washington, DC, USA
James Q. Del Rosso, DO, FAOCD
Dermatology Residency Program Director, Valley Hospital
Medical Center, Las Vegas, NV; Clinical Professor
(Dermatology), Touro University College of Osteopathic
Medicine, Henderson, NV; Dermatology and Cutaneous Surgery,
Las Vegas Skin and Cancer Clinics, Las Vegas, NV and
Henderson, NV, USA
Catherine M. DiGiorgio, MS, MD
Clinical Research Fellow, Center for Clinical Studies,
Dermatological Association of Texas, Houston, TX, USA
Zoe D. Draelos, MD
Consulting Professor, Department of Dermatology, Duke
University School of Medicine, Durham, NC, USA
William H. Eaglstein, MD
Consultant, IHP Consulting, Inc.; Chairman Emeritus,
Department of Dermatology, University of Miami, Miller School
of Medicine, FL, USA
Kim Edhegard, MD
Immuno-Dermatology Fellow, Department of Dermatology,
Duke University School of Medicine, Durham, NC, USADirk Elston, MD
Managing Director, Ackerman Academy of Dermatopathology,
New York, NY, USA
Jason J. Emer, MD
Resident Physician, Department of Dermatology, Mount Sinai
School of Medicine, New York, NY, USA
Steven R. Feldman, MD, PhD
Center for Dermatology Research, Departments of
Dermatology, Pathology and Public Health Sciences, Wake Forest
University School of Medicine, Winston-Salem, NC, USA
Ashley N. Feneran, DO
Internal Medicine Resident, Carilion Clinic, Roanoke, VA,
USA
Laura K. Ferris, MD, PhD
Assistant Professor, Department of Dermatology, University of
Pittsburgh, Pittsburgh, PA, USA
Seth B. Forman, MD
Private Practice, Forman Dermatology and Skin Cancer
Institute, Tampa, FL, USA
Mark S. Fradin, MD
Clinical Associate Professor of Dermatology, University of
North Carolina at Chapel Hill, NC, USA
Algin B. Garrett, MD
Professor and Chairman, Department of Dermatology, Virginia
Commonwealth University Medical Center, Richmond, VA, USA
Joel M. Gelfand, MD, MSCE
Medical Director, Clinical Studies Unit; Assistant Professor of
Dermatology and Epidemiology; Senior Scholar, Center for
Clinical Epidemiology and Biostatistics, University of
Pennsylvania, Philadelphia, PA, USAJennifer G. Gill, PhD, MD
Graduate student, Washington University School of Medicine,
St Louis, MO, USA
Michael Girardi, MD
Associate Professor; Residency Director, Department of
Dermatology, Yale University School of Medicine, New Haven,
CT, USA
Tobias Goerge, MD
Assistant Professor of Dermatology, Department of
Dermatology, University Hospital Münster, Germany
Cristina Gómez-Fernández, MD
Dermatologist, Department of Dermatology, University Hospital
La Paz, Madrid, Spain
Kenneth B. Gordon, MD
Professor of Dermatology, Northwestern University, Feinberg
School of Medicine, Chicago, IL, USA
Malcolm W. Greaves, MD, PhD, FRCP
Emeritus Professor of Dermatology, Cutaneous Allergy Clinic,
St John’s Institute of Dermatology, St Thomas’ Hospital; The
London Allergy Clinic, London, UK
Aditya K. Gupta, MD, PhD, MBA/HCM, MA (Cantab),
CCI, CCTI, CCRP, DABD, FAAD, FRCPC
Professor, Division of Dermatology, Department of Medicine,
University of Toronto, Toronto, ON, Canada
Anita N. Haggstrom, MD
Associate Professor, Dermatology and Pediatrics, Indiana
University, Indianapolis, IN, USA
Kassie A. Haitz, MD
Center for Clinical Studies, Houston, TX, USARussell P. Hall, III., MD
J. Lamar Callaway Professor and Chair, Department of
Dermatology, Duke University School of Medicine, Durham, NC,
USA
Peter W. Heald, MD
Professor of Dermatology, Department of Dermatology, Yale
University School of Medicine, New Haven, CT, USA
Michael P. Heffernan, MD
Private Practice, Central Dermatology, St Louis, MO, USA
Yolanda R. Helfrich, MD
Assistant Professor, Dermatology, University of Michigan
Medical School, Ann Arbor, MI, USA
Adam B. Hessel, MD
Dermatologist, Private Practice, Buckeye Dermatology, Dublin;
Clinical Assistant Professor, Division of Dermatology, The Ohio
State University College of Medicine and Public Health,
Columbus, OH, USA
Whitney A. High, MD, JD, MEng
Associate Professor, Dermatology and Pathology; Vice Chair,
Clinical Affairs, University of Colorado Health Sciences Center,
Denver, CO, USA
Ginette A. Hinds, MD
Assistant Professor of Dermatology; Director, Ethnic Skin
Program; Director, Department of Dermatology, Johns Hopkins
Bayview Medical Center, Baltimore MD, USA
Sylvia Hsu, MD
Professor of Dermatology, Department of Dermatology, Baylor
College of Medicine; Chief of Dermatology, Ben Taub General
Hospital, Houston, TX, USA
Michael J. Huether, MD
Medical Director, Arizona Skin Cancer Surgery Center,Tucson, AZ, USA
Michael S. Kaminer, MD
Assistant Professor of Dermatology, Yale Medical School, New
Haven, CT and Dartmouth Medical School, Hanover, NH;
Dermatologist, SkinCare Physicians, Chestnut Hill, MA, USA
Swetha Kandula, MD FACP
Resident, Dermatolgy, Indiana University School of Medicine,
Indianapolis, IN, USA
Sewon Kang, MD
Noxell Professor and Chairman, Department of Dermatology,
Johns Hopkins School of Medicine, Baltimore, MD, USA
Marshall B. Kapp, JD, MPH
Director, Center for Innovative Collaboration in Medicine and
Law; Professor, Department of Geriatrics; Courtesy Professor,
College of Law; Florida State University, Tallahassee, FL, USA
Francisco A. Kerdel, MD
Voluntary Professor of Clinical Dermatology, Department of
Dermatology, University of Miami School of Medicine; Director,
Dermatology Inpatient Services, Cedars Medical Center, Miami,
FL, USA
Susun Kim, DO
Adjunct Assistant Professor (Dermatology), Touro University
College of Osteopathic Medicine, Henderson, NV; Dermatology
and Cutaneous Surgery, Las Vegas Skin and Cancer Clinics, Las
Vegas, NV and Henderson, NV, USA
Grace K. Kim, DO
Dermatology Resident, Valley Hospital Medical Center, Las
Vegas, NV, USA
Youn H. Kim, MD
Joanne and Peter Haas Jr. Professor for Cutaneous Lymphoma
Research; Director, Multidisciplinary Cutaneous LymphomaProgram; Medical Director, Photopheresis Service, Stanford
University School of Medicine, Stanford, CA, USA
Melanie Kingsley, MD
Director of Cosmetic Dermatology & Laser Surgery; Assistant
Professor of Dermatology, Indiana University School of Medicine,
Indianapolis, IN, USA
Melanie Kingsley, MD
Director of Cosmetic Dermatology & Laser Surgery; Assistant
Professor of Dermatology, Indiana University School of Medicine,
Indianapolis, IN, USA
Dana M. Klinger, MD
Dermatology Resident, LSU Department of Dermatology, New
Orleans, LA, USA
Alfred L. Knable, Jr., MD
Associate Clinical Professor of Dermatology, University of
Louisville, Louisville, KY, USA
Sandra R. Knowles, BScPhm
Lecturer, Faculty of Pharmacy, University of Toronto; Drug
Safety Pharmacist, Sunnybrook Health Sciences Center, Toronto,
Canada
John Y.M. Koo, MD
Professor and Vice Chairman, Department of Dermatology;
Director, Psoriasis Treatment Center, University of California
Medical Center, San Francisco, CA, USA
Shiva S. Krishnan, PhD
Research Associate, Division of Cancer Epidemiology and
Biomakers Prevention, Georgetown University Lombardi Cancer
Center, Washington DC, USA
Carol L. Kulp-Shorten, BS, MD
Clinical Professor of Medicine, Division of Dermatology,
University of Louisville School of Medicine, KY, USAMario E. Lacouture, MD
Dermatologist, Dermatology Service, Department of Medicine,
Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Megan N. Landis, MD
Dermatology Resident, Department of Dermatology, Mayo
Clinic, Jacksonville, FL, USA
Sinéad M. Langan, MRCP, PhD NIHR
Clinician Scientist and Honorary Consultant Dermatologist,
London School of Hygiene and Tropical Medicine and St John’s
Institute of Dermatology, London, UK
Whitney J. Lapolla, MD
Clinical Research Fellow, Center for Clinical Studies, Houston,
TX, USA
Amir Larian, MD
Clinical Instructor, Department of Dermatology, Mount Sinai
School of Medicine, New York, NY, USA
Sancy A. Leachman, MD, PhD
Professor, Department of Dermatology; Director, Melanoma &
Cutaneous Oncology Program, Huntsman Cancer Institute at the
University of Utah, Salt Lake City, UT, USA
Keith G. LeBlanc, Jr., MD
Chief Resident, Division of Dermatology, Georgia Health
Sciences University, Augusta, GA, USA
Mark G. Lebwohl, MD
Professor and Chairman, Department of Dermatology, Mount
Sinai School of Medicine, New York, NY, USA
Chai S. Lee, MD, MS
Dermatologist, Department of Dermatology, Kaiser
Permanente, Milpitas, CA, USASamantha M. Lee, BSE
Medical Student, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA, USA
Katherine B. Lee, MD, MA
Resident Physician, Department of Dermatology, Indiana
University Medical Center, Indianapolis, IN, USA
Craig L. Leonardi, MD, FAAD
Clinical Professor of Dermatology, Saint Louis University
School of Medicine; Private Practice, Central Dermatology, St
Louis, MO, USA
Michelle M. Levender, MD
Center for Dermatology Research, Department of Dermatology,
Wake Forest University School of Medicine, Winston-Salem, NC,
USA
Stanley B. Levy, MD
Adjunct Clinical Professor of Dermatology, Department of
Dermatology, University of North Carolina at Chapel Hill; Clinical
Associate in Medicine, Duke University Medical School, Durham,
NC, USA
Amy B. Lewis, MD, PC
Dermatologist, Private Practice, New York, NY; Clinical
Assistant Professor, Department of Dermatology, Yale University
School of Medicine, New Haven, CT, USA
Andrew N. Lin, MD, FRCPC
Associate Professor, Division of Dermatology and Cutaneous
Science, University of Alberta, Edmonton, AB, Canada
Benjamin N. Lockshin, MD
Clinical Instructor, Department of Dermatology, Johns Hopkins
University, Baltimore; DermAssociates PC, Silver Spring, MD,
USA
Thomas A. Luger, MDProfessor and Chairman, Department of Dermatology,
University of Münster, Germany
George D. Magel, MD
Clinical Research Fellow, Department of Dermatology, Indiana
University School of Medicine, Indianapolis, IN, USA
Lawrence A. Mark, MD, PhD
Assistant Professor of Dermatology, Department of
Dermatology, Indiana University, Indianapolis, IN, USA
Linda F. McElhiney, PharMD, RPh, FIACP, FASHP
Compounding Pharmacy Operations Coordinator, Pharmacy,
Clarian Health Partners Inc, Indianapolis, IN, USA
Stephanie Mehlis, MD
Associate Professor of Dermatology, University of Chicago
Pritzker School of Medicine, Chicago, IL, USA
Natalia Mendoza, MD
Center for Clinical Studies, Houston, TX, USA
Andrei I. Metelitsa, MD, FRCPC, FAAD
Assistant Professor of Dermatology, Division of Dermatology,
University of Calgary, Calgary, AB, Canada
Brent D. Michaels, DO
Dermatology Resident, Valley Hospital Medical Center, Las
Vegas, NV, USA
Ginat W. Mirowski, DMD, MD
Adjunct Associate Professor, Departments of Oral Pathology;
Medicine; Radiology, Indiana University School of Dentistry,
Indianapolis, IN, USA
Anjali V. Morales, MD, PhD
Department of Dermatology, Stanford University Medical
Center, Redwood City, CA, USAWarwick L. Morison, MB, BS, MD, FRCP
Professor, Department of Dermatology, Johns Hopkins
University School of Medicine, Baltimore, MD, USA
Kiran Motaparthi, MD
Dermatology Resident, Department of Dermatology, Baylor
College of Medicine, Houston, TX, USA
Nico Mousdicas, MBCHB, MMED, MD
Director, Contact Dermatitis Center; Clinical Associate
Professor, Dermatology, Indiana University, Indianapolis, IN,
USA
Christian Murray, MD, FRCPC, FACMS
Assistant Professor, Division of Dermatology, Department of
Medicine, University of Toronto, Women’s College Hospital,
Toronto, ON, Canada
Cindy E. Owen, MD
Assistant Professor of Medicine; Assistant Program Director,
Division of Dermatology, University of Louisville, Louisville, KY,
USA
Timothy J. Patton, DO
Assistant Professor of Dermatology, Department of
Dermatology, University of Pittsburgh, Pittsburgh, PA, USA
Rhea M. Phillips, MD
Dermatologist, Department of Dermatology, St Francis
Memorial Hospital, San Francisco, CA, USA
Sarika M. Ramachandran, BS, MD
Instructor, Department of Dermatology, New York University,
New York, NY, USA
Jaggi Rao, MD, FRCPC
Associate Clinical Professor of Medicine, Division of
Dermatology and Cutaneous Sciences, University of Alberta,
Edmonton, AB, CanadaJennifer Reddan, PharmD
Manager, Drug Use Policy/Quality, Clarian Health Partners,
Indianapolis, IN, USA
Kathleen A. Remlinger, MD
Associate Professor of Dermatology, Rush-Presbyterian St.
Luke’s Medical Center, Chicago, IL; Central DuPage Physician
Group, Central DuPage Hospital, Winfield, IL, USA
Elisabeth G. Richard, MD
Assistant Professor, Department of Dermatology, Johns
Hopkins University, Baltimore, MD, USA
Alyx C. Rosen, BSofE
Clinical Research Fellow, Department of Medicine,
Dermatology Service, Memorial Sloan-Kettering Cancer Center,
New York, NY, USA
Theodore Rosen, MD
Professor of Dermatology, Department of Dermatology, Baylor
College of Medicine; Chief, Dermatology Service, Michael E.
DeBakey VA Medical Center, Houston, TX, USA
Katherine Roy, MD
Dermatology Resident, Department of Dermatology, University
of North Carolina, Chapel Hill, NC, USA
Dana L. Sachs, MD
Assistant Professor of Dermatology, Department of
Dermatology, University of Michigan Medical School, Ann Arbor,
MI, USA
Naveed Sami, MD
Assistant Professor, Department of Dermatology, University of
Alabama, Birmingham, AL, USA
Marty E. Sawaya, MD, PhD
Director, InflamaCore, University of Miami Miller School ofMedicine, Miami, FL, USA
Courtney R. Schadt, MD
Clinical Instructor, Department of Medicine, Division of
Dermatology, University of Louisville, Louisville, KY, USA
Bethanee J. Schlosser, MD, PhD
Assistant Professor; Director, Women’s Skin Health Program,
Department of Dermatology, Northwestern University Feinberg
School of Medicine, Chicago, IL, USA
Lori E. Shapiro, MD, FRCPC
Assistant Professor of Medicine, University of Toronto, Staff
Dermatology and Drug Safety Clinic, Sunnybrook Health
Sciences Centre, Toronto, ON, Canada
Neil H. Shear, BASc, MD, FRCPC, FACP
Professor and Chief of Dermatology, University of Toronto and
Sunnybrook Health Sciences Center; Professor of Medicine,
Departments of Pediatrics, Pharmacy and Pharmacology;
Director, Drug Safety Research Group and Drug Safety
Clinic,Toronto, Canada
Michael Sheehan, MD
Dermatology, Indiana University School of Medicine,
Indianapolis, IN, USA
Pranav B. Sheth, MD, FAAD
Director, Dermatology Research Center of Cincinnati, General
Dermatology and Psoriasis Practice; Group Health Associates,
Trihealth, Cincinnati, OH; Volunteer Associate Professor,
Department of Dermatology, University of Cincinnati College of
Medicine, OH, USA
Nowell Solish, MD, FRCP
Assistant Professor of Dermatology, Division of Dermatology,
Department of Medicine, University of Toronto, ON, Canada
Najwa Somani, MDAssociate Director of Dermatopathology; Assistant Professor of
Dermatology; Departments of Dermatology and Pathology and
Laboratory Medicine, Indiana University, Indianapolis, IN, USA
Ally-Khan Somani, MD, PhD, FAAD
Assistant Professor; Director of Dermatologic Surgery &
Cutaneous Oncology,
Department of Dermatology, Indiana University School of
Medicine, Indianapolis, IN, USA
Brandie T. Styron, MD
Private Practice, Associates in Dermatology, Westlake, OH,
USA
Eunice Y. Tsai, MD
Associate Physician, Department of Dermatology, Kaiser
Permanente, Union City, CA, USA
Stephen K. Tyring, MD, PhD, MBA
Clinical Professor of Dermatology, Microbiology/ Molecular
Genetics and Internal Medicine, University of Texas Health
Science Center, Houston, TX, USA
Susan J. Walker, MD, FAAD
Director, Division of Dermatology and Dental Products, Center
for Drug Evaluation and Research, Food and Drug
Administration, Silver Spring, MD; Visiting Consultant, National
Capital Consortium Dermatology Residency Program, Walter
Reed National Military Medical Center, Bethesda, MD, USA
Michael R. Warner, MD
Founder and President, Private Practice, The Cosmetic and
Skin Surgery Center, Frederick, MD, USA
Christine H. Weinberger, MD
Mohs Micrographic Surgeon; Assistant Professor, Division of
Dermatology, Department of Medicine, The University of
Vermont, Fletcher Allen Health Care, Burlington, VT, USAStephen E. Wolverton, MD
Theodore Arlook Professor of Clinical Dermatology,
Department of Dermatology, Indiana University School of
Medicine; Chief of Dermatology, Roudebush VA Medical Center,
Indianapolis, IN, USA
Henry K. Wong, MD, PhD
Associate Professor of Medicine, Division of Dermatology, Ohio
State University, Gahanna, OH, USA
Blair K. Young, DO
Pre-residential Fellowship, Neuro-ophthalmology, Michigan
State University, East Lansing, MI, USA
John A. Zic, MD
Associate Professor of Medicine and Dermatology, Division of
Dermatology, Vanderbilt University School of Medicine,
Nashville, TN, USA
Matthew J. Zirwas, MD
Assistant Professor, Department of Dermatology, University of
Pittsburgh, Pittsburgh, PA, USA
Jeffrey P. Zwerner, MD, PhD
Assistant Professor, Medicine, Division of Dermatology,
Vanderbilt University, Nashville, TN, USA'
Preface
This third edition of Comprehensive Dermatologic Drug Therapy has been both a
challenge and a joy to edit. The challenge has been primarily in keeping up with
the rapidly changing landscape of dermatologic therapy. The joy has been the
continued refinement of an approach to summarizing vast quantities of information
on dermatologic drugs in various formats that have been popular with readers.
Furthermore, it is a creative challenge to evolve towards a combination of print and
electronic media in medical book publishing (more later on this important area).
Counting the original book, Systemic Drugs for Skin Diseases, published in
1991, the contents have grown from 17 chapters to 50 ( rst edition of the current
title), further increasing to 60 chapters in the second edition of the current title,
and now containing 70 chapters in this third edition of Comprehensive Dermatologic
Drug Therapy. While continuing to focus on editorial improvements to assist the
clinician/learner of dermatologic pharmacology, I will brie, y relate how the third
edition of Comprehensive Dermatologic Drug Therapy addresses three related
questions: ‘What is new?’, ‘What is the same?’, and ‘What is electronic?’
Again in this section, I thank a fantastic group of authors for sharing their
knowledge and expertise, their clinical experience, and their creativity in
producing the 70 chapters in this book: thanks for a job well done! I trust that all of
you will enjoy the product of your hard work and expertise.
What is new?
New chapters: The following chapters are either totally new topics or are derived
from earlier chapters divided* to expand topic coverage and emphasis:
Chapter 4Adherence to drug therapy
Chapter 7Drugs taken off the market: important lessons learned
Chapter 11Systemic antiparasitic agents*
Chapter 15Mycophenolate mofetil and mycophenolic acid
Chapter 26Interleukin 12/23 inhibitors
Chapter 27Rituximab and future biologic therapies
Chapter 33Systemic anticancer agents: dermatologic indications and adverse
events
Chapter 39Topical antiparasitic agents*
Chapter 49Chemical peels
Chapter 50Products for the care of chronic wounds
Chapter 53 Irritants and allergens: when to suspect topical therapeutic agents
Chapter 57Injectable dermal and subcutaneous fillers
Chapter 63Neurologic adverse effects from dermatologic drugs
Biologic agents in dermatologic therapeutics: New chapters 26 and 27 above,
along with Appendix I, continue to expand emphasis on this rapidly evolving and
exciting ‘new’ area of dermatologic pharmacology.
Chapters related to dermatologic surgery/procedural dermatology: Chapter 49'
'
(Chemical Peels) and Chapter 57 (Injectable Dermal and Subcutaneous Fillers) are
added to expand emphasis on the growing procedural aspects of our eld. The
addition of Chapter 50 on Products for the Care of Chronic Wounds also
supplements earlier chapters on Local Anesthetics and Botulinum Toxin for this
growing area of dermatology.
New authors: A total of 12 new senior authors have contributed totally new
chapters, with six new senior authors updating earlier chapters.
Important questions: Just under 800 questions (up from roughly 500 in the
second edition) located at the beginning of each chapter help to guide the reader
towards speci c text locations for answers to challenging areas of central
importance to our field.
What is the same?
Monitoring guidelines boxes: This tradition of the prominent ‘drug safety’ theme
throughout the book is continued and updated.
Drug interactions tables: These tables are derived from Facts and Comparisons,
Epocrates, The Medical Letter of Drugs and Therapeutics, and Hansten and Horn’s
Top 100 Drug Interactions databases, formatted by (1) similar drug interaction
types, and (2) keeping drugs grouped and compared by category.
Indications and contraindications boxes: This theme is another tradition that is
continued and yet updated and refined.
General philosophy: I continue to strive to assist authors in providing concise,
practical, and relevant information in just under 800 pages of text.
Emphasis on rapid retrieval of information: The continued emphasis on using
numerous tables and boxes, coupled with formatting with multiple headings and
subheadings, are all of value in this priority for the busy clinician.
What is ‘electronic’?
Maximize utilization of the print version of the book:
• Use handheld electronic device or laptop computer to retrieve information
immediately for patient care decisions.
• Search individual diseases or drugs listings in the textbook in a traditional
database search format.
‘Value added’ electronic features that will be steadily developed over the
upcoming months include (but are not limited to) the following …
• Informed consent documentation forms – similar to dapsone form in the print
version of the book; in the coming months there will be online availability of at
least 10–12 more consent forms on other systemic drugs.
• Questions at the beginning of each chapter will be indexed and searchable by
category (mechanism, clinical use, interactions, etc.) for maximum
educational value for clinical use or Boards preparation.
• Newly released drugs – concise summaries in PDF format (similar to Appendix I
in the book’s print version) will be released on a regular basis.
• Disease treatment option hierarchies – on a gradual basis we will release in
downloadable PDF format structured concise lists of treatment options forcommon and important dermatoses.
• And many, many other drug information tools …
Enjoy the learning process!
Stephen E. Wolverton, MDD e d i c a t i o n
This book is dedicated to the following individuals:
To my wife Cheryl, for her support and help over the past 22 months of the
book development and the editorial process, let alone our 32 years of marriage.
To our sons Jay Edward (age 26) and Justin David (age 24), now wrapping up
their college and postgraduate years, for having a wonderfully diverse set of
interests and for being a source of continuing joy – and occasional challenge – over
the past 2+ decades.
To my parents Elizabeth Ann (1924–2000) and Dr George M. Wolverton Sr.
(1925–2011), for the passion, wisdom, compassion and encouragement provided
throughout their lives; these traits continue to have a positive in4uence on my life
on a daily basis.
And to my wonderful (and large) nuclear family with three sisters (Anne,
Cynthia, and Pam) and 6ve brothers (George [1951–1996], Greg, Je9, Doug, and
Dan), for their kindness to and consideration for others, and their ongoing
camaraderie no matter what challenges we have all faced.*
*
*
Acknowledgements
I would like to sincerely thank and applaud the following individuals for their
energetic and kind support of my journey through the book development and
editorial process for the third edition of Comprehensive Dermatologic Drug Therapy. I
am indebted to all of you for your efforts.
From the UK (with Elsevier ties)
Martin Mellor (project development editor) for the frequent conference calls over
much of the past 18 months and for the plethora of e-mails to authors utilizing his
diplomatic assertiveness (and ‘gentle’ persistence) to keep chapters moving through
first and second draft phases for all 70 chapters.
Sukanthi Sukumar (project manager) for her remarkable attention to detail and
tremendous e( ciency, from nding duplicate or incomplete references, to insightful
questions on content, to formatting the book in a easy to read fashion.
Belinda Kuhn, and her predecessor Rus Gabbedy (acquisitions editors), for the
early book development and oversight and for coordinating the multiple
departments involved with the book publication.
WB Saunders (the imprint of this book) and Elsevier for the broader role in
oversight from the beginning of the book development through marketing the nal
product.
From the ‘States’ (with Indiana University Department of
Dermatology ties)
My colleagues from Indiana University Department of Dermatology – Nico
Mousdicas, Gary Dillon, Lawrence Mark and Joanne Trockman – who provided
coverage for a signi cant number of my clinics and consult duties, enabling the
3day weekends and entire weeks off so critical for the book editing process.
My colleagues (current and past) from Indiana University Department of
Dermatology who contributed chapters: Marc Darst, Anita Haggstrom, Swetha
Kandula, Melanie Kingsley, Kathy Lee, Ben Lockshin, George Magel, Lawrence Mark,
Ginat Mirowski, Nico Mousdicas, Michael Sheehan, Ally-Khan Somani, Najwa Somani
and Brandie Tackett Styron.
The team of four second-year medical students (now fourth-year medical
students) at the Indiana University School of Medicine who assisted greatly in the
information retrieval on a wide variety of controversies and di( cult questions
throughout the book. This team included Lina Gordy, Brittany Hedrick, Theresa
Tassey and Anthony Zabel, who also helped me with a wide variety of early
organizational tasks for the book project.
From the ‘States’ and the World (the authors)
The 132 authors for this edition who responded very, very well to the task of
updating earlier chapters and creating totally new ones. These authors responded in
a superb fashion to the challenges I set them. In particular, I wish to highlight the
following individuals:?
?
The authors who contributed to all four versions of the books I have edited
(including the original title Systemic Drugs from Skin Diseases, 1991 edition): Brian
Berman, Je Callen, Charles Camisa, Loree Davis, Marshall Kapp and Carol
KulpShorten.
The international cast of 12 authors from Canada and Europe: Robert
Bissonnette, Tobias Goerge, Malcolm Greaves, Aditya Gupta, Sandra Knowles,
Andrew Lin, Thomas Luger, Christian Murray, Jaggi Rao, Lori Shapiro, Neil Shear
and Nowell Solish.
The authors who contributed to two or more chapters: Andrew Lin (three
chapters), plus Je Callen, Charles Camisa, Seth Forman, Melanie Kingsley, John
Koo, Megan Landis, Chai Sue Lee, Ben Lockshin, Andrei Metelitsa, Katherine Roy
and Neil Shear who contributed two chapters each.
Finally, thanks to all remaining authors who took time away from their full-time
roles as clinicians and educators while providing fresh ideas along with tremendous
personal experience and expertise for the remaining chapters of this third edition of
Comprehensive Dermatologic Drug Therapy.
A dozen suggestions to help the reader optimally
utilize this book
• If you want general concepts and references concerning drug use for a specific
dermatologic condition, there are three related solutions in this book. The
Indications and Contraindications boxes, the well-formatted, easy to locate
pertinent text sections, and the grouping of references by topic will guide your
way for information to treat specific patients.
• If you want to retrieve information or learn about the complicated subject of
drug interactions, the Drug Interactions tables will assist in both tasks. Over
30 Drug Interactions tables are continued from the previous edition to
summarize four distinct respected databases, formatted for e& cient
information retrieval and to facilitate understanding general concepts of drug
interactions.
• If you want to prepare for pharmacology and therapeutics components of the
Dermatology Board Examination or Recerti cation Examination (let
alone e& ciently gain a general understanding of drugs utilized in
dermatology), the signi) cantly expanded important questions at the beginning
of each chapter will assist you in all these goals. The answers for each question
are easily found in the text, referenced by page number and marked with a
distinctive icon.
• If you want to gain a general understanding of how drugs work, all chapters
discussing speci) c drugs have Mechanism of Action sections. These sections
focus on the mechanisms for a drug’s therapeutic bene) ts and potential
adverse e. ects, with many summarized in table format. In addition, more
indepth knowledge concerning drug mechanisms can be derived from carefully
footnoted and highlighted Drug Mechanism figures.
• If you want drug pharmacology concepts and product information in a
‘nutshell’, there are tables for drugs discussed in the chapter and Key
Pharmacology Concepts for most systemic drugs and many topical therapies as
well.
• If you want to maximize systemic drug safety with appropriate monitoring of
laboratory tests, related tests or special examinations for a given drug, the
Monitoring Guidelines boxes continue to demonstrate an appropriate standard
of care for early detection of the various drugs’ most important potential
adverse effects.
• If you want to gain a broad understanding of a given drug or drug group’s
adverse e ects, each chapter has an Adverse E. ects section for each major
drug discussed. A substantial number of chapters have an Adverse E. ects box
summarizing, grouping, and prioritizing important potential drug risks; also,
seven of the chapters (Chapters 60–66) focus speci) cally on important
potential drug adverse effects.
• If you want a general understanding of drug structures, particularly in
comparing di. erent drugs in the same class, there are roughly 100 drug
structures throughout the book to assist your visual understanding of thesedrugs.
• For drugs recently released (or that have recently gained prominence) after
the chapter contents were relatively ) xed, Appendix I addresses a number of
these drugs in a concise fashion.
• If you would like to evaluate a representative written informed consent form
(for dapsone) that likewise serves as a patient information form, Appendix II
provides such an example: this will be greatly expanded in the electronic
version of this book (see Preface).
• If you would like to read supplemental information on a given drug or drug
group, or a related topic in pharmacology, the Bibliography: Important
Reviews and Chapters following the text for each chapter lists about 6–8
relatively recent reviews, chapters and books on the various topics under the
chapter title.
• Or, if you just want to learn or relearn any topic covered in Comprehensive
Dermatologic Drug Therapy in a complete yet e& cient fashion, then the
wellformatted chapters with a substantial number of tables, boxes, and ) gures will
maximize the learning (or relearning) process. Just be sure to enjoy the
process on this very interesting educational journey!
Stephen E. Wolverton, MD
References for drug interaction tables
CliniSphere 2.0 CD-ROM. Facts & Comparisons. St. Louis. 2006.
The Medical Letter Adverse Drug Interactions Program 2005. The Medical Letter of
Drugs and Therapeutics. New Rochelle, NY. 2005.
E-pocrates Online Premium Reference. Epocrates. San Mateo, CA. 2006.
Hansten PD, Horn JR. The top 100 drug interactions: a guide to patient
management. Freeland, WA: H & H Publications, 2006.Part I
Introduction

<


1
Basic principles of pharmacology
Stephen E. Wolverton
Questions
Q 1 - 1 What are the simplest de nitions of ‘pharmacokinetics’, ‘pharmacodynamics’, and
‘pharmacogenetics’? (Pg. 1, Table 1-1)
Q1-2 What are several drugs or drug families for which the absorption may be altered by (a) food, (b)
cations such as iron, calcium, and magnesium, and (c) variations in gastric pH? (Pg. 2)
Q1-3 What are some of the pros and cons to the decision of whether to calculate drug dose on (a) actual
body weight, (b) ideal body weight? (Pg. 2)
Q1-4 What are several examples in which sustained exposure to a drug may give reduced positive or
negative pharmacologic effects at the drug receptor level? (Pg. 4, Table 1-4)
Q1-5 What are several of the most important agonists and antagonists at the level of speci c receptors?
(Pg. 4, Table 1-5)
Q1-6 What are several of the most important examples in which drugs inhibit speci c enzymes? (Pg. 5,
Table 1-6)
Q1-7 What are several important examples of active drug and active metabolite relationships? (Pg. 8,
Table 1-9)
Q1-8 What are several of the most important examples of prodrug and active drug relationships? (Pg. 8,
Table 1-8)
Q1-9 Pertaining to drug excretion, (a) what are three important routes of drug excretion, and (b) what is
the overall general change in the active drug properties that makes excretion possible? (Pg. 8)
Q1-10 What are 5 of the most important basic components that determine percutaneous absorption of
topical medications? (Pg. 9)
Q1-11 What are the some of the additional cutaneous properties and therapeutic maneuvers that alter the
degree of percutaneous absorption in individual patients? (Pg. 10, Table 1-10)
Introduction
This chapter is a relatively brief overview of basic principles of pharmacology, intended as a primer to
maximize understanding of the remaining chapters of the book. There is by design some overlap with other
chapters in the book, in order to address relevant issues from a number of vantage points. Of particular
relevance to this chapter are the following: Chapter 2 Principles for Maximizing the Safety of Dermatologic
Drug Therapy; Chapter 60 Hepatotoxicity of Dermatologic Drug Therapy (contains detailed information on
hepatic metabolism of drugs); and Chapter 65 Drug Interactions. The reader is encouraged to pursue further
detailed information and references (cited in the respective chapter for speci c drugs) for drug examples
used to illustrate basic principles of pharmacology in this chapter. In this chapter only a bibliography format
for references on pharmacologic general principles is used.
The primary focus of this chapter will be on pharmacologic principles related to systemic drugs. A
relatively brief section on percutaneous absorption will conclude the chapter. The basic goal of this chapter
(and for the rest of the book) is to describe and illustrate pharmacologic principles that will enable the
clinician to maximize the e; cacy and minimize the risk (adverse e ects, drug interactions) of dermatologic
drug therapy. It is my hope that this chapter will provide a broad foundation for true understanding of
pharmacology to enable clinicians to achieve:
1. More efficient assimilation of new information on medications,
2. Adaptability to the many unpredictable responses of patients to medications, and
3. Better long-term retention of important information on all aspects of drug therapy.
Outline for the chapter
Q1-1 Traditionally, discussions on basic pharmacology divide the topic into two domains (Table 1-1):<
pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body).
As a relatively novel way of presenting this information, I will discuss topics in sequence as seen through the
‘eyes’ of the drug as it progresses through the human body. In broad strokes, the sequence will be:
1 . Pharmacokinetics (part I – absorption, distribution, bioavailability): the drug must enter the body,
travel to, and be ‘available’ at the site of desired pharmacologic action;
2. Pharmacodynamics: the drug interacts with a receptor/e ector mechanism, producing both desirable
and undesirable effects; and
3 . Pharmacokinetics (part II – metabolism, excretion): the drug and/or its metabolites must leave the
body.
Table 1-1 Three ‘entry level’ definitions
Term Definition
Pharmacokinetics What the body does to the drug – from entry into the body until excretion of the drug
and/or its metabolites
Pharmacodynamics What the drug does to the body – once at site of action; from receptor binding
through the definitive effect (desired or adverse)
Pharmacogenetics Interindividual genetic alterations that produce variations in both pharmacokinetic
and pharmacodynamic aspects of drug therapy
Each of the above steps has a number of variables (with both predictable and unpredictable
components) for which the clinician should have at least a baseline working knowledge. These variables will
be presented and illustrated under each chapter heading that follows.
Pharmacokinetics – part I (Tables 1-2 and 1-3)
Drug absorption (The drug has to be absorbed and enter circulation)
The routes of drug administration most pertinent to dermatology, in order of descending frequency of use,
are topical, oral, intramuscular, and intralesional. Intravenous drug administration is uncommonly ordered
by the dermatologist. Typically, drugs must be relatively lipophilic (non-ionized, non-polar) to ‘enter’ the
body by topical or oral routes, whereas relatively hydrophilic (ionized, polar) drugs can still ‘enter’ by
intramuscular and intravenous routes. Upon absorption, drugs still must traverse other cell membranes in
order to reach the intended destination(s). Again, a drug with lipophilic qualities is rewarded by the ability
to traverse these lipid bilayers in order to arrive at the site of desired pharmacologic action.
Table 1-2 Pharmacokinetics – major components*
Component Most important issues
Absorption Relatively lipophilic drugs are more optimally absorbed through the GI tract; lipophilic
or hydrophilic drugs are relatively equal for parenteral absorption
Distribution Body compartments to which the drug is dispersed; important subcomponents include
fatty tissues and blood–brain barrier
Bioavailability Percentage of administered drug reaching circulation; also relates to free (active) versus
protein-bound drug
Metabolism Lipophilic drugs are converted to more hydrophilic metabolites to enable excretion
Excretion The above conversion to hydrophilic metabolites allows renal or biliary excretion; other
synonyms – clearance, elimination
* These components as related to oral (enteral) or parenteral administered drugs.<

Table 1-3 Definitions and concepts central to understanding pharmacokinetics
Term Definition
Bioactivation Either (a) conversion of prodrug to any active drug, or (b) conversion of the active
drug to a reactive, electrophilic metabolic intermediate
Bioequivalence* Generally referring to overall ‘equal’ bioavailability between two comparable drugs;
usually between generic and trade name formulations of a drug
Biotransformation In general, the metabolic change of a lipophilic drug to a more hydrophilic
metabolite allowing renal or biliary excretion
Blood–brain Protective mechanism for brain neurons; due to tight junctions (and lack of
barrier intercellular pores) in brain capillaries; highly lipophilic drugs may ‘overcome’ this
barrier
Detoxification The metabolic conversion of a reactive, electrophilic intermediate to a more stable,
usually more hydrophilic, compound
Enteral Gastrointestinal administration of a drug
Enterohepatic Sequence of initial GI absorption of drug followed by hepatic excretion into bile and
recirculation small bowel, followed by subsequent GI reabsorption
First-pass effect Drugs which have significant metabolism in the liver, prior to widespread systemic
distribution – occurs after GI absorption, by way of portal vein to liver
Half-life Duration of time for 50% of the absorbed and bioavailable drug to be metabolized
and excreted
Parenteral Literally ‘around enteral’; either intravenous, intramuscular, or subcutaneous
administration
Pharmacogenetics The inherited aspects of drug pharmacokinetics and pharmacodynamics which alter
the likelihood of various pharmacologic effects (positive or negative)
Prodrug A pharmacologically inactive precursor of the biologically active ‘drug’
Steady state A balance between the amount of drug being absorbed and the amount being
excreted; in general the time to reach steady state is 4–5 ‘half-lives’
Terminal Elimination/clearance of drug from all body compartments to which the drug is
elimination distributed
Therapeutic index The ratio of (a) the drug dose required to give a desired pharmacologic response to
(b) the drug dose which leads to significant adverse effects
Therapeutic range Range of circulating drug levels deemed to give optimal efficacy and minimal
adverse effects
Tissue reservoirs Body locations to which a given drug is distributed, from which the drug is very
slowly released – includes sites such as fatty tissues, stratum corneum
* The US FDA de nition for ‘bioequivalence’ requires that the bioavailability of the proposed generic drug
must have a 95% confidence interval between 80% and 120% of the trade name drug’s bioavailability.
Several other variables may a ect the absorption of drugs by oral administration. Q1-2 Certain drugs
are absorbed less e; ciently in the presence of food. In descending order the impact of food on tetracycline
family drug absorption is as follows: tetracycline > doxycycline > minocycline. Divalent and trivalent
cations in milk (calcium), various traditional antacids (aluminum-, magnesium-, calcium-containing), and
iron-containing products can reduce the absorption of the above tetracyclines, as well as Kuoroquinolone

