HUMIRA - HUMIRA - CT 4863 - English version
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HUMIRA - HUMIRA - CT 4863 - English version

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14 Pages


Introduction HUMIRA 40 mg, solution for injection in pre-filled syringe Pack of 2 x 0.8 ml pre-filled glass syringes with two alcohol wipes (CIP: 362 230-5) HUMIRA 40 mg, solution for injection in pre-filled pen Pack of 2 x 0.8 ml pre-filled pens with two alcohol wipes (CIP: 378 014-5) Posted on Oct 24 2007 Active substance (DCI) adalimumab ATC Code L04AA17 Laboratory / Manufacturer ABBOTT HUMIRA 40 mg, solution for injection in pre-filled syringe Pack of 2 x 0.8 ml pre-filled glass syringes with two alcohol wipes (CIP: 362 230-5) HUMIRA 40 mg, solution for injection in pre-filled pen Pack of 2 x 0.8 ml pre-filled pens with two alcohol wipes (CIP: 378 014-5) Posted on Oct 24 2007



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Published 24 October 2007
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OPINION  24 October 2007   HUMIRA 40 mg, solution for injection in pre-filled syringe Pack of 2 x 0.8 ml pre-filled glass syringes with two alcohol wipes (CIP: 362 230-5)  HUMIRA 40 mg, solution for injection in pre-filled pen Pack of 2 x 0.8 ml pre-filled pens with two alcohol wipes (CIP: 378 014-5)   Applicant: ABBOTT  adalimumab   List I Medicinal product for initial annual hospital prescription. Prescription restricted to specialists in rheumatology, gastroenterology, digestive medicine or internal medicine.  Date of Marketing Authorisation (MA): September 8, 2003  Date of latest revision of MA: June 7, 2007 (extension of indication for Crohn’s disease)   Exception drug status   Reason for request: Inclusion on the list of medicines reimbursed by National Insurance and approved for use by hospitals for Crohn’s disease.            Health Technology Assessment Division  
Active ingredient adalimumab  
Indication Indications prior to the application  Rheumatoid arthritis HUMIRA in combination with methotrexate is indicated for: - to severe, active rheumatoid arthritis in adult the treatment of moderate patients when the response to disease-modifying anti-rheumatic drugs including methotrexate has been inadequate. - of severe, active, progressive rheumatoid arthritis in adults not treatment previously treated with methotrexate.  HUMIRA may be given as monotherapy in cases of methotrexate intolerance or where continued treatment with methotrexate is inappropriate.  Humira has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate.   Psoriatic arthritis Humira is indicated for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate.  Ankylosing spondylitis Humira is indicated for the treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.  New indication applied for:  Crohn's disease  Humira is indicated for treatment of severe, active Crohn’s disease, in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies. For induction treatment, Humira should be given in combination with corticosteroids. Humira can be given as monotherapy in case of intolerance to corticosteroids or when continued treatment with corticosteroids is inappropriate  
Dosage Treatment with HUMIRA must be initiated and supervised by a specialist experienced in the diagnosis and treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or Crohn’s disease. Patients being treated with HUMIRA will be given a special alert card.  After proper training in injection technique, patients may self-inject with Humira if their physician determines that it is appropriate and with medical follow-up as necessary.  
 Adults Crohn's disease The recommended Humira induction dose regimen for adult patients with severe Crohn’s disease is 80 mg at Week 0 followed by 40 mg at Week 2. In case there is a need for a more rapid response to therapy, the regimen 160 mg at Week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days), 80 mg at Week 2, can be used with the awareness that the risk for adverse events is higher during induction. After induction treatment, the recommended dose is 40 mg every other week via subcutaneous injection. Alternatively, if a patient has stopped Humira and signs and symptoms of disease recur, Humira may be re-administered. There is little experience from re-administration after more than 8 weeks since the previous dose. During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines. Some patients who experience decrease in their response may benefit from an increase in dose intensity to 40 mg Humira every week. Some patients who have not responded by Week 4 may benefit from continued maintenance therapy through Week 12. Continued therapy should be carefully reconsidered in a patient not responding within this time period.  Elderly patients No dose adjustment is necessary.  Children and adolescents There has been no experience in children.  Patients with kidney or liver failure The use of HUMIRA has not been studied in these patient populations. No dosage can be recommended.  For other indications already evaluated by the Transparency Committee, refer to the SPC.
ATC Classification (2007) L : Antineoplast L04 : Immunosupp L04A : Immunosupp L04AA : Selective im L04AA17 : Adalimumab
ic and immunomodulating agents ressants ressants munosuppressants  
Medicines in the same therapeutic category Comparator medicines Only one anti-TNF has MA for severe Crohn’s disease, resistant to corticosteroids and immunosuppressants: Remicade (infliximab)  
Medicines with a similar therapeutic aim - Azathioprine - High-dose corticosteroids (oral/IV administration) -use established but do not have an MA in this Drugs which have had their indication: methotrexate, 6-mercaptopurine, cyclosporin    
3.1. Efficacy The efficacy of HUMIRA (adalimumab) as an induction and maintenance treatment for Crohn's disease was evaluated in three studies which included more than 1,400 patients.  3.1.1. Induction treatment for Crohn's disease Two placebo-controlled studies were submitted: - I, 299 patients without any anti-TNF treatment CLASSIC - 325 patients who are intolerant to or have had secondary failure with GAIN, infliximab.  CLASSIC I1trial (anti-TNF naïve patients)  Objective: HUMIRA dose-ranging study for initiating clinical remission in Crohn’s disease.  Methodology - Double-blind, randomised, placebo-controlled study.  - criteria: Inclusion o Adults aged between 18 and 75 years o Moderate to severe Crohn’s disease (220 < CDAI* < 450), diagnosed for over 4 months o No previous anti-TNF treatment received.  
                                            1 Hanauer et al. Human anti-Tumor Necrosis Factor monoclonal antibody (adalimumab) in Crohn’s Disease: the CLASSIC-I Trial. Gastroenterology 2006; 130: 323-333.
  - Treatments  299 patients were randomised and split into 4 groups to receive in Week 0 (W0) and in Week 2 (W2): o HUMIRA 40 mg in W0 and 20 mg in W2 o HUMIRA 80 mg in W0 and 40 mg in W2 o 160 mg in W0 and 80 mg in W2 HUMIRA o in W0 and W2 placebo  Authorised concomitant treatments: 5-aminosalicylates (5 ASA), prednisone ( 20 mg/day), budesonide ( mg/day), azathioprine, 6-mercaptopurine, methotrexate 9 (MTX), antibiotics.  - duration: 4 weeks Study  - Primary endpoint: clinical remission after W4 based on a Crohn’s Disease Activity Index2 (CDAI) points. This is a criterion validated by the 2006lower than 150 European consensus conference3on the management of Crohn’s disease.  Results The characteristics of patients in both groups were similar on inclusion.  Patients included in the CLASSIC I trial do not correspond to the MA population: “severe Crohn's disease”. In fact, none of the patients included had severe Crohn’s disease (CDAI>450). Additionally, half (50%) of the patients were neither on corticosteroids nor on immunosuppressants at baseline.  These characteristics were discussed at the EMEA. The laboratory was requested to provide the percentage of severe patients (CDAI>450) included in this study. No patient with a CDAI score > 450 was included. The laboratory proposed a definition of severe patients as those with a CDAI score > 300, simultaneously receiving corticosteroids and/or immunosuppressants. This definition was accepted by the EMEA and covers all 299 patients included in the study.              
                                            2Standard measurement of the treatment’s efficacy, evaluating the disease’s signs and symptoms. It includes 8 items: the weekly number of liquid or very soft stools, the level of abdominal pain, general well-being, other events linked to the disease (fistula, arthritis, fever, uveitis), any abdominal mass, taking of antidiarrhoeal drugs, haematocrit and weight. The score ranges from 0 to 600. When there is a reduction in the CDAI score greater than or equal to 70 or 100, this is considered to be a clinical response. The disease’s activity is assessed according to the CDAI score value: 150 > CDAI > 220: mild CD, 220 > CDAI > 450: moderate CD, CDAI> 450: severe CD. 3Stange. European evidence based consensus on the diagnosis and management of Crohn’s disease: definition and diagnosis. Gut 2006; 55(Suppl I): i1-i15.