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antibiotics. Gastric pH is yet another variable that inKuences drug absorption. An example would be the
necessity for a relatively low gastric pH for ketoconazole and itraconazole to be optimally absorbed, whereas
gastric pH is not a critical determinant for Kuconazole absorption. The above absorption variables are the
basis for a number of drug interactions that do not involve the cytochrome P-450 (CYP) system.
A few other points are worth considering under this heading. Some drugs have negligible absorption
with oral administration, yet can have a pharmacologic value in the GI tract. Several examples would be the
use of oral cromolyn sodium (Gastrochrome) for the GI manifestations of mastocytosis, as well as the use of
nystatin for reduction of bowel Candida levels. A number of medications are available in sustained-release
preparations, in which the drug vehicle is modi ed to allow a steady, slow rate of drug absorption. Finally,
the addition of a vasoconstrictor (epinephrine) to local anesthetics will slow absorption of the anesthetic and
therefore prolong the duration of anesthesia after intralesional injection of the anesthetic.
Distribution (The drug has to travel to the site of intended action or to a reservoir)
This somewhat mundane component of pharmacokinetics has several applications in dermatologic
therapeutics. With oral administration of drugs for dermatologic purposes, there are at least four
compartments of great interest to which a drug can be distributed:
1. Circulation: important to widespread drug effects, both desirable and adverse;
2. Cutaneous: logically of central importance to the desired pharmacologic effects;
3. Fatty tissue: at both cutaneous and internal sites; very important to highly lipophilic drugs, creating a
‘reservoir’ for prolonged release of the drug (as with etretinate); and
4 . Past the ‘blood–brain barrier’: of importance to dermatology primarily for lipophilic drugs with the
potential for sedation or other central nervous system adverse e ects ( rst-generation H1
antihistamines, sedation; minocycline, dizziness).
Fortunately, there are alternatives to the above drugs which do not readily cross the blood–brain barrier
(second-generation H1 antihistamines; doxycycline, tetracycline).
Q1-3 Many systemic drugs discussed in this book have dosages based on body weight. Included are
drugs with doses calculated per kilogram of body weight (isotretinoin, etretinate) and dose calculated per
meter squared (bexarotene – Targretin). The question arises as to what to do with dosage calculations for
very obese patients. There are both drug cost implications and potential adverse e ect implications for very
high drug doses. I tend to calculate dosages based more on ‘ideal weight’ for several reasons. Aside from
treatment of panniculitis, there are virtually no indications for which the site of desired pharmacologic effect
is in fatty tissue. Highly lipid-soluble drugs are readily distributed to fatty tissues, but when a steady state is
reached there is steady release back into the circulation. When considering e; cacy, risk, and cost, all three
point toward maximizing the dosage using calculations based on ideal (or close to ideal) body weight (IBW),
perhaps allowing for a small ‘fudge factor’ on the high side for very heavy patients who do not respond to
traditional doses. One set of formulas from the life insurance industry for calculating ‘ideal weight’ is as
follows: (1) females IBW = 100 lb for 5 ft tall + 5 lb/inch over 5 ft, and (2) males IBW = 106 lb for 5 ft
tall + 6 lb/inch over 5 ft, and (3) an upward ‘adjustment’ up to 10% based on a ‘large frame’.
Conceptually, there are three drug ‘reservoirs’ of signi cant interest to dermatology. The first is in
systemic circulation, in the form of drug–protein binding. The bound drug is pharmacologically inactive,
whereas the unbound drug = free drug = pharmacologically active drug. Acidic drugs are most commonly
bound to albumin, whereas basic drugs bind preferentially to α-1 acidic glycoprotein. There are noteworthy
exceptions regarding lipophilic drugs with intracellular physiologic receptor–e ector systems such as
corticosteroids and retinoids. There is a large circulatory reservoir for highly protein-bound drugs such as
methotrexate. Sudden increases in the free drug levels due to displacement of methotrexate from circulatory
protein-binding sites by aspirin, non-steroidal anti-inKammatory drugs, and sulfonamides can markedly
increase the risk for pancytopenia (although the body can adjust to this drug displacement over time). The
second drug reservoir of interest is in various fatty tissues (including, but not limited to, subcutaneous fat)
for highly lipophilic drugs, as discussed in the preceding paragraph. The third drug reservoir (the stratum
corneum) pertains just to percutaneous absorption for topically applied medications. In all three settings the
free drug and the drug in the reservoir are in equilibrium. As the free drug is metabolized and excreted,
corresponding amounts of the drug in these tissue and circulatory reservoirs are released into the free/active
drug fraction.
Bioavailability (The drug has to be ‘available’ at the site of intended action)
Bioavailability is expressed as the percentage of the total drug dose administered that reaches the
circulation. For a drug taken orally, the ‘ rst-pass e ect’ of hepatic metabolism reduces bioavailability. The
bioavailability calculations include both free and bound forms of the drug. A systemic drug with a relatively
low bioavailability is acyclovir; the prodrug for acyclovir, valacyclovir, has at least three times greater<

bioavailability. At the other end of the spectrum are the Kuoroquinolones, for which oral absorption (and
resultant bioavailability) is so complete that the oral and intravenous doses for many members of this drug
group are identical. A more optimal method (if it were more practical) would be to calculate bioavailability
at the site of intended action; for drugs discussed in this book, it would be based on tissue levels at the site of
intended action, the various skin structures. At present such ‘ideal’ bioavailability calculations are not
routinely available.
For most chapters in this book that discuss systemic drugs there are tables that present data for the
following: (1) % bioavailable and (2) % protein binding. The ‘% bioavailable’ is typically factored into ideal
oral drug dosage calculations, which will produce circulating drug levels in a reasonably safe and e ective
‘therapeutic range.’ The ‘% protein binding’ is important to the subject of drug interactions as previously
discussed, with methotrexate an important example. Changes in albumin levels in disease states such as
severe liver or renal disease will often necessitate drug dosage adjustments for drugs (such as methotrexate)
that are highly protein bound.
Creating drug formulations with a more optimal bioavailability is a daunting task for the
pharmaceutical industry. In the past two decades there have been updated formulations of older drugs with
higher bioavailability, more predictable bioavailability, or both. For drugs with a relatively narrow
therapeutic index (cyclosporine, methoxsalen), improved predictability of the drug absorption and resultant
bioavailability are very important. The release of Neoral (in place of the previous cyclosporine formulation,
Sandimmune) is an example for both improved % bioavailability and more predictable bioavailability of the
newer formulation. Likewise, Oxsoralen Ultra demonstrates improvement in both of the above parameters.
In a separate example, the need for improved e; cacy from griseofulvin led to the progression from the
original griseofulvin formulations → microsize formulations → ultramicrosize formulations. Each step of this
progression resulted in improved bioavailability and smaller griseofulvin dosages required for an adequate
therapeutic response.
Pharmacodynamics (the drug produces the desired pharmacologic effect)
The subject of pharmacodynamics is very complicated. In essence, this topic is the ‘basic science’ behind
drug mechanisms of action. Considering all the diverse mechanisms of actions discussed in this book (let
alone the diversity of drug mechanisms the whole of medicine), it is not possible to summarize general
principles behind all of them. In contrast, it is possible to cover a few areas of central importance to
understanding pharmacodynamics. These include the concepts of drug receptors, enzyme inhibition by
drugs, signal transduction, and transcription factors.
Definitions (Table 1-4)
In general, the de nitions used in pharmacodynamics tend to be less familiar to most clinicians than the
comparable terms in pharmacokinetics. These terms overall tend to relate to factors that:
1. Address aspects of drug binding to receptor (ligand, affinity);
2. Relay the drug ‘signal’ to the definitive effector mechanism (signal transduction, second messenger);
3. Increase the desired pharmacologic response (drug agonists, partial agonists);
4. Reduce an undesirable physiologic or pharmacologic response (drug antagonists or receptor blockers);
or
5 . Q1-4 Result in a loss of a desirable or undesirable pharmacologic response through repeated use
(tolerance, cross-tolerance, refractoriness, downregulation, tachyphylaxis).
Table 1-4 Definitions and concepts central to understanding pharmacodynamics
Term Definition
Active A drug metabolite which retains the same/similar pharmacologic properties as the parent
metabolite drug
Affinity A physical measurement which reflects the attraction of the drug ligand to a given
(binding) receptor molecule
Agonist Drug which binds to a given receptor initiating an effector mechanism → pharmacologic
response
Antagonist Drug which binds to a receptor, but fails to activate the effector mechanism<
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Cross (see tolerance) Reduced pharmacologic effect when exposed to a new, chemically-related
tolerance drug
Down Reduced receptors number/availability, presumably due to a negative feedback
regulation mechanism
Inverse Drug which stabilizes receptors which have some constitutive activity to an inactive
agonist conformation
Ligand Any molecule (drug) which binds to the drug receptor; binding can be by hydrogen
bonds, ionic forces, or covalent forces
Partial Drug which binds to a receptor and weakly initiates an effector mechanism and resultant
agonist response
Receptor The molecule to which the drug (ligand) binds to initiate its effector response; location
can be cell membrane, cytosolic, or intranuclear
Refractoriness (synonyms – desensitization, tachyphylaxis) Temporary lack of responsiveness to a drug
Second Biochemical mediator (commonly calcium or cyclic AMP) that serves to relay the signal
messenger initiated by the receptor/effector in signal transduction
Signal Cellular biochemical pathways which relays a second messenger ‘signal’ from the
transduction receptor to the effector mechanism
Tachyphylaxis A diminished pharmacologic response after repeated drug administration; can be due to
down regulation or receptor sequestration (transiently ‘unavailable’ to the drug)
Tolerance Diminished effect (generally adverse effect) after repeated drug administration (most
common is tolerance to sedating drugs such as antihistamines)
Only a proportion of these concepts can be realistically addressed in the remainder of this section on
pharmacodynamics.
Drug receptors
The broadest de nition of a drug receptor is given in Table 1-4. In this de nition, any molecule to which a
drug binds, thus initiating an e ector mechanism leading to a speci c pharmacologic response, is a drug
receptor. In contrast, proteins involved in drug ‘protein binding’ are merely drug storage (reservoir) or
transportation sites, and thus, are not receptors.
The drug receptor subtypes that are easiest to characterize are cell surface receptors for endogenous
neurohormonal ligands. Similar receptors are operant for various growth factors and other cytokines. Q1-5
Such ‘drug’ receptors are common targets in current therapeutic strategies and in drug development. In
addition, lipophilic drugs easily absorbed through cellular membranes may have cytosolic drug receptors.
Common examples using these cytosolic physiologic receptors include both systemic and topical versions of
corticosteroids and retinoids. The ‘catch’ regarding receptors for these two drug categories is that both
desirable (therapeutic e ects) and undesirable (adverse e ects) e ects are mediated through the same
physiologic receptor. A ‘dissociation’ of the drug receptors for the therapeutic anti-inKammatory bene ts of
methotrexate (such as methionine synthetase) and adverse e ects (dihydrofolate reductase, DHFR) is of
interest. Folic acid (folate) supplementation can competitively antagonize the DHFR inhibition of
methotrexate and minimize the adverse e ects of methotrexate without compromising therapeutic bene ts.
A few examples of drugs that are either antagonists or agonists at well-de ned cellular receptors are given in
Table 1-5.
Table 1-5 Pharmacodynamics – selected receptor antagonists and agonists
Drug Receptor affected Biologic outcome
Receptor antagonists (receptor ‘blockers’)
H H antihistamine Antagonize histamine effects via receptor – vasodilation,1 1
antihistamines receptor increased vascular permeability, etc.

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H H antihistamine Antagonize histamine effects via receptor – decreased gastric2 2
acid secretion, suppressor T-cell effectsantihistamines receptor
Spironolactone, Androgen receptor* Antagonize testosterone and dihydrotesterone effects via
flutamide receptor – variable hair effects depending on scalp or face
location; also reduced sebum secretion
Selective Serotonin transport Antagonize serotonin reuptake mechanism (net effect
serotonin protein increased persistence of serotonin as neurotransmitter)
reuptake
inhibitors
Hormonal receptor agonists
Corticosteroids Corticosteroid Augment both the desirable pharmacologic effects and the
receptor adverse effects mediated through same receptor
Calcipotriene Vitamin D receptor Augment vitamin D effects via receptor – include3 3
keratinocyte and fibroblast differentiation
Retinoids Retinoic acid Augment various vitamin A mediated effects via gene response
receptor (RAR) elements
Retinoid X receptor
(RXR)
* Primary pharmacologic (diuretic) e ects of spironolactone are mediated through the mineralocorticoid
receptor; anti-androgen e ects are mediated via the androgen receptor for dihydrotestosterone and
testosterone.
Few drugs are ideally speci c for a given drug receptor molecule. The ability of both tricyclic
antidepressants (such as doxepin) and rst-generation H antihistamines (such as diphenhydramine,1
hydroxyzine) to also bind muscarinic anticholinergic receptors can produce objectionable anticholinergic
adverse e ects such as dry mouth, blurred vision, and orthostatic hypotension. Relatively selective drug
receptor binding was achieved in later ‘generations’ of related drug groups. Selective serotonin reuptake
inhibitors (such as Kuoxetine, sertraline) and second-generation H1 antihistamines (such as fexofenadine,
loratadine) have had a signi cant improvement in the adverse e ect pro le due to much more selective
drug receptor binding. It is of interest to note that ‘tolerance’ to the sedative adverse e ects can occur with
prolonged use of the first-generation H antihistamines.1
Enzyme systems inhibited by drugs
Q1-6 For comparison purposes, a number of speci c examples for drugs that selectively inhibit an enzyme
system are listed in Table 1-6. Drugs that inhibit enzyme systems of importance to nucleotide synthesis have
signi cant potential for use in neoplastic diseases or as immunosuppressants in autoimmune dermatoses. A
number of drugs representing antimicrobial agents for bacterial, viral, and fungal infections capitalize on
vital enzyme systems, which are more readily inhibited in the infectious organism than in the human host.
Finally, a number of drugs inhibit enzyme systems that contribute important downstream mediators to an
inKammatory response. For all three categories of enzyme listed in this table, the drug receptor may be the
enzyme itself (methotrexate and DHFR) or may work indirectly through another receptor/e ector
mechanism (as with corticosteroid inhibition of phospholipase A2, probably mediated through
lipomodulin1).
Table 1-6 Pharmacodynamics – selected examples of enzymes that specific drugs inhibit
Drug Enzyme inhibited Biologic outcome
Enzymes important to DNA synthesis
Methotrexate Dihydrofolate Reduced formation of fully reduced folate precursors for purine and
reductase thymidylate synthesis

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Mycophenolate Inosine Inhibition of de novo pathway for purine (guanosine) nucleotide
mofetil monophosphate synthesis – preferentially affects various WBC subsets (other cells
dehydrogenase can utilize salvage pathway)
Enzymes important to microbial growth and survival
Sulfonamides, Dihydropteroate Affects bacterial version of this enzyme far more readily than the
dapsone synthetase mammalian enzyme; first step of two enzyme pathway essential for
folate reduction
Trimethoprim, Dihydrofolate Affects bacterial version of this enzyme far more readily than the
methotrexate reductase mammalian enzyme; second step of two enzyme pathway essential
for folate reduction
Itraconazole, Lanosterol 14-α Triazole inhibition of this enzyme inhibits formation of ergosterol,
fluconazole demethylase an essential component of fungal cell wall
Terbinafine, Squalene Allylamine inhibition of this enzyme decreases ergosterol, and
naftifine epoxidase increases squalene accumulation
Acyclovir, DNA polymerase Triphosphorylated forms of these drugs* preferentially inhibit viral
valacyclovir, DNA polymerase >> human version of enzyme
famciclovir
Other enzymes of importance to inflammatory response
Retinoids Ornithine This is rate-limiting enzyme in polyamine pathway, which is
decarboxylase initiated by protein kinase C (PKC) activation
Dapsone Myeloperoxidase This enzyme in neutrophils and macrophages is essential to
microbial killing by these cells (also in eosinophils)
Cyclosporine, Calcineurin This calcium-dependent signal transduction enzyme is key to
tacrolimus increased IL-2 production dependent on NFAT-1†
Corticosteroids Phospholipase Inhibition probably mediated through lipomodulin-1; net effect is
A reduced prostaglandins, leukotrienes, and other eicosanoids which2
are important to inflammatory responses
* See regarding prodrug and active relationship of these drugs.Table 1-8
† NFAT-1 (nuclear factor activated T-cells) is a transcription factor essential to increased T-cell production of
IL-2 and upregulation of IL-2 receptors.
Signal transduction and transcription factors
These two aspects of pharmacodynamics have a number of conceptual similarities, albeit with very
distinctive mechanisms of action. Signal transduction is a series of intermediary steps in relaying a
druginitiated signal or message to the de nitive e ector mechanism. Tremendous details on the various
receptor/signal transduction categories (6 main families) are beyond the scope of this chapter but are
available in the Bibliography. This de nitive e ector mechanism is commonly accomplished through DNA
transcription and subsequent new protein translation. In many cases the signal transduction ‘passes through’
a DNA transcription factor. This sequence and the resultant overlap of topics is best illustrated by the
socalled ‘signal one’ in activated T-cells upon T-cell receptor binding to antigen, which is ampli ed by
subsequent IL-2 binding to the IL-2 receptor. The rough sequence of steps is as follows: (1) T-cell receptor
binding to antigen, (2) CD3 molecule-based T-cell activation, and (3) calcineurin-based production of
NFAT-1, a DNA transcription factor important to IL-2 upregulation. Cyclosporine and tacrolimus both
interfere with this signal transduction pathway through inhibition of calcineurin activity, with a resultant
decrease in activity of the transcription factor NFAT-1.
Second messengers are also important to this discussion. Probably the two most important second
messengers pertinent to pharmacology are calcium and cyclic AMP (cAMP). Calcium is an important
component of the above T-cell signal transduction system in two locations; calcineurin is a
calciumdependent enzyme, with a calcium-binding protein (calmodulin) playing an important role as well.







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Although not directly related to dermatology, the role of cAMP as a second messenger in the bene cial
e ects of β-agonists in therapy of asthma is of interest. The concept of tachyphylaxis as de ned in Table 1-4
has been well characterized for β-agonists used in this setting.
Two more examples of important drugs and their e ects on signal transduction (retinoids) and
transcription factors (corticosteroids) can be presented. The polyamine pathway creates a process known as
inKammatory hyperplasia, which is an important component of the pathogenesis of both psoriasis and
various malignancies. Retinoids inhibit the activity of ornithine decarboxylase, the rate-limiting enzyme in
the polyamine pathway. This signal transduction enzyme inhibition is important to the bene ts of systemic
retinoids in both psoriasis therapy and retinoid chemoprevention of cutaneous malignancies in
transplantation patients.
Corticosteroids inhibit the actions of the transcription factor, nuclear factor B (NF B) by two
mechanisms. Corticosteroids both increase production of the inhibitor of NF B (known as I B) and directly
bind to and inactivate NF B. This transcription factor is pivotal in the upregulation of a multitude of
cytokines of central importance in the inKammatory response to a wide variety of stimuli. There is
tremendous ampli cation potential of the inKammatory response through this NF B pathway. Likewise, a
major portion of the anti-inKammatory bene ts of corticosteroids (topical or systemic) are probably
accomplished through the inhibition of this important transcription factor. It is unclear whether the
relatively common occurrence of tachyphylaxis noted with class I topical corticosteroids relates to
downregulation of receptors involved in this particular pathway.
Pharmacokinetics – part II
Metabolism (The drug becomes more hydrophilic to favor renal and biliary excretion)
This topic is extensively discussed in Chapter 60 on Hepatotoxicity of Dermatologic Drug Therapy. A
relatively brief synopsis will be presented here. Most drugs are metabolized by phase I (oxidation reactions)
and phase II (conjugation and detoxi cation reactions). The initial oxidation reactions in phase I are
accomplished by various CYP isoforms, which are largely present in the liver (but also available in many
other organ sites, including the skin). The result of these enzymes is a somewhat more hydrophilic
(watersoluble) metabolite, which may provide a site of attachment for subsequent conjugation reactions. To
complicate matters, reactive electrophilic intermediates are often created, which in the absence of adequate
phase II detoxi cation systems may induce important metabolic or immunologic complications (Table 1-7).
Phase II conjugation reactions (glucuronidation, sulfonation, acetylation) and the various detoxi cation
systems (such as glutathione and epoxide hydrolase) will generally accomplish the production of both
signi cantly increased hydrophilicity of the drug metabolites and stabilization of the aforementioned
reactive intermediates, respectively. Q1-7 It is important to note here that many drug metabolites retain the
parent drug’s pharmacologic activity (Table 1-8). An example of this principle would be the itraconazole
metabolite hydroxyitraconazole, which also has signi cant antifungal activity. In the great majority of drugs
metabolism renders the drug inactive.
Table 1-7 Definitions related to adverse effects
Term Definition
Adverse effect Negative or undesirable effect from a drug (either at toxic or pharmacologic drug
doses)
Idiosyncratic Unexpected adverse effect from a drug
Immunologic Unexpected adverse effect from a drug occurring on an immunologic basis (usually
idiosyncrasy due to hypersensitivity)*
Metabolic Unexpected adverse effect from a drug occurring due to a metabolic byproduct
idiosyncrasy (reactive intermediate)
Pharmacologic Positive or negative effect from a drug, expected at normal doses and/or drug
effect levels
Side effect Synonym for adverse effect (prefer to use ‘adverse effect’ to address undesirable
quality of drug effect)
Toxicity/toxic Undesirable effects expected from a drug due to excessive doses and/or drug levels
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* Confusing reality is that immunologic hypersensitivity may occur due to excessive quantities of a reactive
metabolite, rendering immunogenic a previously normal endogenous protein (see Chapter 60 –
Hepatotoxicity).
Table 1-8 Some examples of prodrugs important to dermatology
Prodrug Active drug
Antiviral agents
Valacyclovir Acyclovir
Famciclovir Penciclovir
Corticosteroids
Prednisone Prednisolone
Cortisone Hydrocortisone (cortisol)
Other immunosuppressants
Azathioprine 6-mercaptopurine → 6-thioguanine
Mycophenolate mofetil Mycophenolic acid
Cyclophosphamide Phosphoramide mustard
Antihistamines
Terfenadine Fexofenadine
The topic of pharmacogenetics largely addresses genetically based variations in the above metabolic
enzyme systems. At times these genetic alterations can explain idiosyncratic adverse e ects of medications.
Examples pertinent to the above phase I and phase II metabolic systems include the following genetic
polymorphisms:
1. CYP2D6 polymorphisms with at least 50-fold variation in activity of this important isoform: One result
is unexpected profound sedation from various antidepressants (including doxepin) and other sedating
medications in ‘poor metabolizers.’
2. ‘Slow acetylators’: One result of this polymorphism is more frequent occurrence of drug-induced lupus
erythematosus.
3 . Glutathione depletion (which in part may be acquired due to malnutrition or HIV infections): This
results in markedly increased risk of hypersensitivity to sulfonamide medications in these populations.
The key research agenda for this important topic is the development of predictive tests to anticipate
which patients are at increased risk for important adverse e ects from drugs. These tests would be
analogous to the baseline G6PD determinations for dapsone patients and baseline thiopurine
methyltransferase determinations for azathioprine patients, which in both cases enables better prediction of
patients at risk for important adverse e ects. Genetic predictive testing for polymorphisms of CYP2D6, 2C9,
and 2C19 are currently commercially available.
The most important numerical parameter under the heading of drug metabolism is the drug ‘half-life.’
The discussion of the multiple subtypes of drug half-life, such as terminal elimination half-life, is beyond the
scope of this chapter. A given drug’s half-life is important in determining the time to reach a steady state
once drug therapy is initiated (4–5 half-lives) and the time for virtually complete drug clearance after drug
therapy is discontinued (likewise 4–5 half-lives).
Q1-8 One Kaw of the linear model presented here for discussing pharmacodynamics between the two
sections on pharmacokinetics relates to prodrugs (Table 1-9). These prodrugs are pharmacologically inactive
until ‘metabolic’ conversion to the active drug, typically through hydrolysis of an ester or amine linkage. The
conversion of prednisone (prodrug) to prednisolone (active form) is dependent on a hepatic-based enzyme,
which in end-stage liver disease may not produce therapeutically adequate quantities of the active drug
form prednisolone. Once the prodrug is metabolized to the active drug, the principles of interest follow
through the distribution, bioavailability, and pharmacodynamics sections as with other drugs already in




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active form once absorbed.
Table 1-9 Some examples of active drug, active metabolite relationships
Active drug Active metabolite(s)
Antihistamines
Hydroxyzine Cetirizine → levo-cetirizine
Loratadine Desloratadine
Antidepressants
Doxepin Nordoxepin
Citalopram Escitalopram
Antifungal
Itraconazole Hydroxyitraconazole
Excretion (The hydrophilic drug metabolites must leave the body)
Q1-9 Conceptually there are three common routes by which systemically administered medications leave the
body. These are (1) renal excretion, (2) biliary excretion of a more hydrophilic metabolite through the GI
tract, and (3) orally administered medications may in part be excreted through the GI tract after failing to
be absorbed. The excreted drug can be the parent drug, drug metabolites, or combinations of both.
Relatively hydrophilic drugs can be excreted unchanged through the kidney. An example would be
Kuconazole, which because of its relatively hydrophilic properties has a signi cant portion of the
administered drug excreted through the kidney unchanged. Relatively lipophilic drugs typically must be
rendered more hydrophilic by the aforementioned phase I and II metabolic steps, before excretion is possible
through renal or biliary routes. In particular, greater hydrophilicity favors renal excretion, which has a
much larger overall capacity for drug excretion than the hepatobiliary route.
In reality, the drugs discussed in this book are frequently excreted by several of the above routes, both
as free drug and as a variety of metabolites. Refer to the various ‘Pharmacology Key Concepts’ tables used
for systemic drugs in this book for illustrations of this point. The reader should also be aware that many
drugs conjugated in the liver, and excreted into bile, will subsequently undergo hydrolysis in the small
intestine and be reabsorbed (enterohepatic recirculation) through many cycles; eventually the de nitive
excretion may be through the kidney.
It is very important to recognize that disease-induced or age-dependent reduction in renal function
should prompt the clinician to signi cantly reduce dosages of drugs with signi cant renal clearance. An
example would be the increased risk for pancytopenia and other complications with methotrexate when
standard doses are administered to patients with either disease- or age-related reduction in renal function.
Likewise, drugs that have signi cant liver metabolism and excretion should have dosage reductions with
advanced liver disease.
Percutaneous absorption
General principles
There is a wealth of scienti c and practical information in Tables 1-10 and 1–11. Q1-10 Probably the 5
most important determinants of percutaneous absorption of topical dermatologic products are:
1. Stratum corneum thickness and integrity of ‘barrier function’;
2. Drug partition coe; cient – the ability of the drug to ‘depart from’ the speci c vehicle and enter the
stratum corneum;
3. Drug di usion coe; cient – the ability of the drug (due to innate molecular properties) to penetrate
through all layers of skin once in the stratum corneum;
4. Drug concentration – the specific drug concentration of a given topical product; and,
5. Superficial dermal vascular plexus – site of systemic absorption for topically applied drugs.
Table 1-10 Percutaneous absorption variablesVariable Biologic result
Drug variables
Concentration PCA is directly related to concentration, and not volume of topical medication applied to
a specific skin site
Lipophilicity Most topically effective drugs are at least somewhat lipophilic
Molecular size Most effective topical medications have a molecular weight
Vehicle variables (see Table 1-11)
Lipid content Ointment is strongest vehicle due to most optimal partition coefficient in transferring
drug to stratum corneum lipids (solution typically weakest vehicle)
Irritancy Irritating vehicles will alter skin barrier function and may ↑ PCA
Innate skin variables
Stratum Rate-limiting site for PCA; thickness of stratum corneum is inversely related to PCA
corneum
thickness
Cutaneous Increased cutaneous vasculature can increase both local and systemic drug effects
vasculature
Area of Increased surface area to which drug is applied will ↑ PCA total overall, but not ↑ PCA at
absorptive a specific site (concentration most important variable at a specific site)
surface
Mucosal Far less innate barrier function, generally less well developed stratum corneum; consider
surfaces that any mucosal route of administration can produce systemic effects
Diseased skin variables
Inflamed skin Overall ↑ PCA, due both to altered barrier function and increased vasodilation
Ulceration Topical application responds as if systemic administration of medication (bacitracin
anaphylaxis risk after application to a leg ulcer)
Other variables
Additional Hydrating skin (by various means) prior to application of topical medication will ↑ PCA
skin
hydration
Occlusion of Topical occlusion locally (food wrap) or widespread (‘sauna suit’) with marked ↑ PCA;
medication conceptually transdermal application of ‘systemic medications’ utilizes somewhat similar
process
Age of patient Increased total body surface area to body volume ratio in infants and young children;
therefore, increased risk of systemic effects from topical therapy due to relatively high
absorptive surface
PCA = percutaneous absorption.
Table 1-11 Clinical comparisons of various vehicles – generalities<

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Q1-11 Measures that increase percutaneous absorption can always be considered a ‘two-edged sword.’
The desired pharmacologic result is enhanced by these measures. For instance, use of a high-potency topical
corticosteroid in an ointment base, after skin hydration, and with total body occlusion, will do wonders for
extensive psoriasis. The counterpoint is that all of these measures will markedly increase systemic absorption
of the topical corticosteroid, potentially giving a net prednisone-like e ect from the topical corticosteroid.
For a short period of time there will be relatively few trade-o s. After 2–3 weeks or more, important
systemic adverse e ects such as weight gain, Kuid retention, hypertension, hypokalemia, and cushingoid
changes are all possible with this undesirable long-term approach to topical corticosteroid administration. It
is important to note here that all topical drug absorption occurs via passive diffusion.
Topical medications applied in several clinical settings can produce immediate hypersensitivity
(Coombs–Gell type I) reactions. In particular, topical application to ulcerated skin can give the applied
medication almost immediate access to systemic circulation. There have been reports of anaphylaxis to
topical bacitracin or neomycin in this setting. Likewise, mucosal applications of medications (such as
eyedrops, vaginal suppositories, and rectal foam or suppositories) can result in signi cant systemic levels of
various drugs and freedom from ‘ rst-pass e ect’ due to the small intestine and liver. Although the risk from
topical application of medications to these above sites is usually small, the clinician should always be
mindful of this systemic absorption potential.
Vehicles
Much of the art and science of dermatology revolves around choosing the appropriate vehicle for topical
medications (Table 1-11). In general, the choice of vehicle is just as important as choosing the proper active
ingredient. Two common consequences of certain vehicles are the following:
1. Irritancy: most notably from high concentrations of propylene glycol; other ‘alcohols’ or certain acidic
vehicle ingredients also may be irritants, particularly when applied to diseased skin with altered barrier
function.
2 . Contact allergy/sensitization: common with preservatives in various water-based (creams, lotions,
solutions) topical products, and include various parabens along with ‘formalin releasers’ (such as
quaternium-15, imidazolidinyl urea, and diazolidinyl urea).
The astute clinician will be mindful of the potential adverse e ects of the vehicle, particularly if the
patient fails to improve or worsens with topical therapy. The simplest and safest way to minimize the risk of
these vehicle-induced adverse e ects is to choose topical products that lack the most common potential
irritants and allergens. See Chapter 40 on Topical Corticosteroids and Chapter 53 Irritants and Allergens:
When to Suspect Topical Therapeutic Agents for additional information on this topic.
Tachyphylaxis
In my experience tachyphylaxis is a relatively common clinical event with very high-potency (class I) topical
corticosteroids. (See Chapter 4 Adherence with Drug Therapy for some ‘counterpoints’ on this controversial
topic.) The measures previously discussed, which can produce excessive systemic absorption, also predispose
to diminished therapeutic bene t from the topical drug over time. The clinician should be aware that
continued daily or twice-daily application of a class I topical corticosteroid to minimally inKamed skin
(without any other maneuvers to increase percutaneous absorption) commonly leads to tachyphylaxis after
2–4 weeks of continuous therapy. The good news is that this is an easily reversible process, particularly if the
clinician is mindful of the potential for tachyphylaxis. Weekend-only or alternate-day applications of these