 Table 1: Characteristics of patients included in the CLASSIC I trial  Concomitant treatments   CDAI  Immuno- Corticosteroids5-ASA  (mean ± s.d.) suppressants - incl. budesonide - incl. systemic drugs HUMIRA 40/20 mg (23%) 17 (31%) 23299 ± 57 (50%) 37 (n=74)- 6 (8%) - 11 (15%) mg (53%) (43%) 40 (28%) 32301 ± 60 21 HUMIRA 80/40 (n=75)- 12 (16%) - 20 (27%) HUMIRA 160/80 39 (32%) (51%) 22295 ± 52 24 (29%) mg- 12 (16%) (n=76)- 12 (16%) placebo 25 (30%) 22296 ± 60 (50%) 37 (34%) (n=74)- 8 (11%) -17 (23%)  ITT analysis: the percentage of patients in clinical remission in Week 4 was considerably higher in the group that received HUMIRA 160 mg in Week 0, followed by 80 mg in Week 2 (27/76, 36%) than in the placebo group (9/74, 12%), p<0.001. No difference was highlighted between the placebo group and the HUMIRA 40/20 mg and 80/40 mg groups.  The quality of life evaluated as a secondary endpoint by the Inflammatory Bowel Disease Quality of Life (IBDQ) questionnaire after 4 weeks was significantly improved with HUMIRA 160 mg/80 mg and 80 mg/40 mg compared with placebo.
This induction dose-ranging study indicated that HUMIRA administered at a dosage of 160 mg, then 80 mg is effective to induce clinical remission in patients with Crohn’s disease.  There was no statistically significant difference highlighted between the HUMIRA 80/40 mg group and the placebo group in terms of clinical remission in Week 4 (primary endpoint). However, the 80/40 mg dosage of HUMIRA was chosen by the EMEA as the first-line dosage for the induction treatment for Crohn’s disease. In fact, additional analyses were carried out by the laboratory in Weeks 8 and 30, at the request of the Committee for Human Medicinal Products (CHMP) These analyses indicated a similar efficacy for the 160/80 mg and 80/40 mg induction doses for clinical remission in Week 8: 38% vs. 36%. Furthermore, the incidence of adverse events, particularly severe and serious effects (perianal abscesses and pneumonia) at 12 weeks was higher with the 160/80 mg dose than with 80/40 mg. The EMEA therefore felt that the 160/80 mg regimen could be used in patients where it was necessary to achieve a quicker response to treatment, even though there is a higher risk of adverse events with this dosage.         
                                            4 et al. Adalimumab Induction Therapy for Crohn’s Disease Previously Treated with Infliximab. Ann Sanborn Intern Med 2007; 146:829-838.  
 GAIN trial4(patients previously treated with infliximab)  Objective: To evaluate the efficacy of HUMIRA in patients with Crohn’s disease, with a loss of response and/or intolerance to infliximab.   Methodology - Double-blind, randomised, placebo-controlled study.  - criteria: Inclusion o Adults aged between 18 and 75 years o Moderate to severe Crohn’s disease (220 < CDAI < 450) oLoss of response and/or intolerance to infliximab: patients must have responded to an initial dose of infliximab and have received at least 2 doses of infliximab 5mg/kg every 8 weeks. They must have discontinued infliximab at least 8 weeks before inclusion.   - Treatments  325 patients were randomised and received either: o HUMIRA 160 mg in W0 and 80 mg in W2, or o placebo in W0 and W2 Authorised concomitant treatments: 5 ASA, prednisone (20 mg/day), budesonide ( 9 mg/day), azathioprine, 6-mercaptopurine, MTX, antibiotics.   Study duration: 4 weeks - - Primary endpoint: clinical remission (CDAI < 150 points) in W4  Results The characteristics of patients in both groups were similar at baseline.  Compared to the population of the CLASSIC I trial, the condition of the patients in the GAIN trial was more severe. A higher proportion of patients had previously been treated with corticosteroids and/or immunosuppressants. However, 30% of the included patients had never received corticosteroids and/or immunosuppressants. This means, contrary to European recommendations, that these patients had not received the conventional treatments before receiving infliximab.
Table 2: Characteristics of patients included in the GAIN trial  Concomitant treatments   CDAI Immuno- Corticosteroids  (mean ± s.d.) suppressants HmUg M(InR=A1 519)6 0/80 313 73 (46%) 55 (35%) placebo (n=166)313 85 (51%) 73 (44%)  Patients who had primary failure with infliximab were not included.        