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high-potency topical products typically prevents tachyphylaxis; a week or so o therapy altogether allows
upregulation of the corticosteroid receptor molecules and a resultant return of the desired therapeutic
benefit upon resumption of the topical corticosteroid.
Transdermal medication formulations
One nal routine of topical administration of medications that is tangentially related to dermatology
deserves mention here. The potential for certain drugs to have reduced bioavailability through excessive
hepatic and small intestine rst-pass metabolism can be circumvented by transdermal administration. An
excellent example would be transdermal estrogen administration, which allows the drug to be absorbed
directly into systemic circulation. This avoids the signi cant rst-pass metabolism typical of orally
administered estrogens, with resultant improved drug bioavailability. There are numerous other medications
that can be administered in various transdermal delivery systems for steady, continuous percutaneous
delivery of the active ingredient.
Given the central importance of understanding percutaneous absorption, the interested reader is
encouraged to pursue further information on this subject from the chapters listed in the Bibliography.
Hopefully through the principles, clinical examples, and tables presented on this subject, all readers can
achieve an adequate basic understanding of the most important concepts of percutaneous absorption and
the importance of the drug vehicle to the optimal clinical response. Each chapter in the three major book
sections on topical medications (Chapters 36–55) will expand on and illustrate these principles of
percutaneous absorption.
Bibliography: important reviews and chapters
Systemic drugs
Buxton ILO, Benet LZ. Pharmacokinetics: the dynamics of drug absorption, distribution, metabolism, and
elimination. In: Brunton LL, Chabner BA, Knollman BC. Goodman and Gilman’s the pharmacologic basis of
therapeutics. 12th ed. New York: McGraw Hill; 2011:17–39.
Blumenthal DK, Garrison JC. Pharmacodynamics: molecular mechanisms of drug action. In: Brunton LL,
Chabner BA, Knollman BC. Goodman and Gilman’s the pharmacologic basis of therapeutics. 12th ed. New York:
McGraw Hill; 2011:41–72.
Gonzales FJ, Coughtrie M, Tukey RH. Drug metabolism. In: Brunton LL, Chabner BA, Knollman BC. Goodman
and Gilman’s the pharmacologic basis of therapeutics. 12th ed. New York: McGraw Hill; 2011:123–143.
Relling MV, Giacomina KM. Pharmacogenetics. In: Brunton LL, Chabner BA, Knollman BC. Goodman and
Gilman’s the pharmacologic basis of therapeutics. 12th ed. New York: McGraw Hill; 2011:145–168.
Percutaneous absorption
Burkhart C, Morell D, Goldsmith L. Dermatogic pharmacology. In: Brunton LL, Chabner BA, Knollman BC.
Goodman and Gilman’s the pharmacologic basis of therapeutics. 12th ed. New York: McGraw Hill; 2011:1803–
1832.&
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2
Principles for maximizing the safety of
dermatologic drug therapy
Stephen E. Wolverton
Questions
Q2-1 What four words characterize the overall approach to maximizing drug
safety, and what general concepts are represented by these words? (Pg. 12)
Q2-2 How are the ‘standards of care’ for drug therapy determined? (Pg. 13)
Q2-3 What are several of the typical characteristics of the most worrisome
adverse effects to systemic drug therapy (Pg. 13)
Q2-4 In general, what are the most important issues to discuss with a patient
prior to initiating systemic drug therapy which has a signi cant element of
risk? (Pg. 14)
Q2-5 What are three broad categories for mechanisms for drug interactions,
which can assist clinicians in anticipating important potential drug
interactions? (Pg. 15)
Q2-6 What are three to four examples of major drug risks ‘discovered’ many
years after the drug’s release? (Pg. 15)
Q2-7 When considering a ‘teamwork’ approach to maximize drug safety, name
at least ve di, erent ‘individuals’ with a key role in this drug safety process
for a given patient. (Pg. 17)
Q2-8 What are the most important common clinical scenarios which require
more frequent (compared to normal monitoring frequencies) laboratory
monitoring? (Pg. 18)
Q2-9 What are some important examples of ‘thresholds of concern’ and ‘critical
values’ for laboratory tests commonly utilized in drug monitoring? (Pg. 18)
Q2-10 What are several important options available for a speci c abnormal lab
value? (Pg. 18)
Q2-11 In the event a potentially serious complication of drug therapy does
occur, what are some of the most important management options available to
clinicians? (Pg. 19)
Introduction
This chapter is unique in the context of the entire book. The principles that follow
are a blend of science, literature reports, personal experience, and common sense.
Rather than provide references for the principles and examples used in this
chapter, the reader is encouraged to selectively pursue more detailed information
and literature references pertaining to examples cited here in the various chapters&
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devoted to the respective drug or drug category. Most of the examples provided
deal with systemic drug therapy in dermatology, given that the systemic drugs
commonly prescribed pose a signi cantly greater potential risk to the patient than
topical or intralesional therapeutic options.
Q2-1 Four words summarize the proactive approach to maximizing the safety
of dermatologic drug therapy discussed in this chapter: anticipation, prevention,
diagnosis, and management. The primary goals of maximizing drug safety are:
1 . Anticipation of which patients (comorbidities and other drugs the patient
receives) and which drug regimens are at risk for various important adverse
effects;
2. Prevention of adverse e, ects of potential concern by taking appropriate safety
measures;
3. Diagnosis at an early, reversible stage should an adverse effect occur; and
4. Management of the adverse effect in a safe and effective manner.
I will present a number of general principles regarding how to maximize the
safety and e: cacy of systemic drug therapy. Each principle will be illustrated with
several pertinent drug examples.
Unlike many medical specialties, dermatologists in general must take greater
precautions with systemic drug therapy, for the following reasons. Systemic drugs
used in this eld have typically been developed for specialties such as
rheumatology, oncology, infectious diseases, and transplantation surgery. These
specialties in general care for patients with more serious, possibly life-threatening,
illnesses than the majority of conditions for which dermatologists prescribe the
various systemic drugs. Clinicians in any eld are obliged to avoid creating a
greater risk with drug therapy than the innate risk (in that speci c patient) of the
underlying disease to be treated. This statement is the underlying principle behind
the need for careful monitoring of systemic drug therapy in dermatology. It is
essential to maximize the safety and minimize the risk of this drug therapy.
How to optimally anticipate, prevent, diagnose, and manage speci c drug
adverse e, ects in order to maximize drug safety is a central theme of this chapter
and of the book as a whole. This is a broader viewpoint than merely ‘monitoring’
for adverse e, ects. The goals of this broader approach are to (1) maximize overall
drug safety for the patient, (2) improve the ‘comfort’ of systemic drug therapy for
the patient and physician, and (3) follow the appropriate ‘standards of care’ in
order to minimize medicolegal risk. These overlapping goals are interdependent.
For example, when appropriate standards of care are followed, the patient safety is
the focus of these standards. In addition, when the patient’s safety and emotional
comfort during drug therapy are truly of central importance to the physician, the
medicolegal risk is negligible. This is particularly true if the patient assumes an
active role in all aspects of any systemic drug therapy regimen, in turn forming a
‘therapeutic partnership’ with the prescribing physician.
It is somewhat challenging to de ne the de nitive sources of these so-called
‘standards of care.’ Q2-2 In general, such standards come from one or more of the
following sources:
1 . Specialty-based formal guidelines such as the American Academy of
Dermatology ‘Guidelines of Care’;&
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2. Individual pharmaceutical company guidelines for speci c drugs, such as the
therapeutic guidelines and informed consent packet for isotretinoin (iPLEDGE)
in women of childbearing potential;
3. FDA Advisory Committee recommendations, such as those guidelines proposed
in the early 1980s for monitoring the hematologic complications of dapsone;
4. Consensus conference publications, such as the consensus guidelines published
in 2004 for isotretinoin therapy in acne patients; and
5 . ‘Dear Health Care Professional’ letters (formerly ‘Dear Doctor’ letters) from
pharmaceutical companies, with careful oversight by the FDA, updating
physicians and other healthcare providers nationally regarding recent ndings
on specific adverse effects.
The reality is that the standards of care for a given drug are often a blend of
several of these sources, with a certain amount of ambiguity as would be expected
from such a mix.
Historically, these standards of care were based on local practices in the
‘community’ in which the physician practiced. Currently the realities of the
‘information age’ in which we practice tend to create a trend towards national, if
not global, standards of care. Such standards should be considered guidelines, and
not mandates, with room for Dexibility as the patient’s individual circumstances
and scientific ‘evidence’ justify.
As far as possible, special e, orts must always be made to ensure that the most
serious adverse e, ects ‘never’ occur. Q2-3 Characteristics of the most serious
adverse e, ects given the highest priority in this chapter, and throughout the book,
include at least several of the following: (1) a sudden, precipitous onset, (2) no
early warning symptoms, (3) no predictive laboratory tests, (4) potentially
irreversible, and (5) a potentially serious outcome. Examples of such high-priority
adverse e, ects include (1) hematologic complications (pancytopenia from
azathioprine or methotrexate, agranulocytosis from dapsone), (2) isotretinoin
teratogenesis, (3) corticosteroid osteonecrosis, and (4) opportunistic infections from
TNF (tumor necrosis factor) inhibitors. Principles to minimize the likelihood of
these and other complications follow in the four major sections of this chapter.
First, a few ‘baseline concepts.’ No matter how careful a physician may be,
sooner or later ‘bad things’ will happen to a patient from drug therapy that he or
she initiates. No medical risk reduction system is perfect, given the
unpredictabilities of the human body. If the patient and physician can form a
strong therapeutic partnership, and if the physician continues to work with the
patient to promptly diagnose and manage any drug-induced complications, there
can be a number of positive results: (1) the patient’s medical outcome is optimized,
(2) the physician’s ethical obligations are met, and (3) the medicolegal risk is
minimized. Nevertheless, the physician must take a ‘lifelong learner’ approach to
any such unexpected complications, carefully analyzing the events leading to the
speci c drug complication, and learning how to minimize the likelihood of a
similar therapeutic outcome in the future.
On the following pages of this chapter, 33 ‘principles’, with over 80 speci c
drug therapy examples, are used to illustrate principles for maximizing the safety
of dermatologic drug therapy.
Anticipation&
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This section is broken down into ve subsections: (1) patient selection, (2) patient
education, (3) baseline laboratory and related tests, (4) concomitant drug therapy
– drug interactions, and (5) evolving guidelines – risk factors.
Patient selection
Principle #1
Carefully compare the ‘risk’ of the disease to be treated with the ‘risk’ of the
drug regimen planned (in that particular patient); thus a ‘risk–risk’
assessment.
• The risk of high-dose systemic corticosteroids in severe pemphigus vulgaris
versus the risk from the same corticosteroid regimen in patients with either
pemphigus foliaceus or localized epidermolysis bullosa acquisita.
• The risk of 6–12 months of cyclosporine for a patient with limited plaque-type
psoriasis versus the risk of the same regimen in a patient with debilitating and
extensive pyoderma gangrenosum.
Principle #2
Choose patients who can comprehend and comply with important
instructions for preventing and monitoring the most serious potential
complications of systemic drug therapy. Examples in which this principle is
most important include the following:
• The importance of avoiding abrupt cessation of long-term, high-dose
prednisone therapy – risk of HPA axis complications such as an addisonian
crisis.
• The pregnancy prevention measures which are of central importance in
isotretinoin therapy for women of childbearing potential.
• The importance of avoiding signi cant amounts of alcohol with long-term
methotrexate therapy for severe psoriasis or in women of childbearing
potential on long-term acitretin therapy for psoriasis.
Principle #3
All patients are not ‘created equal’ regarding the risk for various adverse
e4ects. Examples of patients at signi5cantly increased risk for the following
adverse effects (beyond the specifics of the drug regimen) include:
• Methotrexate hepatotoxicity: obesity, alcohol abuse, diabetes mellitus, renal
insufficiency.
• Corticosteroid osteoporosis: postmenopausal women, especially those who are
thin and inactive.
• Corticosteroid osteonecrosis: recent signi cant local trauma, alcohol abuse,
cigarette smoking, and presence of underlying hypercoagulable conditions.
• TNF inhibitor use in patients with a personal or family history of multiple
sclerosis.
The bottom line is that individual patients must be carefully ‘matched’ with&
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the safest and most e, ective drug regimen for the unique presentation of their
dermatosis. This ‘match’ hinges on the various risk factors and demographic
variables with which a speci c patient presents. Perhaps the best example is the
lesson provided by the specialty of rheumatology regarding the apparent lesser risk
of methotrexate in rheumatoid arthritis (RA) patients compared to the historical
risk of the same methotrexate therapy in psoriasis patients. This risk reduction was
accomplished by (1) more careful patient selection of patients by rheumatologists,
and (2) by the much lower risk of ‘metabolic syndrome’ in RA patients than in
psoriasis patients.
Patient education
The multiple variables regarding a given course of systemic drug therapy are often
very di: cult for physicians to master. Thus, it should come as no surprise that the
specific drug regimens and risks of these various therapies discussed are much more
di: cult for patients (who typically lack medical training) to understand. Q2-4 The
patient needs to understand at least the following information: (1) how to take the
medication, speci cally the correct dose and timing, (2) the expected adverse
e, ects, (3) what symptoms to report, and (4) the speci c monitoring using
laboratory and related diagnostic tests. Particularly when signi cant risks to
important organs or body systems are discussed, the understandable emotional
reaction of most patients makes long-term retention very di: cult. The above points
and other concepts form the basis of the following principles.
Principle #4
Careful and reasonably thorough patient education is essential to truly
‘informed consent’ (see Chapter 68).
• Patients need to be active participants in therapeutic decision-making, which
requires physicians to present the information in an understandable fashion.
• In addition, the patient must be provided the opportunity to ask questions and
be given adequate time to consider the therapeutic options presented.
Principle #5
Use patient handouts, written at a very understandable level, to reinforce
important information and instructions concerning the drug therapy chosen.
• The physician must emphasize the key information contained in the handout,
but handouts are never a substitute for appropriate physician–patient
communication.
• The patient should be instructed to notify the physician if there are any
questions pertinent to the handout provided.
• The patient should be instructed to report any significant new symptoms that
may develop subsequently (even if they are not sure these symptoms are due
to the specific drug).
• Sources for these handouts include National Psoriasis Foundation (major
systemic therapies for psoriasis, including biologics), various pharmaceutical
companies (acitretin/Soriatane), and the American Medical Association
(corticosteroids and many others). Consider creating your own personalized&
patient education handouts regarding specific drugs you commonly prescribe.
Principle #6
Educate your patients regarding groups or clusters of symptoms, which
together are important for the detection of potentially serious drug-induced
complications. The grouping of these symptoms may not be emphasized in
the above-mentioned handouts.
• Corticosteroid osteonecrosis: focal, signi cant joint pain (especially hip, knee,
shoulder) with decreased range of motion of the affected joint.
• Isotretinoin pseudotumor cerebri: headache, visual change, nausea and
vomiting.
• TNF inhibitor opportunistic infections: fever plus localizing symptoms such as a
cough.
• Dapsone hypersensitivity syndrome: fever, fatigue, sore throat, adenopathy, and
morbilliform rash.
A ‘two-way street’ of open communication between patient and physician is
essential in maximizing the safety of systemic drug therapy. Any extra time the
physician spends in this communication process should pay great dividends with
regard to improved therapeutic outcomes.
Baseline laboratory and related tests
Any organ system with potential for drug-induced complications requires a baseline
evaluation before initiating therapy. There are very few exceptions to this principle.
It stands to reason that existing pathology in an organ system, for which a given
drug has the potential to induce abnormalities, will increase the likelihood of
further injury to this organ system.
Principle #7
Assess the baseline status of any potential target organ or site of excretion
for a given drug. Similarly, if a drug can induce a metabolic abnormality,
check for baseline presence of this metabolic defect if such testing is
currently available.
• Baseline liver function tests and hepatitis viral serology: methotrexate
hepatotoxicity (methotrexate ‘target’ organ).
• Baseline renal function assessment; at least testing serum creatinine, and
possibly creatinine clearance: methotrexate hepatotoxicity or pancytopenia
(site of methotrexate excretion).
• Baseline eye examination for presence of cataracts: PUVA therapy (PUVA
‘target’ organ).
• Baseline testing for hyperglycemia or hyperlipidemia: prednisone therapy
(metabolic abnormalities aggravated by prednisone).
Principle #8
Use the most optimal tests that predict which patients are at increased risk&
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for a speci5c adverse e4ect. Typically such tests are ordered only at
baseline. (Ideally many more of these predictive tests will be available in the
future.)
• Baseline G6PD level: predicts magnitude of risk for dapsone hemolysis. (This
test does not predict which patients are at risk for dapsone agranulocytosis or
dapsone hypersensitivity syndrome.)
• Baseline thiopurine methyltransferase level: predicts risk for azathioprine
hematologic complications as well as guiding optimal drug dosing. (This test
does not predict azathioprine hepatotoxicity or hypersensitivity syndrome
reactions.)
There are a few select tests for which a baseline determination is not required.
Near the end of long-term high-dose prednisone therapy, an AM cortisol
determination (usually ~ 8AM) may be of value in assessing HPA
(hypothalamopituitary axis) function; a baseline determination is virtually never
indicated. Some tests may require a delayed baseline determination. I request a
‘delayed baseline’ ultrasound-guided liver biopsy for methotrexate patients after 6–
12 months of therapy, once it is clear that the patient tolerates the drug, bene ts
from the drug, and requires long-term methotrexate therapy. Still, overall the
general rule holds: if you plan on monitoring a speci c test during therapy with a
given systemic drug, it is prudent to determine the baseline status of that speci c
test.
Concomitant drug therapy – drug interactions
Chapter 65 is devoted entirely to the subject of drug interactions of importance to
the dermatologist and other physicians using similar medications. However, a few
principles must still be addressed in this setting. The vast majority of drug
interactions can be anticipated, and thus prevented. Truly life-threatening drug
interactions are quite uncommon and virtually always have been well publicized.
Q2-5 The following are principles dealing with three categories of drug interactions
of central importance to maximizing the safety of systemic drug therapy.
Principle #9
Anticipate (and avoid) drug combinations that have overlapping target
organs of potential toxicity.
• Tetracycline or minocycline plus isotretinoin: pseudotumor cerebri.
• Hydroxychloroquine plus chloroquine: antimalarial retinopathy. (It is
acceptable practice to combine quinacrine with either of these two drugs, as
quinacrine alone does not induce a retinopathy.)
• Methotrexate and a second-generation retinoid (previously etretinate, now
acitretin): probably an increased risk for hepatotoxicity.
Principle #10
Anticipate interactions involving two drugs that alter the same metabolic
pathway.
• Methotrexate and trimethoprim/sulfamethoxazole: increased risk for&
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pancytopenia, given that these drugs inhibit folate metabolism.
• Azathioprine and allopurinol: increased risk for hematologic complications, as
these drugs affect parallel purine metabolic pathways.
Principle #11
Anticipate (and avoid) drug combinations metabolized by the same
cytochrome P-450 (CYP) pathway, particularly if there is a narrow
therapeutic index for one of the drugs involved.
• Rifampin (CYP3A4 enzyme inducer) plus hormonal contraceptives: loss of
efficacy of the contraceptive with the potential for an unintended pregnancy.
• Ketoconazole or erythromycin (CYP3A4 enzyme inhibitors) plus cyclosporine:
increased risk for renal toxicity due to increased cyclosporine blood levels.
This area of medicine is very complicated and it is very di: cult to stay
‘current’ (see Chapter 65). At times recently released drugs have important,
potentially life-threatening interactions which are discovered only years later. The
potential for torsades de pointes with life-threatening cardiac arrhythmias from
terfenadine, astemizole, or cisapride (elucidated several years after the drugs’
release) in the presence of certain CYP enzyme inhibitors illustrates this point. Do
your best to stay current: liberally use the numerous electronic resources for
information on drug interactions. Frequent use of your hospital’s drug information
pharmacists is highly recommended in order to more e, ectively deal with this
challenging area of medicine.
Evolving guidelines – risk factors
Typically, with the passage of time the magnitude of risk for various systemic drugs
becomes clari ed. The level of concern can go in one of two directions: over time
there is either increased concern or decreased concern about various risks
subsequent upon the publication of new data. Furthermore, speci c new risk
factors can be elucidated as new scientific information is reported.
Principle #12
Q2-6 Certain risks or risk factors for systemic therapies may be discovered
many years after a speci5c drug is released. It is imperative to ‘stay tuned’
regarding standards of care, as discussed in the Introduction.
• PUVA therapy: an increased risk for squamous cell carcinoma of the male
genitalia (speci c risk factor – male gender, without clothing protection for the
groin region during PUVA treatments).
• PUVA-induced melanoma: probably an increased risk in patients receiving
more than 250–350 treatments over a lifetime (speci c risk factor – very large
number of PUVA treatments).
• Minocycline hypersensitivity syndrome or minocycline-induced lupus
erythematosus: the magnitude of risk for these complications was not clari ed
until over a decade after the drug’s release.
• Ketoconazole hepatotoxicity: magnitude of risk overall and potential for fatal
outcomes were not clarified until several years after the drug’s release.&
Principle #13
In contrast, the perceived magnitude of risk for a particular adverse e4ect
may decrease over time as new scientific evidence accumulates.
• Antimalarial retinopathy: markedly lower risk than originally perceived, largely
due to more careful antimalarial dosing schemes, and perhaps also to greater
use of hydroxychloroquine rather than chloroquine.
• PUVA cataracts: primarily a risk in patients who fail to comply with current
regimens regarding UVA-protective wraparound sunglasses.
• Prednisone bursts and osteonecrosis risk: although this issue is still cloudy in the
legal system, the scienti c evidence ‘rules against’ there being a true risk of
this bone complication with short courses (‘bursts’) of systemic corticosteroids.
Principle #14
In many clinical scenarios, physicians must make decisions about measures
to prevent important potential drug risks before all necessary information is
published concerning whether there truly is an increased risk of a speci5c
complication.
• TNF inhibitors (etanercept, adalimumab, inDiximab) and TB risk: at least
ordering a baseline PPD (and selectively ordering a chest X-ray in higher-risk
patients) prior to initiating therapy.
• TNF inhibitors (etanercept, adalimumab, inDiximab) and risk of demyelinating
diseases: at least check personal and family history closely for multiple
sclerosis and related demyelinating disorders prior to initiating therapy.
As challenging as it may be, physicians are obliged to stay ‘current’ with the
latest published information on the magnitude of risk from the drugs we use. Truly
important ‘new risks’ tend to be widely and repeatedly disseminated to physicians,
with the so-called ‘Dear Health Care Professional’ letters from the FDA being a
common vehicle for the dissemination of such information.
Prevention
This section of the chapter will be divided into three subsections as follows: (1)
patient measures to reduce risks, (2) therapeutic interventions to minimize drug
risk, and (3) timing of risk and medication errors.
Patient measures to reduce risks
Principle #15
Patients should take all reasonable protective measures to prevent important
adverse effects.
• Prevention of squamous cell carcinoma of male genitalia due to PUVA therapy:
wearing a ‘jockstrap’ or underwear during a PUVA treatment.
• Prevention of cataracts in PUVA therapy: wearing opaque goggles during the
PUVA treatment and wearing wraparound UVA-protective sunglasses when&
&
&
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exposed to outdoor light, at least until sundown the day of the PUVA
treatment.
Therapeutic interventions to minimize drug risk
There are many occasions in which the patient would bene t from a speci c
systemic drug, yet there are worrisome risk factors for a given adverse e, ect. If the
drug regimen is essential for the patient, concomitant medical therapy to reduce
the negative impact of the adverse effect is logical and appropriate in most cases.
Principle #16
Use all reasonable adjunctive therapeutic measures to minimize the risk of
various adverse effects.
• Daily folic acid therapy in patients receiving methotrexate: prevention of GI
adverse e, ects and minimization of pancytopenia risk. (Ideally, folic acid
should be used in all methotrexate patients.)
• Calcium, vitamin D, and possibly estrogens, bisphosphonates, PTH analogs or
nasal calcitonin: use in patients receiving long-term systemic corticosteroid
therapy at or above physiologic doses. (Use a greater number of these
preventative therapies in higher-risk patients.)
Timing of risk and medication errors
The prevention of many adverse e, ects requires either heightened awareness with
more frequent monitoring (drugs with a speci c timing of greatest risk) or careful
patient education (for potentially serious medication errors). In either setting a
proactive physician style is preferred to maximize safety.
Principle #17
For the most potentially serious adverse e4ects of systemic drugs, learn the
timing of greatest risk for the drug-induced complication while monitoring
the patient most carefully during this period.
• Dapsone agranulocytosis or dapsone hypersensitivity syndrome: both are
primarily an issue between weeks 3 and 12 of therapy. (Minocycline
hypersensitivity syndrome: timing of greatest risk is roughly in the same
interval, particularly in the first 2 months of therapy.)
• Methotrexate or azathioprine pancytopenia: the risk is greatest primarily in the
rst 4–6 weeks of therapy, unless a drug interaction is a precipitating factor
later in the course of therapy.
• Prednisone osteonecrosis: the risk begins to increase substantially by months 2–
3 of pharmacologic dose corticosteroid therapy. (This risk tends to parallel the
overall development of cushingoid changes in the patient.)
Principle #18
Medication errors are largely preventable with careful patient education
and, if necessary, cross-checks on potentially unreliable patients. These
medication errors can be due to either dose omissions or dose duplications.&
&
&
&
&
• Methotrexate weekly dosing scheme: the literature has many reports of
pancytopenia due to inadvertent daily dosing of methotrexate. If necessary,
another caregiver or family member should place the drug in the slot for just
one speci c day each week in a weekly pill container, particularly for older
patients.
• Hormonal contraceptives and isotretinoin or thalidomide: pregnancy prevention
is critical in women of childbearing potential. Omission of oral contraceptives
for even a day can be hazardous in patients prescribed these potent teratogens.
Diagnosis
This section is divided into ve subsections as follows: (1) evolving guidelines for
monitoring, (2) a teamwork approach for maximizing the safety of drug therapy,
(3) use of the most optimal diagnostic tests, (4) higher-risk scenarios, and (5)
efficient and thorough record keeping.
Evolving guidelines for monitoring
As discussed under the section ‘Anticipation’, newer scienti c evidence commonly
leads to new or revised guidelines for standards of care. As before, the level of
concern can increase or decrease over time with the release of this new scienti c
information.
Principle #19
Stay current with changing guidelines for diagnosing important
complications of systemic drug therapy at an early, reversible stage.
• Methotrexate chest X-rays for pneumonitis: pneumonitis from methotrexate is a
signi cant risk in rheumatoid arthritis patients. In contrast, the negligible risk
for this complication in psoriasis patients led to elimination of a previous
yearly requirement for chest X-rays in more recent methotrexate guidelines.
• TNF inhibitors (etanercept, adalimumab, inDiximab) and tuberculin skin test or
interferon-γ releasing assays (IGRA): the recent overall resurgence in incidence
of tuberculosis and the TNF-α role in stabilizing granulomatous responses
leads to this guideline for screening patients for TB prior to initiating therapy.
A teamwork approach for maximizing the safety of drug therapy
Despite recent trends in managed care to fragment care and limit access to various
medical specialties in the name of cost savings, a teamwork approach for risk
reduction is imperative. Q2-7 A ‘team’ consisting of the prescribing physician, the
patient, and, in many cases, the patient’s primary physician or another specialist, is
of central importance. In addition, pharmacists and members of the physician’s
office staff have key roles in this ‘team.’ Each member of the team has an important
role in maximizing the safety of systemic drug therapy.
Principle #20
In addition to the importance of patient awareness to report symptoms
suggesting the early phases of selected complications, the patient often has a
role in home monitoring for selected complications.&
&
• Cyclosporine or corticosteroids and hypertension: with a growing number of
patients using home blood pressure cu, s or electronic blood pressure
monitoring devices, this is a relatively easy area of home surveillance for
adverse e, ects. The patient merely needs to be told what levels of blood
pressure elevation should be reported to the prescribing physician and/or
primary physician.
• Corticosteroids and home glucose monitoring: even though the history of
diabetes mellitus should lead to careful scrutiny regarding the necessity of
systemic corticosteroids, there are many circumstances in which prednisone
therapy is essential in diabetic patients. Home glucose monitoring provides for
relatively easy surveillance and follow-up.
• Corticosteroids and weight gain: the simple bathroom scale can provide useful
information on the progression of cushingoid changes or for signs of increasing
Duid overload in patients with previously well-compensated congestive heart
failure.
Principle #21
The prescribing physician’s examination is essential for detection or
verification of important early signs of various drug complications.
• Full skin examination for PUVA or patients on systemic immunosuppressive
therapy: detection of melanoma, squamous cell carcinoma, and basal cell
carcinoma (and precursors thereof).
• Neurologic examination (screening style) for dapsone motor neuropathy or
thalidomide sensory neuropathy: screening done by the prescribing physician,
possibly verified by a consultant.
• Morbilliform eruption and related hypersensitivity syndrome ndings due to
dapsone, minocycline, or azathioprine: reported by the patient but veri ed by
the prescribing physician.
Principle #22
Co-management with another consultant is commonly an essential part of
this ‘teamwork’ approach to maximizing the safety of systemic drug therapy.
• Interventional radiologist: for ultrasound-guided liver biopsies with long-term
methotrexate therapy.
• Ophthalmologist: integral part of monitoring guidelines for PUVA and
antimalarial therapy.
• Primary physician: for management decisions regarding elevated blood glucose
or blood pressure with corticosteroid therapy or for management of
hyperlipidemia in patients on long-term systemic retinoid or cyclosporine
therapy.
Use of the most optimal diagnostic tests
Principle #23
Stay current regarding the most optimal diagnostic tests that have improved
sensitivity and precision for early diagnosis of important adverse e4ects at a&
&
reversible stage.
• Corticosteroid osteonecrosis diagnosis: magnetic resonance imaging is far
superior to conventional X-rays for early diagnosis, and can allow timely
performance of core decompression to salvage the affected bone or joint.
• Corticosteroid osteoporosis diagnosis: dual-energy X-ray absorptiometry
(Dexascan) has much greater sensitivity than conventional X-rays for early
recognition of bone density loss.
• Methotrexate hepatotoxicity diagnosis: ultrasound-guided liver biopsies give
much greater technical precision to avoid trauma to large vessels and bile
ducts, thus providing greater safety for liver biopsies.
Principle #24
Realize that many diagnostic tests provide complementary information for
the clinician.
• Transaminase values and liver histology for methotrexate hepatotoxicity: one
method of testing (transaminases) assesses hepatocellular toxicity, whereas the
other method (liver biopsy/histology) assesses the potential for slow
progression from fatty liver changes to focal brosis to cirrhosis; both tests in
combination are essential for proper hepatic monitoring.
• Ordering both transaminases (SGOT/AST and SGPT/AST) for detection of
dapsone, azathioprine, and methotrexate hepatotoxicity: improved sensitivity
and speci city when ordering both tests; subsequently, tests for hepatobiliary
obstruction (bilirubin, alkaline phosphatase, GGT) can be useful adjuncts if
significant transaminase elevation has already occurred.
Higher-risk scenarios
As discussed earlier, patients are not all created equal when it comes to risk factors
for adverse e, ects from systemic drug therapy. The more a physician knows about
relatively high-risk clinical scenarios (with corresponding increased surveillance for
adverse e, ects in these settings), the more that physician can maximize the safety
of the drug therapy in that particular patient.
Principle #25
Q2-8 Laboratory monitoring and related diagnostic tests should be
performed more frequently with (1) higher-risk patients, (2) abnormal test
results, and (3) at high-risk periods – typically early in therapy.
Principle #26
Q2-9 Become familiar with thresholds of concern (levels at which to consider
dose reduction and/or more frequent monitoring) and ‘critical values’ (levels
at which therapy should be stopped, possibly inde5nitely) for various
laboratory tests and related monitoring procedures. (First value listed below
is the ‘threshold of concern,’ the second on right is the ‘critical value.’)
• WBC count&
&
• 10–11
Hemoglobin
• Platelet
count
• >700–800
Triglycerides
• Creatinine 30% increase >40–50% (increase from the baseline value)
• AST/ALT 1.5–2.0 times >2.5–3.0 times increase (increase above the
upper normal value)
• Dexascan T-score – 1.0 T-score
to −2.5
Q2-10 It is of tremendous importance for the reader to realize that the above
test result ranges are merely rough guidelines for clinicians to use. The rapidity of
change and the overall trend of the laboratory values are of at least equal
importance to recognize. Regardless of the actual laboratory test abnormality or
the rapidity of change, the clinician should be mindful of four possible options
(depending on the clinical circumstances in an individual patient):
1. Discontinue the drug therapy temporarily or indefinitely;
2. Reduce the drug dose;
3. Increase the frequency of test monitoring; and
4. Treat the adverse effect while carefully continuing the therapy.
These are not mutually exclusive options: generally, several of the above steps
are instituted simultaneously. Again, the key is to know which circumstances
constitute a high-risk clinical scenario, and subsequently to proceed therapeutically
with greater caution in these clinical settings.
Efficient and thorough record keeping
It is quite di: cult to stay ‘current’ regarding scienti c advancements related to
dermatologic therapeutics. It is at least an equal challenge to keep track of the
following aspects of medical record keeping for the ve general steps of
maximizing safety presented in this chapter. The issues here include (to name a
few):
1. Documenting informed consent discussions;
2. The changing frequency of laboratory tests any given patient should have,
depending on the stage of therapy and the dose of the drug;
3 . Keeping track of which patients did not get laboratory tests done when
scheduled;
4. Notifying patients about laboratory test results, particularly abnormal results,
and the resultant algorithm regarding how to respond to these abnormal&
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results; and
5. How to efficiently document steps ‘2’ through ‘4’ above.
What is a busy practitioner to do?
Fortunately, the electronic/information era in which we practice has provided
some solutions. I previously kept written test result Dow sheets on patients I
followed in the 1980s, but through the 1990s and into the 21st century most
laboratories are capable of printing computer-generated Dow sheets of test results.
Similarly, most electronic medical records (EMR) can provide a summary of test
results over time. If a clinician can readily nd the last 2–3 sets of test results, most
decision-making proceeds without much difficulty.
There should be a cross-check system regarding missed appointments and
missed laboratory tests for patients on systemic drug therapy. In general, it is
helpful to have a patient call about test results (in a speci ed time frame) if not
previously noti ed about test results by mail or a phone call from the physician’s
o: ce. A less time-consuming step is a policy that only abnormal test results require
noti cation to the patient. The reality is that even with normal test results, the
physician (or physician’s sta, ) must commonly contact the patient regarding drug
dose changes, and hence the need to document and to communicate this decision.
A few principles need to be listed, some of which overlap with other chapters
(such as Chapter 68, ‘Informed Consent and Risk Management’).
Principle #27
An important medicolegal dictum states that ‘if it was not written, it was not
done.’ An individual physician needs to 5nd a balance of thoroughness and
eF ciency. Personally, I believe that dictated chart notes more readily allow
this optimal balance – I believe voice recognition software is the most
efficient manner of documenting important informed consent discussions.
Principle #28
When possible, with relatively high-risk medications, create backup systems
in case the patient, the physician, the oF ce sta4, or the laboratory
personnel have (hopefully rare) oversights.
Principle #29
Use any electronic means available to keep track of important information
needed to maximize the safety of systemic drug therapy.
Management
This section of the chapter will be divided into two subsections as follows:
1. What to do if problems arise – relatively minor complications; and
2. What to do if problems arise – potentially serious complications.
What to do if problems arise – relatively minor complications
The vast majority of complications from systemic drug therapy are relatively minor
and are xable. Provided that communication channels are kept open, the&
physician remains non-defensive and a solutions-based approach to these
complications is used, keeping the patient’s best interests in mind, serious medical
complications and adverse medicolegal outcomes are relatively unlikely. This
relatively brief section will address a general approach to managing adverse e, ects
if the ‘anticipation’ and ‘prevention’ steps are not fully successful. Parenthetically,
these same principles also apply to any complication of topical or intralesional
therapy.
Principle #30
When in doubt, have the patient stop the drug in question if a potentially
serious adverse e4ect has occurred. The physician generally has at least a
few days (subsequent to discontinuation of the drug) to consider the
management options, and to communicate with the necessary consultants.
Important factors in this decision-making process include:
• The severity of the underlying disease being treated.
• The magnitude of risk from the adverse e, ect the patient experienced,
particularly if the complication can worsen precipitously with continued use of
the responsible drug.
• Whether the drug in question is uniquely effective for the disease being treated.
• Whether there is a signi cant risk due to abrupt discontinuation of the
responsible drug – most notably the risk of abrupt cessation of high-dose
longterm systemic corticosteroid therapy and the potential for an addisonian crisis.
Principle #31
With less serious medical complications in the setting of a systemic drug
essential for the patient, speci5c medical therapy directed at this
complication is quite acceptable.
• Retinoid or corticosteroid hyperlipidemia: concomitant treatment with ‘statins’
or gemfibrozil.
• Corticosteroid or cyclosporine hypertension: any of a wide variety of medical
options for blood pressure control. One should be mindful that the therapeutic
choice for cyclosporine-induced hypertension needs to preserve optimal renal
blood flow as well.
What to do if problems arise – potentially serious complications
Principle #32
Q2-11 More serious complications generally have a speci5c remedy,
although frequently these management steps come at signi5cant cost or
present a lifelong risk to the patient.
• Corticosteroid osteonecrosis: core decompression (if diagnosed relatively early)
or joint replacement surgery (if there is more advanced osteonecrosis).
• Methotrexate pancytopenia: if recognized early, ‘Leucovorin rescue’ will be
quite e, ective, as is routine for high-dose methotrexate therapy in oncology
settings.&
• Methotrexate, ketoconazole, dapsone liver failure: worst-case scenario is that
the patient may require a liver transplant.
• Corticosteroid or PUVA cataracts: this outcome is far less catastrophic than even
a decade or two ago, given the availability of safe and reliable lens implants
after cataract extraction.
Principle #33
A few complications cannot be ‘fixed’ and should be avoided at all costs.
• Retinoid or thalidomide teratogenesis: absolute and complete pregnancy
prevention is essential.
• Antimalarial retinopathy: although therapeutic and monitoring approaches
used in the current era minimize the likelihood of this complication.
Parting thoughts
The bottom line is as follows: it would be an ideal goal that physicians reading this
chapter, and who used the principles presented, never had a patient su, er a major
complication from systemic drug therapy in their respective careers. In reality, this
is not likely. The mindset that is more realistic goes as follows:
1. The physician should thoroughly learn the measures necessary to anticipate the
most important risk factors and strive to prevent important complications of
systemic drug therapy.
2 . When important adverse e, ects rarely occur, which is inevitable despite
meticulously following all principles discussed in this chapter, the clinician
should move quickly to diagnose the condition at an early and reversible stage.
3. Once diagnosed, management of these complications of therapy should proceed
in an e: cient manner, using appropriate consultants when necessary; the
patient’s best overall wellbeing is always rst and foremost a guide to medical
decision making.
4. The more potentially serious and less reversible the complication, the greater
the e, orts should be sure that this complication never occurs (retinoid or
thalidomide teratogenesis as examples).
5 . With a proactive mindset for the prevention of and monitoring for adverse
e, ects, and forming a true therapeutic partnership with the patient, the
medicolegal risks of systemic drug therapy becomes quite negligible.
6 . Should an important drug complication occur (virtually inevitable in any
physician’s career) the most successful and professional approach has three
parts:
(a) ‘Stand by’ and work with the patient’s management, regardless of the
circumstances.
(b) For future patients’ benefit, learn everything possible from the undesirable
therapeutic outcome.
(c) Focus on the numerous patients who have benefited from (and will continue
to benefit from) the same drug or therapeutic approach throughout your
career.&
&
The grati cation that patients and physicians alike receive from successful
outcomes of carefully planned and appropriately monitored systemic drug therapy
is immense. Please use the principles discussed in this chapter carefully and
e, ectively, reinforced by additional strategies detailed in speci c chapters
throughout this book, and look forward to the numerous safe and successful
therapeutic results for your patients.
Bibliography: important reviews and chapters
Wolverton SE. Systemic drugs for psoriasis. The most critical issues. Arch Dermatol.
1991;127:565–568.
Wolverton SE. Monitoring for adverse effects from systemic drugs used in
dermatology. (CME Article). J Am Acad Dermatol. 1992;26:661–679.
Wolverton SE. Major adverse effects from systemic drugs: defining the risks. Curr
Probl Dermatol. 1995;7:1–4.3
Polymorphisms
why individual drug responses vary
Cynthia M.C. DeKlotz, Stephen E. Wolverton, Benjamin N. Lockshin
Questions
Q3-1 How are ‘polymorphism’ and ‘variability’ defined in the most basic sense? (Pg. 21)
Q3-2 Regarding the CYP isoforms discussed in this chapter, (a) which 5 isoforms are most important to
drug interactions, and (b) which of these 5 isoforms have polymorphisms? (Pg. 22)
Q3-3 Which 3 CYP isoforms are most important for drug metabolism based on the percentage of drugs
metabolized by the respective isoform? (Pg. 22, Table 3-2)
Q3-4 What are the terms regarding the rate of drug metabolism (and their respective abbreviations) for
the 4 major groups in various populations, given that a polymorphism is present? (Pg. 22)
Q3-5 Regarding the CYP2C9 isoform, what are (a) the frequency of polymorphisms in various
populations, and (b) the key alleles a/ ecting drug metabolism (and the clinical result)? (Pg. 23, Table
3-4, Table 3-5)
Q3-6 Regarding the CYP2C19 isoform, what are (a) the frequency of polymorphisms in various
populations, and (b) the key alleles a/ ecting drug metabolism (and the clinical result)? (Pg. 23, Table
3-6, Table 3-7)
Q3-7 Regarding the CYP2D6 isoform, what are (a) the frequency of polymorphisms in various
populations, and (b) the key alleles a/ ecting drug metabolism (and the clinical result)? (Pg. 24, Table
3-8)
Q3-8 Regarding thiopurine methyltransferase, what are (a) the frequency of polymorphisms in various
populations, and (b) the net clinical effect of the polymorphisms? (Pg. 26, Table 3-10)
Q3-9 Regarding N-acetyl transferase (NAT ), what are (a) the frequency of polymorphisms in various2
populations, and (b) the net clinical effect of the polymorphisms? (Pg. 28, Table 3-11)
Q 3-10 Regarding glucose-6-phosphate dehydrogenase (G6PD), what are (a) the frequency of
polymorphisms in various populations, and (b) the net clinical e/ ect of the polymorphisms? (Pg. 29
Table 3-12, Table 3-13)
Introduction
This chapter focuses on the intrinsic and extrinsic factors that a/ ect systemic medications. Adverse drug
reactions (ADR) often are associated with drug toxicity, but ADR can also account for decreased drug
e; cacy. An understanding of drug interactions and drug metabolism is imperative for selecting the
appropriate medications.
ADR occur frequently and result in a substantial cost burden on the healthcare system. In a prospective
1study of over 18 000 patient admissions by Pirmohamed and associates, ADR were responsible for 6.5% of
all admissions. Furthermore, it has been speculated (in a very controversial study) that 100 000 deaths each
2year in the United States are due to ADR.
Given that the primary focus of this chapter is on polymorphisms, it is important to provide a clear-cut
deAnition of the terms variability and polymorphism. Q3-1 The deAnitions can relate to receptor
a; nity/avidity and a variety of other biologic properties, although for the purposes of this chapter the
deAnitions will be applied to activity for phase I and phase II enzymes important for drug metabolism.
Conceptually, ‘variability’ is deAned by a single ‘bell-shaped curve,’ whereas ‘polymorphism’ is deAned by
two or more distinct ‘bell-shaped curves.’ Genetically this correlates with speciAc mutations of a single allele
(SNP, single nucleotide polymorphism). A ‘polymorphism’ is a variation that occurs in more than 1% of the
3studied population.
Evaluating the patient
Initial patient evaluation should include a detailed history with focus on the patient’s demographics,comorbidities, current medications, and allergies. Renal function declines with age, accounting for
decreased clearance of many medications. In addition to evaluating renal function, any presence of liver
dysfunction or disease must be determined prior to administration of most medications. Ethnicity can
occasionally help predict genetic variability in enzyme levels responsible for drug metabolism. A complete
list of the patient’s prescription medications along with all vitamins, herbals, and over-the-counter (OTC)
medications is imperative. When seeking information on a given patient’s drug allergies, inquire if there are
any medications that the patient cannot take, and what speciAcally happens when the medication is taken.
This will help distinguish between potential life-threatening ADR and drug intolerances.
Factors that influence medication effects (including adverse effects)
There can be considerable variability in virtually every point along a medication’s course from absorption to
excretion. It is important to be aware of many factors that can ultimately a/ ect the patient’s medication
tolerability and treatment outcomes.
Absorption
Gastrointestinal tract
Extrinsic and intrinsic factors can result in altered absorption in the gastrointestinal (GI) tract. Antacids alter
the stomach’s pH, which can inEuence medication absorption. Ketoconazole is a classic example of a
4medication which is better absorbed in an acidic milieu (Table 3-1). Other medications can act as binding
resins in the GI tract, and thus inhibit absorption. There is evidence that iron will bind mycophenolate
5mofetil, thereby inhibiting its absorption (Table 3-1). GI transit times are thought to play only a small role
4in drug absorption variability. Anticholinergic agents can slow down transit times, whereas some medical
conditions such as Crohn’s disease and ulcerative colitis can markedly increase transit times.
Absorption of important dermatologic drugs4,5Table 3-1
AbsorptionDrug Take home point
location
Ketoconazole GI tract Improved absorption in an acidic environment
Mycophenolate GI tract Do not give with iron: binds with iron, which inhibits
mofetil absorption
Cyclosporine PGP Affects bioavailability
P-glycoprotein
P-glycoprotein (PGP), a membrane-bound transport protein, a/ ects drug absorption in the GI tract.
Functioning as part of the ‘Arst-pass e/ ect’ in the gut, PGP acts as a pump to remove drugs from the cell by
6active ATP hydrolysis. Cyclosporine is just one example of a medication in which PGP can a/ ect drug
4bioavailability (Table 3-1). High levels of PGP are also found in the kidneys and liver, where it functions in
drug elimination.
Phase I and Phase II drug metabolism
Drug metabolism is a process that facilitates drug clearance by (1) increasing solubility, or (2) being
responsible for converting prodrugs to their active drug form (along with the formation of potentially toxic
4metabolites). Classically, drug metabolism is divided into two general components, designated phase I and
phase II reactions. Despite what the nomenclature suggests, there is no order in which these reactions take
place. Phase I reactions involve intramolecular modiAcations: oxidation, reduction, and hydrolysis. Phase II
reactions result in conjugation of the drug with an endogenous substance by acetylation, glucuronidation,
sulfation (also called sulfonation), and methylation. Most commonly, the phase I oxidative reactions create a
site for subsequent attachment of larger polar side chains in phase II reactions. Both phase I and II reactions
function to make the drug more water soluble, thereby facilitating renal or hepatobiliary excretion.
Drug metabolism – Phase I reactions
Cytochrome P-450 enzyme system overviewThe cytochrome P-450 (CYP) enzyme group plays a paramount role in drug metabolism. Various CYP
7enzymes are responsible for catalyzing 70–80% of all phase I reactions. These enzymes are located within
the endoplasmic reticulum of most cells, but are found in variable concentrations. As expected, hepatocytes
have the greatest concentration of CYP enzymes.
Nomenclature
CYP enzymes are classiAed by a hierarchical nomenclature system. The Arst number represents the enzyme
family followed by a letter designating the subfamily. The Anal number is for the individual gene. There is
at least 40% homology in amino acid sequences within a family, whereas subfamilies have 77% or more
homology.
Q3-2 Although there are more than 50 families of CYP enzymes, only 6 CYP isoforms (CYP1A2, 2C9,
72C19, 2D6, 2E1, and 3A4) appear to play a signiAcant role in drug metabolism (Table 3-2). Of these 6
isoforms, all but CYP2E1 play a prominent role in drug interactions important to dermatologists. CYP1A2,
72C9, 2C19, and 2D6 all have polymorphisms. Q3-3 Based on the percentage of drugs metabolized by the
7respective isoforms, CYP2C9, 2D6, and 3A4 are most important for drug metabolism (Table 3-2).
Fraction of drugs metabolized by various CYP isoforms7Table 3-2
CYP isoform Percentage of all drugs metabolized by isoform
CYP1A2*† 5
CYP2A6 2
CYP2B6 2–4
CYP2C8 1
CYP2C9*† 10
CYP2C19*† 5
CYP2D6*† 20–30
CYP2E1 2–4
CYP3A4* 40–45
CYP3A5
* CYP isoforms most commonly involved in drug interactions
† CYP isoforms with polymorphisms
CYP polymorphisms
Q3-4 Many CYP isoforms show signiAcant genetic polymorphism. Approximately 40% of human
CYP8dependent drug metabolism is carried out by polymorphic CYP enzymes. This can translate into variable
enzyme activity between individuals. Depending on the enzyme activity, individuals are designated as:
1. ‘Poor metabolizers’ (PM) if they have very low to no enzyme activity;
2. ‘Intermediate metabolizers’ (IM) if there is reduced activity;
3. ‘Extensive metabolizers’ (EM) if there is average enzyme activity; or
4,74. ‘Ultrarapid metabolizers’ (URM) if there is exceptionally high enzyme activity.
This has important clinical relevance for medications that have a narrow therapeutic index. If a
clinician can predict that a patient is a PM of a speciAc medication, a relatively low starting dose would be
indicated to avoid unwanted adverse e/ ects. On the other hand, if the patient was an URM, a clinician
could more aggressively up-titrate a medication to reach a therapeutic level with a greater assurance that
the patient could safely tolerate the more aggressive dosing.
Aside from genetic variability of the CYP isoforms, drug metabolism can be inEuenced by other
medications as well as physical factors. Medications can a/ ect the various CYP isoforms by either inhibition
or induction of enzyme activity.Drug inhibition or induction of CYP isoforms
Drug-induced inhibition of various CYP isoforms plays an important role in many ADR. Inhibition reduces
the metabolizing e/ ects of the a/ ected cytochrome. In turn, CYP inhibition increases drug levels and
toxicity. This can occur after just 1–2 doses of a medication, with maximal inhibition being observed once
4the steady state is achieved. This inhibition is typically competitive. However, few drugs are
noncompetitive inhibitors that result in CYP alteration, inactivation, or destruction.
Induction of a CYP isoform causes an increase in its metabolic activity by increasing either the enzyme
level or its activity. This is a much slower (up to a week or more) process than CYP enzyme inhibition,
because induction relies on synthesis of additional CYP enzyme. Once an inducing agent is removed, the
duration of enzyme induction is dependent on the degradation of the newly formed enzyme.
CYP1A2 polymorphism
CYP1A2 functions primarily to metabolize several antipsychotic medications and theophylline.
Environmental and genetic factors are shown to inEuence the activity of CYP1A2. These can account for up
to a 60-fold di/ erence in activity. Tobacco byproducts produced from smoking and oral contraceptive
9 9steroids have been well established as CYP1A2 inducers. Ca/ eine is a common substrate of CYP1A2.
Polymorphisms have been observed in the gene encoding CYP1A2, accounting for 16 known alleles. These
9genetic factors account for approximately 35–75% of the variation in CYP1A2 activity. The frequency of
these polymorphisms varies between di/ erent ethnic groups. A lower CYP1A2 activity has been found in
Asian and African populations than in Caucasians. Among non-smokers, the frequency of poor metabolizers
9was found to be 5% in Australians, 14% in Japanese, and 5% in Chinese.
CYP3A4 variability
CYP3A4 is responsible for 40–45% of all phase I reactions and accounts for up to 70% of gastrointestinal
4,7 10CYP activity. CYP3A4 is co-expressed with P-glycoprotein in the liver and intestine. Despite little
genetic variability between populations, there appears to be as much as a 20-fold interindividual ‘variability’
4of enzyme activity. CYP3A4*1B appears to be the most common variant allele (Table 3-3) and is
10associated with decreased CYP3A4 activity. Obesity has been shown to reduce CYP3A4 activity, resulting
in increased substrate activity. A number of medications and supplements can inEuence the activity.
10Importantly, ivermectin is a known substrate for CYP3A4. See Chapter 65 on Drug Interactions for
additional details on CYP3A4 substrates, inhibitors, and inducers.
Prevalence of CYP3A4 variant alleles10Table 3-3
Population CYP3A4*1B CYP3A4*3
Caucasian (%) 4–9 2
African (%) 69–82 0
Ghanaian (%) 71 0
CYP2C9 polymorphism
Overall, 10% of drug metabolism is carried out by CYP2C9. Q3-5 Although there have been over 100 SNP
identiAed, only 2 allelic variants (CYP2C9*2 and CYP2C9*3) have been shown to signiAcantly reduce
substrate a; nity through inhibiting CYP activity (Table 3-4). Only the homozygote CYP2C9*3/*3,
comprising 0.5% of most populations, is considered to have marked clinical signiAcance with very low
11CYP2C9 activity. The CYP2C9*3 variant may also play a role in phenytoin-induced cutaneous adverse
12drug reactions (see ADR section below). With regard to the activity of CYP2C9, the *1/*1 genotype
demonstrates normal activity; the *1/*2 genotype has a minor reduction in activity; and, the *2/*2, *1/*3,
11and *2/*3 genotypes all show moderately reduced activity (Table 3-4). Epidemiologic studies show
varying prevalences of the di/ erent CYP2C9 genotypes among di/ erent ethnic populations (Table 3-4 and
Table 3-5). Caucasians show marked variability in CYP2C9, with *2 being the most common mutant allele,
whereas people of African and Asian descent have predominantly normal activity with the presence of the
15,16*1/*1 genotype. There are no allelic variants known to be inducers. Warfarin is the most clinically
signiAcant substrate for CYP2C9. Fluconazole inhibition of CYP2C9 can result in markedly elevated levels of
warfarin, with a resultant risk of hemorrhage. CYP2C9 polymorphism activity: frequency in various populations11,13,14Table 3-4
Prevalence of CYP2C9 genetic polymorphisms15–17Table 3-5
CYP2C19 polymorphism
General issues
Proton pump inhibitors and numerous anticonvulsants are the primary substrates metabolized by the
CYP2C19 isoform. This isoform comprises approximately 5% of all drug metabolism.
Specific alleles of importance
18Q3-6 There are several allelic variants (CYP2C19*2–8) that show no enzymatic activity, which translates
into a PM phenotype. This phenotype is observed in 1–23% of persons, with Asians having the highest
19incidence and African-Americans and Caucasians having the lowest (Table 3-6). Detailed prevalence of
some of the CYP2C19 genotypes may be seen below, where *2/*2, *2/*3, and *3/*3 are the poor
16,17metabolizers (Table 3-7).
CYP2C19 poor metabolizer frequency in various populations19Table 3-6
Population # Studied PM %
Japanese 399 19.5
Korean 309 12.1
Filipino 52 23.1Chinese 538 15.6
Middle East 537 3.0
African 684 3.9
Whites – European 2291 2.9
African American 291 1.4
Whites – American 422 2.6
Prevalence of CYP2C19 genetic polymorphisms16,17Table 3-7
In addition to acting as a strong CYP3A4 inhibitor, ketoconazole inhibits the CYP2C19 isoform,
although it is not a substrate of this isoform. This dual inhibition is important, given that many medications
19metabolized by the CYP2C19 isoform are also metabolized by CYP3A4.
CYP2D6 polymorphism
General issues
CYP2D6 shows signiAcant pharmacogenetic variation (polymorphism) and is integral in the metabolism of
numerous medications, especially psychiatric and cardiac mediations. Q3-7 With over 90 documented
allelic variants reported, CYP2D6 displays remarkable polymorphism. Overall, 20–30% of drugs are
4,7metabolized through this pathway (Table 3-2) and because of these important issues CYP2D6 has been
20extensively studied. In contrast to CYP2C9, CYP2D6 alleles that alter enzymatic activity are common. The
7enzymatic activity can vary up to 1000-fold between allele types. Clinically this translates to at least a
50fold di/ erence in drug doses tolerated between various individuals; this principle is illustrated by the wide
dosing range of the CYP2D6 substrate doxepin.
Specific alleles of importance
21CYP2D6 polymorphisms are classiAed according to level of activity: PM, IM, EM, and URM. The EM
phenotype, which is expressed by the majority of the population, is considered the norm. In Europeans, four
alleles, CYP2D6*3, *4, *5, and *6, are most closely associated with the reduced enzyme, also known as PM
20,22phenotypes. These PM phenotypes are seen in 1.5–10% of Caucasians, but in only 0–1.2% of many
Asian populations (Thai, Chinese, Japanese) (Table 3-8). Importantly, 6% of Caucasians lack the CYP2D6
3enzyme altogether as a result of the presence of two null alleles.
CYP2D6 polymorphism frequency in various populations20,21,23–27Table 3-8
22Many individuals, particularly those in certain African and East Asian regions, have the IM genotype.
Among those with IM, CYP2D6*10 is common in East Asians and CYP2D6*17 is common among African
22populations.
Gene duplication
Gene duplication occurs with the CYP2D6*2 allele, which generally confers an URM phenotype, resulting in
very low drug levels with standard drug dosing. Population studies reveal considerable variation in the
prevalence of CYP2D6*2 gene duplication. Genotypic studies of CYP2D6*2 gene duplication in various
European countries demonstrate a prevalence of 1–10%, depending on the country studied. Up to 29% of
20black Ethiopians and 21% of Saudi Arabians have CYP2D6*2 gene duplication.
CYP2D6 testing
Despite the fact that CYP2D6 polymorphisms have been known for over 30 years, genotyping still has not
22entered routine clinical practice.
Sources for additional information on CYP-based interactions
Physicians should be cognizant of potential CYP-based drug interactions when prescribing systemic
medications. The website www.drug-interactions.com is a valuable reference tool evaluating for CYP-based
28interactions. It has a comprehensive list of medications that are substrates, inducers, or inhibitors for the
28major CYP isoforms of clinical signiAcance. This website links the reader to pertinent references for the
28interactions listed.On the horizon, commercially available testing (see section on Tests for Genetic Polymorphisms) is
likely to be available on a widespread basis for the major CYP isoforms with polymorphisms. Currently, this
is primarily available only at certain reference laboratories.
Dihydropyrimidine dehydrogenase
29Another example of phase I drug metabolism involves the metabolism of 5-Euorouracil (5-FU). 5-FU is a
chemotherapeutic agent used to treat solid tumors, with topical formulations designed to treat some
cutaneous premalignant lesions (actinic keratoses) and nonmelanoma skin cancers. Treatment can be
limited by unwanted ADR. A number of functional genetic variants are present in the main enzyme that
metabolizes 5-FU, dihydropyrimidine dehydrogenase (DPD), and in the target of 5-FU, thymidylate synthase
30,31(see below section for details on thymidylate synthase polymorphisms).
As more than 80% of a given dose of 5-FU is rapidly metabolized by DPD, it is not surprising that
30patients with DPD deAciency have been reported to have severe neurotoxicity from 5-FU treatment.
Severe gastrointestinal and hematological toxicity has been reported in a DPD-deAcient patient who applied
32 33topical 5-FU to the scalp. As a result, topical 5-FU is contraindicated in patients with DPD deficiency.
Many genetic variants in the DPD gene have been described. The most common polymorphism is a
30splice site mutation, recognized as the DPD*2A allele, which leads to an enzymatically deAcient DPD. The
30DPD*2A allele is associated with 5-FU-induced toxicity, speciAcally leukopenia and mucositis. In a study,
this e/ ect depended strongly on gender, given that heterozygosity for DPD*2A was associated with
FU30induced toxicity in men, but not in women.
Genetic testing for the DPD*2A allele may be performed in many laboratories. Additionally, a DPD
enzyme deAciency test may be carried out in speciAc laboratories. One example is the DPD enzyme assay
34performed by ITT laboratories, which cost $450 US in 2009 (www.ittlabs.com). Approximately 1% of the
29population is heterozygous for the DPD polymorphism; however, the clinical relevance or indications for
DPD genetic testing remain unclear at present. Currently, routine screening for DPD enzyme deAciency is
not standard of care prior to the topical application of 5-FU.
Drug metabolism – Phase II reactions (Table 3-9)
P-Glycoprotein
General issues
Permeability-glycoprotein (P-glycoprotein, PGP), an ATP-activated pump, has gained increased attention in
the past few years because of its role in multidrug resistance, in particular to chemotherapeutic agents.
Essentially, PGP involves pumping molecules from intracellular to extracellular spaces, counteracting the
e/ ects of passive di/ usion, most notably in the gastrointestinal tract, with a resultant decrease in net drug
35absorption. This has been shown to have a greater effect on drug absorption than clearance.
Polymorphisms of phase II enzymes3,8,30,34,37,39,42,40,49,53,58,59,61Table 3-9Polymorphisms of PGP
Genetic polymorphisms have been identiAed in the multidrug resistance-1 (MDR1) gene that encodes PGP.
Various alleles have been linked to lower PGP expression in the small intestine. This decreased PGP
expression correlated with increased drug concentration when digoxin was administered in a study by
36Hoffmeyer and co-workers.
Ethnic variability has been demonstrated in the MDR1 gene. Testing for MDR1 gene expression may
37help identify populations who are at increased risk for PGP drug interactions.
Clinical importance of PGP polymorphisms
38There appears to be signiAcant overlap of substrate speciAcity between PGP and CYP3A4. This overlap
has complicated assessment of the role of PGP polymorphisms and drug interactions. Although evidence
suggests that PGP likely has a signiAcant role in drug–drug interactions, this currently appears to be of
limited clinical application.
Thiopurine methyltransferase
General issues
Q3-8 Thiopurine methyltransferase (TPMT) functions as a catalyst for the metabolism and inactivation of
azathioprine, 6-mercaptopurine (6-MP), and thioguanine. The enzyme functions by converting
6mercaptopurine to inactive methylmercaptopurine nucleotides and by converting 6-thioguanine to inactive
39,42metabolites (Figure 3-1). Decreased TPMT activity results in increased 6-thioguanine levels, leading to
40increased toxicity. SpeciAcally, high levels of accumulated 6-thioguanine nucleotides (6-TGN) seen in
41patients with TPMT deAciency appear to be associated with myelosuppression. Conversely, TPMT
deAciency leads to a decreased amount of 6-methyl mercaptopurine (6-MMP) nucleotides because TPMT is
not available to convert 6-MP to 6-MMP. Since 6-MMP is correlated with azathioprine-induced
hepatotoxicity, TPMT-intermediate and -deAcient patients are at a lower risk for developing
41hepatotoxicity. For these reasons, it is important to determine TPMT activity prior to dosing these
immunosuppressive agents. This is recommended to ensure therapeutic drug levels and to reduce the risk of
potentially life-threatening adverse reactions.Figure 3-1 Azathioprine metabolic pathways.
With permission from el-Azhary RA. Azathioprine: current status and future considerations. Int J Dermatol
2003;42:335–41.
Polymorphism of TPMT
TPMT displays genetic polymorphism accounting for variable phenotypes. Approximately 89–90% of the
general Caucasian population has high (normal) TPMT activity, which corresponds with homozygous
3,42 43expression of TPMT*1. Approximately 17 allelic variants of TPMT have been identiAed. Of these,
three mutant alleles (TPMT*3C, *3A, and *2) account for over 95% of individuals with decreased TPMT
activity. TPMT*3A is the predominant mutant allele in Caucasians, whereas TPMT*3C is the most common
42mutant allele in Asians and Africans. Heterozygous expression of any of these alleles, along with TPMT*1,
42results in intermediate TPMT activity. Approximately 10–11% of the general population falls into this
3intermediate category. Low to no TPMT activity is seen in approximately 0.3% of the Caucasian
population. These persons are either homozygous or heterozygous with two mutant alleles with decreased
enzyme activity and are at high risk for severe bone marrow suppression during treatment with
3,42azathioprine. Epidemiologic studies show these percentages to vary signiAcantly among various ethnic
43-48groups (Table 3-10).
Thiopurine methyltransferase polymorphisms in various populations43–48Table 3-10
Specific testing methods for TPMT polymorphism and clinical applications
Patient evaluation is becoming more accessible to community physicians. There are a number of reference
laboratories performing TPMT evaluation. Two general testing methods are available: (1) TPMT phenotypes
40can be assessed by measuring the TPMT activity in erythrocytes, through peripheral red blood cell lysates,
and (2) DNA-microarray studies can be performed, which have resulted in more rapid and cost-e/ ective
TPMT genotyping. TPMT assays based on enzyme activity or genotype are both valuable screening tools that
8are available in selected laboratories; however, each has drawbacks and limitations. Enzyme activity can
be inEuenced by physiological or environmental factors: medications, recent blood transfusions, tobacco
43use, and impaired renal function all can cause an inaccurate result. TPMT genotyping studies have shown
some discordance between phenotype and genotype, which was most commonly observed in the
intermediate activity groups. Studies have noted concordance rates from 76% to 99%. With
DNAmicroarrays including an increasing number of less common alleles, genotyping studies appear to be better
43correlated with phenotype testing. Also, newly introduced rapid genetic polymerase chain reaction
(PCR)restriction fragment length polymorphism (RFLP) TPMT*3A and *3C allele tests are likely available in49standard laboratories. It is thought that these tests should allow more widespread screening of TPMT
polymorphisms to be performed prior to treatment with azathioprine.
Recommended doses of azathioprine have been determined based upon the patient’s genetic TPMT
polymorphisms. If a patient is homozygous for the wild type, TPMT*1, then a standard dose of 2–2.5
42 mg/kg/day may be administered. In patients who are heterozygous with one TPMT*1 allele and one
mutant allele (intermediate activity), the dose of azathioprine should be reduced by 15–50%. Limited case
reports have demonstrated both improved e; cacy and safety in treating severe atopic dermatitis in
41heterozygote TPMT-deficient children with azathioprine at 50% reduced doses. For patients found to have
two ‘mutant’ alleles with known associated markedly decreased TPMT activity (TPMT*3A, *3C, or *2), it is
recommended that they not be treated with azathioprine or, if they must be treated, treatment should be at
42a dose reduced by 90% (see also Chapter 14 – Azathioprine).
N-Acetyltransferase
General issues
N-Acetyltransferase-2 (NAT ) is responsible for acetylation of numerous xenobiotic substances. The addition2
of an acetyl group to a parent compound increases the drug’s water solubility, facilitating drug elimination.
Polymorphism of NAT2
In the 1950s, high variability in individual rates of excretion of isoniazid was found among patients being
3treated for tuberculosis. This was later determined to be caused by polymorphisms in NAT , which2
metabolizes isoniazid.
Q3-9 At least 25 allelic variants of the NAT gene have been identiAed, some being correlated with2
50,51altered enzyme activity that varies in prevalence among di/ erent ethnic populations (Table 3-11).
NAT enzyme activity is often reported as rapid, intermediate, or slow (analogous to EM, IM, PM). Rapid2
3acetylation is seen in persons who are homozygous for NAT2*4, NAT2*12, and NAT2*13. Rapid
acetylators require higher doses of medications to minimize the likelihood of treatment failure. NAT2*5, *6,
3*7, *14S comprise virtually all of the alleles associated with slow or intermediate acetylation. These slow
acetylators are more likely to develop toxic adverse e/ ects, including drug-induced lupus from
procainamide and hydralazine, neuropathy from isoniazid, and toxic epidermal necrolysis from
3sulfonamides. Studies have also demonstrated that slow acetylators may have an increased risk for certain
52solid tumors and for some IgE-mediated food allergies seen in children. However, as approximately 40–
70% of Caucasians are slow acetylators, and as severe adverse drug reactions (ADR) are rare, there are
8likely other underlying factors that contribute to these associations and ADR. Hence, the practicality of
testing for these NAT polymorphisms is questionable in daily clinical practice.2
-acetyl transferase (NAT ) polymorphisms in various populations51Table 3-11 N 2Glucose-6-Phosphate dehydrogenase
General issues
Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the Arst reaction in the pentose phosphate pathway
(PPP), leading to the reduction of NADP to NADPH throughout the body. NADPH plays an important role in
53reducing glutathione, which is central to preventing cellular damage by oxidative stress. Since
erythrocytes lack mitochondria, the PPP is the only source of NADPH, thus making G6PD-deAcient
erythrocytes exquisitely sensitive to oxidative stressors, resulting in signiAcant hemolysis. This became
clinically evident when primaquine caused hemolysis in some patients with malaria.
Polymorphism of G6PD
In the 1950s, polymorphisms of the G6PD gene on the X chromosome were noted to be the genetic cause for
anemia, occurring in a certain subset of African patients taking primaquine. A/ ected individuals had low
3levels of the functioning activity of the G6PD enzyme. The cause of this decreased activity was found in a
single base substitution, asparagine to aspartic acid, resulting in hemolytic anemia.
Q3-10 Although there are over 400 identiAed variants, only 30 SNP mutations are associated with
54altered G6PD function. Epidemiologic studies have identiAed higher incidences of G6PD deAciency in
55–57areas where malaria is endemic, because of its protective role against this infection (Table 3-12).
Glucose-6-phosphate dehydrogenase (G6PD) deficiency in various populations55–57Table 3-12
Population # Studied Deficiency
African Americans 6366 11.4% males
2.5% females
Kuwait 1080 6.5%
United Arab Emirates 496 9.1%
Mexican 4777 0.71%
Indian 3166 10.5%
Caucasian Italians 85,437 0.9%
Nigeria (Yoruba Tribe) 721 23.9% males
4.6% women
Specific drugs of importance to G6PD
Approximately 2 dozen drugs have been shown to cause varying degrees of hemolysis in G6PD-deAcient
53patients (Table 3-13). This is germane to dermatologists who use sulfones (particularly dapsone) and
sulfonamides, as these drugs rely on G6PD for phase II metabolism. Although primaquine causes hemolysis
in G6PD-deAcient patients, there appears to be minimal hemolysis with other antimalarial medications used
in dermatology (chloroquine and hydroxychloroquine). See Chapter 19 on Antimalarials.
Drugs with phase II metabolism altered by G6PD deficiency53Table 3-13
Drug category Specific examples
Antimalarials Primaquine
Sulfonamides
Sulfanilamide
Sulfacetamide
Sulfapyridine
SulfamethazoleOther antimicrobial agents Nitrofurantoin
Spiramycin
Sulfones
Dapsone
Triazolesulfone
Other drugs
Acetanilide
Furazolidone
Glibenclamide
Isobutylnitrite
Niridazole
Phenylhydrazine
Phenazopyridine
Related chemicals
Aniline dyes
Methylene blue
Naphthalene (mothballs)
Toluidine blue
Urate oxidase
Fava beans, infections, and physiological stressors have also been noted to induce hemolysis in
G6PDdeficient persons.
Specific G6PD testing methods and limitations
Screening for G6PD deAciency has become regular practice before starting dapsone and other medications
that increase oxidative stress on erythrocytes. Quantitative evaluation is the most common method of
screening for a G6PD deAciency. G6PD activity is measured by its ability to reduce NADP to NADPH in
58erythrocytes. The Euorescent spot test, which allows for direct visualization of a Euorescently tagged
NADPH, is the most commonly employed testing method. However, inaccurate G6PD test results can occur
in certain patient populations. For example, because of chromosome X inactivation, women with a
heterozygous G6PD mutation can have two populations of erythrocytes, one with and the other without
58G6PD activity.
In contrast to the Euorescent spot test, which measures the activity in a population of erythrocytes,
methemoglobin or Nile blue sulfate reduction studies are more accurate because they evaluate individual
58erythrocytes. Nonetheless, recent hemolysis and blood transfusions can both yield inaccurate results. In
these situations, G6PD determination can be made by testing family members; they can function as a
reliable surrogate, as there are very low rates of spontaneous mutations in the G6PD gene. Another option is
58to genotype the patient. This is reliable in all patient populations provided the mutation is already known.
Glutathione S-transferase
Glutathione S-transferase is an enzyme involved in the detoxiAcation of carcinogenic derivatives of coal
8tar. Approximately 50% of European Caucasians have low or absent activity of glutathione S-transferase
8(GST) owing to the presence of the GSTM1-null genotype. After applying 2% coal tar topically to the skin,
GSTM1-null individuals were found to have twice the amount of urinary 1-hydroxypyrene excreted as
8individuals with normal enzyme activity. Hence, when GSTM1-null individuals are treated with topical
8coal tar, they have a greater mutagen exposure. Genotyping for GSTM1 may be performed via PCR
59analysis in selected research laboratories.
Thymidylate synthase and other polymorphisms in the folate pathway
Methotrexate, a drug frequently used in dermatology, is a structural analogue of folic acid which
60competitively inhibits dihydrofolate reductase (DHFR). Methotrexate also directly inhibits thymidylate
synthase (TS). Via downstream e/ ects of DHFR, methotrexate also inEuences the activity of methylene
tetrahydrofolate reductase (MTHFR), which converts homocysteine to methionine. Methotrexate-associatedADR, including hepatotoxicity, gastrointestinal symptoms, and acute myelosuppression, result in up to 30%
60,61of patients discontinuing therapy. These ADR have been associated with polymorphisms of TS and
MTHFR.
Evidence suggests that a polymorphism in the promoter region of the TS gene may a/ ect methotrexate
61metabolism and clinical response. The thymidylate synthase (TS) 5′-untranslated region (UTR) 3R/3R
homozygous genotype has been signiAcantly linked with ADR in psoriasis patients taking methotrexate
40,61when folic acid is not administered. Additionally, the TS 5′-UTR 3R allele has been associated with a
61poor therapeutic response to methotrexate. The TS 3′UTR 6 bp deletion allele has also been associated
40,61with increased methotrexate-induced toxicity, including up to an 8-fold increased risk of developing
61elevated ALT transaminase levels in the absence of folic acid supplementation. The importance of folic
acid administration was conArmed as patients not receiving it were twice as likely to discontinue
methotrexate, and many of the ADR attributed to these polymorphisms were attenuated or resolved with
61folic acid supplementation.
5-FU is a chemotherapeutic medication that strongly inhibits thymidylate synthase (TS), which is
30considered to be its major drug target. In contrast to methotrexate, the TS 2R/3R or 3R/3R genotypes
30have been associated with a lower risk for 5-FU-induced ADR, speciAcally diarrhea. The TS 2R/2R
30genotype, on the other hand, has been reported to increase the risk for 5-FU-induced toxicity.
The C677T polymorphism of MTHFR, observed in 8% of the normal population, leads to a thermolabile
60variant subsequently reducing its activity to about 30% of the wild type. The C677T polymorphism has
been associated with an increased risk of discontinuing methotrexate because of ADR, mainly elevated liver
60 60enzymes, postulated to be related to increased homocysteine levels. However, di/ erent studies have
yielded conEicting results, some which show no association between MTHFR C677T and methotrexate
61toxicity.
Additionally, studies on the e/ ects of MTHFR polymorphisms in regards to treatment with Euorouracil
have yielded varying clinical results. Some studies suggest that MTHFR 677C>T is correlated with better
clinical response to FU; however, the impact of MTHFR polymorphisms on severe FU-induced toxicity seems
30negligible based on prospective data.
Because methotrexate interacts with the folate pathway, studies analyzing the e/ ects of reduced folate
carrier (RFC) polymorphisms have been performed. The RFC 80A allele has recently been associated with
61methotrexate-induced toxicity.
Severe cutaneous adverse drug reactions linked to genetic polymorphisms
For many clinicians the future of ‘personalized medicine’ brings great hope, with the ideal future allowing
physicians both to increase the e; cacy of medicines and to reduce unwanted side e/ ects and adverse
reactions. In fact, ADR cause approximately 6% of hospitalizations and over 100 000 deaths per year in the
40United States. Causes of ADR are likely multifactorial, and individual responses can be a/ ected by age,
renal and hepatic function, drug–drug interactions, as well as genetic polymorphisms that inEuence drug
40metabolism thereby altering drug efficacy and toxicity.
Recent studies and advances have increased our understanding of these genetic risks. Currently some
genetic tests are commercially available that can be used to determine the risk. Some of the genetic
variations now associated with ADR include speciAc HLA alleles (Table 3-14). In a drug-speciAc manner,
HLA-B*1502 has been associated with carbamazepine-induced Stevens–Johnson syndrome and toxic
40,62,63epidermal necrosis (SJS/TEN) among Han Chinese patients. However, HLA-B*1502 is not
associated with the more benign morbilliform eruption or hypersensitivity syndrome triggered by
40carbamazepine. Additionally, the HLA-B*1502 associated carbamazepine-induced SJS/TEN is ethnically
40,62,63specific, being found in Asians, specifically Han Chinese, but not in Caucasians.
Table 3-14 HLA genetic markers for severe cutaneous adverse drug reactions
Drug Genetic marker for severe ADR Ethnic associations
Carbamazepine HLA-B*1502 Han Chinese38,62
Allopurinol HLA-B*5801 Han Chinese64
Abacavir HLA-B*5701, HLA-DQ3, HLA-DR762 Nevirapine HLA-B*3505 (rash) HIV-infected Thai
HLA-DRB1*0101 (hypersensitivity syndrome ± (B*3505)65
rash)66
Additionally, the HLA-B*5801 allele was found to be present in 100% of 51 Han Chinese patients
experiencing allopurinol-induced severe cutaneous ADR, but was only present in 15% of 135
allopurinol64 62tolerant patients. Unfortunately, HLA testing is expensive at present, which can limit routine screening.
40Similarly, the HLA-B*5701 allele has been associated with abacavir hypersensitivity. The
combination of HLA-B*5701, HLA-DQ3, and HLA-DR7 is 100% predictive of an abacavir-associated
62hypersensitivity reaction.
Nevirapine, an inexpensive nonnucleoside reverse transcriptase inhibitor, is often prescribed in
65resource-limited countries to treat HIV infection. There are data to suggest that HLA-B*3505 is a predictor
65for all types of nevirapine-induced cutaneous drug reactions in Thai patients. Additionally, data suggests
an association of HLA-DRB1*0101 with nevirapine hypersensitivity involving combinations of hepatitis,
66fever, and/or rash, but not with isolated rash. These nevirapine-induced ADR occur more frequently in
65,66patients with higher pre-treatment CD4 levels. It is thought that CD4-positive T lymphocytes must be
65present in a high enough number to induce the associated ADR. It is now recommended that nevirapine
67be avoided in women with CD4 counts > 250 cells/µL and in men with CD4 counts > 400 cells/µL.
Other genetic markers are being evaluated for possible associations with severe cutaneous ADR. In
studies of Japanese patients, Toll-like receptor 3 gene polymorphisms, certain Fas ligand polymorphisms,
68-70and IL-13 gene polymorphisms were found to be associated with SJS/TEN.
Phenytoin, also known as diphenylhydantoin, is known to be a cause of severe cutaneous ADR. In
recent years, a study on a small group of patients with phenytoin-induced cutaneous ADR found a possible
12 28association with the CYP2C9*3 variant, a known poor metabolizer. From a practical standpoint, one
might consider testing for the CYP2C9*3 variant prior to prescribing phenytoin in an attempt to help avoid
severe ADR.
As previously mentioned, slow acetylators of NAT may be at higher risk of sulfonamide-induced TEN2
3,8and SJS.
Tests for genetic polymorphisms and clinical significance
40Testing for speciAc polymorphisms could help address ADR in approximately 10–20% of patients.
Although many of the tests for such polymorphisms are not widely accessible, several have become more
readily available in recent years (Table 3-9 and Table 3-15). A DNA microarray analyzing genetic
62polymorphisms of CYP2D6 has also been developed in recent years. In 2008, the FDA issued a safety
warning to all healthcare professionals that ‘serious and sometimes fatal hypersensitivity reactions (HSR)
caused by abacavir therapy are signiAcantly more common in patients with a particular human leukocyte
antigen (HLA) allele, HLA-B*5701.’ The name of the pharmacogenetics test for the HLA-B*5701
31polymorphism is the ‘HLA-B5701 test’.
Table 3-15 Clinically relevant available tests for genetic polymorphisms
Genetic polymorphism Test
CYP2D6 polymorphisms DNA-microarray analysis62
General HLA polymorphisms PCR-based HLA typing63
Sequence-based typing63
Specific HLA polymorphisms Specific HLA typing
HLA-B*5701 polymorphism HLA-B5701 test31
HLA B*1502
HLA B*1502 ‘carbamazepine sensitivity’ test
Thiopurine Phenotyping: measures TPMT activity in erythrocytes though peripheral red
methyltransferase (TPMT) blood cell lysates408GenotypingDNA-microarray study
PCR, ‘Prometheus TPMT Genetics’ (www.mayomedicallaboratories.com)
Genetic allele testing: rapid PCR-RFLP TPMT*3A and *3C allele testing49
Dihydropyrimidine Genetic testing for DPD*2A allele; e.g., ‘TheraGuide® 5-FU’ test (full
dehydrogenase (DPD) sequencing of , and analysis of gene ( )71DPD TYMS www.myriadtests.com
polymorphisms
DPD enzyme deficiency test, e.g., the DPD enzyme assay performed by ITT
laboratories (cost $450 in 2009) (www.ittlabs.com)
Glucose-6-phosphate Fluorescent spot test, measures G6PD activity in population of
dehydrogenase (G6PD) erythrocytes58
Methemoglobin or Nile blue sulfate reduction G6PD studies, evaluate
individual erythrocytes58
G6PD genotyping58
The FDA has issued similar recommendations for other medicines, including azathioprine, where it was
recommended on the Imuran (azathioprine) drug label that genotype or phenotype for TPMT should be
31considered in patients. Testing for TPMT may be performed in several ways. One method is to order a test
called ‘Prometheus TPMT Genetics.’
Additionally, on the Efudex (topical 5-FU) drug label there is a warning that the medicine ‘should not
31be used in patients with dihydropyrimidine dehydrogenase (DPD) deAciency’. The dihydropyrimidine
dehydrogenase and thymidylate synthase polymorphisms may be tested by ordering the ‘TheraGuide® 5-FU’
71test. Testing for DPD deficiency is described in the above section on DPD.
There is also a warning on the Tegretol (carbamazepine) label stating that genetically at-risk patients
31should be screened for HLA-B*1502 prior to starting treatment. SpeciAcally, the FDA has concluded that
Asian patients should be screened before initiating treatment with carbamazepine. This may be done by
ordering an ‘HLA B*1502 carbamazepine sensitivity’ test.
It is our hope that similar genetic tests for all polymorphisms will become readily available in the near
future so that future ADR may be minimized. Until this becomes a commonplace reality, clinicians must
62focus on family and personal histories as a means of screening patients that might be at high risk for ADR.
Additionally, although costs remain high, clinicians must optimize the use of available genetic tests
primarily in high-risk patients.
Conclusions and future directions
An understanding of drug metabolism and drug interactions is of paramount importance in an era when
many patients are taking multiple medications. This chapter presents a brief overview of how genetic factors
can alter the likelihood of various drug interactions and related adverse e/ ects in the absence of drug
interactions. New information on drug metabolism, including polymorphisms, is constantly being accrued.
New tests that have clinical application are being developed and commercialized at a staggering pace.
Electronic and print sources for this information are essential for all clinicians. A general understanding of
how drugs are metabolized, along with recognition of the genetic and environmental factors that can
inEuence drug metabolism, and their clinical e/ ects, will prove to be an invaluable asset when choosing
appropriate systemic and topical medications.
Pharmacogenomics is an emerging Aeld that applies information and technology gained from the
Human Genome Project towards the goals of optimizing drug e; cacy, minimizing ADR, facilitating drug
40development, and reducing healthcare costs. For ethical and legal reasons, pharmacogenomic proAling
should only predict patients’ responses to drugs and not test speciAcally for disease-causing genetic
8mutations.
Although pharmacogenomics is important for future drug development, its applications in drug
approval processes are still being debated. Currently, authorities in the USA (FDA), Europe (EMEA), and
Japan (MHLW) have issued guidelines for new drug development that address the genetic heterogeneity of
40target patient populations. In particular, the Food and Drug Administration (FDA) has approved
31modiAcations on 58 drug labels that contain pharmacogenetic information. Additionally, since March
2008, through the Public Law No. 110–85, 121 Stat. 823, the FDA has the power to mandate that a genetic31test be performed as part of a plan to optimize safety or efficacy of a new drug.
Expect an exciting future as the medical applications of pharmacogenomics, and the speciAc testing for
various polymorphisms, gradually unfold.
Bibliography: important reviews and chapters
Correia Maria A. ‘Chapter 4. Drug Biotransformation’ (Chapter). Katzung BG: Basic & Clinical Pharmacology,
11e http://www.accessmedicine.com/content.aspx?aID=4515730
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Ingelman-Sundberg M, Sim SC, Gomez A, et al. Influence of cytochrome P450 polymorphisms on drug
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Johansson I, Ingelman-Sundberg M. Genetic polymorphism and toxicology–with emphasis on cytochrome
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Wecker: Brody’s Human Pharmacology, 5th ed. Chapter 2–Pharmacokinetics: Absorption, Distribution,
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CYP2D6 polymorphism
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CYP2D6 in Croatian population. Croat Med J. 2003;44:425–428.
27 Niewinski P, Orzechowska-Juzwenko K, Hurkacz M, et al. CYP2D6 extensive, intermediate, and poor
phenotypes and genotypes in a Polish population. Eur J Clin Pharmacol. 2002;58:533–535.
Sources for additional information on CYP-based interactions
28 Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of
Medicine (2009). http://medicine.iupui.edu/clinpharm/ddis/table.aspx. (
Dihydropyrimidine dehydrogenase
29 Weinshilboum R. Inheritance and drug response. N Engl J Med. 2003;348:529–537.
30 Schwab M, Zanger UM, Marx C, et al. Role of genetic and non-genetic factors for fluorouracil
treatmentrelated severe toxicity: A prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol.
2008;26:2131–2138.
31 Flockhart DA, Skaar T, Berlin DS, et al. Clinically Available Pharmacogenetic Tests. Clin Pharmacol Ther.
2009;86:109–113.
32 Johnson MR, Hageboutros A, Wang K, et al. Life-threatening toxicity in a dihydropyrimidine
dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. Clin Cancer Res. 1999;5:2006–
2011.
33 Gupta AK, Weiss JS, Jorizzo JL. 5-Fluorouracil 0.5% cream for multiple actinic or solar keratoses of the face
and anterior scalp. Skin Therapy Lett. 2001 Jun;6(9):1–4.
34 www.ittlabs.com/dpd.html, 2009. DPD Enzyme Assay
P-glycoprotein
35 Balayssac D, Authier N, Cayre A, et al. Does inhibition of P-glycoprotein lead to drug-drug interactions?
Toxicol Lett. 2005;156:319–329.
36 Hoffmeyer MR, Jones SP, Ross CR, et al. Myocardial ischemia/reperfusion injury in NADPH
oxidasedeficient mice. Circ Res. 2000;87:812–817.
37 Ameyaw MM, Regateiro F, Li T, et al. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon
26 is significantly influenced by ethnicity. Pharmacogenetics. 2001;11:217–221.
38 Lin JH, Yamazaki M. Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet.
2003;42:59–98.
Thiopurine methyltransferase polymorphism39 Evans WE. Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther Drug Monit.
2004;26:186–191.
40 Pincelli C, Pignatti M, Borroni RG. Pharmacogenomics in dermatology: from susceptibility genes to
personalized therapy. Exp Dermatol. 2009;18:337–349.
41 Murphy LA, Atherton DJ. Azathioprine as a treatment for severe atopic eczema in children with a partial
thiopurine methyl transferase (TPMT) deficiency. Pediatr Dermatol. 2003;20:531–534.
42 el-Azhary RA. Azathioprine: current status and future considerations. Int J Dermatol. 2003;42:335–341.
43 Schaeffeler E, Fischer C, Brockmeier D, et al. Comprehensive analysis of thiopurine S-methyltransferase
phenotype-genotype correlation in a large population of German-Caucasians and identification of novel
TPMT variants. Pharmacogenetics. 2004;14:407–417.
44 Hamdy SI, Hiratsuka M, Narahara K, et al. Genotype and allele frequencies of TPMT, NAT2, GST, SULT1A1
and MDR-1 in the Egyptian population. Br J Clin Pharmacol. 2003;55:560–569.
45 Kumagai K, Hiyama K, Ishioka S, et al. Allelotype frequency of the thiopurine methyltransferase (TPMT)
gene in Japanese. Pharmacogenetics. 2001;11:275–278.
46 Rossi AM, Bianchi M, Guarnieri C, et al. Genotype-phenotype correlation for thiopurine
Smethyltransferase in healthy Italian subjects. Eur J Clin Pharmacol. 2001;57:51–54.
47 Ganiere-Monteil C, Medard Y, Lejus C, et al. Phenotype and genotype for thiopurine methyltransferase
activity in the French Caucasian population: impact of age. Eur J Clin Pharmacol. 2004;60:89–96.
48 Zhang JP, Guan YY, Wu JH, et al. Phenotyping and genotyping study of thiopurine S-methyltransferase in
healthy Chinese children: a comparison of Han and Yao ethnic groups. Br J Clin Pharmacol. 2004;58:163–
168.
49 Oender K, Lanschuetzer CM, Laimer M, et al. Introducing a fast and simple PCR-RFLP analysis for the
detection of mutant thiopurine S-methyltransferase alleles TPMT*3A and TPMT*3C. J Eur Acad Dermatol
Venereol. 2006;20:396–400.
N-Acetyltransferase polymorphism
50 Fretland AJ, Leff MA, Doll MA, et al. Functional characterization of human N-acetyltransferase 2 (NAT2)
single nucleotide polymorphisms. Pharmacogenetics. 2001;11:207–215.
51 Meyer UA, Zanger UM. Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev
Pharmacol Toxicol. 1997;37:269–296.
52 Bakayev VV, Mohammadi F, Bahadori M, et al. Arylamine N-acetyltransferase 2 slow acetylator
polymorphisms in unrelated Iranian individuals. Eur J Clin Pharmacol. 2004;60:467–471.
Glucose-6-phosphate dehydrogenase polymorphism
53 Mehta A, Mason PJ, Vulliamy TJ. Glucose-6-phosphate dehydrogenase deficiency. Baillières Best Pract Res
Clin Haematol. 2000;13:21–38.
54 Mason PJ. New insights into G6PD deficiency. Br J Haematol. 1996;94:585–591.
55 Sukumar S, Mukherjee MB, Colah RB, et al. Molecular basis of G6PD deficiency in India. Blood Cells Mol Dis.
2004;33:141–145.
56 Zaffanello M, Rugolotto S, Zamboni G, et al. Neonatal screening for glucose-6-phosphate dehydrogenase
deficiency fails to detect heterozygote females. Eur J Epidemiol. 2004;19:255–257.
57 Ademowo OG, Falusi AG. Molecular epidemiology and activity of erythrocyte G6PD variants in a
homogeneous Nigerian population. East Afr Med J. 2002;79:42–44.
58 Beutler E. G6PD deficiency. Blood. 1994;84:3613–3636.
Glutathione S-transferase
59 Davies MH, Elias E, Acharya S, et al. GSTM1 null polymorphism at the glutathione S-transferase Ml locus:
phenotype and genotype studies in patients with primary biliary cirrhosis. Gut. 1993;34:549–553.
Thymidylate synthase
60 Warren RB, Griffiths CEM. The potential of pharmacogenetics in optimizing the use of methotrexate for
psoriasis. Br J Dermatol. 2005;153:869–873.
61 Campalani E, Arenas M, Marinaki AM, et al. Polymorphisms in folate, pyrimidine, and purine metabolism
are associated with efficacy and toxicity of methotrexate in psoriasis. J Invest Dermatol. 2007;127:1860–
1867.
Severe cutaneous drug reactions linked to genetic polymorphisms
62 Pereira FA, Mudgil AV, Rosmarin DM. Continuing medical education: toxic epidermal necrolysis. J Am AcadDermatol. 2007;56:181–200.
63 Yang G, Deng YJ, Qin H, et al. HLA-B*15 subtypes distribution in Han population in Beijing, China, as
compared with those of other populations. Int J Immunogenet. 2010 Jun;37(3):205–212.
64 Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse
reactions caused by allopurinol. Proc Natl Acad Sci U S A. 2005;102:4134–4139.
65 Chantarangsu S, Mushiroda T, Mahasirimongkol S, et al. HLA-B*3505 allele is a strong predictor for
nevirapine-induced skin adverse drug reactions in HIV-infected Thai patients. Pharmacogenet Genomics.
2009 Feb;19(2):139–146.
66 Martin AM, Nolan D, James I, et al. Predisposition to nevirapine hypersensitivity associated with
HLADRB1*0101 and abrogated by low CD4 T-cell counts. AIDS. 2005;19:93–99.
67 Martin A, Nolan D, Almeida CA, et al. Predicting and diagnosing abacavir and nevirapine drug
hypersensitivity: from bedside to bench and back again. Pharmacogenomics. 2006;7:15–23.
68 Ueta M, Sotozono C, Inatomi T, et al. Toll-like receptor 3 gene polymorphisms in Japanese patients with
Stevens-Johnson syndrome. Br J Ophthalmol. 2007;91:962–965.
69 Ueta M, Sotozono C, Inatomi T, et al. Association of Fas Ligand gene polymorphisms with Stevens-Johnson
syndrome. Br J Ophthalmol. 2008;92:989–991.
70 Ueta M, Sotozono C, Inatomi T, et al. Association of combined IL-13/IL-4R signaling pathway gene
polymorphism with Stevens-Johnson syndrome accompanied by ocular surface complications. Invest
Ophthalmol Vis Sci. 2008 May;49(5):1809–1813.
71 https://www.myriadpro.com/test-offerings/chemotherapy-management/theraguide, 2012.
References*
3 Lowitt MH, Shear NH. Pharmacogenomics and dermatological therapeutics. Arch Dermatol. 2001;137:1512–
1514.
4 Shapiro LE, Shear NH. Drug interactions: Proteins, pumps, and P-450s. J Am Acad Dermatol. 2002;7:467–484.
quiz 485–6
6 Evans WE, McLeod HL. Pharmacogenomics – drug disposition, drug targets, and side effects. N Engl J Med.
2003;348:538–549.
7 Ingelman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past,
present and future. Trends Pharmacol Sci. 2004;25:193–200.
8 Ameen M, Smith CH, Barker JNWN. Pharmacogenetics in clinical dermatology. Br J Dermatol. 2002;146:2–6.
9 Zhou SF, Yang LP, Zhou ZW, et al. Insights into the substrate specificity, inhibitors, regulation, and
polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J. 2009;3:481–494.
12 Lee A-Y, Kim M-J, Chey W-Y, et al. Genetic polymorphism of cytochrome P450 2C9 in
diphenylhydantoininduced cutaneous adverse drug reactions. Eur J Clin Pharmacol. 2004;60:155–159.
17 Yang ZF, Cui HW, Hasi T, et al. Genetic polymorphisms of cytochrome P450 enzymes 2C9 and 2C19 in a
healthy Mongolian population in China. Genetics and Molecular Research. 2010;9(3):1844–1851.
21 Bernard S, Neville KA, Nguyen AT, et al. Interethnic differences in genetic polymorphisms of CYP2D6 in the
U.S. population: clinical implications. Oncologist. 2006 Feb;11(2):126–135.
22 Daly AK. Pharmacogenetics and human genetic polymorphisms. Biochem J. 2010;429:435–449.
28 Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of
Medicine (2009). http://medicine.iupui.edu/clinpharm/ddis/table.aspx. (
30 Schwab M, Zanger UM, Marx C, et al. Role of genetic and non-genetic factors for fluorouracil
treatmentrelated severe toxicity: A prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol.
2008;26:2131–2138.
31 Flockhart DA, Skaar T, Berlin DS, et al. Clinically Available Pharmacogenetic Tests. Clin Pharmacol Ther.
2009;86:109–113.
40 Pincelli C, Pignatti M, Borroni RG. Pharmacogenomics in dermatology: from susceptibility genes to
personalized therapy. Exp Dermatol. 2009;18:337–349.
62 Pereira FA, Mudgil AV, Rosmarin DM. Continuing medical education: toxic epidermal necrolysis. J Am Acad
Dermatol. 2007;56:181–200.
63 Yang G, Deng YJ, Qin H, et al. HLA-B*15 subtypes distribution in Han population in Beijing, China, as
compared with those of other populations. Int J Immunogenet. 2010 Jun;37(3):205–212.
65 Chantarangsu S, Mushiroda T, Mahasirimongkol S, et al. HLA-B*3505 allele is a strong predictor for
nevirapine-induced skin adverse drug reactions in HIV-infected Thai patients. Pharmacogenet Genomics.
2009 Feb;19(2):139–146.
66 Martin AM, Nolan D, James I, et al. Predisposition to nevirapine hypersensitivity associated with
HLADRB1*0101 and abrogated by low CD4 T-cell counts. AIDS. 2005;19:93–99.* Only a selection of references are printed here. All other references in the reference list are available
online at www.expertconsult.com.+