45 (28%) 60 (36%)
Table 3: Characteristics of the patients included in the GAIN study reasons for discontinuing -treatment with infliximab. n  d sponse auqta eerIanede rse nsveAdr etopsedanIauqestneve es events adver (Hn U=M 1I5R9A) 160 mg/80 mg  (57%) 9587 (53%) (13%) 21  Control (n = 166) (48%) 95 77 (12%) (60%) 19  ITT analysis: the percentage of patients in clinical remission in Week 4 was considerably higher in the HUMIRA 160/80 mg group (4/159, 21%) than in the placebo group (12/166, 7%), p<0.001.  Purely exploratory subgroup analyses indicated that going into remission with HUMIRA was not dependent on the reason for the failure with infliximab (loss of efficacy and intolerance) and the presence or absence of anti-infliximab antibodies. The quality of life evaluated as a secondary endpoint by the IBDQ after 4 weeks was significantly improved with HUMIRA (30.2 point increase in score) compared with placebo (15.1 point increase in score).  In light of the results from the GAIN trial, HUMIRA might be considered as an alternative in patients who are intolerant or desensitised to infliximab. However, the EMEA did not grant this description of indication for the following reasons: - the definition of loss of response to infliximab was too vague - the study ought to have had an infliximab arm - the definition of intolerance to infliximab was inadequate - would have been interesting to have patients in this study who had primary failure it with infliximab.   3.1.2. Maintenance treatment for Crohn's disease The maintenance of clinical remission with HUMIRA was evaluated in a placebo-controlled study entitled CHARM (n = 854).  CHARM trial5  Objective: To evaluate the efficacy and safety of HUMIRA for maintaining clinical remission in patients with Crohn's disease who responded to the induction treatment with HUMIRA during the open-label phase.  Methodology - randomised, placebo-controlled study. Double-blind,  - criteria: Inclusion o aged between 18 and 75 years Adults o Moderate to severe Crohn’s disease (220 < CDAI < 450), having responded to induction treatment with HUMIRA.   Treatments -This study comprised two phases (induction and maintenance). A first 4-week open-label, induction phase during which the 854 patients included were given HUMIRA 80 mg in Week 0, then 40 mg in Week 2.  
                                            5 Colombel et al. Adalimumab for maintenance of clinical Response and Remission in Patients With Crohn’s Disease : The CHARM Trial. Gastroenterology 2007; 132 : 52-65.
At the end of the induction phase (Week 4), the patients were stratified according to their clinical response to the treatment (reduction in the CDAI score70 = CR-70 response) and were randomised in 3 groups to receive the treatment for a second 52-week phase (maintenance of remission): o 40 mg every other week HUMIRA o 40 mg weekly HUMIRA o placebo  A concomitant treatment at a stable dose (5-ASA, MTX, azathioprine, corticosteroids) was authorised. Patients who had previously been treated with another anti-TNF had to have discontinued this treatment at least 12 weeks before inclusion. The gradual decrease in corticosteroids was authorised after Week 8. Study duration: 56 weeks   < 150 points) in W26 and W56ima y endpoints: clinical remission (CDAI  -Pr r - Secondary endpoints: CR-70, CR-100, IBDQ, closure of fistulas, cessation of corticosteroids.  Results The patients had an average age of 37.1 years and their average CDAI score was 313. Table 4: CHARM trial - concomitant or previous treatments  Anti-TNF Corticosteroids Immuno-n (%) - incl. prednisone suppressants - incl. budesonide Total number of patients (n = 854) 376 (49.6%) 399 (44.0%) 24 (46.7%) 244 (28.6%) -- 100 (11.7%)  The modified ITT (mITT) population had been defined in the protocol as being the randomised patients who had a clinical response of CR-70 in W4.  In Week 4 58% (499/854) of patients had a clinical response. Among these patients 48% had been treated previously with an anti-TNF.  The baseline characteristics of these patients were as follows: average age: 36.7 years, average CDAI score: 317, concomitant or previous treatments: corticosteroids (42%), immunosuppressants (48%), anti-TNF (48%).  The percentage of patients in clinical remission in Week 26 and 56 was considerably higher with HUMIRA than with placebo. No difference was highlighted between the two HUMIRA groups in terms of clinical remission.  