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4
Adherence to drug therapy
Michelle M. Levender, Steven R. Feldman
Questions
Q4-1 What is the most basic de nition of adherence in clinical practice? (Pg.
34)
Q4-2 What is the estimated cost to the US healthcare system of poor adherence
in terms of (a) percentage of hospital admissions, and (b) total monetary
cost? (Pg. 34)
Q4-3 How is the ‘medication possession ratio’ defined? (Pg. 34)
Q4-4 How are the following terms de ned (a) acceptance, (b) persistence, and
(c) quality of execution? (Pg. 35)
Q4-5 What are several important ‘internal’ factors a ecting patient adherence?
(Pg. 35, Table 4-1)
Q4-6 What are several important ‘external’ factors a ecting patient adherence?
(Pg. 36, Table 4-1)
Q4-7 What are some of the most important (a) o. ce environmental factors, and
(b) physician behavior characteristics, that a ect patient adherence? (Pg.
36x2, Box 4-1)
Q4-8 How does the physician’s explanation of treatment options, choice of
vehicle for topical medications, and complexity of treatment a ect patient
adherence? (Pg. 37x3, Box 4-2)
Q4-9 How does the real or perceived risk of adverse e ects a ect patient
adherence? (Pg. 37)
Q 4 -10 How do (a) written instructions, (b) motivational interviewing
techniques, and (c) measures to allow the use of pre-existing habits improve
medication adherence? (Pg. 37, 38x2)
Introduction
This book describes the panoply of medications available to treat a broad array of
skin diseases. The outcomes of these treatments are not entirely predictable. In
clinical trials, treatment response varies among research subjects. This variability is
even greater in the clinic setting and has resulted in the development of the eld of
Pharmacogenomics; but, a key underlying and often under-appreciated
determinant of the outcome of dermatologic treatment is simply how well patients
use their medications, a concept subsumed under the term ‘adherence.’ Q4-1
Adherence (previously known as ‘compliance’) is the degree to which a patient’s
1behavior coincides with the recommendations of their healthcare provider.
@

+

Poor adherence is ubiquitous across all elds of medicine. Q4-2 Improving
patients’ adherence behavior may be a quick, low-cost e ective way to improve
medical outcomes. Non-adherence to medication regimens is responsible for 10%
of all hospital admissions and costs the US healthcare system $100–300 billion
2–4annually.
The problem of non-adherence manifests in many ways in the treatment of
dermatologic disease, particularly with chronic topical treatment. The well-known
problem of tachyphylaxis (‘the more you use the medicine, the less it works’) is
commonly a manifestation of poor adherence (‘the less you use the medicine, the
less it works’). Other phenomena that are best explained by patients’ adherence (or
lack of adherence) include the resistance of scalp psoriasis to topical treatment and
the tendency of children with atopic dermatitis previously ‘resistant’ to topical
treatment to clear rapidly – in just 2 or 3 days – with topical treatment
administered in the hospital setting.
This chapter will (1) describe how adherence is measured, (2) examine the
magnitude of the problem of adherence, (3) describe the variables that in uence
adherence behavior, and (4) identify principles and practical strategies to improve
patients’ adherence to treatment.
Measures of adherence
Assessing adherence can be challenging. Self-reporting of adherence is not a
5,6particularly reliable methodology. A more objective measure to monitor
adherence is blood test monitoring for drug levels, but even this approach often
overestimates adherence because patients tend to be better about using their
medications around the time of an o. ce visit, a phenomenon called ‘white coat
compliance’ (one of the best examples of this phenomenon is the tendency for
7people to floss more before going to the dentist).
In the past, studies on adherence in dermatology relied on surveys, pill counts
or medication weights. In an anonymous survey of psoriasis patients, roughly 40%
reported non-adherence to their treatment regimen; we suspect most of the other
8,960% simply were not completely honest. Counting pills or weighing a topical
medication may appear to be a more objective way to assess adherence, but
patients are wily and may dump their medication to hide their poor adherence
behavior. Some creativity may help. To encourage honest responses, the physician
may ask, ‘It can be hard to use the medicine every day. How often are you missing
doses: every day or every other day?’ To improve the reliability of pill counts,
instead of prescribing 60 tablets for a bid dosing and having the patient return in a
month, either prescribe 70 tablets or prescribe 60 but have patients come back
before the month is over. That way, if the bottle is empty, the physician can
distinguish a bottle that has been emptied due to good adherence from one that
10was emptied to hide poor adherence.
Other approaches have been used to more reliably assess patients’ use of their
medications in research studies. Q4-3 Pharmacy data can be used to tell whether
patients lled a prescription. Combined with data on re lls, pharmacy data can
establish an upper limit on patients’ use of medication by describing how many
days’ worth of medication the patient obtained over the course of treatment. The
standard metric for this is the ‘medication possession ratio’. The medication





possession ratio is calculated as the number of days of supply for dispensed
prescriptions divided by the number of days between prescription refills.
Pharmacy data are useful for determining whether patients procure
medication, but they are a step removed from whether the patient uses the
treatment. Q4-4 Objective electronic monitors in the caps of medication containers
– such as the Medication Electronic Monitoring System (MEMS) – provide more
direct information on patients’ use of medication. These devices record the data
and time each time the bottle or tube is opened. Electronic monitoring of
adherence can be used to elucidate the various patterns of poor adherence. The
initial phase of adherence is acceptance, when the patient lls and begins
treatment. Patients with poor ‘acceptance’ may not ll the medication, or may
begin taking it after some delay. ‘Persistence’ refers to how long patients stay on
therapy. Poor persistence implies that patients discontinued their treatment early.
During the period when patients are using their medication, ‘quality of execution’
refers to how well the patient is using the medication. Patients may skip doses at
regular intervals, take drug holidays, or over-treat. The typical patient probably is
doing some combination of all of these.
The magnitude of poor adherence in dermatology
Electronic monitors and prescription re ll data have opened up new vistas in our
understanding of how well patients use the medication we prescribe. Pharmacy
data reveal that many prescriptions are never lled. A groundbreaking Danish
study found that 4 weeks after the doctor visit, 30% of dermatologic prescriptions
11had not been lled; 50% of the psoriasis prescriptions had not been lled. In a
study population of North Carolina Medicaid patients (for whom the costs for
procuring medication were very low), the medication possession ratio was only
1235% for non-biologic psoriasis treatments. For biologics, the medication
possession ratio was considerably better, at 66%, but this indicates that on average
those patients missed taking at least one-third of recommended doses.
Studies of pharmacy data inform us about how much medication the patient
received; electronic monitors reveal how often medication was used. In a study of
patients with psoriasis, adherence to twice daily 6% topical salicylic acid was
measured over 8 weeks using self-report diaries, medication weights, and MEMS
caps. While the subjects reported adherence rates of 90–100% in their treatment
diaries and medication weights, the MEMS caps revealed an overall average
adherence of only 55%, with a drop in adherence of approximately 20% every 5
7weeks. Electronic medication monitors have revealed that patients’ adherence
behavior is far worse than previously thought.
Certain patient populations are notoriously non-adherent, particularly
teenagers. In one small study of teenage acne patients, electronically monitored
adherence to a once-daily treatment regimen was 82% on day 1, dropping to 45%
13at the end of 6 weeks. In a study of children with atopic dermatitis, electronic
monitors were used to assess adherence to topical triamcinolone over 8 weeks.
Mean adherence was an abysmal 32%, with a drop of 60–70% in adherence over
14the first 3 days of the study.
Much of the data on adherence come from patients who are knowingly
enrolled in studies of adherence (though they usually do not know how adherence+
+
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is being measured). Thus, patients in these studies are probably motivated to be
more adherent than they would under normal circumstances. Yet, even in these
clinical studies, lasting no more than a few weeks to months, adherence rates are
15suboptimal. One can imagine just how poor adherence must be in regular
dermatology practice, particularly among patients with chronic diseases who
require daily medications, not just for a few weeks or months, but for a lifetime.
Factors that influence adherence behavior
Adherence behavior is a ected by many interacting variables. There is a complex
relationship between adherence behavior, treatment and outcome. Q4-5 The
factors that a ect adherence can be classi ed as internal and external (Table 4-1).
A major internal factor a ecting adherence is the patient’s motivation to get better.
Some patients may not be particularly motivated to get better, or they may not be
bothered by their condition. Other patients may be seeking secondary gain from
their condition. One might expect that patients with severe disease would be very
motivated to use their medications, but in fact patients with worse quality of life
16are less likely to be adherent. Perhaps these patients feel hopeless and simply
resign themselves to the realities of their condition. Sometimes patients want to get
better but may not have understood the medication instructions, or they may be
forgetful or unable to physically apply the medication.
Table 4-1 Factors contributing to poor adherence
Internal factors External factors
Age Weak physician–patient relationship
Poor motivation to get well Complex treatment regimen (frequent
dosing and/or multiple agents)Secondary gain from illness
Poorly tolerated vehicleFeeling of
hopelessness/resignation Adverse effects and toxicities
about condition Slow-acting medication
Poor understanding of the Cannot afford treatment
disease Limited access to treatment
Unrealistic or inaccurate Inadequate instructions provided on howexpectations of treatment to use medications
Psychiatric comorbidities Long interval between follow-up visits
Lack of trust in the doctor
Lack of trust in or fear of the
treatment
Fear of adverse effects
Patients may have psychiatric comorbidities such as depression that interfere
with their ability to carry out their treatment. Age is another important factor, as
children and teenagers are less likely to adhere to treatment. Additionally, patients’


+
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understanding of their disease and the expectations for treatment signi cantly
a ect their adherence behavior, as does their understanding of the treatment itself,
in particular expectations about adverse e ects. Of profound importance is the
patient’s trust in their doctor and the quality of the physician–patient relationship.
Overall, 70% of adherent patients reported that they were using their medication
17because they believed their provider was a compassionate advocate.
Q4-6 External factors a ecting adherence behavior include (1) complexity of
regimen, (2) cost of and access to treatment, (3) vehicle choice in topical
medications, and (4) adverse e ects. In addition, (5) the time it takes a medication
to work is critical, as is (6) the patient’s response to treatment. For example, if a
medication takes weeks to work but the patient is expecting a ‘quick x,’ then that
patient may stop using the medication, thinking that it failed. Conversely, if the
patient has rapid initial success with a particular treatment, he or she may be more
likely to continue using it. Other important considerations over which physicians
have considerable control include the quality of the physician–patient relationship,
plans for follow-up visits, and clarity of instructions provided.
Strategies to improve adherence behavior
The physician–patient relationship
In nding ways to improve adherence it is helpful to consider the many steps
involved in a patient using their medication (Figure 4-1). Breakdowns may occur
anywhere along the way. A strong physician–patient relationship provides the
foundation for medical practice. The physician–patient relationship will in uence
whether the patient voices concerns with choice of treatment when the treatment is
initially selected, lls the prescription, uses the medication, and accurately reports
back to the physician on their experience with the medication.
Figure 4-1 Steps necessary to achieve and maintain adherence.
18Q4-7 Patients should feel they are seeing a caring, trustworthy doctor.@
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Patients’ perceptions of their doctor are in uenced by their experience of the initial
contact with the o. ce. Front desk sta should be friendly and professional. The
general appearance of the o. ce is important, and it should be tidy and pleasant.
Posted signs can send subtle (and not so subtle) messages to patients about the
priorities of the physician. If the only signs in view are in regard to making
payments, returned check policies and the like, patients may believe their doctor is
more concerned about making money than patients’ wellbeing. Instead, o. ce signs
can show that a practice values service and may help to reinforce a feeling of
caring in the practice, thanking patients for referrals or wishing them a nice day.
Q4-7 When meeting a patient, the physician should make eye contact, smile,
and shake their hand. The patient should feel cared for and not rushed. Overall,
72% of physicians interrupt patients an average of 23 seconds into giving their
history; uninterrupted, patients require only an additional 6 seconds to complete
19their opening monologue. By simply allowing patients to tell their story,
physicians send a strong message that caring for the patient is their number one
priority. Body language during an encounter is important too. Patients perceive a
17visit as lasting longer if the provider is sitting down. Active listening and
empathetic statements further reinforce the patient’s perceived sense of being taken
care of. Summarizing a patient’s story and telling it back to them, or asking
questions to re ect understanding, help the patient to see their physician is paying
close attention.
Patients want to know they received a thorough examination. Laying hands on
a patient is an integral component of the encounter that has important therapeutic
value. Touching the patient’s skin during an examination helps convey that the
physician is performing a careful examination; a lighted magni er is another prop
that can be used to reinforce this perception. The encounter o ers an opportunity
to educate patients about their condition and plans for treatment. Use language
20that the patient can understand and take the time to solicit additional questions.
Finally, it is helpful to provide contact information in case patients have questions
later. This serves a practical purpose and reinforces the message that the priority is
caring for patients. Incorporating these basic steps into practice helps provide the
foundation of a strong physician–patient relationship, which in turn facilitates good
adherence and good patient outcomes (Box 4-1).
Box 4-1
Ways to strengthen the physician–patient relationship
• Office staff should be friendly and professional
• Office is clean and well-maintained
• Posted signs convey message that patient care is the priority
• Make eye contact, smile, and shake hands with the patient
• Sit down during the encounter
• Do not interrupt the patient’s opening monologue
• Be an active listener
• Show empathy
• Touch the patient’s skin during examination+
+
+
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• Solicit patient input and questions
• Give patients contact information
Choice of treatments
Once a diagnosis has been made, a treatment plan should be developed that takes
patients’ preferences into consideration. A variety of treatment factors have an
impact on adherence (Box 4-2) . Q4-8 Treatment options should be clearly
explained and the patient should be an active participant in choosing among those
options. Their opinion should be solicited directly, in a non-judgmental way. Some
patients may prefer their doctor to choose the medicine, but other patients may
have past experiences that have left them with strong ideas about a particular
treatment.
Box 4-2
Treatment considerations to maximize adherence
• Explain all treatment options clearly
• Involve the patient in choice of treatment
• Solicit the patient’s opinion and beliefs about treatment options
• Choose a vehicle that the patient will use
• Create a simple treatment regimen: use less frequent dosing and combination
products when possible
• Explain side effects and use them to advantage when possible
• Be aware of the cost of medicines and do not prescribe medications that the
patient cannot afford
• Ensure the patient can access the treatment
Q4-8 In the case of topical medications, selection of the appropriate vehicle is
21essential. Patients should be involved in this decision. Past teaching suggested
that ointments are the most e ective vehicles for dry skin conditions such as
psoriasis; the most e ective vehicle, however, is usually the one the patient is most
willing to use. Newer, less messy non-ointment vehicles are highly e ective
22,23psoriasis treatments. Testing samples of di erent products may help patients
decide which vehicle is best for them.
Q4-8 The complexity of treatment is also an issue. Greater adherence will be
achieved with once- or twice-daily dosing than with more frequent dosing
schedules. Combination products that include two or more medications in one
product can help improve adherence. Streamlining treatment is particularly
important for patients with refractory disease. Although our instinct with these
patients may be to add penetration enhancers or switch to more potent and risky
treatments, the opposite approach may be more e ective. As the lesson of the
dramatic e ect of hospitalization in children with severe AD teaches us, poor
adherence is usually the culprit in patients with seemingly refractory disease. Using
riskier medications may be counterproductive if the patient did not use the rst
treatment because of perceived risks. Adding additional medicines to a treatment+
+
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regimen may be counterproductive if poor adherence was caused by the
complexity and time-consuming nature of the initial treatment. For many patients
the treatment should be simpli ed as much as possible, paring it down to a single
medication for once- or twice-daily use. Remarkably, patients may achieve rapid
10improvement using a treatment that had previously been ‘ineffective’.
Q4-9 Adverse e ects of treatment, both real and perceived, are important to
consider. This is a particularly common issue in the treatment of infants and young
children. Patients may have very speci c ideas or concerns about the adverse
e ects of a particular medication, perhaps due to something they read or learned
from a friend. Sometimes, for example in the case of topical calcineurin inhibitors,
there may be little or no scienti c basis for a particular concern. The strength of
the physician–patient relationship may help overcome these fears. A simple
discussion with a trusted physician can reassure the patient that the proposed
medication is safe enough to use.
Some medications have very real adverse e ects and potential toxicities that
warrant discussion. These risks should be put into perspective to help minimize
anxiety. Unexpected adverse e ects can quickly lead to discontinuation of a
medication. For example, forewarning patients that burning or dryness is a normal
reaction to the medication and will subside with use – or better yet, that such a
reaction is ‘a sign the drug is working’ – may keep patients from discontinuing
treatment. While telling a patient ‘a burning sensation is a sign the medication is
working’ may be a stretch, it is true that if the patient is experiencing such an
adverse e ect, it means he or she is using the medication, and so it probably is
17working.
Cost and availability are important considerations that may be overlooked by
the physician, but can potentially represent very real obstacles to adherence. If an
expensive medication is used, discuss the cost with the patient. Warn patients if a
particular medication is not widely available.
Stress good initial adherence
If patients do not see that their treatment is working well, they may be discouraged
and discontinue it. In order to ensure that treatment does work well and quickly,
securing good initial adherence is essential. There are a variety of techniques that
can be used to help attain a high level of initial adherence (Box 4-3). A fast-acting
medicine should be used. If a slow-acting medication is necessary, perhaps it can
be paired with a fast-acting medication, at least at the start of treatment, to help
secure good initial adherence. Much in the same way that rst impressions are
important, seeing good results early on will help the patient to trust their doctor, to
trust in their medication and to continue using the treatment long term, thus
achieving better long term adherence.
Box 4-3
Techniques to improve initial adherence
• Use fast-acting medications; if a slow-acting medication is being used, pair it
with a fast-acting medication initially
• Provide written instructions on treatment
• Educate the patient about their condition and provide realistic expectations for
treatment outcome
• Schedule an early follow-up visit
• Use motivational interviewing techniques
• Help the patient to identify memory aids to help them remember to use the
medicine
Q4-10 Patients need to know how to use their medicines. Instructions for the
use of medication can quickly get complicated, especially in the case of multiple
medications. Most verbal directions given in a patient encounter are forgotten by
24the time the patient gets home. Ideally, physicians should provide clear written
instructions explaining how to use all medications. Whenever possible, having
written materials available for patients is helpful. If a speci c handout is
unavailable, the Internet can be a great resource for information.
An especially powerful tool to promote good initial adherence is ‘white coat
6,7compliance.’ Adherence improves around the time of o. ce visits. An early
follow-up visit, ostensibly to check on how well the medication is working, can
dramatically improve how well patients use their treatments. Scheduling a quick
follow-up visit improves initial adherence and improves short-term outcomes,
which in turn helps to secure good long-term adherence. The many follow-up visits
in clinical trials are likely a strong contributor to the tendency for medications to
work better in clinical trials than they do in clinical practice.
Q4-10 Motivational interviewing techniques can be used to improve
adherence. The physician should express empathy and acknowledge that it can be
challenging to use the medication as prescribed. They should praise the patient for
good adherence behavior: positive reinforcement goes a long way. The physician
can ask the patient if they feel adherence is important, and if it is, what things the
patient might do that would improve their adherence to treatment.
Q4-10 Incorporating a new habit into everyday life can be challenging. It is
easy for even the most motivated individual to forget to use their medicine. Simple
memory aids can help patients maintain good adherence. A common suggestion is
to tie the medication to an already established habit. This could mean taping a
topical acne medication to the toothpaste tube, or placing topical antifungal
medication on top of the shoes.
Achieving adherence in special groups
Several patient populations present unique challenges in adherence (Table 4-2).
These include children, teenagers, and adherence-resistant patients. In children
with chronic skin diseases all the usual barriers to adherence exist, along with
additional challenges. The child is often not a motivated participant, and especially
in the case of topical medications may be very uncooperative in the application of
the medication, which is typically done by the parent. A daily battle may ensue,
which over time can whittle away at the parent’s motivation to apply the medicine.
Work and other social demands on caregivers may leave little time or energy for
treating the child. Also, in households with two caregivers, each might think the
other is responsible for treatment. On top of all this, parents may be particularly
10fearful of the potential adverse effects of treatment on their child.+