Table 5: Maintenance of clinical remission (primary endpoint) in the CHARM trial  Placebo HUMIRA 40 mg every 2 HUMIRA 40 mg every weeks week  n = 170 n = 172 n = 157  Clinical remission in W26 17 % 40 %* 47 %* Clinical remission in W56 12 % 36 %* 41 %*  * p < 0.001 for HUMIRA versus placebo, paired comparisons of percentages  Table 6: Results for the secondary endpoints in the CHARM trial  Placebo HUMIRA 40 mg every 2 HUMIRA 40 mg every weeks week   Clinical response (CR-70)   W26 48/170 (28%) 93/172 (54 %)* 88/157 (56 %)* W56 30/170 (18%) 74/172 (43%)* 77/157 (49 %)* Clinical response (CR-100)   W26 45/170 (27%) 89/172 (52%)* 82/157 (52%)* W56 28/170 (17%) 71/172 (41 %)* 75/157 (48 %)*    Patients in remission without corticosteroids for90 daysa   W26 2/66 (3%) 11/58 (19%)** 11/74 (15%)** W56 3/66 (5 %) 17/58 (29 %)* 20% (15/74)**   * p < 0.001 for HUMIRAversusplacebo, paired comparisons of percentages ** p < 0.02 for HUMIRAversusplacebo, paired comparisons of percentages aAmong those initially treated with corticosteroids  The percentage of patients with a clinical response of CR-70 and CR-100* in Week 26 and 56 (secondary endpoints) was considerably higher with HUMIRA than with placebo.  The percentage of patients who had discontinued the corticosteroids for at least 3 months and remained in clinical remission was considerably higher with HUMIRA (20-30%) than with placebo (3-5%) in Week 26 and 56.  The quality of life evaluated by the IBDQ was considerably improved with HUMIRA compared to the placebo.  The fistula data was considered by the EMEA not to be sufficiently robust to be taken into consideration.   Extension phase: CLASSIC II trial The efficacy of HUMIRA in maintaining clinical remission in Crohn's disease was also evaluated in the extension phase of the induction study CLASSIC I.  This 5-year extension of the CLASSIC I trial is in progress. Results for year 16are available.  After 4 weeks of treatment with HUMIRA (CLASSIC I), 276 patients from the CLASSIC I trial were included in the CLASSIC II trial and split into 2 cohorts: one randomised (n = 55) and one open-label (n = 221). The primary endpoint was the maintenance of clinical remission after 56 weeks.  
                                            * reduction in CDAI score100 6Sandborn et al. Adalimumab for Maintenance treatment of Crohn’s disease : Results of the CLASSIC II trial. Gut published online 13 Feb. 2007; doi:10.1136/gut.2006.106781
The results of this study were not described by the laboratory : Furthermore, the small number of patients included in the randomised cohort makes it difficult to interpret the results of this study.  3.1.3. Other studies Four open-label studies (Study M03-602, Peyrin-Biroulet et al, Youdim et al, Hinojosa et al) and a retrospective study (Papadakis et al) involving small numbers of patients (24, 24, 7, 50 and 15) were submitted by the laboratory. The details have not been given for these studies due to their methodological weaknesses.  3.1.4. Comparative data No study has compared HUMIRA with infliximab in the treatment of Crohn’s disease.  Indirect comparison Details of the indirect comparison elements submitted by the laboratory cannot be detailed due to methodological differences between the ACCENT 1 (REMICADE) and CHARM (HUMIRA) trials. Table 7: ACCENT I & CHARM studies  ACCENT I CHARM Design Randomisation of responders in Week 2 Randomisation of responders in Week 4 Inclusion criteria - Exclusion of patients who had already - Inclusion of patients who had received  received anti-TNF treatment anti-TNF treatment (49%) in certain cases  (responders, then discontinuation,  inadequate response, intolerant) Exclusion criteria - Exclusion of patients with fistulised - Involvement of patients with fistulised Crohn’s disease Crohn’s disease Number of patients 580 854 % of patients who took 573 (99%), including 335 responders 778 (91%), including 499 responders part in the entire study (58%) (58%) Primary endpoint(s) Duration of maintenance of response Remission in Weeks 26 and 56 Remission in Week 30 Secondary endpoints W54: response CR-70, remission, IBDQ, W56: CR-70 and CR-100 responses, cessation of corticosteroids duration of remission, duration of response, cessation of corticosteroids, duration of cessation of corticosteroids, IBDQ and healing of fistulas   
Adverse events The HUMIRA safety data for Crohn’s disease has mainly come from the CLASSIC I, GAIN, CHARM and CLASSIC II clinical trials, which included over 1,400 patients.  In all these studies, HUMIRA’s safety profile was comparable to that already known for anti-TNF drugs, especially with regard to the risk of infection. 58% of patients had at least one infection. The percentage of patients who had infections possibly linked to the treatment was 2%. Twenty-eight patients (26 with HUMIRA and 2 with placebo) had opportunistic infections. Among these 28 cases 14 were considered as being possibly linked to the treatment, including three cases of tuberculosis.  The most common adverse events (³5%) were: injection site reactions, headaches, nausea, arthralgia, nasopharyngitis, stomach pain, fatigue, aggravation of Crohn’s disease.  Two deaths were reported (a 72-year-old man from a pulmonary embolism, a 56-year-old woman from acute leukaemia).