@

Table 4-2 Techniques to improve adherence in special populations
Especially adherence-Children Teenagers
resistant patients
Keep the burden of Acknowledge Take the responsibility
treatment low the teenager for treatment out of
before the the hands of theLimit the time horizon of
parent patienttreatment by scheduling
an early follow-up visit Speak directly Utilize home health
to the servicesAvoid the use of
anxietyteenagerinducing language when Add a daily
discussing treatment Use fast-acting phototherapy session
(’topical anti- medications to the treatment plan,
inflammatory’ rather then apply the topicalCapitalize on
than ‘steroid’) medication in-officethe desire to
after each sessionCreate reward systems fit in
For oral medications,Use written action plans Use memory
consider switching toaids
an office-Avoid using administered weeklyparental injectionreminders,
which may
reduce
adherence
To address these concerns it is important to keep the apparent burden of
treatment low by limiting the time horizon of treatment. An early return visit will
help in this regard. The risk of treatment should be put into perspective. It may
help to let parents know that the child will be treated with a ‘topical
antiin ammatory’ rather than subject them to unwarranted fears of the e ects of evil
‘steroids.’ Children are particularly motivated by reward systems and praise.
Sometimes just a simple weekly calendar, in which the child gets to apply a star or
sticker for each successful medication application, works wonders. A written action
25plan (WAP) can be used to empower the child and their caregivers.
Teenagers represent a challenging population because they are at a
developmental stage in which they are becoming, but are not yet fully,
independent. Relationships with parents are strained and there is often a strong
desire to rebel. Teenagers may struggle with delayed grati cation, and so
fast17acting medications should be used when possible. Teenagers have a strong desire
to t in with other teenagers, which can be used to improve adherence. In treating
acne, the physician can simply state that the recommended medicine is one that
most teenagers use to control their acne. On the other hand, telling a teenager,
‘most teenagers aren’t compliant with the treatment,’ is likely to be
counterproductive. Finally, the role of the parent in treatment can be tricky, as
10,17parental reminders may reduce use of the medication in some patients.
+
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Some patients are particularly resistant to using their medications, such that
taking the responsibility for treatment out of the hands of the patient may be the
best approach. Success can often be achieved with physician-administered
treatments. Home health services may be possible. Patients on methotrexate can be
given a weekly injection. For patients with psoriatic plaques that are unusually
resistant to topical agents, consider adding daily o. ce-based phototherapy; the
nurse can apply the topical medication at the light treatment visits (if the o. ce
does not o er standard phototherapy, using a Woods lamp to provide the
‘phototherapy’ may be a su. cient). While the implementation of
provideradministered treatment can be challenging, it is often possible to nd creative ways
to get the treatment to the patient and the improvements in outcomes can be great.
Conclusions
There is a wealth of evidence to demonstrate that adherence is suboptimal across
all elds of medicine, and especially in dermatology. Patients’ adherence to
treatment should be considered at every visit, and it may be best to assume that
patients are not completely adherent. Adherence behavior is complex, a ected by
numerous internal and external factors, with many potential pitfalls. With a better
understanding of the factors a ecting adherence and by employing creative
strategies, physicians can exert a great degree of control over patients’ adherence.
Key elements include (1) the establishment of trust in the physician–patient
relationship, (2) considering patients’ preferences in the choice of treatment, and
(3) timing the return visit to encourage good initial adherence. Rather than
spending time and money developing new medications, energy should be focused
on finding new ways to get patients to use the medications we already have.
Bibliography: Important reviews and chapters
Baldwin HE. Tricks for improving compliance with acne therapy. Dermatol Ther.
2006;19(4):224–236.
Chisolm SS, Taylor SL, Balkrishnan R, et al. Written action plans: potential for
improving outcomes in children with atopic dermatitis. J Am Acad Dermatol.
2008;59(4):677–683.
Feldman SR, Horn EJ, Balkrishnan R, et al. International Psoriasis Council. Psoriasis:
improving adherence to topical therapy. J Am Acad Dermatol. 2008;59(6):1009–
1016.
Gupta G, Mallefet P, Kress DW, et al. Adherence to topical dermatological therapy:
lessons from oral drug treatment. Br J Dermatol. 2009;161(2):221–227.
Thiboutot D, Dréno B, Layton A. Acne counseling to improve adherence. Cutis.
2008;81(1):81–86.
Yan AC, Treat JR. Beyond first-line treatment: management strategies for
maintaining acne improvement and compliance. Cutis. 2008;82(2 Suppl 1):18–25.
web References
Introduction
1 Gupta G, Mallefet P, Kress DW, et al. Adherence to topical dermatological therapy:lessons from oral drug treatment. Br J Dermatol. 2009;161(2):221–227.
2 Aliotta SL, Vlasnik JJ, Delor B. Enhancing adherence to long-term medical therapy:
a new approach to assessing and treating patients. Adv Ther. 2004;21(4):214–231.
3 Bender BG, Rand C. Medication non-adherence and asthma treatment cost. Curr
Opin Allergy Clin Immunol. 2004;4(3):191–195.
4 Vermeire E, Hearnshaw H, Van Royen P, et al. Patient adherence to treatment:
three decades of research. A comprehensive review. J Clin Pharm Ther.
2001;26(5):331–342.
Measures of adherence
5 Greenlaw SM, Yentzer BA, O’Neill JL, et al. Assessing adherence to dermatology
treatments: a review of self-report and electronic measures. Skin Res Technol.
2010;16(2):253–258.
6 Carroll CL, Feldman SR, Camacho FT, et al. Adherence to topical therapy decreases
during the course of an 8-week psoriasis clinical trial: commonly used methods of
measuring adherence to topical therapy overestimate actual use. J Am Acad
Dermatol. 2004;51(2):212–216.
7 Feldman SR, Camacho FT, Krejci-Manwaring J, et al. Adherence to topical therapy
increases around the time of office visits. J Am Acad Dermatol. 2007;57(1):81–83.
8 Richards HL, Fortune DG, O’Sullivan TM, et al. Patients with psoriasis and their
compliance with medication. J Am Acad Dermatol. 1999;41(4):581–583.
9 Brown KK, Rehmus WE, Kimball AB. Determining the relative importance of
patient motivations for nonadherence to topical corticosteroid therapy in
psoriasis. J Am Acad Dermatol. 2006;55(4):607–613.
10 Feldman SR. Practical Ways to Improve Patients’ Treatment Outcomes. Winston
Salem, North Carolina: Medical Quality Enhancement Corporation; 2009.
Magnitude of poor adherence in dermatology
11 Storm A, Andersen SE, Benfeldt E, et al. One in 3 prescriptions are never
redeemed: primary nonadherence in an outpatient clinic. J Am Acad Dermatol.
2008;59(1):27–33.
12 Bhosle MJ, Feldman SR, Camacho FT, et al. Medication adherence and health care
costs associated with biologics in Medicaid-enrolled patients with psoriasis. J
Dermatol Treat. 2006;17(5):294–301.
13 Yentzer BA, Alikhan A, Teuschler H, et al. An exploratory study of adherence to
topical benzoyl peroxide in patients with acne vulgaris. J Am Acad Dermatol.
2009;60(5):879–880.
14 Krejci-Manwaring J, Tusa MG, Carroll C, et al. Stealth monitoring of adherence to
topical medication: adherence is very poor in children with atopic dermatitis. J
Am Acad Dermatol. 2007;56(2):211–216.
15 Yentzer BA, Yelverton CB, Pearce DJ, et al. Adherence to acitretin and home
narrowband ultraviolet B phototherapy in patients with psoriasis. J Am Acad
Dermatol. 2008;59(4):577–581.
Factors that influence adherence behavior
16 Zaghloul SS, Goodfield MJ. Objective assessment of compliance with psoriasistreatment. Arch Dermatol. 2004;140(4):408–414.
17 Baldwin HE. Tricks for improving compliance with acne therapy. Dermatol Ther.
2006;19(4):224–236.
Strategies to improve adherence behavior
18 Uhas AA, Camacho FT, Feldman SR, et al. The relationship between physician
friendliness and caring, and patient satisfaction: Findings from an Internet-based
survey. The Patient. 2008;1(2):91–96.
19 Marvel MK, Epstein RM, Flowers K, et al. Soliciting the patient’s agenda: have we
improved? JAMA. 1999;281(3):283–287.
20 Feldman SR, Horn EJ, Balkrishnan R, et al. Psoriasis: improving adherence to
topical therapy. J Am Acad Dermatol. 2008;59(6):1009–1016.
21 Wilson R, Camacho F, Clark AR, et al. Adherence to topical hydrocortisone
17butyrate 0.1% in different vehicles in adults with atopic dermatitis. J Am Acad
Dermatol. 2009;60(1):166–168.
22 Warino L, Balkrishnan R, Feldman SR. Clobetasol propionate for psoriasis: are
ointments really more potent? J Drugs Dermatol. 2006;5(6):527–532.
23 Feldman SR. Approaching psoriasis differently: patient-physician relationships,
patient education and choosing the right topical vehicle. J Drugs Dermatol.
2010;9(8):908–911.
24 Ong LM, de Haes JC, Hoos AM, Lammes FB. Doctor-patient communication: a
review of the literature. Soc Sci Med. 1995;40(7):903–918.
25 Chisolm SS, Taylor SL, Gryzwacz JG, et al. Health behavior models: a framework
for studying adherence in children with atopic dermatitis. Clin Exp Dermatol.
2010;35(3):228–232.
References*
1 Gupta G, Mallefet P, Kress DW, et al. Adherence to topical dermatological therapy:
lessons from oral drug treatment. Br J Dermatol. 2009;161(2):221–227.
6 Carroll CL, Feldman SR, Camacho FT, et al. Adherence to topical therapy decreases
during the course of an 8-week psoriasis clinical trial: commonly used methods of
measuring adherence to topical therapy overestimate actual use. J Am Acad
Dermatol. 2004;51(2):212–216.
8 Richards HL, Fortune DG, O’Sullivan TM, et al. Patients with psoriasis and their
compliance with medication. J Am Acad Dermatol. 1999;41(4):581–583.
9 Brown KK, Rehmus WE, Kimball AB. Determining the relative importance of
patient motivations for nonadherence to topical corticosteroid therapy in
psoriasis. J Am Acad Dermatol. 2006;55(4):607–613.
10 Feldman SR. Practical Ways to Improve Patients’ Treatment Outcomes. Winston
Salem, North Carolina: Medical Quality Enhancement Corporation; 2009.
11 Storm A, Andersen SE, Benfeldt E, et al. One in 3 prescriptions are never
redeemed: primary nonadherence in an outpatient clinic. J Am Acad Dermatol.
2008;59(1):27–33.
14 Krejci-Manwaring J, Tusa MG, Carroll C, et al. Stealth monitoring of adherence to
topical medication: adherence is very poor in children with atopic dermatitis. J
Am Acad Dermatol. 2007;56(2):211–216.16 Zaghloul SS, Goodfield MJ. Objective assessment of compliance with psoriasis
treatment. Arch Dermatol. 2004;140(4):408–414.
17 Baldwin HE. Tricks for improving compliance with acne therapy. Dermatol Ther.
2006;19(4):224–236.
* Only a selection of references are printed here. All other references in the
reference list are available online at www.expertconsult.com.Part II
Important Drug Regulatory Issues5
The FDA drug approval process
William H. Eaglstein
Questions
Q5-1 In the broadest sense, what are the general areas of oversight by the US FDA? (Pg. 41)
Q5-2 Concerning the Food Drug and Cosmetic Law of 1938 and the Kefauver–Harris Drug
Amendment of 1962, what is (a) the scope of the laws, and (b) the key impetus for passage
of each? (Pg. 41x2)
Q5-3 Of drugs reaching clinical trials, what percent pass (a) phase I, (b) phase II, (c) phase
III, and (d) receive an approved New Drug Application (NDA)? (Pg. 42)
Q5-4 What is involved in defining a drug ‘label’ and the related ‘off-label use’? (Pgs. 42, 43)
Q5-5 How does the pharmacovigilance process after drug release for marketing di6er in the
US versus several European countries? (Pgs. 43, 44)
Q5-6 What are the most important elements of the Prescription Drug User Fee Act of 1992?
(Pg. 43)
Q5-7 Concerning a given FDA Advisory Panel, what is (a) the composition of members, (b)
its primary purpose, and (c) its role in approving drugs or taking drugs o6 the market?
(Pg. 43)
Q5-8 What general changes were allowed by the FDA Modernization Act of 1997? (Pg. 43)
Q5-9 Concerning bioequivalence testing for generic products and product reformulations,
what are the testing requirements for (a) systemic drugs, (b) topical corticosteroids, and
(c) other topical drugs? (Pgs. 44x2)
Q5-10 What are some issues regarding FDA regulation of ‘compassionate use’ (or
‘compassionate treatment’) IND? (Pg. 44)
Introduction
Q5-1 The US Food and Drug Administration (FDA) is the federal agency charged with
regulating all of our foods, human and veterinary drugs, medical devices, biologicals, and
cosmetics. Although the general public assumes that physicians know a great deal about the
FDA, in fact physicians actually receive little education about the FDA in medical school,
residency, or other postgraduate training. This may be partly because most FDA e6orts deal
largely with legal issues or social policy. However, science and medical research information is
fundamental to carrying out the FDA’s missions, and the agency’s policies have a tremendous
impact on public health and on the practice of medicine. The FDA regulatory jurisdiction
(direct and indirect control) is estimated to encompass an enormous 25 cents of every dollar
Americans spend. The FDA is part of the Health and Human Services Department, which is in
the executive branch of the federal government. Thus, the FDA Commissioner is appointed by
the President, with advice from and the consent of Congress. Until the 1992 imposition of ‘user
fees,’ the FDA budget for the drug approval process was almost totally derived from Congress,
which also has oversight responsibility for the FDA. The FDA now spends about $290 million on
approving, labeling and monitoring drugs, with more than 2000 people throughout the agency
involved in this process. This amount compares favorably with the $47 million spent in 1992,
before the prescription drug user fees were instituted. Overall, the Cscal year 2010 FDA budget
request was $3.2 billion (including $828 million in user fees), with approximately 11 000
employees. Clearly the FDA budget is too small, with too few employees to actively make orsupervise all of the decisions a6ecting 25% of the gross national product. The system therefore
depends on a great deal of voluntary self-regulation from the pharmaceutical industry. This
chapter focuses primarily on the approval process for prescription drugs, although much of the
information is also applicable to biologicals and devices.
Federal legislation for drug safety and efficacy
Food drug and cosmetic law
Q5-2 The Crst federal Food Drug and Cosmetic Act was enacted in 1938 (Table 5-1).
Considerable credit for its passage is given to the author, Sinclair Lewis, whose books describing
conditions in the meat packing industry are said to have led to public outrage, and Cnally,
congressional action. Physicians, however, were also active in promoting and creating federal
standards. Prior to the 1938 Act there were no federal standards regarding drug safety or
eE cacy. This was the era of ‘snake oil’ and elixirs. However, the original Act only required that
drugs be proved safe. It was assumed that doctors and patients could work out which drugs
were e6ective, and that market forces would assure the success of only eE cacious drugs. The
current high cost of drug development has led some to call for a reversion to this standard by
approving all safe drugs and allowing clinical experience and market forces to pick out those
indications for which the drugs are truly effective.
Table 5-1 Timeline for major pharmaceutical legislation in the US
Year Legislation regulating pharmaceutical industry
1938 Food Drug and Cosmetic Act
1962 Kefauver–Harris Amendment
1983 Orphan Drug Act
1984 Drug Price Competition and Patent Restoration Act
1992 Prescription Drug User Fee Act
1997 Food and Drug Administration Modernization Act (FADAMA)
Kefauver–harris drug amendment
Q5-2 Although thalidomide was never approved by the FDA and was never sold in the US, the
birth defects the drug caused alarmed the US population so much that in 1962 Congress passed
a comprehensive FDA reform bill known as the Kefauver–Harris Drug Amendment. This
Amendment added the requirement that drugs also be proved e6ective before they could be
marketed. Since then, all potential drugs have been required to be proved both safe and
effective before approval for marketing (premarket approval).
General testing required prior to marketing
To satisfy the premarketing requirements, sponsors (usually pharmaceutical companies) test
drugs by a variety of methods, including bioassays, animal models, and Cnally, human trials
(Table 5-2). The process is quite costly (from $600 million to $900 million) and takes about 15
years (which is double the time needed in 1964). The wide range in development costs reGects
not only the variations inherent in the type of drug and the sponsor’s eE ciency, but also a
variety of accounting methodologies. For example, the cost of ‘losers’ (drugs that fail at some
point in the development process) is typically added as a cost of developing the ‘winners.’ Other
factors accounting for the wide range of drug development costs include whether the cited cost
is in pre-tax or after-tax dollars, and whether the lost interest income on the dollars invested in
the development process is included.Table 5-2 FDA approval process
Drug development stage Description Average # years
– Laboratory and animal studies 6.5*
File IND with FDA
– Clinical studies
Phase 1 Pharmacological profile 1.5
Phase 2 Safety and limited efficacy 2.0
Phase 3 Extensive trials 3.5
File NDA with FDA
– FDA review and approval 1.5
Total for drug development process 15.0
* Patents usually issue relatively early in this time period.
Phase I–IV testing
Q5-3 For every 5000 pharmaceutical compounds evaluated or screened, 5 reach the stage of
clinical trials, and only about 1 of these 5 actually reaches the market after FDA approval (see
Table 5-2). Of those compounds reaching clinical trials, 70% pass Phase I, 33% pass Phase II,
27% pass Phase III, and 20% (1 in 5) receive an approved New Drug Application (NDA). The
sponsors conduct and pay for those studies needed to prove safety and eE cacy. The FDA
evaluates and judges the test results, but rarely does drug testing. However, the FDA is involved
in the sponsor’s test plans, especially those concerning human testing. As potential new drugs
have not been proved safe and e6ective, they may not be given as therapy. The sponsor may
give the investigational drug to patients for evaluation (testing) only after submitting an
Investigative New Drug (IND) exemption.
Phase I testing
FDA guidelines for human testing divide the premarket testing process into three phases: I, II,
and III. In Phase I, patients or healthy volunteers receive the drug in order to study its safety,
along with metabolic and pharmacologic proCles. Usually, Phase I testing involves 20–80
subjects and the safety testing is general as well as speciCc, depending upon the toxicities
detected in animal studies. Phase I is intended to give enough pharmacokinetic and
pharmacologic information to allow the design of controlled clinical studies to be used in Phase
II.
Phase II testing
In Phase II studies the drug is tested for safety and eE cacy to determine the optimal dose or
duration to be used in Phase III. Phase II usually involves several hundred subjects with the
targeted condition.
Phase III testing
Phase III studies involve larger numbers of patients, usually several hundred to several
thousand, most often in randomized controlled trials (RCT), to evaluate eE cacy and safety in a
larger, well-controlled setting. Q5-4 Phase III studies will also provide suE cient data to allow
the development of a beneCt–risk relationship and the development of a ‘label.’ FDA considersany written, printed, or graphic matter that is aE xed to, or appears on, a drug or its package to
be a label. Labels are required on all drugs involved in interstate commerce or held for sale
after shipment or delivery in interstate commerce. Each word of a drug’s label has been
scrutinized and often negotiated by both the FDA and the sponsor. The Physician’s Desk
Reference is largely a collection of drug labels. Use of a drug for a condition or in a manner not
described on the label gives rise to the phrase ‘o6-label use.’ For totally new drugs (new
molecular entities, NME), eE cacy and safety must be demonstrated in at least two RCT. In
RCT, patients receive either the drug being tested (the ‘active drug’) or the control drug
(frequently a placebo). Usually RCT are double-blinded, which means that neither the patients
nor the investigators know which agent – active or control – a given patient is receiving. All
human (and animal) testing is approved by institutional review boards (IRB) at each
investigative site.
Pharmacovigilance process
Q5-5 At the end of Phase III testing a new drug has usually been received by 1000–3000
patients. Given these numbers, it is not surprising that uncommon adverse e6ects are often not
discovered until a drug has been on the market for several years. (See also Chapter 6 on
Pharmacovigilance.)
Overall, 51% of approved drugs have serious adverse e6ects not detected before FDA
approval. It is interesting to note that some other countries (unlike the US) have the
postmarketing safety monitoring done by an organization separate from the organization that gives
initial approval to a drug. For example, in the UK, drug approval and safety monitoring
processes are entirely separate. The safety monitoring unit may order changes in product
labeling or the outright withdrawal of a marketed drug. France has a well-developed network of
regional pharmacovigilance centers, a national database for practitioners, and a drug safety
journal. The recent FDA action severely restricting the use of the blockbuster diabetes drug
rosiglitazone indicates a serious intent toward enhancing the response to post-marketing safety
findings.
Phase IV studies
Occasionally the FDA approves a drug but requires additional studies or reporting. These
studies are referred to as post-marketing, or Phase IV, studies. Until recently many of these
postmarketing or post-approval studies were never carried out, but recent FDA action has resulted
in far better compliance. In a related action FDA has developed a mandatory system for public
reporting of all FDA-approved study results.
Prescription Drug User Fee Act
Q5-6 The Prescription Drug User Fee Act of 1992 was passed to help shorten the time needed
for FDA to review New Drug Approval applications. By requiring sponsors to pay the FDA a fee
(‘user fee’) to have their mandated studies evaluated, this law provided designated money with
which FDA hired 600 new sta6, mostly aimed at drug review, and reduced the time required
for evaluation of NDA to between 12 and 18 months. The Prescription Drug User Fee Act was
renewed in 1997 for a second 5-year period, and again in 2002. User fees have also been
applied to the approval process for devices (2002) and animal drugs (2003).
FDA advisory panels
In order to assist in reaching decisions on a drug’s safety, eE cacy, and beneCt–risk ratio, the
FDA often asks for advice from its standing, or ad hoc, advisory panels. Q5-7 These panels are
composed of experts who are not full-time government employees. They are usually physicians,
scientists, and statisticians who are special government employees for the time they serve,
which is usually 1–2 days, once or twice a year. The panel members individually review the
written information before their formal public meeting. At the FDA Advisory Panel meetings
participants hear from the sponsor, the FDA, and other interested parties. The panels areconvened to answer speciCc questions posed by the FDA about the drug application. The
questions almost always include the broad issue of whether the sponsor has demonstrated safety
and eE cacy for the intended drug use. The FDA is not required to follow the advice of the
advisory panels, but usually does. The panels’ conclusions are often mentioned in the popular
press, leading patients to the misunderstanding that a new drug has been approved and is on
the market. FDA Advisory Panels are not required for all new drugs.
Off-label drug use
General principles
Q5-4 Traditionally, once a drug was approved, it could only be marketed/promoted for the
disease indication studied (intended use). Other uses are called ‘o6-label’ because the
FDAapproved written instructions and information (‘label’) are based on information just for the
uses formally studied. O6-label treatment is fully legal and is very commonly used. For
example, most pediatric treatments are o6-label because few drugs have been developed and
studied in populations of children. Even changing the total dosage or frequency of drug
administration can make its use o6-label. Many of the combination chemotherapy regimens
used in oncology have not been approved by FDA, are not described on the label, and are often
considered o6-label. Examples of o6-label uses common in dermatology include cyclosporine
for atopic dermatitis and pentoxifylline for venous ulcers. Congress has been clear in its intent
that the FDA should not interfere with the practice of medicine. As long as the physician is
prescribing an approved drug for an o6-label use to help the wellbeing of an individual patient,
and has a reasonable scientiCc basis for expecting success, the o6-label use is within the
appropriate context of the practice of medicine. Such therapy may be referred to as innovative
therapy. It should be noted that on occasion sponsors do seek label changes, and toward that
end studies are submitted to FDA for approval. FDA approval of cyclosporine for use in psoriasis
and Botox for hyperhidrosis are examples pertinent to dermatology.
Food and Drug Administration Modernization Act
Q5-8 In 1998, the Food and Drug Administration Modernization Act (FADAMA) of 1997 was
changed, allowing pharmaceutical companies to promote (teach about and recommend to
physicians) o6-label uses of an approved drug. Typically this role is in the domain of ‘Medical
Science Liaisons’ for pharmaceutical companies. Such o6-label use promotion is allowed only if
there are signiCcant published data supporting the drug’s o6-label use as both safe and
e6ective, and showing that the sponsor is committed to conducting further studies of the drug
for the o6-label use. In addition to the changes on the promotion of o6-label uses, the new Act
allowed companies to advertise directly to consumers for approved prescription drugs. Some
critics believe that direct-to-consumer advertising has reduced drug safety by expanding the
number of people using drugs for marginal indications.
Generic drugs
Systemic drugs bioequivalence
Q5-9 When patents on the brand-name or pioneer drugs expire, generic formulations become
available at prices generally much lower than those for brand-name drugs. Originally, generics
were produced and sold by so-called generic drug companies. Recently, generic drugs have also
been manufactured (and marketed by) the brand-name producers. Generic drugs must also be
approved by FDA before being marketed. As noted earlier, to secure FDA marketing approval
the pioneer drug must be shown to be safe and e6ective in clinical trials. However, after
marketing, the pioneer drugs are often reformulated. The FDA standard for reformulated
pioneer drugs and for generic drugs is that they must be shown to be the bioequivalent of the
pioneer drug formulation. Bioequivalence is assumed to equal therapeutic equivalence.
Bioequivalence is demonstrated by showing similar peak serum concentrations and
area-underthe-curve values after a single oral dose of the generic or reformulated drug.Topical drug testing required
Q5-9 As topical drugs usually do not have signiCcant serum values, generic topical products
and formulations, even if identical to the brand-name or pioneer drug, must be tested in clinical
trials similar to those needed for pioneer drug approval. For generic topical corticosteroids, the
Stoughton vasoconstrictor assay has been approved as a surrogate endpoint suE cient to allow
marketing approval. No serious therapeutic di6erences between brand-name original (pioneer)
drugs and FDA-approved generics have been reported for topical products.
Special drug approval categories
Compassionate use regulations
Q5-10 Treating patients with drugs under investigation, but not approved, for marketing in the
US for any indication is very complicated. Regulations developed since the acquired
immunodeCciency syndrome (AIDS) epidemic make it possible for patients to ‘import’
nonapproved drugs for personal use under a physician’s care. ‘Compassionate use’ (also known as
‘compassionate treatment’) IND (as compared to study IND) are typically limited to patients
who have received the test drug under protocol and who still need it after completion of the
protocol. Drugs sold under a treatment IND are priced to recover only ‘costs’ rather than to
achieve a profit.
Drug Price Competition and Patent Restoration Act
Many other laws have indirect, but important, general e6ects on the drug development and
approval process. For example, because proving safety and eE cacy is so time-consuming, the
Drug Price Competition and Patent Restoration Act of 1984 gives the sponsor back some of the
patent protection time consumed by meeting the premarketing approval requirements.
Orphan Drug Act
Similarly, the Orphan Drug Act of 1983 o6ers tax and other incentives to encourage companies
to prove the safety and eE cacy of drugs whose potential market (number of potential patients)
is too small to allow recovery of their drug development costs.
Related issues
Regulation of over the counter drugs, biologicals, and generics
It is important to recognize that the approval process for devices, biologicals, and
over-thecounter (OTC) drugs is similar to, but somewhat di6erent from, the approval process for
prescription drugs. For example, OTC drug status is dependent upon a much higher level of
safety and a need for patients to be able to recognize independently when the drug is indicated.
Also, many OTC products are marketed based on complying with an OTC monograph (for a
drug group) requirement, rather than being based on conducting extensive premarket testing.
Biologicals have not been subject to generic competition because of the many chemical and
other technical di6erences between these large molecules and the traditional small molecular
drugs. However, in very near future the FDA intends to deCne a pathway for the development
of generic biological drugs, also known as biosimilars.
Regulation of combination products
The advent of agents composed of a device and a drug (such as vascular stents that release
antithrombosis drugs) have led to the creation of an FDA oE ce of combination products, which
assigns such combination products to the proper reviewing authority within the FDA.
Furthermore, physicians should recognize that there is not an FDA regulatory process for
surgery.
Comparisons of FDA regulation with other countriesQ5-5 It should also be noted that the FDA’s drug regulatory process is considerably di6erent
from the drug regulatory process used in many other countries. For example, in some countries
a non-governmental organization evaluates the data and submits a recommendation, which the
government usually accepts. In other countries only safety data are required. However, the FDA
processes are highly regarded by other countries, some of which use US FDA approval as the
basis for their own country’s approval of a given drug. The FDA is proud of the fairly low
number of approved drugs subsequently recalled or taken o6 of the market. At the same time,
critics often lament the ‘drug lag’ that results in many drugs being available in other countries
significantly before release in the US.
Some final thoughts
Finally, it is important to recognize that the laws governing the drug-approval process are
drafted to meet broad public health and social policy considerations. The regulations developed
to implement these laws quickly become complicated and are constantly Cne-tuned to meet
new circumstances and speciCc situations. In addition to Federal ‘Regulations,’ the FDA also
issues ‘Guidances.’ Unlike Regulations, which are legally binding, Guidances represent the
FDA’s current thinking and recommendations, but are not legally binding.
Common abbreviations utilized in this chapter
FADAMA Food and Drug Administration Modernization Act
FDA Food and Drug Administration
IND Investigative new drug
IRB Institutional review board
NDA New drug application
NME New molecular entity
OTC Over the counter
RCT Randomized controlled trial(s)
Bibliography: important reviews
eMedicinehealth. FDA Overview [Online].
http://www.emedicinehealth.com/script/main/art.asp?articlekey=59287&pf=3&page=1, 22
September 2010.
FDA How Drugs are Developed and Approved. [Online]
http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved.htm,
12 August 2010.
FY 2010 Summary of the FDA’s FY 2010 budget. [Online]
http://www.fda.gov/aboutfda/reportsmanualsforms/reports/budgetreports/ucm153154.htm,
16 September 2010.
Okie S. Reviving the FDA. New Engl J Med. 2010;363(16):1492–1494.6
Pharmacovigilance
verifying that drugs remain safe
Joel M. Gelfand, Sinéad M. Langan
Questions
Q6-1 How is pharmacovigilance defined? (Pg. 46)
Q6-2 What are some recent examples of drugs removed from the market by the FDA as a result of the
pharmacovigilance process (as well as the reason for the drug being removed)? (Pg. 47)
Q6-3 What are the three main categories of adverse effects used in pharmacovigilance? (Pg. 47)
Q6-4 What are some of the most important limitations of randomized controlled trials in generating drug
safety data? (Pg. 47)
Q6-5 What is the public health impact of drug adverse effects? (Pg. 48)
Q6-6 Why are ‘new’ adverse e, ects of medications so frequently discovered after a drug has already been
approved for marketing as safe and effective? (Pg. 49)
Q6-7 How is a ‘signal’ de/ ned, regarding an important potential adverse e, ect due to a drug; likewise,
how are these ‘signals’ generated in the pharmacovigilance process? (Pg. 50)
Q6-8 What are registries and how can they be used to monitor drug safety? (Pg. 51)
Q6-9 What are the advantages and disadvantages of meta-analyses in analyzing drug safety? (Pg. 52)
Q6-10 What are the key concepts for interpreting safety studies under the following headings (a)
statistical issues, (b) study design, (c) outcomes analysis, and (d) assessing causality? (Pg. 52, Table
63)
Do not be the first to prescribe a new medication, and do not be the last to prescribe an old one.
Sir William Osler
Introduction
Q6-1 Pharmacovigilance is de/ned as, ‘…the activities involved in the detection, assessment, understanding,
1and prevention of adverse e, ects or any other drug related problems…’. All drugs have the capacity to
cause adverse e, ects and no drug is completely safe. Medication safety is of particular concern for
dermatologists, as most treatment indications involve diseases that are not life-threatening and are often
chronic, requiring years of medical therapy. Although skin diseases can create substantial morbidity,
physicians, regulatory agencies and society generally have less tolerance for risk when treating skin diseases.
This chapter reviews the 8 key principles related to interpreting information related to drug safety.
Knowledge of these principles is fundamental to making informed treatment decisions and to aid in the
discussion of risk with patients.
Principle #1
The history of drug safety is marked by numerous examples of public health crises related to
medical products initially thought to be safe when approved for use in humans.
The most dramatic events have resulted in a major regulatory response from government. Drugs
previously thought to be ‘safe’ often have unknown adverse e, ects that only become apparent after years of
use. Safety issues are particularly di>cult to discover if they are rare or delayed in onset (e.g. cancer). The
discovery of previously unknown serious adverse e, ects after a drug has been approved for marketing is
2common. Therefore, it is very important that physicians scrutinize the safety of medications they prescribe
and be aware of new safety information as it becomes available. Instructive examples of drug safety issues
include:
• In 1937, 107 deaths, many in children, occurred in the United States from the use of a cough syrup that
used diethylene glycol as a solvent. This event led to the 1938 Food Drug and Cosmetic Act, which for
the first time required proof of safety prior to marketing.=
<
• In 1955, over 40 000 children developed abortive polio (51 of whom were permanently paralyzed) and
5 died from a polio vaccine made by Cutter Laboratories that was not e, ectively inactivated during
manufacturing. The incident also sparked a polio epidemic in the families and communities of those
immunized with the defective vaccine, leading to an additional 113 people who were paralyzed and 5
more deaths. In ensuing lawsuits it was determined that pharmaceutical companies could be held liable
3for harm from their products even if there was no negligence (e.g. liability without fault).
• In 1961, over 10 000 children worldwide developed severe birth defects (phocomelia) related to in utero
exposure to thalidomide. In the United States this event led to the Kefauver–Harris Amendment, which
strengthened the requirements for safety testing and for the /rst time required proof of e>cacy prior to
a drug being marketed. This public health disaster also spurred the development of formal spontaneous
reporting systems for pharmcovigilance which are still the primary method of identifying safety issues in
approved medications.
• In the 1970s it was discovered that diethylstilbestrol caused clear cell adenocarcinoma of the cervix and
vagina in women exposed in utero decades earlier.
• In 1984, PUVA was de/nitively linked to an increased risk of squamous cell carcinoma, approximately
410 years after the /rst description of PUVA therapy for psoriasis. It took over 20 years to establish a
5link between PUVA and melanoma, which remains controversial.
• Over the past 4 decades more than 130 medications have been withdrawn from the market because of
safety concerns. One-third of drug withdrawals occur within 2 years of being approved for marketing,
7and half occurred within 5 years of marketing. Q6-2 Recent examples (since 1997) of prescription
drugs removed from the market include classes of medications that are commonly prescribed, such as
antihistamines (e.g. astemizole, terfenadine), non-steroidal anti-inHammatory agents (bromfenac,
valdecoxib), antibiotics (trovaHoxacin), lipid-lowering medications (cerivastatin) and an
immunosuppressant for the treatment of psoriasis (efalizumab – progressive multifocal
6leucoencephalopathy).
• 51% of approved drugs have serious adverse effects not detected prior to approval.
Principle #2
Adverse reactions to medications are divided into three classes. Q6-3 These categories are based on
whether the adverse e4ect is: (1) pharmacologic – type A, (2) idiosyncratic or allergic – type B, or
(3) an effect that increases the risk of new morbidities over time – type C.
Type A e, ects are those related to pharmacological e, ects of the drug. Type A e, ects are usually
common, dose related, and can be mitigated by using doses that are appropriate for the individual patient.
An example would be cheilitis related to isotretinoin. Type A e, ects are generally well described by the time
a drug is approved for marketing. Type A e, ects may be di>cult to identify if they occur in only a very few
patients (i.e. bone marrow suppression from azathioprine in patients with thiopurine methyltransferase
de/ciency), or when the phenomenon is trivial or the mechanism is unclear. An example would be Hushing
with alcohol intake in patients treated with topical tacrolimus.
Type B e, ects are those which are often idiosyncratic or allergic and typically are rare (<1 in=""
1000="" _people29_.="" type="" b="" e, ects="" are="" often="" not="" detected="" before="" a=""
drug="" is="" approved.="" usually="" discovered="" through="" spontaneous="" reports="" to=""
pharmaceutical="" companies="" and="" the="" food="" administration="" _28_fda29_.="" because=""
very="" rare="" occur="" close="" proximity="" initiation="" of="" new="" _medication2c_="" such=""
events="" offer="" compelling="" evidence="" that="" caused="" observed="" adverse="">
Type C e, ects are those that introduce new morbidities by altering the risk of diseases that occur over
time. For example, chronic PUVA therapy increases the risk of squamous cell carcinoma. Type C e, ects can
often have a substantial impact on public health. However, because they are relatively rare and often
delayed, they are often not detected before a drug is approved for marketing. Type C e, ects typically
require analytic studies in order to investigate the association of the drug with the effect in question.
Principle #3
Drugs are approved for marketing based on data from preclinical animal studies and randomized
controlled trials (RCT) in patients. Although RCT are the gold standard for proving the e cacy of a
medication, they have several important limitations with respect to de ning the safety of a
medication.
Q6-4 The limitations of safety data generated from the RCT used to approve a drug for marketing must
be considered when interpreting safety data.
• RCT typically are short term, whereas real-world exposure to the medication may occur over a period of
many years. For example, clinical trials of systemic psoriasis medications are typically 2–3 months in8duration; however, in clinical practice these medications are used for much longer periods. Therefore,
adverse e, ects that may be delayed in onset, or that may be related to duration of exposure, are
unlikely to be uncovered by short-term RCT.
• RCT typically occur in highly selected patient groups of individuals who have minimal comorbidities.
Therefore, the safety of using medications in patients with comorbidities such as coronary artery
disease, diabetes, chronic obstructive pulmonary disease, cancer, or the young or elderly or in
pregnancy, is not well defined.
• RCT typically occur in relatively small populations of patients. When a drug is approved for marketing,
typically 500–3000 patients have been treated for a short time (weeks to months) in RCT. Additionally,
another 1000–2000 patients may be treated in uncontrolled con/rmatory studies prior to a drug being
approved. As a result, RCT used to approve medications for marketing usually can only clearly describe
adverse event rates that occur in about 1% of patients, and often cannot begin to detect rare adverse
events (those occurring in <1>
• RCT typically evaluate a single drug, with limitations on other medications the enrolled patient may be
taking. Subsequently, the drug used in clinical practice may be given to patients receiving multiple
medications, allowing the possibility of drug interactions not previously recognized.
The RCT is the gold standard study design for proving causality. However, RCT are limited by the
generalizability of the results. Therefore, caution is advised when prescribing a medication for a patient who
is not typical of patients in the RCT. Importantly, adverse drug reactions have been observed to occur at
increased frequencies in populations not well represented in clinical trials, such as children and the elderly,
9and those with hepatic and renal impairment. Additionally, the incidence of adverse events may vary by
9ethnicity and gender. Also, as RCT are typically of short duration (e.g. months) they provide minimal
information on the safety of long-term exposure to a medication. This limitation is a particular problem for
de/ning type C e, ects, such as cancer, which may have a prolonged latency period from exposure to the
development of the adverse e, ect. Finally, RCT as conducted for the current drug approval process are
generally designed to de/ne just relatively common adverse e, ects (e.g. those a, ecting at least 1% of
patients).
Principle #4:
A study that does not observe an adverse e4ect does not necessarily mean the medication does not
cause the adverse e4ect in question. Large studies are necessary to identify adverse e4ects that,
although rare, can be of public health importance.
The statistical power of a study to detect the adverse event of interest is also a major limitation of many
safety studies. This limitation particularly applies to rare adverse e, ects, which typically occur at rates of
about 1 in 1000. Unfortunately, many serious adverse e, ects that are of concern are ‘rare’. Table 6-1
demonstrates that adverse events that have been concerning to dermatologists (e.g. suicide associated with
isotretinoin, lymphoma associated with immunosuppressive therapy for psoriasis) occur less frequently than
1 in 1000 people per year. To adequately investigate risks that occur at 1 in 1000 patients, approximately
103000 patients exposed to the medication need to be studied.
Incidence rates of various causes of death or serious health outcomes26–28Table 6-1
Cause of death Rate per 100 000 people per year
All causes 847.3
Heart disease 241.7
Cancer 193.2
Acute myocardial infarction 62.3
Chronic lower respiratory disease 43.3
Motor vehicle accidents 15.7
Suicide 11
Lymphoma 8.1
Homicide 6.1=
HIV 4.9
Skin cancer 2.6
Medical and surgical treatment 1
Commercial airline accident 0.032
Lightening strike 0.015
Serious health outcome Rate per 100 000 people per year
Lymphoma 21.7
Melanoma 17
Toxic epidermal necrolysis (TEN) 0.05–0.19
TEN from antibacterial sulfonamides 0.45 per 100 000 exposures
If a study does not observe an adverse e, ect, it is critical to know the statistical power of the study to
detect the adverse e, ect if the medication truly was associated with it. Statistical power is de/ned as the
probability of observing an association, given that one truly exists. By examining the 95% con/dence
interval (CI) of a relative risk or odds ratio, one can determine whether the sample size was adequate to rule
out a potentially important association. For example, in a study of 1252 patients with psoriasis treated with
cyclosporine for an average of 1.9 years, no statistically signi/cant risk of lymphoma was observed
11(incidence ratio 2.0, 95% CI 0.2–7.2). However, because of the small sample size, this study could not
rule out a 7-fold increased risk of lymphoma based on the con/dence interval. Additionally, the ‘rule of
threes’ can be used to carefully scrutinize studies that do not observe an adverse event. To use this rule, one
takes the reciprocal of the number of patients in the study and multiplies it by 3 to determine the range of
results that could be statistically consistent with the observed /ndings based on a 95% CI. In other words, if
the study was repeated 100 times, 95% of the results would occur within the 95% CI. In this approach the
statistics report a range of results that could be consistent with the /ndings, in contrast to the method in the
previous paragraph, in which the statistics report approximate numbers.
For example, if a study followed 300 patients on methotrexate for 1 year and observed no cases of
lymphoma, then the study would be 95% certain that the true rate of lymphoma was no greater than
(1/300) × (3) = 1/100 per person-year. However, the baseline risk of lymphoma is approximately 1/5000
per person-year. Therefore, such a result could be consistent with a 50-fold relative risk of lymphoma,
demonstrating that in this example the study would lack statistical power to determine the risk of lymphoma
in methotrexate-treated patients. This example also demonstrates that the individual clinician cannot rely on
their own experience to determine whether a drug is associated with a rare adverse e, ect, and therefore
must rely on large long-term studies in order to fully capture information on the safety of medications they
prescribe.
Principle #5
Although rare adverse e4ects may be unlikely to a4ect the individual patient, they are of public
health importance because millions of patients may potentially be exposed to the drug. It can take
years to de nitively prove the relationship between a drug and an adverse e4ect, which further
compounds the public health impact.
Q6-5 Some important statistics to consider regarding this principle are:
10• Patients in the US received 3.1 billion prescriptions in 2004, 60% more then a decade earlier. Because
medications are used by such a large population, rare adverse e, ects have the ability to a, ect many
individuals.
• Overall, 4% of patients in ambulatory medical practices experience serious adverse e, ects from
12medications.
• 1.5 million people are hospitalized annually for adverse drug reactions, comprising 5% of all
13admissions.
• An estimated 100 000 Americans die each year (no doubt a controversial study) from adverse drug
13reactions.
An important example of this principle is the impact of cyclooxygenase-2 (COX-2) inhibitors on public
health. When rofecoxib was approved in 1999 it was noted that, based on biologic actions, it could=
<
14theoretically increase the risk for thrombosis. Although an increased rate of thrombotic events was seen in
short-term RCT, these /ndings were not statistically signi/cant as the sample size (about 2200 people) was
inadequate to provide su>cient statistical power. In 2004, a series of large long-term RCT of COX-2
inhibitors de/nitively linked them to the risk of myocardial infarction. Although myocardial infarction is
statistically uncommon, millions of patients were exposed to COX-2 inhibitors. For rofecoxib alone, it is
estimated that 88 000–140 000 excess cases of myocardial infarction occurred during the 5-year period
15when this drug was on the market.
Principle #6
Q6-6 The drug approval process rigorously de nes the e cacy of an agent. However, when a drug
is approved, safety issues such as adverse events which are uncommon, delayed in onset, or occur
at higher frequencies in subpopulations, are not well defined.
The drug approval process represents a trade-o, between minimizing delays in access to new
medications with delays in fully de/ning the safety of a medication. Therefore, pharmacovigilance is a
critical component of ensuring that drugs approved for marketing remain ‘safe’ when used in large
populations of patients. Figure 6-1 summarizes the process of investigating drug safety in the United States
from the point of initial development to post-approval surveillance.
Fig. 6-1 Overview of investigation into drug safety in the United States.
Pharmacovigilance occurs primarily through physicians and patients voluntarily reporting adverse
e, ects to pharmaceutical companies and regulatory agencies, such as the FDA. Since 1968 the FDA has
14collected data on over 8000 drugs and biologic products, cumulating in over 2.5 million reports. The FDA
receives about 370 000 reports annually: only 10% of these are submitted directly to the FDA and 90% are
initially submitted to pharmaceutical companies. Physicians can report adverse reactions to medications,
biologics, and cosmetics through the FDA-sponsored MedWatch program by telephone or via the web,
http://www.fda.gov/medwatch/index.html. Physicians are particularly encouraged to report serious adverse
events (those that result in death, hospitalization, disability, a congenital anomaly, or are life-threatening or
require intervention to prevent permanent impairment of damage) even if they are not certain there is a
causal relationship with the medication in question. The FDA maintains spontaneous reports in the Adverse
Event Reporting System (AERS) database. Additionally, formal spontaneous reporting systems exist in over
1660 countries worldwide, with pharmacovigilance efforts coordinated by the World Health Organization.=
=
Important advantages of spontaneous report programs include:
• Capture data on all prescribers, drugs, patients, and dispensers;
• Relatively inexpensive;
• Can be useful for detecting novel adverse effects.
Reports of adverse events by physicians can be critical in identifying previously unknown reactions to
medications. Dermatologic adverse events can herald important drug safety issues, as demonstrated by
practolol-induced oculomucocutaneous syndrome and L-tryptophan-induced eosinophilic myalgia
17,18syndrome, both of which were identified through spontaneous reports.
Important disadvantages of spontaneous reporting include:
• Adverse e, ects from medications are seriously under-reported, studies having suggested that only about
9,181% of adverse reactions are reported.
• The number of people exposed to a medication in a population captured by spontaneous reporting
systems is not well defined (thus, lacks denominator data).
• Spontaneous reporting systems such as AERS cannot be used to determine the true incidence or risk of an
adverse e, ect, since the number of true cases and the number of individuals exposed are poorly
defined.
• There is substantial bias in the reporting of adverse events. Adverse event reporting is more likely to
occur within the /rst 2 years of drug approval or if there is media attention related to a particular
19adverse event.
• Spontaneous reporting systems generate case report and case series data, and as a result, the causal
nature of these reports usually cannot be determined.
Principle #7
Q6-7 Case reports of adverse events are used as part of signal generation. A signal is de ned as a set
20of data constituting a hypothesis that is relevant to the rational and safe use of a drug in humans.
Signals can be generated by spontaneous case reports, epidemiologic studies, clinical trials, and in vitro
and animal studies. Signals are typically identi/ed by expert clinical reviewers of spontaneous reports.
Additionally, new computer programs using bayesian statistical algorithms are being used to mine
21spontaneous reporting databases for potential safety signals. Case reports provide particularly compelling
signals when the adverse reaction regresses with discontinuation of the drug and recurs if the drug is
22reintroduced. Spontaneous reports are also compelling if the event is very rare. For example, in 2009
efalizumab was withdrawn from the market after 3 confirmed and 1 suspected case of progressive multifocal
6leukoencephalopathy (PML) after more than 46 000 people had been exposed to the drug. Despite the
limitations of case reports, they are the most frequently used form of evidence to withdraw a medication
23from the market or alter a product’s label. Recent examples of safety signals identi/ed by spontaneous
reporting in dermatology include isotretinoin and suicide, biologics and lymphoma, and topical immune
modulators (pimecrolimus, tacrolimus) and lymphoma. In each of these examples no de/nitive drug
causation has been established.
Principle #8
An observed association or ‘signal’ does not necessarily mean causation. A breadth of scienti c data
is necessary to test the hypothesis generated by a ‘signal’ to determine whether drug ‘causation’ is
likely.
Study designs used to investigate drug safety as part of pharmacovigilance are summarized in Table
624,252. Case reports, case series, cross-sectional studies, secular trends and ecologic studies are considered
descriptive studies which are best used to generate hypotheses. Case–control, cohort, case–crossover, and
clinical trials are analytic studies which are designed to test hypotheses. Case–control and cohort studies are
often performed using existing patient databases, which allows for e>ciency in the conduct of these
18studies. Figure 6-2 details the calculation of measures of association from case–control and cohort studies.
Case–control studies generate odds ratios as a measure of association, whereas cohort studies (and clinical
trials) generate relative risks. Odds ratios may overestimate the relative risk if the outcome being studied is
common (e.g. occurs in more than 10% of patients). Cohort studies and clinical trials also allow one to
calculate the attributable risk (also called risk di, erence), which provides information on the excess risk of
disease in those exposed compared to those unexposed. To better understand the magnitude of risk one can
also calculate the number needed to ‘harm,’ which is the number of patients clinicians need to expose to the
factor in order to observe 1 excess case related to that exposure. Owing to the limitations of spontaneousreporting the FDA often requires a commitment to undertaking post-marketing safety studies as a condition
of approval; however, the proportion of completed Phase IV studies has dropped from 62% in 1970 to 24%
26in 1998. The 2007 FDA Administration Amendments Act increased the power of the FDA, enabling them
(1) to require post-marketing studies and to /ne companies if these studies are not completed, and (2) to
27order changes in a drug’s label after approval of that drug. Although RCT are the gold standard for
causality, case–control and cohort studies are often more appropriate to address the hypotheses generated
by case reports and other forms of signal generation.
Table 6-2 Overview of pharmacoepidemiology study designs
Fig. 6-2 Measures of association from analytic studies.
Data from analytic studies are typically analyzed using a 2 × 2 table, as shown above. Case–control studiesyield odds ratios, whereas cohort studies and clinical trials yield relative risks. The magnitude of risk can be
measured by calculating the attributable risk and the number needed to harm.
Two increasingly used modalities for pharmacopidemiology studies are registries and meta-analyses.
Q6-8 BrieHy, a registry is a roster of people with a common characteristic, either a disease or a drug
exposure, where systematic data are collected. An example in dermatology is the registries established to
study the safety of topical calcineurin inhibitors, based on signals from animal studies and data relating to
28oral ingestion of these agents. Registries have the advantage of yielding a well-de/ned ‘numerator’ of
adverse events and a ‘denominator’ of those exposed to the medication, which can aid in signal detection.
Registries require appropriate controls and statistical adjustment in order to test hypotheses raised by safety
signals.
Q6-9 Meta-analyses are used to overcome the lack of power of individual RCT and the lack of a control
group that a, ects many registry designs. Meta-analyses combine data from di, erent studies quantitatively
to determine an overall estimate of relative risk. However, there are some critical issues related to the
29methodology of meta-analysis that investigators using this technique need to be aware of. These include
(1) heterogeneity between study populations and designs, (2) publication bias, (3) need for appropriate
statistical techniques when analyzing rare outcomes, (4) lack of access to original source data for inclusion,
and (5) incomplete retrieval of published studies.
All studies, whether observational (e.g. case–control or cohort) or experimental (e.g. clinical trials),
have important limitations that must be considered. Q6-10 Table 6-3 summarizes the key methodological
issues that must be considered when interpreting studies related to the safety of a medication. If an
association is not due to statistical error (e.g. chance) or issues related to the design of the study (e.g.
confounding or bias) then a causal relationship may be considered.
Table 6-3 Summary of factors to consider when interpreting safety studies Q6-10
Factor to be scrutinized Question to be addressed
Statistical Chance (type I Were the observed findings due to chance? A P value of 0.05 implies that
issues error, α error) there is a 5% probability that the observed finding was due to chance.
Studies looking at multiple outcomes (e.g. cohort studies) may be more
prone to finding statistically significant findings by chance alone due to
multiple comparisons.
Power (type II If the study was negative (no effect), what was the probability of
error, β error) detecting an effect if one was truly present. What magnitude of effect was
the study powered to detect?
Precision How precise is the estimate of effect? What was the range of results
statistically consistent with the observed finding (e.g. 95% confidence
interval)? Did the study’s confidence interval include/exclude the relative
risk that is important to detect?
Study Confounding Is there a third factor that is associated with the exposure of interest and,
design independent of the exposure, is a risk factor for the outcome being
studied? Was it controlled for?
Confounding Is the disease being treated a risk factor for the outcome independent of
by indication the medication?
Information Was the exposure and outcome measured the same way in both groups?
bias
Selection bias Were the two groups enrolled in the study similar with respect to
important determinants of outcome except for the exposure of interest?
Sensitivity Are the findings robust to changes in the definition of exposure or
analyses outcome? What degree of potential confounding or bias would be
necessary to remove the observed association?Generalizability Was your patient well represented in the study? Do the results apply to
your patient?
Outcome Magnitude of What is the magnitude of the increased risk (above the background risk)
risk associated with the exposure? This can be determined through calculation
of the attributable risk and number needed to harm (Figure 6-2).
Risk vs. benefit Does the magnitude of risk associated with the treatment outweigh the
benefit for the patient?
Assessing Time sequences Studies need to clearly demonstrate that the adverse effect occurred after
causality of events the initiation of the medication.
The biologic Understanding the mechanism by which a drug induces an adverse effect
plausibility of is helpful in establishing a causal relationship. However, biologic
the association plausibility is not necessary to establish causation.
Dose response Evidence that a higher dose of a medication is associated with a higher
rate of the adverse event provides compelling evidence of a causal
relationship.
Strength of Analytic studies are more compelling then descriptive studies. Randomized
study design controlled trials are the gold standard for assessing causality. However,
RCT have important limitations for studying safety endpoints (as
described above) and are often impractical.
Strength of High relative risks or odds ratios (e.g. >2 or 3) from cohort studies or
association case–control studies provide more compelling information in support of a
causal relationship.
Consistency Multiple studies with similar findings provides information supporting a
with other causal relationship.
studies
Summary
Tremendous progress has been made in the pharmaceutical treatment of dermatologic disorders. In recent
years we have seen an explosion of new topical and systemic medications that can dramatically improve the
quality of life of patients living with skin disease. As a result, more patients than ever are being treated with
medications on a long-term basis for diseases that are not life-threatening or do not have a risk of permanent
disability. Therefore, the principles of pharmacovigilance are particularly relevant to the current practice of
dermatology. As new safety information becomes available, prescribers need to consider the scienti/c
validity and limitations of such information and the potential risk versus bene/t in making treatment
decisions with the patient.
Common abbreviations used in this chapter
AERS Adverse Events Reporting System
COX-2 Cyclooxygenase-2
FDA Food and Drug Administration
PML Progressive multifocal leukoencephalopathy
RCT Randomized controlled trial(s)
Bibliography: important reviews and chapters
Hennekens CH, Buring JE. Epidemiology in Medicine, Chapter 6. Little, Brown and Company; 1987.
Rothman KJ, Greenland S. Case control studies. Rothman KJ, ed. Modern epidemiology, 2nd ed, Philadelphia:PA Lippincott-Raven, 1998.
Strom B, ed. Pharmacoepidemiology. New York: John Wiley and Sons, Ltd, 2000.
Web references
History of drug safety: principle #1
1 World Health Organization. The importance of pharmacovigilance: safety monitoring of medicinal products.
Geneva: WHO Uppsala Monitoring centre; 2002.
2 Routledge P. 150 years of pharmacovigilance. Lancet. 1998;351(9110):1200–1201.
3 Offit P. The Cutter incident, 50 years later. N Engl J Med. 2005;352(14):1411–1412.
4 Stern R, Nijsten T, Njisten T. Insuring rapid and robust safety assessment. J Invest Dermatol. 2004
Mar;122(3):857–858.
5 Stern R, Nichols K, Väkevä L. Malignant melanoma in patients treated for psoriasis with methoxsalen
(psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. N Engl J Med.
1997;336(15):1041–1045.
6 Tsintis P, La Mache E. CIOMS and ICH initiatives in pharmacovigilance and risk management: overview and
implications. Drug Saf. 2004;27(8):509–517.
7 Seminara N, Gelfand J. Assessing long-term drug safety: lessons (re) learned from Raptiva. Semin Cutan Med
Surg. 2010;29(1):16–19.
Categorization of adverse reactions: principle #2 (no references)
Preclinical trials: principle #3
8 Naldi L, Svensson A, Diepgen T, et al. Randomized clinical trials for psoriasis 1977-2000: the EDEN survey. J
Invest Dermatol. 2003;120(5):738–741.
9 Khong TK, Singer DR. Adverse drug reactions: current issues and strategies for prevention and management.
Expert Opin Pharmacother. 2002;3(9):1289–1300.
Statistical power to detect rare adverse event: principle #4
10 Okie S. Safety in numbers–monitoring risk in approved drugs. N Engl J Med. 2005;352(12):1173–1176.
11 Paul C, Ho V, McGeown C, et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y
cohort study. J Invest Dermatol. 2003;120(2):211–216.
Public health importance rare adverse events: principle #5
12 Gandhi TK, Weingart SN, Borus J, et al. Adverse drug events in ambulatory care. N Engl J Med.
2003;348(16):1556–1564.
13 Strom B. What is Pharmacoepidemiology. In: Strom B, ed. Pharmacoepidemiology. New York: John Wiley and
Sons, LTD; 2000:3–16.
14 Psaty BM, Furberg CD. COX-2 inhibitors–lessons in drug safety. N Engl J Med. 2005;352(11):1133–1135.
15 Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in
patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs:
nested case-control study. Lancet. 2005;365(9458):475–481.
Safety issues remainig after drug approval: principle #6
16 Olsson S. The role of the WHO programme on International Drug Monitoring in coordinating worldwide
drug safety efforts. Drug Saf. 1998;19(1):1–10.
17 Venning GR. Identification of adverse reactions to new drugs. II (continued): How were 18 important
adverse reactions discovered and with what delays? Br Med J (Clin Res Ed). 1983;286(6362):365–368.
18 Rodriguez EM, Staffa JA, Graham DJ. The role of databases in drug postmarketing surveillance.
Pharmacoepidemiol Drug Saf. 2001;10(5):407–410.
19 Kennedy DL, Goldman SA, Lillie RB. Spontaneous Reporting in the United States. In: Strom B, ed.
Pharmacoepidemiology. New York: John Wiley and Sons, Ltd; 2000:151–174.
Drug safety signals: principle #7
20 Meyboom RH, Egberts AC, Edwards IR, et al. Principles of signal detection in pharmacovigilance. Drug Saf.
1997;16(6):355–365.
21 Hauben M. A brief primer on automated signal detection. Ann Pharmacother. 2003:37. (7-8):1117–23
22 Begaud B, Moride Y, Tubert-Bitter P, et al. False-positives in spontaneous reporting: should we worry aboutthem? Br J Clin Pharmacol. 1994;38(5):401–404.
23 Arnaiz JA, Carne X, Riba N, et al. The use of evidence in pharmacovigilance. Case reports as the reference
source for drug withdrawals. Eur J Clin Pharmacol. 2001;57(1):89–91.
Assessing drug causation: principle #8
24 Etminan M, Samii A. Pharmacoepidemiology I: a review of pharmacoepidemiologic study designs.
Pharmacotherapy. 2004;24(8):964–969.
25 Barzilai DA, Freiman A, Dellavalle RP, et al. Dermatoepidemiology. J Am Acad Dermatol. 2005;52(4):559–
573.
26 Psaty B, Charo R. FDA responds to institute of medicine drug safety recommendations–in part. JAMA.
2007;297(17):1917–1920.
27 Schultz W. Bolstering the FDA’s drug-safety authority. N Engl J Med. 2007;357(22):2217–2219.
28 Kapoor R, Hoffstad O, Bilker W, Margolis D. The frequency and intensity of topical pimecrolimus treatment
in children with physician-confirmed mild to moderate atopic dermatitis. Pediatr Dermatol. 2009;26(6):682–
687.
29 Hennekens C, Demets D. The need for large-scale randomized evidence without undue emphasis on small
trials, meta-analyses, or subgroup analyses. JAMA. 2009;302(21):2361–2362.
References*
1 World Health Organization. The importance of pharmacovigilance: safety monitoring of medicinal products.
Geneva: WHO Uppsala Monitoring centre; 2002.
3 Offit P. The Cutter incident, 50 years later. N Engl J Med. 2005;352(14):1411. about 1 of these 5 actually
reaches the market after FDA approval (Table 58-2)2
4 Stern R, Nijsten T, Njisten T. Insuring rapid and robust safety assessment. J Invest Dermatol. 2004
Mar;122(3):857. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)8
6 Tsintis P, La Mache E. CIOMS and ICH initiatives in pharmacovigilance and risk management: overview and
implications. Drug Saf. 2004;27(8):509. about 1 of these 5 actually reaches the market after FDA approval
(Table 58-2)17
7 Seminara N, Gelfand J. Assessing long-term drug safety: lessons (re) learned from Raptiva. Semin Cutan Med
Surg. 2010;29(1):16–19.
9 Khong TK, Singer DR. Adverse drug reactions: current issues and strategies for prevention and management.
Expert Opin Pharmacother. 2002;3(9):1289. about 1 of these 5 actually reaches the market after FDA
approval (Table 58-2)300
10 Okie S. Safety in numbers–monitoring risk in approved drugs. N Engl J Med. 2005;352(12):1173. about 1 of
these 5 actually reaches the market after FDA approval (Table 58-2)6
11 Paul C, Ho V, McGeown C, et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y
cohort study. J Invest Dermatol. 2003;120(2):211. about 1 of these 5 actually reaches the market after FDA
approval (Table 58-2)6
12 Gandhi TK, Weingart SN, Borus J, et al. Adverse drug events in ambulatory care. N Engl J Med.
2003;348(16):1556–1564.
14 Psaty BM, Furberg CD. COX-2 inhibitors–lessons in drug safety. N Engl J Med. 2005;352(11):1133. about 1
of these 5 actually reaches the market after FDA approval (Table 58-2)5
17 Venning GR. Identification of adverse reactions to new drugs. II (continued): How were 18 important
adverse reactions discovered and with what delays? Br Med J (Clin Res Ed). 1983;286(6362):365. about 1 of
these 5 actually reaches the market after FDA approval (Table 58-2)8
19 Kennedy DL, Goldman SA, Lillie RB. Spontaneous Reporting in the United States. In: Strom B, ed.
Pharmacoepidemiology. New York: John Wiley and Sons, LTD; 2000:151. about 1 of these 5 actually reaches
the market after FDA approval (Table 58-2)74
20 Meyboom RH, Egberts AC, Edwards IR, et al. Principles of signal detection in pharmacovigilance. Drug Saf.
1997;16(6):355. about 1 of these 5 actually reaches the market after FDA approval (Table 58-2)65
24 Etminan M, Samii A. Pharmacoepidemiology I: a review of pharmacoepidemiologic study designs.
Pharmacotherapy. 2004;24(8):964. about 1 of these 5 actually reaches the market after FDA approval (Table
58-2)9
29 Hennekens C, Demets D. The need for large-scale randomized evidence without undue emphasis on small
trials, meta-analyses, or subgroup analyses. JAMA. 2009;302(21):2361. about 1 of these 5 actually reaches
the market after FDA approval (Table 58-2)2
* Only a selection of references are printed here. All other references in the reference list are availableonline at www.expertconsult.com.









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7
Drugs taken off the market
important lessons learned
Stephen E. Wolverton, Susan J. Walker
Questions
Q7-1 Concerning product labeling for a speci c drug, (a) what are the 4 components of the ‘label’, (b)
what is the purpose of the label, and (c) what are ways that some exibility is built into the process?
(Pg. 54)
Q7-2 What is the individual purpose of each of following sections of the product label: (a) clinical studies,
(b) adverse reactions, (c) warnings and precautions, and (d) contraindications? (Pgs. 54, 55)
Q7-3 How are the strongest possible warnings and strategies concerning drug risks communicated through
(a) boxed warnings, and (b) risk evaluation and mitigation strategies (REMS)? (Pg. 55)
Q7-4 Concerning ‘Elements to Assure Safe Use’ strategies, what is (a) the purpose of these strategies with
respect to REMS, and (b) a specific example pertinent to the daily practice of dermatology? (Pg. 55)
Q7-5 How do the concepts of ‘signals’ and ‘labeling changes’ relate to FDA Adverse Events Reports? (Pg.
55)
Q7-6 What are 5–6 of the online sources for ‘electronic’ information from the FDA concerning drug safety
information? (Pg. 55)
Q7-7 What are several of the most important issues that the FDA may consider regarding a potential drug
withdrawal? (Pg. 56)
Q7-8 What are several of drugs of potential central or peripheral signi cance to dermatology that have
been taken o8 the market in association with (a) liver toxicity (Table 7-1), (b) cardiac arrhythmias
(Table 7-2), (c) other cardiovascular toxicity (Table 7-3), and (d) neurologic toxicity (Table 7-4)?
Q7-9 What ‘lessons’ can be ‘learned’ from issues leading to drug withdrawal of products listed in the above
4 tables. (See ‘Principles’ #1 through #13 starting Pg. 56)
Introduction
The goal of drug development is to provide safe and e8ective pharmaceutical products for use in the
treatment of clinical diseases and conditions. The vast majority of approved drug products remain on the
market, with routine revisions to labeling as needed. In some instances new safety information may provide
a basis for signi cant safety labeling changes or considerations for market withdrawal. This chapter will
focus on tools that can be used to communicate risk and bene t, and provide examples of products whose
risks were considered to outweigh the benefits.
Q7-1 Product (drug) labeling (including the physician package insert, patient package insert,
carton/container labeling, medication guide) is a summary of the essential scienti c information needed for
the safe and e8ective use of the drug. The approval of original New Drug Applications (NDA) and Biologics
Licensing Applications (BLA) results in product labeling intended to de ne and describe the conditions
under which the product has been determined to be safe and e8ective, with the bene ts outweighing the
risks. This original labeling provides a baseline for continued risk management activities for the product. As
new indications are proposed for marketing approval, or as new safety information becomes known, the
risks and bene ts of the product may change. Drug product labeling is dynamic and intended to be
amended via supplemental labeling applications that keep abreast of new safety and eC cacy information.
This capacity for labeling changes allows new information regarding product risks and bene ts to be
provided for physicians and patients.
Presentation of benefit–risk in labeling
Product labeling describes the conditions under which a product has been determined to be ‘safe and
e8ective:’ in other words, it describes the conditions under which the product has been determined to
provide a reasonable balance of risks and bene ts. Although considerations of risk–bene t assessment are
ultimately informed by the totality of available information, product labeling provides safety information in

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discrete sections with levels of interest. Q7-2 The Clinical Studies section contains primarily eC cacy
information describing the adequate and well-controlled studies that provided the primary support for
e8ectiveness, including the study design and eC cacy outcomes, without an emphasis on safety information.
T he Adverse Reactions section is intended to contain information that would be useful to healthcare
providers making treatment decisions, monitoring and advising patients, including adverse events where a
causal relationship exists, and also rare serious reactions unusual in the absence of drug therapy. Exhaustive
lists of every reported adverse event, including those not plausibly related to drug therapy, are not
considered relevant in this section, as such lists are not informative and tend to obscure more clinically
meaningful information. Warnings and Precautions sections include adverse reactions that are serious or
otherwise clinically signi cant relevant to the indication, events that may require discontinuation of the
drug or dosage adjustment, or may interfere with a laboratory test. Unobserved yet expected adverse
reactions based on pharmacology, chemistry or animal data or related to unapproved uses may be included
in this section.
Q7-2 The Contraindications section describes instances in which risks clearly outweigh any possible
benefit and is intended to capture known hazards only, not theoretical possibilities.
Q7-3 Two additional instruments, the ‘Boxed Warning’ and a Risk Evaluation and Mitigation Strategy
(REMS), may be implemented to address a safety concern. Certain contraindications or serious warnings,
particularly those that may lead to death or serious injury, may be required to be presented in a boxed
warning. The Boxed Warning (traditionally known as a ‘black box warning’) ordinarily must be based on
clinical data, but serious animal toxicity may also be the basis of a boxed warning in the absence of clinical
1data. This warning is intended to highlight for prescribers an event that is (1) so serious with regard to the
potential bene t from the drug (i.e. a fatal, life-threatening or permanently disabling adverse reaction) that
it is essential that it be considered in assessing the risks and bene ts of using the drug; or (2) there is a
serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate use of the
drug (e.g., patient selection, careful monitoring, avoiding certain concomitant therapy, addition of another
drug or managing patients in a speci c manner, avoiding use in a speci c clinical situation). Boxed
Warnings may be updated as new information becomes available. In mid-2011 the FDA Adverse Event
Reporting System (AERS) database and published medical literature provided post-marketing information
on the tumor necrosis factor-α (TNF-α) blockers (in iximab, etanercept, adalimumab, certolizumab,
golimumab) to inform a revision of the Boxed Warning to include the risk of infection from the bacterial
pathogens Legionella and Listeria.
In some instances REMS may also be necessary to ensure that the bene ts of a drug outweigh the risks.
Q7-4 These programs (REMS) are intended to provide for continued availability of products that have been
determined to have signi cant risks that must be mitigated in order to continue marketing of the product.
Isotretinoin is marketed with a REMS, including Elements to Assure Safe Use (ETASU), implemented as the
iPledge program. A summary of Elements to Assure Safe Use may be required if a drug has been shown to be
e8ective but is associated with a serious adverse event, and can be approved only if, or would be withdrawn
unless, such elements are required as part of a strategy to mitigate the specific serious risk(s) listed in the
labeling of the product. Elements to Assure Safe Use may be required for approved products when an
assessment and Medication Guide, patient package insert, or communication plan are not suC cient to
mitigate these risks. The goals of the iPledge program are to (1) prevent fetal exposure to isotretinoin, and
(2) inform prescribers, pharmacists, and patients about isotretinoin serious risks and safe-use conditions.
Product label ‘lifecycle’ changes
In order to change existing labeling, the drug company submits a supplemental application to the FDA for
approval. There are various types of supplements, but generally these are either (1) eC cacy supplements
(intended to add a new indication for an already marketed product), or (2) safety/labeling supplements. An
applicant may submit labeling supplements for review at any time and without prior notification to the FDA;
2however, the FDA was recently given the authority to require safety-related labeling changes based on new
safety information (such as information derived from a clinical trial, adverse event report(s), peer-reviewed
literature, or other scienti c data)that becomes available after product approval. Q7-5 Adverse Events
Reports (spontaneous case reports) have proved to be a primary mechanism by which drug regulatory
agencies detect ‘signals’ regarding emerging post-marketing safety concerns. Generally, applicants will work
voluntarily with FDA to incorporate labeling changes related to new safety information, and the appropriate
labeling changes will be proposed by the application holder and approved by the agency. Important safety
information will be communicated to physicians and patients by the agency, and the FDA currently uses one
safety communication, the ‘Drug Safety Communication’, to provide the public with easy access to
important drug safety information. These communications also provide recommendations for action that can
be taken by patients or caregivers to avoid or minimize the potential for harm from a drug, and are issued
when FDA has information that would help doctors and patients make better treatment choices. This type of
communication is part of FDA e8orts to communicate early with the public when the agency is still








evaluating data and has not reached a conclusion. FDA shares information in the interest of informing
doctors and patients about the issues under review, and when FDA experts anticipate completing their
review. Prior to ordering a safety labeling change, FDA would generally form a multidisciplinary team to
evaluate the information. If the safety information is relevant to more than one member of a drug class, the
a8ected class would be identi ed and the review sta8 in all relevant review divisions and oC ces would
participate. Team discussions and evaluations of new safety information may include internal FDA meetings,
Drug Safety Oversight Board, or FDA Advisory Committee meetings. Public meetings and safety
communication venues are used by FDA to outline available data, obtain public input, and explain the FDA
decision-making process.
RISKS AND BENEFITS: FDA safety information
Q7-6 FDA provides information regarding drug safety in multiple venues. Some examples of physician and
patient communications for drug safety information include:
31. An online ‘Index to Drug Speci c Information’ includes only drugs that have been the subject of a
Drug Safety Communication or equivalent (previously known as Early Communication/Health Care
Professional Information Sheet), and provides direct access to the content of each communication.
42 . MedWatch Alerts contain actionable information that may a8ect both treatment and diagnostic
3choices and provide timely medical product information. The MedWatch gateway provides
opportunities to sign up for MedWatch email updates, subscribe to RSS Feed safety alerts, and follow
MedWatch on Twitter.
53. Daily Med, a website developed with the National Library of Medicine, gives physicians and patients
electronic access to FDA-approved drug labels. The presentation includes a ‘tabbed’ format, providing
quick access to speci c portions of product labeling, including reproductions of the carton and
container.
64. Drugs@FDA , an online database of approved drug products, allows a search for information regarding
drugs and biologic products by drug name or active ingredient. Electronic links to the product approval
history, approval letters, reviews and related documents, labeling information, REMS information and
medication guides are provided.
5. Complete transcripts of FDA Advisory Committee meetings, and schedules of upcoming meetings and
7agendas, are available online.
6. Please also see the Bibliography for various links for additional drug safety information.
8The Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC) is convened to obtain
independent expert advice on scienti c, technical and policy matters. The committee convenes to discuss
approval of new molecular entities proposed for use in dermatology, and has provided substantial input and
advice concerning risk management programs for isotretinoin and thalidomide.
Drug withdrawal
In rare cases FDA may need to reassess and change its approval decision on a drug. A conclusion that a drug
should no longer be marketed is based on the nature and frequency of the adverse events and how the drug’s
risk–bene t balance compares with treatment alternatives. Considerations regarding risk may include
assessments of whether the bene ts outweigh the risks for some de ned population, and whether this can be
addressed in labeling. Q7-7 Discussions concerning risk–bene t and the decision to keep a drug on the
market could include:
• What is the magnitude of the benefit compared to known therapy or to alternatives?
• Does the drug add to existing therapy?
• Is there a subgroup of high responders?
• Is the product effective for patients who failed other therapies?
• Is the product tolerated by patients who cannot tolerate other treatments?
• Is there a substantial convenience factor (frequency, dosage, administration)?
When FDA believes that a drug’s bene ts no longer outweigh its risks, the agency will ask the
manufacturer to withdraw the drug. Q7-8 Specific examples of drugs withdrawn and the associated category
of complication are given in Tables 7-1 through 7-4.Table 7-1 Drugs off the market – liver toxicity
Table 7-2 Drugs off the market – cardiac arrhythmias (torsades de pointes)
Table 7-3 Drugs off the market – other cardiovascular adverse events
Table 7-4 Drugs off the market – (neurologic) progressive multifocal leukoencephalopathy>
>


General principles concerning drug withdrawal decisions Q7-9
Principle #1
At times, the FDA (or a similar agency is other countries) mandates a drug removal; in other
circumstances the pharmaceutical company (sponsor) undertakes voluntary drug withdrawal.
• Mandated withdrawal by FDA – rofecoxib (Vioxx)
• Voluntary withdrawal by pharmaceutical company – valdecoxib (Bextra), efalizumab (Raptiva).
Principle #2
At times drugs taken off the market are a ‘business decision’ by the pharmaceutical company:
• Valdecoxib (Bextra) was voluntarily ‘taken o8’ the market even though the FDA Drug Advisory
Committee involved voted to allow the drug to stay on the market.
• Celecoxib (Celebrex; produced by the same pharmaceutical company as Bextra) stayed on the market;
this drug is a less selective COX-2 inhibitor with less thrombosis risk.
• Within a company, decisions may include re-evaluation of the portfolio, considering future potential
medicolegal risks, market competitors and related expenses; two examples include the above decision,
as well as the recent decision to take the original brand name isotretinoin (Accutane) off the market.
Principle #3
New drugs which are safer and/or more e=cacious than a prior drug in the same drug category
may prompt the previous drug with significant risks to be taken off market:
• Once pioglitazone and rosiglitazone were released as suitable ‘alternatives’, troglitazone was promptly
taken o8 market because of signi cant liver toxicity; these drugs were all thiazolidinediones (‘insulin
sensitizers’).
• In contrast, isotretinoin provides unique eC cacy in the treatment of severe nodular acne vulgaris and
remains on the market, at least partly because no suitable ‘alternative’ is available.
Principle #4
In general, clinicians must ‘learn from history’ for drugs in same group as the drug taken o the
market; issues to emphasize include (1) improved patient selection, (2) drug interactions to avoid,
and (3) improved monitoring guidelines.
• FDA communications concerning terfenadine and astemizole prior to withdrawal from the market
emphasized the need for clinicians to avoid combining the above medications with ketoconazole or
erythromycin (among others), which increased the risk of torsades de pointes.
• In general, physicians need to markedly improve awareness and cooperation with strong FDA suggestions
such as the above to minimize patient risk and preserve the availability of various drugs, including
similar warnings with drugs currently available.
Medical principles – specific examples
Principle #5
Not all drugs in a given class have similar risk profiles:
• Statins – cerivastatin off market; others in this drug group have a much lower risk of rhabdomyolysis.
• Second-generation antihistamines – terfenadine, astemizole were taken o8 the market due to torsades de
pointes; all remaining second-generation H antihistamines lack signi cant QT prolongation and have1
no significant risk for torsades de pointes.
Principle #6 (CYP = cytochrome P-450)
Concerning any drug with the potential to prolong the QT interval, clinicians should be very
cautious about potential drug interactions; examples are listed below involving these CYP3A4
substrates, which were taken o the market due to torsades de pointes, and the CYP3A4 inhibitors
which were commonly involved in these life-threatening interactions:
• CYP3A4 substrates – terfenadine, astemizole, cisapride
• CYP3A4 inhibitors – erythromycin, clarithromycin, ketoconazole, itraconazole.H

>

Principle #7
Any drug which upon release has at least 3–5% of patients in clinical trials with ‘minor, transient
transaminase elevations’ should be followed very carefully from a liver toxicity standpoint; some
examples of this principle that were taken off the market for liver toxicity include:
• Troglitazone
• Trovafloxacin (very limited availability).
Principle #8
Be very cautious with a drug which has a risk for toxicity involving a target organ in patients with
abnormality in that target organ at baseline:
• Cerivastatin – risk of rhabdomyolysis was much greater with pre-existing renal disease.
Principle #9
Be cautious with aggressive dosing regimens when dose relationships to high-risk adverse e ects
have been established:
• A recent example limiting the maximum dose to 40 mg is for atorvastatin (prior maximum dose 80 mg)
in order to minimize the risk of rhabdomyolysis which is more common with the prior maximum dose.
Principle #10
Strong CYP enzyme inducers or inhibitors frequently have a greater risk of liver toxicity:
• CYP inducers – troglitazone and rifampin
• CYP inhibitor – ketoconazole innately with a signi cant risk for liver toxicity (independent of drug
interactions).
Principle #11
Drugs may need to have strategies to mitigate risk in order to be allowed on the market or to stay
on the market:
• A drug that was previously taken o8 the market was reintroduced under a special distribution program –
natalizumab (for multiple sclerosis).
• Original US approval included risk management strategy – thalidomide.
• REMS intended to minimize teratogenicity risk (prevent fetal exposure and inform providers) –
isotretinoin.
• Still available, but on a very limited basis – trovafloxacin.
Medical principles – general issues
Principle #12
We recommend using a new drug gradually until the ‘real world’ risks are clari ed over the next
few years:
• Drugs with risks that occur in 1 in 1000 patients or less are commonly not detected in premarketing
clinical trials.
• Highly ‘controlled’ nature of preclinical trials may limit potential drug interactions, liver or kidney
abnormalities.
• With the above realities in mind, many important signi cant drug risks are not detected until at least 2–
3 years later, when use of the drug is widespread and ‘uncontrolled.’
Principle #13
Pay very careful attention to the following publications by FDA:
• Drug Safety Communications give strong ‘advice’ on potential drug interactions, patient selection, and
monitoring required; such communications may precede drug withdrawal.
• Risk Evaluation and Mitigation Strategies (REMS); widespread clinician attention to details in these
programs may allow specific drugs to stay on the market.Abbreviations used in this chapter
AERS Adverse Event Reporting System
BLA Biologics Licensing Applications
COX-2 Cyclo-oxygenase 2
CYP Cytochrome P-450
DODAC Dermatologic and Ophthalmic Drugs Advisory Committee
ETASU Elements to Assure Safe Use
NDA New Drug Applications
NSAID Nonsteroidal anti-inflammatory drug(s)
REMS Risk Evaluation and Mitigation Strategy
TNF-α Tumor necrosis factor-alpha
Bibliography: important reviews and websites for supplemental information
General information link
FDA ‘Guidance for Industry’ www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
Specific links
Guidance for Industry: Warnings and Precautions, Contraindications, Boxed Warnings. Available at
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM075096.pdf,
October 2011.
Guidance for Industry: Safety Labeling Changes (FDAAA). Available at
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM250783.pdf,
October 2011.
Guidance for Industry: Adverse Reactions Section: Labeling. Available at
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM075057.pdf,
October 2011.
Guidance for Industry – Risk Evaluation and Mitigation Strategies. Available at
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf,
October 2011.
Link to list of approved risk evaluation and mitigation strategies
www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm,
October 2011.
Reviews
Issa AM. Drug withdrawals in the United States: a systematic review of the evidence and analysis of trends.
Curr Drug Saf. 2007;2:177–185.
Temple RJ, Himmel MH. Safety of newly approved drugs. JAMA. 2002;287(17):2273–2275.
Wysowski DK, Swartz L. Adverse drug event surveillance and drug withdrawals in the United States, 1969–
2002. Arch Intern Med. 2005;165:1363–1369.
References
1 21 CFR 201.57(c)(1)
2 Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(o)(4)) added by
section 901 of the Food and Drug Administration Amendments Act of 2007 (FDAAA)
3
www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111085.htm.
4 www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/.
5 dailymed.nlm.nih.gov/dailymed/about.cfm.6 Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.
7 www.fda.gov/AdvisoryCommittees.
8 www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs.Part III
Systemic Drugs for Infectious
Diseases


8
Systemic Antibacterial Agents
Susun Kim, Brent D. Michaels, Grace K. Kim, James Q. Del Rosso
Questions
Q8-1 What are some dermatologic indications of antibiotic use in chronic in ammatory skin disorders,
based on their anti-inflammatory properties? (Pgs. 61, 81x3)
Q8-2 Which antibiotic classes have signi cant alterations in bioavailability due to foods and divalent
cations? (Pgs. 63, 66, 75, 76, 79x2, 88, 90)
Q8-3 Which members of the penicillin family of drugs most frequently induce hypersensitivity reactions?
(Pgs. 63, 64)
Q8-4 What are some of the drugs with the potential for a cross-reaction in patients allergic to penicillins,
and what is the true risk (frequency and magnitude) of such cross-reactions? (Pgs. 64, 67, 68, 69x2)
Q8-5 What are antibacterial agents with a risk of antibiotic-associated colitis due to Clostridium di cile?
(Pgs. 64, 67, 89, 92, 94x2)
Q8-6 What two drugs discussed in this chapter can induce a serum sickness-like reaction? (Pgs. 67, 84)
Q8-7 What are 3–4 of the mechanisms by which bacteria develop resistance to antibacterial agents? (Pgs.
69x2, 78, 88, 93, 95)
Q8-8 What are 2 relatively unique cutaneous ‘hypersensitivity’ reactions to vancomycin? (Pg. 69)
Q8-9 Which drugs/drug groups mechanism is to interfere with bacterial ribosome subunits (a) 30S, (b)
50S, and (c) 23S portion of the 50S subunit? (Pgs. 70, 77, 93, 94, 95x2)
Q8-10 What are several antibiotic classes with signi cant anti-in ammatory activity, and what are
several of the mechanisms for this anti-inflammatory activity? (Pgs. 70, 77, 78)
Q8-11 Concerning macrolides and azalides, what are some important di3erences in (a) infections most
effectively treated, and (b) CYP–drug interactions? (Pgs. 71x3, 72)
Q8-12 What are several of the bacterial enzymes inhibited by antibacterial agents discussed in this
chapter? (Pgs. 75, 87, 92)
Q8-13 Concerning community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections,
what are (a) several of the best oral antibiotic choices, and (b) several antibiotics with a trend towards
increasing resistance? (Pgs. 75, 81, 88, 89, 92, 93, 94, 95)
Q8-14 Which drugs discussed in this chapter are most likely to induce photosensitivity reactions? (Pgs. 76,
83)
Q8-15 What are several relatively unique hypersensitivity and autoimmune reactions due to minocycline?
(Pgs. 84x2, 85)
Q8-16 Which two drug groups discussed in this chapter are listed as pregnancy category D? (Pgs. 85, 95)
Q8-17 What is the scienti c basis for various antibacterial groups possibly reducing the e3ectiveness of
hormonal contraceptives? (Pgs. 85, 90)
Introduction
Systemic antimicrobial agents, especially antibiotics, play a vital role in dermatology, with oral antibiotic
prescriptions estimated to represent approximately 20% of all prescriptions written by dermatologists
1–5annually in the outpatient setting. Dermatologists in ambulatory practice in the United States (US)
accounted for approximately 8–9 million oral antibiotic prescriptions per year over the period 2001–2005,
and at least 5 million oral antibiotic prescriptions written annually by dermatologists have been attributed
1,5to acne vulgaris treatment. As a basis for comparison, the total number of oral antibiotic prescriptions
written by all physician specialties in the US was approximately 250 million per year between 2001 and
12005, predominantly for treatment of infectious disorders. The chronic use of this drug category raises
potential concerns about the emergence of resistant bacterial strains, sometimes with the development of
1,4,5cross-resistance among antibiotics.
Q8-1 In addition to their antibacterial properties, many antibiotic agents, such as tetracycline and
macrolide groups, possess signi cant anti-in ammatory activities which have led to their use for the@

@
2,3treatment of both infectious and non-infectious skin diseases. The biologic e3ects of several antibiotics,
unrelated to their antibiotic or antimicrobial properties, appear to correlate at least partially with their
1,2e cacy in the treatment of in ammatory dermatoses, including acne vulgaris and rosacea. Owing to the
increased prevalence of uncomplicated skin and soft tissue infections (USSTI) caused by
communityacquired methicillin-resistant Staphylococcus aureus (CA-MRSA), the overall pattern of oral antibiotic use in
outpatient dermatology practices has evolved. Such changes in prescribing patterns have been characterized
by increased use of doxycycline, minocycline (immediate-release formulations), and
trimethoprimsulfamethoxazole, and a decrease in the use of oral cephalosporin therapy owing to higher rates of CA-MRSA
1,4–8infection.
Rational antibiotic selection for dermatologic disorders warrants consideration of multiple important
factors to optimize both therapeutic outcome and safety. These factors include:
1. Host-related properties (age, comorbidities, allergy status, pregnancy status, breastfeeding status);
2. Nature of the disease state to be treated (infection vs. inflammatory disease, severity, affected sites);
3. Microbiologic factors if applicable (suspected or con rmed pathogen, virulence, antibiotic sensitivity
and resistance profiles);
4. Applicable antibiotic options (efficacy, adverse reactions, drug interactions);
5 . Antibiotic-speci c pharmacokinetic (PK) properties (route of administrations, oral formulation
differences, sites of infection); and
6. Additionally, speci c adverse reactions to some antibiotics may be more common and more severe in
9immunocompromised patients.
This chapter emphasizes the oral antibacterial agents used primarily for skin and soft tissue infections,
with reference to use in inflammatory dermatoses such as acne vulgaris and rosacea, where applicable.
Penicillins
Penicillin G (benzylpenicillin) is produced naturally by the fungus Penicillium chrysogenum. Subsequent to
the discovery in 1928 of penicillin G, many semi-synthetic penicillins have been developed (Table 8-1). The
rst advance was the development of penicillin V (phenoxymethyl penicillin), which is more stable in the
presence of gastric acid and is better absorbed from the gastrointestinal (GI) tract than penicillin G. The
safety and e cacy of the penicillins have been established overall in the pediatric population (Table 8-1).
The penicillins are rated as category B for use in pregnancy, and penicillin G should be used with caution
11during lactation, as the excretion of low concentrations of penicillins in breast milk has been reported.
12Sensitization of infants has been associated with ampicillin use in nursing mothers.
Table 8-1 Currently available FDA-approved penicillinsPharmacology
Antimicrobial activity
Both penicillin G and penicillin V are categorized as natural rst-generation penicillins. Although penicillin
V generally exhibits lower antibacterial potency than penicillin G, both agents share the same antimicrobial
spectrum against Gram-positive cocci and rods, Gram-negative cocci, and anaerobes. Importantly,
methicillin-sensitive S. aureus (MSSA) and MRSA are almost uniformly resistant to penicillin G and penicillin
5,7V.
10Subsequent generations of penicillins include:
1 . Penicillinase-resistant first-generation penicillins (isoxazolyl penicillins), including the oral agents
dicloxacillin and oxacillin (related to parenteral methicillin), exhibit activity against most strains of
MSSA and other Gram-positive cocci, but MRSA developed subsequently.
2 . Extension of the antimicrobial spectrum of penicillins which includes inhibition of Gram-negative
bacilli is seen with the second-generation agents (aminopenicillins), ampicillin and amoxicillin, which
may be administered orally, and
3 . The third-generation extended-spectrum penicillins (carboxypenicillins) such as carbenicillin, and the
fourth-generation penicillins (ureidopenicillins) such as piperacillin, are both parenteral and exhibit
antipseudomonal activity (piperacillin > carbenicillin), especially when combined with an aminoglycoside
antibiotic.
Unfortunately, hydrolysis by β-lactamases renders these drugs ine3ective against S. aureus or the many
10Enterobacteriaceae species that produce β-lactamases. In addition, some β-lactams have been combined
with a β-lactamase inhibitor to produce resistance of the antibiotic to degradation by β-lactamase (see
10section on β-lactamase and β-lactamase inhibitor combinations).
Pharmacokinetics
Of the β-lactamase-resistant penicillins available for oral use, dicloxacillin exhibits very favorable
pharmacologic and pharmacokinetic (PK) properties. It can be given in doses exceeding 4 g daily; however,
a dose of 2 g daily is easily adequate for the majority of staphylococcal pyodermas not caused by MRSA.
Q82 Because of its vulnerability to gastric acid degradation, GI absorption is optimized by administration 1 h
10before or after a meal. Of the aminopenicillins, amoxicillin is superior to ampicillin, exhibiting greater GI@
@
absorption, a lower incidence of diarrhea, and comparable e cacy. Amoxicillin can also be taken with
10food. The elimination half-lives for most penicillins are short (<_1.5c2a0_h29_. all="" _ceb2_-lactams=""
are="" excreted="" renally="" with="" the="" exception="" of="" _nafcillin2c_="" _oxacillin2c_=""
10and="" _piperacillin2c_="" which="" eliminated="" predominantly="" through="" biliary="">
Clinical use
Dermatologic uses (Table 8-2)
Antibacterial indications
Isoxazolyl penicillins show good coverage for Streptococcus pyogenes and MSSA, and may be used for a wide
range of uncomplicated skin infections, including erysipelas, cellulitis, impetigo, folliculitis, furunculosis,
10bacterial paronychia, and ecthyma. Intramuscular (IM) penicillin administered weekly has been used
successfully to prophylactically inhibit recurrent erysipelas, with the risk of recurrence to pre-treatment
12levels after discontinuation of therapy. Parenterally administered nafcillin may be used in the
management of toxin-induced staphylococcal scalded skin syndrome. Some sexually transmitted diseases
(STD), such as syphilis and chlamydial infections, are susceptible to penicillins. Penicillins have also been
used for the treatment of erysipeloid, scarlatina, cutaneous anthrax, Lyme disease, actinomycosis, listeriosis,
10gas gangrene, gingivostomatosis, and leptospirosis (Weil’s disease). In the clinical setting, individual
selection among the penicillins is highly dependent on the diagnosis and causative organism, with
substantial variability of activity based on the drug chosen.
Table 8-2 Commonly used oral penicillins* – dosage guidelines
Generic name Tablet/capsule sizes (mg) Adult dosage
Amoxicillin 250, 400, 500, 875 500–875 mg bid†
Amoxicillin/clavulanate 250, 500, 875, 1000 500–875 mg bid†
Ampicillin 250, 500 250–500 mg qid
Dicloxacillin 250, 500 125–500 mg qid‡
Oxacillin 250, 500 500–1000 mg
Q4–6h
Penicillin V 250, 500 250–500 mg qid
* All of the drugs in this table have either liquid or suspension formulations available.
† These two drugs can also be dosed at 250–500 mg tid.
‡ Dicloxacillin can also be dosed at 250–500 mg tid for uncomplicated skin infections.
Non-specific penicillin benefits
There are scant data for use of penicillins for their ‘non-speci c’ properties. Penicillin G has been used with
some success to treat dermal brosis in patients with circumscribed and systemic sclerosis, hypothesizing the
10role of Borrelia burgdorferi in the development of scleroderma. Penicillin has been used for pityriasis rubra
10pilaris, although its e cacy is questionable. The addition of benzanthine penicillin therapy (IM) once
every 3 weeks to colchicine therapy reduced the frequency of oral and genital aphthae and bene ted
erythema nodosum-like lesions in patients with Behçet’s disease compared to monotherapy with
14colchicine. A systematic review of the literature has concluded that there is no evidence that
15,16administration of anti-streptococcal antibiotics, including penicillins, improves guttate psoriasis.
Adverse effects
Hypersensitivity reactions
Q8-3 β-lactams are among the group of drugs that have been more commonly associated with drug-induced
17hypersensitivity reactions. The rst β -lactam reported to cause a hypersensitivity reaction was
17benzylpenicillin, with amoxicillin noted to be the most commonly implicated agent more recently. Not
surprisingly, hypersensitivity reactions are the most common diverse e3ects associated with penicillins, with@

"
18-21the severity of these reactions ranging from morbilliform eruptions to urticarial to fatal anaphylaxis. A
skin eruption that is not truly allergic in origin may arise when ampicillin is given to patients with infectious
mononucleosis or lymphocytic leukemia, and is also seen when ampicillin is co-administered with
allopurinol. The eruption is generalized, maculopapular, and pruritic, and typically manifests within 7–10
days after the initiation of the antibiotic, with usual persistence for up to 1 week after ampicillin is
discontinued. This unique ampicillin eruption is not believed to be a contraindication to treatment with
12other penicillins at a later date.
Cross-reaction potential
Q8-4 For practical purposes it should be assumed that all of the penicillins cross-react, and that if a patient
has a true allergic reaction to one form of penicillin they may react to all penicillins, and possibly to
22cephalosporins as well. Therefore, in patients with a history of severe and life-threatening allergic reaction
to a penicillin or cephalosporin, avoidance of the other drugs in these two general categories is advised.
Q83 The aminopenicillins appear to be associated with a higher incidence of allergic reactions than other
23penicillins. Intradermal testing with benzylpenicillin G and penicilloyl polylysine (Pre-Pen) may be
helpful. If an immediate cutaneous reaction does not occur on administration of penicillin, it is highly
unlikely that an immediate or accelerated reaction will occur. On the other hand, a positive reaction to
penicillin testing requires either the use of an alternative antibacterial agent or desensitization. It should be
noted that Pre-Pen (penicilloyl polylysine) was temporarily and voluntarily removed from the market in
2004; however, legal rights were subsequently obtained by Allerquest. According to the Allerquest website,
24,25Pre-Pen is now available on the market after full FDA approval in 2009.
Other important adverse effects
Q8-5 GI disturbances, including nausea and antibiotic-associated diarrhea are not uncommon, and C.
10difficile colitis can occur with use of penicillins. Yogurt or other means of Lactobacillus ingestion may be a
helpful adjuvant to prevent diarrhea-related complications due to alterations in normal gut ora. Other
untoward reactions to penicillins are unusual with oral penicillin forms. Hemolytic anemia, neutropenia,
platelet dysfunction, seizures, and electrolyte disturbances, when seen, are associated with very large doses
26given via parenteral formulations. Shore nails (transverse leukonychia and onychomadesis following
druginduced erythroderma) have been seen with dicloxacillin, and onychomadesis and photo-onycholysis have
27been noted following cloxacillin use. Cholestasis associated with β-lactams, including penicillins, is
28uncommon overall. Local skin reactions, phlebitis, myositis, and even vasospasm have been seen with
10parenteral and intramuscular formulations of penicillins.
Drug interactions
Few clinically signi cant drug interactions are noted with the penicillins. Probenecid prolongs the renal
excretion of penicillins. Oral antibiotics, including β-lactams, may potentially alter the anticoagulant e3ects
of warfarin, warranting closer monitoring of International Normalized Ratio (INR) values. The controversial
topic of whether or not oral antibiotics reduce the e cacy of oral contraceptives is reviewed below under
the Drug Interactions sections for both tetracyclines and rifamycins.
Dosage
Table 8-2 contains dosage guidelines for commonly used oral penicillins. It is suggested that infections with
β-hemolytic streptococci should be treated for 10 days because of possible complications such as acute
glomerulonephritis and rheumatic fever. Scarlatina (formerly known as scarlet fever) may be treated with a
10-day course of oral penicillin V or a single injection of benzanthine penicillin G. A single intramuscular
6injection of 2.4 × 10 U of penicillin G is used to treat primary or secondary syphilis, although latent
syphilis of more than 1 year (or of indeterminate) duration requires 3 weekly injections of this same dose.
For penicillin-susceptible Neisseria gonorrhoeae, one of the aminopenicillins may be given as single-dose
treatment (ampicillin 3.5 g or amoxicillin 3 g) along with probenecid. For other Gram-negative infections
such as Haemophilus in uenzae, ampicillin in daily doses of 2–4 g, divided into three or four doses, is given
with probenecid if higher blood levels are needed.
Cephalosporins
Cephalexin and many others
Most cephalosporins are antibiotics produced and derived as byproducts of the mold Cephalosporium
acremonium. Cephalosporins have a basic structural core consisting of a 4-membered β-lactam ring attached
to a 6-membered dihydrothiazine ring, and therefore are β-lactams. The two-ring combination gives the
29,30cephalosporin structure inherent resistance to β-lactamase enzymes. Penicillins, on the other hand,"
"
di3er from cephalosporins in that they are composed of a 5-membered thiazolidine ring. Most
cephalosporins, especially oral cephalosporins, are considered safe in children. Cephalosporins are generally
pregnancy category B, with a low likelihood of congenital malformations when used during the second and
11third trimesters. Caution is suggested in women who are breastfeeding, as the small quantities of
cephalosporins in breast milk have been associated with reports of diarrhea, candidal infections, and skin
11eruptions in the nursing infants.
Pharmacology
Antimicrobial activity
The cephalosporins have been grouped into ‘generations’ based on their general spectrum of antimicrobial
activity (Table 8-3). There are currently 5 generations of cephalosporins.
Table 8-3 Currently available FDA-approved cephalosporins
First generation
The rst-generation cephalosporins are the most active of all the cephalosporins against staphylococci and
non-enterococcal streptococci. Typically resistant organisms include MRSA, penicillin-resistant Streptococcus
30pneumonia, and Gram-negative organisms including H. in uenzae and enterococci. The rst-generation
cephalosporins are not indicated when Pseudomonas spp, Hemophilus in uenzae, and nosocomial
Gram30negative infections are present. They are active against many of the oral anaerobes, except the Bacteroides
fragilis group. The in vitro antibacterial spectrum among the rst-generation agents is almost identical, with@
@
"
30cefdinir likely to exhibit greater activity against MSSA.
Second generation
Second-generation cephalosporins in general demonstrate increased Gram-negative and decreased
Gram30positive activity overall. Individual agents vary greatly in their spectrum of activity. These agents are
often classi ed into two groups, (1) the true cephalosporins, and (2) the cephamycins (cefoxitin, cefotetan).
The true cephalosporins have increased activity against H. in uenzae, Moraxella catarrhalis, Neisseria
meningitidis, N. gonorrhoeae, and some Enterobacteriaceae. The cephamycins have inferior activity against
30staphylococci and streptococci, but are effective against strains of B. fragilis.
Third generation
Third-generation cephalosporins demonstrate less consistent activity against Gram-positive organisms and
31an increased spectrum of Gram-negative activity due to greater β-lactamase stability. Agents such as
ceftazidime, cefepime, and cefoperazone have antipseudomonal coverage. Cefditoren has a broad spectrum
of coverage, including against an assortment of Gram-positive and Gram-negative organisms, but does not
32provide activity against Pseudomonas aeruginosa. Ceftazidime has the greatest activity against
Pseudomonas aeruginosa, but is not active against S. aureus. Cefdinir has good coverage against both S.
30aureus and S. pyogenes, making this antibiotic effective for USSTI.
Fourth generation
Cefepime is the only fourth-generation cephalosporin approved in the US, is administered parenterally, and
has a broad antibacterial spectrum. Its coverage includes activity against MSSA and non-enterococcal
streptococci, as well as Gram-negative organisms including P. aeruginosa. Cefepime is not effective against B.
fragilis.
Fifth generation
There are two newer fth-generation cephalosporins: ceftobiprole, which is currently seeking FDA approval,
33and ceftaroline, which received FDA approval on October 29, 2010. Importantly, ceftaroline has shown
activity against multidrug-resistant S. aureus, including MRSA, vancomycin-intermediate S. aureus (VISA),
heteroresistant vancomycin-intermediate S. aureus, (hVISA), and vancomycin-resistant S. aureus (VRSA), in
34addition to MSSA and coagulase-negative staphylococci. Ceftaroline has shown weak coverage against
Pseudomonas spp. and is indicated for acute skin infections caused by S. aureus (including MRSA), S.
34pyogenes, S. agalactiae, E. coli and Klebsiella. Ceftobiprole has also shown activity against MRSA, in
addition to S. pneumoniae, Pseudomonas spp and enterococci.
On the horizon, a new antipseudomonal cephalosporin, CXA-101 (previously designated FR264205) has
been shown to have activity against carbapenem-resistant and multidrug-resistant P. aeruginosa clinical
35strains.
Pharmacokinetics
Q8-2 The absorption properties of the currently available cephalosporins vary greatly, with peak serum
30concentrations dependent on their administration in relation to food intake. Cefaclor, cefadroxil,
cephalexin, and cephradine are best absorbed from an empty stomach. Conversely, the bioavailability of
36cefuroxime axetil is increased when taken with food. First- and second-generation cephalosporins are
excreted primarily by the kidneys; thus, dosage adjustments are recommended for patients with signi cant
renal insu ciency. Cefoperazone and ceftriaxone undergo predominantly hepatic metabolism and
37excretion, so renal insu ciency does not generally necessitate dosage adjustments. The half-life of most
parenterally administered cephalosporins varies between 0.5 and 2 hours, although the 6–8-hour half-life of
ceftriaxone permits once-daily dosing. The newer fth-generation cephalosporin, ceftaroline, is administered
intravenously as the inactive prodrug, ceftraline fosamil, and is subsequently converted to the active
34,38metabolite, ceftaroline, with a short half-life of 0.19–0.43 hours and primarily renal excretion.
Clinical use
Dermatologic indications
Oral cephalosporins are used primarily in ambulatory dermatologic practice to treat USSTI such as impetigo,
folliculitis, furuncles, carbuncles, acute bacterial paronychia, cellulitis, ecthyma, erysipelas, and
postoperative wound infections. Severe infections such as complicated cellulitis and necrotizing fasciitis
30,37require intravenous antibacterial agents. Additional special uses of individual cephalosporins include
30selected STDs, diabetic foot infections and Lyme disease. See Table 8-3 for list of cephalosporins classi ed
by generation, and Table 8-4 for dosage guidelines for oral cephalosporins.@
"
(
Table 8-4 Commonly used oral cephalosporins – dosage guidelines
Generic name Tablet/capsule sizes* (mg) Adult dosage
First generation
Cefadroxil 500, 1000 500 mg to 1–2 g/day (qd or bid)
Cephalexin 250, 500 250–500 mg qid
Cephradine** 250, 500 250–500 mg qid
Second generation
Cefaclor† 250, 375‡, 500 250–500 mg tid
Cefprozil 250, 500 250–500 mg/day (qd or bid)
Cefuroxime axetil 125, 250, 500 250–500 mg bid
Loracarbef** 200, 400 200–400 mg bid
Third generation
Cefixime 200, 400 200 mg bid or 400 mg qd
Cefpodoxime proxetil 100, 200 100–400 mg bid
Ceftibuten 400 400 mg qd
* All of the drugs listed in this table have either liquid or suspension formulations available.
** These antibiotics are currently not available in the United States.
† For uncomplicated skin infections, cefaclor 500 mg bid has been used.
‡ Extended release formulation for 375-mg size of cefaclor.
First generation
The most commonly used rst-generation oral cephalosporin since its inception is cephalexin. It is indicated
for USSTI caused by MSSA and S. pyogenes. Although twice-daily dosing has been suggested, the short
halflife (≤1 h) may be associated with bacterial resistance. More frequent dosing, i.e., three to four times daily,
is generally recommended. Cefadroxil, another rst-generation cephalosporin, has a longer half-life and may
13be dosed twice daily.
Second generation
Second-generation agents have been e cacious in treating Gram-negative cellulitis caused by H. in uenzae
or Enterobacteriaceae. Both cefprozil and cefaclor are available in oral formulations. Cefuroxime axetil can
30,39be used to treat selective cases of Lyme borreliosis and gonorrhea.
Third generation
Third-generation cephalosporins have also been used in the treatment of soft tissue abscesses and diabetic
40foot ulcers. One of the newer oral cephalosporins in this generation, cefditoren, can also be used for
USSTI. A single intramuscular injection of ceftriaxone is an e3ective treatment for uncomplicated
gonorrhea, as are single oral doses of cefpodoxime and ce xime. Ceftriaxone may also be used for the
treatment of acute Lyme disease complicated by meningitis, as well as for the later stages of the disease.
Ceftazidime has been e3ective in the treatment of P. aeruginosa infections, including ecthyma gangrenosum,
40diabetic foot ulcers, and infections in burn patients. (Note: fourth-generation cefapime has no speci c
dermatologic clinical use.)
Fifth generation
Most recently, ceftaroline, a fth-generation agent, has been approved for the treatment of acute bacterial
34,38,41skin and skin structure infections, including those caused by MRSA. Additionally, ceftobiprole,
another fth-generation cephalosporin, has also shown promise for the treatment of skin and soft tissue
infections. However, although ceftobiprole is approved in Switzerland and Canada, it is still seeking FDA
42approval in the US for CSSTI, including diabetic foot infections. Ceftobiprole may be used as43,44monotherapy for the treatment of CSSTI that have required combination therapy in the past.
Adverse effects
Q8-5 GI toxicities are relatively frequent with cephalosporin use, presenting commonly as nausea, vomiting,
30,37or diarrhea. Antibiotic-associated colitis is much less common. Mild elevation of liver transaminaes
30,37may occur, but serious hepatic injury is rare. Ceftriaxone has been associated with biliary sludge
formation, which is usually asymptomatic, except in children receiving high doses of prolonged
30,45therapy. The most common adverse e3ects associated with the fth-generation cephalosporin
34,38ceftaroline include diarrhea, as well as nausea, skin eruption, headache and insomnia.
Hypersensitivity reactions and cross-reaction potential
Hypersensitivity reactions, reported in 1–3% of treated individuals, include cutaneous ndings such as
30urticaria, maculopapular eruptions, and pruritus.
Q8-4 Potential cross-reactivity of cephalosporins with penicillins has been traditionally stated to occur
in approximately 5–10% of penicillin-allergic patients. The degree of this cross-reactivity likely depends on
the generation of cephalosporin, and very likely is due to structural di3erences in side chains among
46,47individual cephalosporins. Early rst-generation cephalosporins sometimes contained trace amounts of
penicillins, and this may explain an increased estimation of cross-reactivity between pencillins and
47 30cephalosporins. With the above in mind, the true incidence of cross-reactivity is likely from 1% to 7%.
One report stated that the risk of a reaction to a cephalosporin in a pencillin-allergic patient is no greater
24than the risk of developing a cephalosporin reaction by itself. Another study concluded that
cephalosporins can be considered for patients with penicillin allergy and that the risk of serious adverse
48 49events, and speci cally anaphylaxis, was 0.001%. Although this issue remains controversial, there are
data to show that cephalosporin-allergic reactions occur more commonly in patients with a history of
30penicillin allergy versus those without a penicillin allergy. Thus, it is recommended that cephalosporin use
be avoided in patients with a history of an immediate or accelerated reaction to penicillin (IgE-mediated or
18severe type IV delayed hypersensitivity reactions). Cephalosporin skin testing is much less reliable than
47penicillin skin testing to evaluate hypersensitivity reactions.
Other adverse effects
Other potential adverse e3ects related to cephalosporin use include vaginal infections from overgrowth of
24Candida spp, hematopoietic changes, mental and sleep disturbance, and liver function test alterations.
Q8-6 Among the cephalosporins, serum sickness-like reaction has been reported almost exclusively with
50cefaclor, used more commonly in the past for otitis media in children. The cefaclor-induced serum
sickness-like reaction, presenting as urticaria, fever, and arthralgias, with or without lymphadenopathy or
30,50eosinophilia, has also been suspected in one case with cefprozil. A Jarisch–Herxheimer reaction
occurring during the treatment of Lyme disease has been noted with cefuroxime axetil, with an estimated
24incidence between 12% and 29%. Local reactions such as thrombophlebitis or pain at injection sites have
30been described in up to 5% of cephalosporin-treated patients undergoing parenteral administration. Nail
changes have been described following treatment with cephalexin (acute paronychia) and cephaloridine
27(onychomadesis and photo-onycholysis); the latter is no longer available.
Hematologic effects
With regard to hematopoietic changes, despite a reported rate of 3% Coombs’ antibody positivity, hemolytic
30,51,52anemia is rare in cephalosporin-treated patients. The cephalosporins most often associated with
drug-induced immune hemolytic anemia are cefotetan, ceftriaxone, and pipercillin, with cefotetan suspected
51to be the most common cause. Hypoprothrombinemia may occur with cephalosporins, cefotetan and
cefoperazone, which contain an N-methylthiotetrazole (NMTT) ring. Eosinophilia and neutropenia have also
53been reported.
Nephrotoxicity
Nephrotoxicity is rare, although a reduction in the dosage of most cephalosporins is recommended in
30patients with significant renal insufficiency.
Drug interactions
Some of the most important drug interactions for cephalosporins include the following:
1 . Cephalosporins (such as cefotetan) which contain an NMTT ring have been reported to induce
54disulfiram-like reactions with alcohol ingestion.@
2. The NMTT ring can also prolong prothrombin times as it inhibits production of vitamin-K clotting
12,55factors, which is a consideration in patients on anticoagulation therapy.
3 . Probenecid competes with renal tubular secretion of some cephalosporins. This may increase and
prolong the plasma levels for cephalosporins.
4 . Some cephalosporins may increase the risk of nephrotoxicity when co-administered with
12,56aminoglycosides or potent diuretics.
5. H antihistamine, oral antacids and possibly proton pump inhibitors may reduce the plasma levels of2
57cefditoren.
6. The controversial topic of whether or not oral antibiotics decrease the e cacy of oral contraceptives is
reviewed under the Drug Interactions sections for both tetracyclines and rifamycins.
7 . To date, there are no known drug interaction studies that have been conducted with the newer
34,38cephalosporin ceftaroline. Ceftaroline appears to exhibit minimal interaction with the cytochrome
34,38P-450 (CYP) system.
Dosage
Table 8-4 lists dosage guidelines for oral cephalosporins.
β-lactam and β-lactamases inhibitor combinations
Amoxicillin/clavulanate and others
β-lactamase enzymes render β-lactam antibiotics inactive by irreversibly hydrolyzing the amide bond of the
β-lactam ring. The production of a β-lactamase is controlled by either chromosomal or plasmid genes, and
58transferability of these genetic capabilities among bacterial organisms is possible. β-lactamase inhibitors,
when combined with a β-lactam antibiotic, act in concert to inhibit β-lactamase produced by
59Enterobacteriaceae, S. aureus, and Gram-negative anaerobes. In the US, clavulanate, sulbactam, and
tazobactam are the β-lactamase inhibitors approved for clinical use. Combination β-lactam antibiotic and
βlactamase inhibitor formulations include (1) amoxicillin–clavulanate, (2) ampicillin–sulbactam, (3)
ticarcillin–clavlanate, and (4) piperacillin–tazobactam (trade names in Table 8-1).
Antibacterial activity
β-lactamase inhibitors alone do not possess relevant antibacterial activity, but when they are combined with
a β-lactam antibiotic they act by inhibiting plasmid-mediated β-lactamase, thereby restoring the spectrum
31,60of activity of the β-lactams. Signi cant activity against β-lactamase produced by MSSA, Haemophilus
spp, Klebsiella spp., E coli, Proteus spp., and B. fragilis has been noted. However, the β-lactamase inhibitors
have not been found to provide e3ective inhibition of β-lactamases produced by Pseudomonas aeruginosa,
31Enterobacter and Citrobacter spp.
Pharmacokinetics
When clavulanate is given orally with amoxicillin (Amox/Clav), it is rapidly absorbed, with peak
concentrations reached 40–60 minutes after ingestion, and bioavailability not signi cantly a3ected by
60,61food. Ampicillin–sulbactam (Amp/Sulb), ticarcillin–clavulanate (Ticar/Clav) and piperacillin–
tazobactam (Pip/Tazo) are administered intravenously. Amp/Sulb can also be administered
intramuscularly. In patients with renal impairment, it has been found that the half-life of the
β-lactam/βlactamase combination of drugs is prolonged and blood levels are elevated, thus warranting dosage
31adjustment in some cases.
Clinical use
Dermatologic indications
The broad-spectrum antimicrobial coverage provided by Amox/Clav, Amp/Sulb, Ticar/Clav, and Pip/Tazo
makes these agents useful for the treatment of polymicrobial infections. The recommended oral agent for
treatment of animal or human bites infected by combined aerobic and anaerobic pathogens is
58Amox/Clav. Ticar/Clav and Pip/Tazo exhibit an even broader antibacterial spectrum, and are e3ective in
63,64treating CSSTI such as diabetic foot ulcers, infected decubiti, and burn wounds.
Adverse effects
Adverse e3ects most often associated with Amox/Clav and Pip/Tazo are GI complaints, most commonly
59diarrhea. Diarrhea appears to occur less frequently when Amox/Clav is administered with food. Q8-4Hypersensitivity reactions from the β-lactam/β-lactamase inhibitor combinations are similar to those seen
from the β-lactams alone. Ticarcillin and piperacillin can prolong bleeding times and cause platelet
65aggregation dysfunction. Hypernatremia has been reported with both ticarcillin and piperacillin
59administration. Transient elevation of transaminases, positive Coombs’ test, thrombocytopenia,
66neutropenia, and eosinophilia have also been reported with these agents. Cholestatic injury has been
28reported in up to 1 in 100 000 prescriptions of Amox/Clav, but not with amoxicillin alone. Sulbactam has
67been associated with pain at the intramuscular injection sites.
Drug interactions
When administered concomitantly with β-lactam/β-lactamase inhibitor combinations, oral probenecid slows
the rate of renal tubular secretion of the β-lactam agent, resulting in an increase in serum concentration and
68,69delayed renal excretion. The controversial topic of whether or not oral antibiotics reduce the efficacy of
oral contraceptives is reviewed below under the Drug Interactions sections for both tetracyclines and
rifamycins.
Dosage
Amox/Clav is administered orally. The adult dosage is 250–500 mg every 8 hours, although the 875 mg
formulation twice daily is increasingly used. The tablets and suspension contain either a 2 : 1 or a 4 : 1 ratio
of the drugs. Table 8-2 contains dosage guidelines for oral penicillins.
Carbapenems and monobactams
Both of these drug groups have limited applicability in dermatology as they are available only in parenteral
forms.
70–77Carbapenems
1. Imipenem, the rst carbapenem available in the US, is combined with cilastatin, a natural inhibitor of
renal dehydropeptidase enzyme responsible for the metabolism, and provides renal toxicity
70protection.
70,712. Other carbapenems include meropenem and ertapenem.
3. Overall, carbapenems probably demonstrate the most complete range of antibacterial coverage of any
70–74antibiotic class. They are active against most aerobic and anaerobic Gram-negative bacteria,
72,73including most P. aeruginosa strains, and anaerobic organisms including the B. fragilis group.
4 . Q8-4 Skin test studies have shown a high degree of cross-reactivity between carbapenems and
penicillin. The incidence of allergic-type reactions to a carbapenem was 5.2 times greater in patients
76,77who were reportedly allergic to penicillin.
5. Carbapenems may lower the seizure threshold, and should be administered with caution in a patient
with a history of seizures.
78–82Monobactams
1. Aztreonam, the only monobactam currently available in the US, exhibits an antimicrobial spectrum of
78–80activity limited to aerobic Gram-negative organisms.
2. The drug has been employed as a sole agent in treating Gram-negative cutaneous infections, including
postoperative wounds, ulcers, burns, and ecthyma gangrenosum, and in conjunction with other drugs
80that inhibit Gram-positive or anaerobic flora.
3. Aztreonam has an adverse e3ect pro le similar to that of other β-lactam antibacterial agents, including
81rare cases of erythema multiforme, toxic epidermal necrolysis, urticarial, and exfoliative dermatitis.
824. Q8-4 Patients who are allergic to penicillin can be safely given aztreonam.
Other systemic agents affecting the bacterial cell wall
Vancomycin
Vancomycin, a glycopeptide antibiotic, was isolated in 1956 from the actinomycetes Streptomyces orientalis,
83and approved by the US FDA in 1958. It inhibits the synthesis of the bacterial cell wall via a mechanism
di3erent from that of the β-lactams. Vancomycin is pregnancy category C, is excreted in breast milk, and is
approved for use in children.

Pharmacology
Antibacterial activity
Vancomycin is structurally classi ed as a tricyclic glycopeptide. It is e3ective only against Gram-positive
organisms, exhibiting ‘slow’ bactericidal activity against staphylococci and streptococci, and bacteriostatic
83–85activity against most enterococci. One of the most important clinical applications of vancomycin is in
the treatment of staphylococcal infections that are resistant to several more conventional antibiotics, such as
93,84those caused by MRSA and methicillin-resistant coagulase-negative staphylococci.
Q8-7 Resistance to vancomycin is reportedly mediated by a plasmid that reduces the permeability of
83the drug, and reduces binding of vancomycin to receptor molecules in the bacterial cell wall. Over 3
decades of use pathogens resistant to vancomycin have emerged, including vancomycin-resistant
84,85staphylococci and streptococci. Increasing numbers of therapeutic failures have been observed with
vancomycin for MRSA infections, due in large part to increases in minimum inhibitory concentrations (MIC)
85of vancomycin for many Gram-positive pathogens, including MRSA. Other organisms showing increasing
resistance to vancomycin, predominantly in the hospital setting, include vancomycin-intermediate S. aureus
(VISA), vancomycin-resistant S. aureus (VRS), and vancomycin-resistant enterococci (VRE).
Pharmacokinetics
Vancomycin is administered parenterally because of its minimal absorption from the GI tract, and is used
86orally only for the treatment of C. di cile diarrhea. Owing to its lack of extensive metabolism, 90–100%
of vancomycin is excreted by glomerular ltration. The serum half-life of vancomycin is 4–8 hours after
intravenous injection with normal renal function, with the need for dosage modi cation in patients with
marked renal insufficiency.
Clinical use
Dermatologic indications
Vancomycin is used for the treatment of SSTI caused by MRSA and methicillin-resistant coagulase-negative
staphylococci. It is mostly used for the treatment of hospital-acquired MRSA (HA-MRSA), but may be
indicated for the treatment of fulminant and deeply invasive CA-MRSA infections. Q8-7 In general,
CAMRSA derives its resistance pattern via staphylococcal cassette type IV chromosome mec element (SCC-MEC
IV). Most CA-MRSA infections seen in dermatologic practice cause USSTI that are susceptible to incision and
drainage (when presenting as abscesses) and oral therapy with minocycline, doxcycycline, clindamycin, or
TMP-SMX; however, exceptions exist and the patterns of resistance to vancomycin, such as strains of S.
88aureus, are among the most common infections treated in hospitals today, often presenting as CSSTI. The
increasing prevalence of this resistance to major pathogens, such as S. aureus and VRE, has prompted the
89development of multiple new antibiotic classes that are currently under investigation. Some of these
lipoglycopeptides, uoroquinolones, oxazolidinones, and dihydrofolate inhibitors are discussed later in this
chapter.
Adverse effects
Cutaneous reactions and hypersensitivity
Q8-8 Red man syndrome and shock secondary to histamine release can be caused by rapid transfusion of
vancomycin. Rarely, toxic epidermal necrolysis (TEN) has been reported; however, di3erentiation of TEN
from a variant presentation of linear IgA bullous dermatosis (LABD) caused by vancomycin is
83,90–95warranted. Vancomycin is one of the most common causes of drug-induced LABD, developing after
83,90,91the initiation of vancomycin and also upon rechallenge. Multiple cases of vancomycin-induced
92–95LABD mimicking TEN have been reported. In some cases, vancomycin-induced LABD has presented as
96morbilliform eruption without blistering. Although the target antigens in idiopathic LABD are believed to
be heterogeneous, IgA antibodies to LAD285 and dual response antibody formation (IgA and IgG) to BP180
97have been reported in 2 cases of vancomycin-induced LABD.
Other adverse effects
Dose-related hearing loss has been reported in patients with renal failure, likely due to the accumulation of
vancomycin. Nephrotoxicity can occur, particularly when administered along with aminoglycoside
83antibiotics. Other adverse e3ects include fever, neutropenia, thrombocytopenia, and phlebitis at the
infusion site.
Drug interactions

Concurrent administration of vancomycin with aminoglycosides increases the risk of nephrotoxicity.
12Vancomycin may enhance the activity of non-deporlarizing muscle relaxants.
Macrolides
Erythromycin, azithromycin, and clarithromycin
Macrolide antibiotics contain a macrocyclic lactone ring structure and are either products of actinomycetes
(soil bacteria) or semi-synthetic derivatives of these bacteria. Q8-9 Unlike β-lactams, macrolides are
bacteriostatic antibiotics which bind reversibly to the large (50S) subunit of the bacterial ribosome,
98–100inhibiting RNA-dependent protein synthesis. Q8-10 Macrolides have also been reported to
demonstrate speci c anti-in ammatory properties, unrelated to their antibiotic activities, which may
potentially contribute to their therapeutic bene t in in ammatory facial dermatoses such as acne and
101–103rosacea. Macrolides, azalides, and ketolides are listed in Table 8-5.
Table 8-5 Currently available FDA-approved macrolides, azalides, and ketolides
Traditional macrolides
Erythromycin is the prototype macrolide, available for either oral or parenteral use. In the past,
erythromycin was a consistently good substitute for penicillins in patients who are allergic to β-lactams;
however, the emergence of widespread S. aureus resistance to erythromycin, as well as some resistant
streptococcal strains, has signi cantly limited the clinical utility of this drug in both adults and
1,4,5children. In the management of acne vulgaris, the use of oral erythromycin has markedly declined in
the US and other countries due to widespread emergence of resistant P. acnes strains, with resistance rates as
1,4,5high as 50%. Additionally, oral erythromycin is associated with other clinically relevant drawbacks,
including erratic oral bioavailability, a short half-life requiring frequent administration, and the frequent
104development of GI adverse e3ects, such as nausea and abdominal discomfort. Finally, the use of
erythromycin is sometimes prevented by its relatively strong inhibition of CYP3A4 and 1A2, leading to
reduced clearance and increase risk of toxicity to a wide variety of drugs (see Drug Interactions section for
105details).
Azalides
The azalide antibiotics, based on a structural modi cation of the macrolide nucleus, include clarithromycin
104and azithromycin. These azalide agents exhibit a broad range of clinical uses, including for a variety of
cutaneous infections.
Ketolides
Another group structurally similar to macrolides, called the ketolides, incorporates substitutions on the
14membered macrolide ring. The rst ketolide introduced in the US was telithromycin, with reported bene ts
for penicillin- and macrolide-resistant strains of S. pneumoniae. Telithromycin had not been adequately
106,107studied in the treatment of skin infections at the time of its release in the US. Major safety issues with@
"
telithromycin have since emerged, including symptomatic hepatotoxicity, including several deaths,
prolongation of the QTc interval, and the need to avoid use in patients with myasthenia gravis (see Adverse
108-110E3ects section). Cethromycin is a newer ketolide submitted for FDA approval in 2008 for treatment
of mild to moderate community-acquired pneumonia (CAP) that exhibits inhibition of both Gram-positive
111–112and Gram-negative respiratory organisms. Interestingly, cethromycin was granted ‘orphan drug’
status for the prevention of post-exposure anthrax. CEM-101 is the newest ketolide for which the structure of
telithromycin has been modi ed somewhat, with enhanced activity against telithromycin-resistant
113organisms.
Pharmacology
Antimicrobial activity
Macrolide antibiotics are e3ective against most Gram-positive organisms, with the notable exceptions of
MRSA and enterococcus. Q8-11 Compared to erythromycin, clarithromycin is 2–4 times more potent than
114erythromycin against Gram-positive organisms such as staphylococci and streptococci. Although the in
vitro activity of azithromycin against Gram-positive organisms is 2–4 times less than that of erythromycin,
its e cacy is enhanced by its ability to achieve high levels in several tissues. Unlike erythromycin,
clarithromycin and azithromycin possess increased activity against several Gram-negative pathogens,
115including H. in uenzae. Azithromycin has activity against E. coli, N. gonorrhoeae, Haemophilus ducreyi,
116Ureaplasma urealyticum, and Chlamydia trachomatis. Azithromycin also has activity against organisms
117contacted via animal bites, including Pasturella multocida and human bites such as Eikenella corrodens.
Both clarithromycin and azithromycin are e3ective against atypical mycobacteria such as Mycobacterium
118–120avium-intracellulare, Mycobacterium leprae, and Mycobacterium chelonei. Clarithromycin is the most
active macrolide against M. leprae. Both clarithromycin and azithromycin demonstrate activity against
121–123Toxoplasma gondii, Treponema pallidum, and B. burgdorferi.
Pharmacokinetics
Erythromycin, the azalides, and the ketolides may be given orally. Unless administered in an enteric-coated
form, erythromycin base is vulnerable to gastric acid inactivation and must be taken on an an empty
stomach. Erythromycin is also available as an acid-stable salt (stearate), ester (ethyl succinate and
116propionate), or salt of an ester (estolate). The stearate must be taken on an empty stomach, whereas the
other formulations may be taken without regard to food ingestion. Erythromycin and azithromycin are also
available in parenteral forms.
104The azalides have improved oral bioavailability, with clarithromycin equally well absorbed with or
without food, although azithromycin absorption is decreased with food (best taken 1–2 hours before a
meal). Renal elimination is signi cant route of excretion for clarithromycin and less so for erythromycin,
with dosages for both drugs warranting modification in significant renal failure. As azithromycin is primarily
metabolized by the liver, no adjustments are required in renal disease. The elimination half-life of
azithromycin initially is 11–14 hours, followed by a more prolonged half-life of 68 hours.
Clinical use
Dermatologic indications
Indications for cutaneous infections
Q8-11 The macrolides are e3ective in the treatment of various skin and soft tissue infections, with an overall
favorable safety pro le; erythromycin has been used since 1952. These agents, especially oral formulations,
have been used for several types of USSTI, including pyodermas, abscesses, infected wounds, infected ulcers,
and erysipelas; however, erythromycin use is no longer optimal in many cutaneous infections owing to the
marked increase in bacterial resistance to this agent, especially with S. aureus and some streptococcal
1,4–7,124–126 6,7strains. MRSA is not responsive to treatment with macrolide or azalide antibiotics. Other
potential mucocutaneous indications for erythromycin include Lyme disease, erythrasma, anthrax,
erysipeloid, rheumatic fever, non-gonococcal urethritis, syphilis, chancroid, and lymphogranuloma
116venereum. Data exist to overall support the efficacy for most of these indications with azalides as well.
Q8-11 Among the azalide subcategory of macrolides, azithromycin has been shown to be e3ective in
116the treatment of donovanosis, cat-scratch disease, toxoplasmosis, and Mediterranean spotted fever.
Additionally, the high activity against N. gonorrhoea and C. trachomatis renders a single dose of
azithromycin e3ective for treatment of uncomplicated urethritis or cervicitis. Azithromycin is an excellent
choice for infections associated with animal and human bites, given its activity against Pasteurella and
Eikenella spp. Clarithromycin has been shown to be e3ective in the treatment of leprosy, as well as the

atypical mycobacterial skin infections with M. chelonei, M. simiae, M. avium complex (MAC), M. kansasii,
127and M. intracellulare.
Indications for inflammatory dermatoses
Erythromycin, and to a much lesser extent azithromycin, has been used for the treatment of in ammatory
facial dermatoses with an infectious component, including acne vulgaris, rosacea, and perioral
1,4,128–132dermatitis. Owing to the high prevalence of erythromycin-resistant P. acnes, the use of
1,4,5erythromycin for the treatment of acne has waned in the US and several other countries. Selective use
of azithromycin for acne vulgaris and rosacea may be helpful in some patients who are intolerant to
tetracycline agents, with azithromycin shown to be as e3ective as tetracycline in one study for
128,129rosacea. Owing to the long elimination half-life and persistent tissue levels with azithromycin,
various intermittent dosing regimens have been used, such as 250 mg three times weekly, after an initial
128–132‘tissue load,’ with daily dosing for 5 days. Data on oral macrolide use for perioral dermatitis are
133limited.
As with penicillins, a systematic review of the literature has concluded that there is no evidence that
15,16administration of anti-streptococcal antibiotics, including macrolides, improves guttate psoriasis.
116Macrolides have been used successfully to treat con uent and reticulated papillomatosis. A few reports
134,135have suggested efficacy of erythromycin in the treatment of pityriasis rosea.
Adverse effects
Common adverse effects
The most common adverse e3ects of erythromycin are nausea, abdominal pain, and diarrhea, reported to
136occur in 15–20% of patients, depending on the oral formulation used. Erythromycin binds to motilin
receptors throughout the GI tract, releasing motilin, which stimulates migrating digestive contractions, thus
137,138inducing a higher incidence of GI disturbance than with the azalide and ketolide subcategories.
Erythromycin has also been reported to be a rare cause of skin eruptions and allergic reactions ranging from
116mild to severe, as well as reversible hearing loss at high doses. Ototoxicity was reported at higher doses
136or in patients with hepatic or renal dysfunction. Cardiac conduction abnormalities have been associated
116,139with macrolide use. One study reviewed the cardiac safety pro le of macrolides and found that
erythromycin carried the greatest risk of QT prolongation and torsades de pointes compared to other
macrolides, with the risk of cardiotoxicity increased with advanced age, higher dosages, rapid
139administration, and history of cardiac diseases. Clarithromycin may cause a metallic or bitter taste, xed
drug eruption, leukocytoclastic vasculitis, and hypersensitivity reactions. Azithromycin has been associated
with irreversible deafness, angioedema, photosensitivity, hypersensitivity syndrome, and contact dermatitis.
Telithromycin has been implicated in cases of symptomatic hepatotoxicity, including acute hepatic failure
108–110,140,141and liver injury, and exacerbation of myasthenia gravis. Overall, macrolide antibiotics have
116rarely been associated with cholestatic hepatitis.
Use in infants
Macrolides are excreted into breast milk, and therefore infant exposure to these drugs during lactation has
142,143been reported to increase the risk of hypertrophic pyloric stenosis. An increased risk of
cardiovascular malformation and pyloric stenosis in infants who were exposed to erythromycin in utero has
11,144been noted. However, a more recent prospective controlled observational study of 55 infants exposed
to macrolides via lactation found no association with pyloric stenosis or any other serious adverse
145reacton. Larger prospective studies are required to substantiate these findings.
Use in pregnancy
In general, most clinicians consider oral erythromycin to be safe in pregnancy as only low concentrations
cross the placenta. Even so, the safety of chronic use in pregnancy for acne vulgaris, rosacea, or perioral
dermatitis has not been adequately addressed. Short-term use of macrolides in the latter trimesters of
pregnancy should be considered a di3erent risk–bene t analysis. The following are some factors to consider
with regard to prolonged administration of oral erythromycin during pregnancy. With oral erythromycin use
in pregnancy, fetal concentrations of the drug are low, given some placental crossing of erythromycin. Fetal
147–148levels are reported to increase after multiple doses. Also, the estolate salt of erythromycin used for
longer than 3 weeks in pregnancy has been associated with maternal hepatotoxicity, with approximately
10% of 161 pregnant women treated with oral erythromycin in the second trimester developing elevated
11,149transaminase levels, which returned to normal after therapy was discontinued.
The observation that erythromycin may be rarely associated with cardiotoxicity raises additional
116,139concerns regarding prolonged use of erythromycin in pregnancy. A case–control study designed to
assess oral erythromycin use in early pregnancy and possible association with fetal cardiac abnormalities
150evaluated outcomes from 3 Swedish health registries. The ndings were compared between infants with
cardiac defects unrelated to genetic causation (n=5015) and a control group consisting of all infants born
in Sweden between 1995 and 2001 (n=577 730). ‘Potential’ associations between cardiac defects and the
use of a variety of drugs, including erythromycin, were noted. There were a total of 1588 erythromycin
exposures, with 27 cases of cardiac defects in infants noted, although it is uncertain whether erythromycin
150was causative. Lastly, a surveillance study conducted in Michigan evaluated 229 101 pregnant women
who were Medicaid recipients, with 6972 newborns exposed to oral erythromycin during the rst
151trimester. Major birth defects occurred in 4.6% of infants exposed to erythromycin, compared to an
expected rate of 4.0%. Cardiovascular abnormalities were noted in approximately 1.0% of
erythromycinexposed newborns, which was the same as the expected rate in this population. It remains wise to minimize
152erythromycin exposure in pregnancy for non-infectious indications. Erythromycin has been evaluated in
the third trimester of pregnancy to safely reduce maternal and infant colonization with group B β-hemolytic
streptococcus, and to reduce rates of pregnancy loss and low-birthweight infants in women with genital
151mycoplasma infections.
Drug interactions
Q8-11 Erythromycin, and to a lesser extent clarithromycin, inhibits the hepatic and intestinal (‘ rst-pass’)
CYP system, primarily CYP3A4, leading to decreased metabolic clearance of a number of drugs, often
105,153relatively rapidly after initiation of erythromycin/clarithromycin therapy. These two macrolide
agents (erythromycin > clarithromycin) inhibit the metabolism, raise plasma levels, and prolong the
clearance of many drugs that are administered chronically, including (Table 8-6):
153–1551. Carbamazepine and phenytoin;
2. Theophylline;
3. Certain benzodiazepines (i.e., triazolam, midazolam);
4. Warfarin, with potential for severe bleeding complications;
5. Cyclosporine, with potential for renal toxicity and HBP;
153,156,1576. Drugs with potential for QT prolongation and torsades de pointes (terfenadine, astemizole,
cisapride, and pimozide; all but pimozide have been withdrawn from the market); and
7 . Some HMG-CoA reductase inhibitors or ‘statins’ (i.e., atorvastatin, simvastatin, lovastatin), thereby
105,153,154enhancing their risk for toxicity such as rhabdomyolysis.
8. Clarithromycin may reduce the absorption of zidovudine (AZT) by 20% and may also reduce the serum
158,159levels of didanosine (ddI).
9 . In contrast, clarithromycin may signi cantly increase linezolid serum concentrations when
co160administered.
10. Several cases of macrolide antibiotic-induced digoxin toxicity have been reported, including with the
azalide and ketolide subcategories, possibly due to alterations in gut ora or via telithromycin
161–167alterations of P-glycoprotein.
Table 8-6 Drug interactions – macrolides, azalides, and ketolides
Interacting drug
Examples and comments
group
These drugs may ↑ serum levels (and potential toxicity) of erythromycin, clarithromycin – CYP3A4
inhibition
Antiarrhythmic Amiodarone
agents
Antidepressants – Fluoxetine, fluvoxamine
SSRI
Antifungal – azoles Ketoconazole >> itraconazole > fluconazole (also voriconazole)
Calcium channel Diltiazem, verapamil; only these two drugs are CYP3A4 inhibitorsblockers
Foods and Grapefruit, grapefruit juice
beverages
HIV drugs – other Delavirdine
HIV drugs – Amprenavir, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir
protease inhibitors
Immunosuppressive Cyclosporine
agents
These drugs ↓ serum levels (loss of efficacy) of macrolides and azalides – CYP3A4 induction
Antibacterial – Rifampin, rifabutin, rifapentine
rifamycins
Anticonvulsants Carbamazepine, oxcarbazepine, phenobarbital, phenytoin
Miscellaneous Nevirapine
drugs
Retinoids Bexarotene
(‘rexinoid’)
Erythromycin and clarithromycin ↑ serum levels (and potential toxicity) of these drugs – CYP3A4
substrates
Alzheimer’s disease Donepezil
drugs
Antiarrhythmic Amiodarone, disopyramide, dofetilide, flecainide, propafenone, quinidine; risk for
agents† arrhythmias including QT prolongation (torsades de pointes)
Anticoagulants† Warfarin; ↑ anticoagulant effect (risk of hemorrhage), also a 1A2 substrate
Anticonvulsants† Carbamazepine, ethosuximide, felbamate, oxcarbazepine, valproate; check levels
Antidepressants Buspirone, maprotiline, nefazodone, trazodone, venlafaxine, various tricyclics,
including amitriptyline, imipramine
Antipsychotic Aripiprazole, haloperidol, pimozide, quetiapine, risperidone
agents
Calcium channel All calcium channel blockers are substrates of CYP3A4
blockers†
Chemotherapeutic Bortezomib, docetaxel, geftanib, imatinib, paclitaxel, vinblastine, vincristine
agents†
Corticosteroids Budesonide, fluticasone (inhaled), methylprednisolone, mometasone (inhaled)
Diabetes drugs Glipizide, glyburide, metformin, pioglitazone, tolbutamide; monitor glucose
Erectile dysfunction Silderafil, tadalafil, vardenafil
drugs†
HIV drugs – other† Delavirdine, efavirenz, nevirapine
Hormonal Oral, transdermal, injectable forms – may ↑ risk of intrahepatic cholestasis
contraceptives
Immunosuppressive Cyclosporine, tacrolimus – ↑ risk for nephrotoxicity, neurotoxicity, ↑ BP
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agents†
Miscellaneous Aprepitant, bromocriptine, cinacalcet, colchicine, digoxin, mifepristone
drugs
Narcotics† Alfentanil, buprenorphine, fentanyl, meperidine, methadone, sufentanil; monitor
for excessive sedation
Retinoids Bexarotene; monitor lipids, amylase, TSH, transaminases
(‘rexinoid’)†
Sedatives – Alprazolam, midazolam, triazolam; monitor for excessive sedation
benzodiazepines
Statins† Atorvastatin, lovastatin, simvastatin; ↑ risk of myopathy, rhabdomyolysis,
hepatotoxicity, ↓ cholesterol
Erythromycin can ↑ the serum levels (and potential toxicity) of these drugs – CYP1A2 subtrates
Antiarrhythmic Mexiletine; risk for arrhythmias including QT prolongation (torsades de pointes)
agents†
Bronchodilators – Theophylline – risk of CNS toxicity particularly important
xanthine†
Chemotherapeutic Erlotinib; also a CYP3A4 substrate
agents
Foods and Caffeine; this ‘drug’ used in preclinical studies for assessing 1A2 metabolism
beverages
Lipoxygenase (5- Zileuton; risk for hepatotoxicity
LO) inhibitor†
Note: Risk for interactions involving CYP3A4 greatest with erythromycin, moderate with clarithromycin,
negligible with azithromycin; CYP1A2 inhibition primarily by erythromycin (clarithromycin, azithromycin are
azalides).
*Astemizole, cisapride, grepa oxacin, terfenadine withdrawn from US market due to torsades de pointes, ↑
risk in presence of CYP3A4 inhibitors such as clarithromycin, erythromycin; also cerivastatin withdrawn due to
rhabdomyolysis.
† Drug interactions with CYP3A4 and 1A2 substrates with a ‘narrow’ therapeutic index leading to a greater risk
of toxicity.
Adapted from Facts & Comparisons, The Medical Letter Drug Interactions Program, E-pocrates, Hansten and Horn –
references on pg. xxii.
Azithromycin does not signi cantly a3ect CYP isoenzymes, and so may be safely co-administered with
153, 168,169other drugs. However, there have been reports of toxicity related to co-administration of
170,171azithromycin and lovastatin, warfarin, cyclosporine, disopyramide, and theophylline. The
controversial topic of whether or not oral antibiotics reduce the e cacy of oral contraceptives is reviewed
below under the Drug Interactions sections for both tetracyclines and rifamycins.
Dosage
The dosing schedule of the various macrolide antibiotics for treatment of cutaneous infections varies
signi cantly depending on the speci c drug (Table 8-7). The usual adult dosing schedule for erythromycin
base is 250–500 mg every 6–12 hours, and for erythromycin ethyl succinate 400–800 mg every 6–12 hours.
The adult dosage of clarithromycin is 250–500 mg every 12 hours, though a newly available XL formulation
(500 mg) permits once-daily dosing. For azithromycin, the adult dosage is 500 mg given as a single dose on
the rst day of therapy, followed by 250 mg once daily for 4 additional days. For the treatment of
uncomplicated chlamydial infections azithromycin is administered as a single 1- g dose. Localized
gonococcal infections may be treated with a single 2- g oral dose. Azithromycin is available in 250, 500,
600 mg tablets, a 2 g extended-release oral suspension, a 250 mg/5 mL pediatric liquid preparation, and an
intravenous formulation. Table 8-7 gives dosage guidelines for commonly used oral macrolides and related

drugs.
Table 8-7 Commonly used oral macrolides – dosage guidelines
Generic name Tablet/capsule sizes (mg) Adult dosage
Azithromycin* 250, 500, 600 500 mg day 1, then 250 mg qd 3 4†
Clarithromycin* 250, 500 250–500 mg bid
Erythromycin base 250, 333, 500 250–500 mg qid‡
Erythromycin ethyl succinate* 400 400 mg qid
* These drugs are available in either suspension or liquid formulations.
† Azithromycin PO QD for 3 days is also an approved dosage schedule (product also supplied in 250-mg tablets
36 tablets or 500-mg 33 tablets).
‡ Enteric-coated formulations are available.
Fluoroquinolones
There are many uoroquinolones (FQ) currently available in the US (Table 8-8), with those used more
commonly in dermatology reviewed in more detail below. The ‘modern day’ FQ exhibit a broader spectrum
of concentration-dependent bactericidal activity than older quinolones, such as nalidixic acid, and their
longer serum half-lives allow for once- or twice-daily administration in most instances. Other advantages of
FQ include high oral bioavailability (except in the presence of certain metal cations), and extensive tissue
172penetration into human cells, resulting in antimicrobial activity against intracellular pathogens. Q8-12
FQ interfere with bacterial DNA replication via inhibition of DNA gyrase (bacterial topoisomerase II), an
enzyme that regulates supercoiling of bacterial DNA, and topoisomerase IV, an enzyme that allows
173separation of the topologically linked daughter chromosomes during DNA replication.
Table 8-8 Currently available FDA-approved oral fluoroquinolones
11The FQ are pregnancy category C and are excreted in breast milk. They have been found to impair
cartilage formation in immature animals, and therefore are usually not recommended for use in
174,175children. This issue will be covered in detail in the Adverse Effects section for FQ.
Pharmacology
Antimicrobial activity
The FQ are e3ective against most Gram-negative organisms, particularly the Enterobacteriaceae, and in
vitro are active against some Gram-positive bacteria, such as S. aureus, including MRSA. FQ are generally
applicable as oral agents for treatment of USSTI caused by susceptible pathogens, although some exceptions
5–7do exist in clinical practice. Cipro oxacin, the rst oral FQ antibiotic agent brought to market in the US,
has remained overall the most active of the FQ against P. aeruginosa, although some strains have become
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176ciprofloxacin-resistant over time.
FQ show variable e cacy against Gram-positive organisms, with emergence of cipro
oxacin-non177susceptible S. pyogenes isolated from a healthy pediatric population. Levo oxacin and moxi oxacin are
reported to be e cacious against S. aureus and S. pyogenes. Q8-13 Importantly, although some FQ exhibit
high activity in vitro against MRSA, including CA-MRSA strains, there are increasing reports of treatment
5–7,178,179failure due to FQ-resistant staphylococci. Therefore, FQ are not considered rst-line agents for
USSTI caused by CA-MRSA, but may be used in selected cases when other options are limited by speci c
circumstances. Cipro oxacin is also active against Bacillus anthrax. The FQ possess minimal anaerobic
activity. Cipro oxacin, o oxacin, and levo oxacin are active against Mycobacterium spp, including M.
180–183tuberculosis, M. fortuitum, and M. kansasii.
Pharmacokinetics
Q8-2 With the exception of norfloxacin, the oral bioavailability of the FQ is excellent and minimally affected
by food, except in the presence of some metal ions co-administered in high concentration, such as in
105,173 184antacids, and vitamin/mineral supplements. Half-lives of FQ vary from 3 to 13 hours. Except for
moxi oxacin, FQ are mainly excreted renally, and thus require dosage adjustment in patients with
185significantly impaired renal function.
Clinical use
Dermatologic indications
Because of high drug levels in the skin and its appendages, the oral FQ are ideal agents for treating USSTI
caused by Gram-negative bacteria, including those caused by multiresistant organisms such as folliculitis,
173abscesses, cellulitis, infected ulcers, and wound infections. FQ can be used as an alternative to penicillins
or β-lactams to treat USSTI caused by susceptible organisms in patients allergic or hypersensitive to
186penicillins or other β-lactams. These agents are also useful in treating Gram-negative toe web-space
infections, infected diabetic foot ulcers, and puncture wounds. Single doses of cipro oxacin or o oxacin are
e3ective in the treatment of gonorrhea caused by FQ-susceptible strains; however, caution is advised as
FQresistant strains of N. gonorrhoeae are emerging in the US. Fluoroquinolones are e3ective against
173donovanosis and chancroid. Ciprofloxacin is a treatment of choice for cutaneous anthrax.
Although there have been a limited number of reports suggesting e cacy of FQ for acne vulgaris, the
128,129,152use of FQ for this indication is not generally recommended. Rare exceptions may include brief
use for highly refractory cases. Prolonged administration of FQ is not suggested in order to preserve the
128,129,152utility of oral FQ for indications where they are regularly depended upon for e cacy. Oral FQ
may be helpful in some cases of Gram-negative folliculitis, including persistent ‘hot tub folliculitis’ caused by
Pseudomonas spp. In patients with Gram-negative folliculitis other than the ‘hot tub’ variety, treatment with
oral FQ is sometimes curative, with antibiotic selection optimally based on bacterial culture and sensitivity
results. However, treatment with oral isotretinoin may be needed for refractory cases and/or recurrences.
Adverse effects
Common adverse effects
The most common adverse reactions associated with FQ involve the GI tract, such as nausea, vomiting, and
173–187diarrhea. Common central nervous systemic (CNS) adverse e3ects range from milder reactions such
as headaches, dizziness, agitation, and sleep disturbances to more severe reactions including seizures,
173–187,188psychotic reactions, hallucinations, and depression. The mechanism of at least some CNS
173reactions may relate to FQ antagonism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).
Use in children – cartilage formation alteration
As discussed above, based on animal studies FQ may impair cartilage formation, and therefore these agents
174,175,189are generally avoided in children except for selected cases with extenuating circumstances.
A retrospective observational study completed through an automated database identi ed patients <19
years="" of="" _age2c_="" 6124="" whom="" were="" treated="" with="" at="" least="" 1="" 3=""
_fq2c_="" receiving="" _cipro oxacin2c_="" _levo oxacin2c_="" or="" o oxacin="" _28_active=""
174study="" _group29_="" and="" _15c2a0_073="" who=""> Potential cases of tendon or joint disorders
(TJD) occurring within 60 days of a prescription for one of the study antibiotics were identi ed based on
diagnosis coding and were veri ed. The incidence of veri ed TJD diagnosed within 60 days of prescribing
either an FQ antibiotic or azithromycin was <_125_ in="" both="" study="" groups.="" despite="" this=""
_information2c_="" cautious="" prescribing="" of="" fq="" children="" is="" _wise2c_="" particularly=""





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175when="" other="" drug="" categories="" are="" equally="">
Tendinitis and tendon rupture have been observed with FQ, and may be delayed in onset after initiation
173,190,191of FQ use. Risk factors for FQ-induced tendinopathy and tendon rupture are corticosteroid use,
patient age, sports participation, history of renal failure, diabetes mellitus, hyperparathyroidism, rheumatic
190,191disease, gout, and a history of tendinopathy.
Hypersensitivity and photosensitivity reactions
Hypersensitivity reactions and photosensitivity have also been reported, and photo-onycholysis has been
17,192,193described. Q8-14 In order of decreasing photosensitivity potential, these agents include
192lome oxacin, cipro oxacin, nor oxacin, and o oxacin. Evening dosing of these agents may minimize
193phototoxic potential. Blue-black pigentation of the legs similar to minocycline dyschromia, with
demonstration of iron particles within the cytoplasm of dermal macrophages, has been reported with
194perfloxacin therapy.
As a class, quinolones are generally well tolerated; however, more serious anaphylactoid or
195anaphylactic reactions have been reported with cipro oxacin use. Patients may present with edema of
the face, di culty breathing, hypotension, tachycardia, fever, pruritus, and/or di3use erythroderma, with
195the reactions tending to occur up to 3 days following the initial dose of IV or oral ciprofloxacin therapy.
Liver and other major toxicity
Trova oxacin has been associated with hepatic injury and is available in the US just on a very limited
28basis. Gati oxacin and moxi oxacin are associated with QTc interval prolongation, with gati oxacin
188,196withdrawn from the US market in 2006 owing to reports of serious dysglycemia in older adults.
Use in pregnancy and lactation
Although congenital anomalies associated with FQ use during pregnancy are inconsistent, FQ are not
suggested during pregnancy, especially as a rst-line therapy, although accidental exposure is not a
11definitive indication for medical abortion.
Drug interactions (Table 8-9)
Q8-2 Essentially all FQ show decreased bioavailability when administered with calcium-, aluminum-, or
magnesium-containing antacids, with a marked reduction in GI absorption noted with many oral FQ, likely
105,173due to the formation of cation–FQ complexes that are poorly absorbed. The concurrent ingestion of
calcium with cipro oxacin within 15 minutes has been shown to reduce ciproxacin absorption by 40%, and
ingestion of cipro oxacin within 4 hours after an aluminum/magnesium-containing antacid results in a 75%
105,197,198reduction in cipro oxacin absorption. Similarly, decreased GI absorption of FQ has been noted
with co-administration of sucralfate and iron- or zinc-containing products. A practical guideline useful in
clinical practice is to instruct patients to take their FQ antibiotic at least 1–2 hours before, and not within 4
105,198hours after, the ingestion of the above drugs/products.
Table 8-9 Drug interactions – fluoroquinolones
Interacting drug
Examples and comments
group
Drugs that may ↓ fluoroquinolone levels (loss of efficacy) through chelation*
Antacids Divalent (calcium, magnesium) and trivalent (aluminum) cations; will ↓ GI
absorption of fluoroquinolones through chelation
Miscellaneous Didanosine (is buffered), sucralfate (an aluminum salt of sulfated sucrose)
drugs
Nutritional Iron and zinc salts; chelation of fluoroquinolones by these products
supplements
Fluoroquinolones ↑ serum levels (and potential toxicity) of these drugs – CYP1A2 inhibition
Antiarrhythmic Mexiletine; risk for arrhythmias, QT prolongation (torsades de pointes)
agents†