SPIRIVA - SPIRIVA RESPIMAT - SPIRIVA - CT 9435 - English version

SPIRIVA - SPIRIVA RESPIMAT - SPIRIVA - CT 9435 - English version

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Introduction SPIRIVA 18 microgram, inhalation powder, hard capsule B/30 capsules with inhaler (CIP code: 368 692-0) SPIRIVA RESPIMAT 2.5 microgram/dose, solution for inhalation B/60 doses with inhaler (CIP code: 381 920-3) Posted on May 25 2011 Active substance (DCI) tiotropium ATC Code R03BB04 Laboratory / Manufacturer BOEHRINGER INGELHEIM FRANCE SPIRIVA 18 microgram, inhalation powder, hard capsule B/30 capsules with inhaler (CIP code: 368 692-0) SPIRIVA RESPIMAT 2.5 microgram/dose, solution for inhalation B/60 doses with inhaler (CIP code: 381 920-3) Posted on May 25 2011

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Published 25 May 2011
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 The legally binding text is the original French version 
TRANSPARENCY COMMITTEE  OPINION  25 May 2011   Examination of the file for the proprietary medicinal product included for a period of 5 years by the Decree of 26 April 2006 (Journal Officielof 10 May 2006).  SPIRIVA 18 microgram, inhalation powder, hard capsule B/30 capsules with inhaler (CIP code: 368 692-0)   Applicant: BOEHRINGER INGELHEIM FRANCE  Tiotropium ATC code: R03BB04  List I  Date of Marketing Authorisation (mutual recognition): 8 July 2005   Joint renewal:  SPIRIVA RESPIMAT 2.5 microgram/dose, solution for inhalation B/60 doses with inhaler (CIP code: 381 920-3)  Date of Marketing Authorisation: 13 November 2007    Reason for request: Renewal of inclusion on the list of medicines refundable by National Health Insurance.          Medical, Economic and Public Health Assessment Division
 
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CHARACTERISTICS OF THE MEDICINAL PRODUCT
1.1. Active ingredient Tiotropium  
1.2. Indications “Tiotropium is indicated as a maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD).”  
1.3. Dosage “SPIRIVA 18mg, inhalation powder, hard capsule  The recommended dosage of tiotropium bromide is inhalation of the contents of one capsule once daily with the HandiHaler device at the same time of day. The tiotropium bromide powder contained in the capsule should only be inhaled with the HandiHaler.  SPIRIVA RESPIMAT 2.5mgmg/dose, solution for inhalation  The cartridge can only be inserted and used in the Respimat inhaler. The recommended dosage for adults is 5 microgram tiotropium given as two puffs from the Respimat inhaler once daily, at the same time of the day.  The recommended dose should not be exceeded.  Special populations Elderlycan use tiotropium bromide at the recommended dose.: Geriatric patients   Renal impairment: Renally impaired patients can use tiotropium bromide at the recommended dose. For patients with moderate to severe renal impairment (creatinine clearance 50 ml/min), the product should be used only if the expected benefit outweighs the potential risk. To date there is no long-term experience in patients with severe renal impairment.  Hepatic impairment: Hepatically impaired patients can use tiotropium bromide at the recommended dose. Liver insufficiency is not expected to have any significant influence on tiotropium bromide pharmacokinetics since the product is predominantly cleared by renal elimination (74% in healthy volunteers) and simple non-enzymatic ester cleavage to pharmacologically inactive products.  Paediatric patientsand effectiveness of tiotropium bromide inhalation powder in: safety paediatric patients have not been established and therefore it should not be used in patients under 18 years of age.” 
 
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2 REMINDER OF THE COMMITTEE’S OPINIONS AND CONDITIONS OF INCLUSION   Transparency Committee of 2 November 2005 The actual benefit of SPIRIVA is substantial. SPIRIVA shares the level IV improvement in actual benefit of long-acting beta2 agonist bronchodilators in the usual medical treatment of patients with COPD.   Transparency Committee of 7 October 2009 The actual benefit of SPIRIVA RESPIMAT 2.5 microgram/dose, solution for inhalation, is substantial. SPIRIVA RESPIMAT 2.5 microgram/dose, solution for inhalation, does not provide any improvement in actual benefit compared with SPIRIVA 18 µg, inhalation powder, hard capsule.    
 
3 SIMILAR MEDICINAL PRODUCTS
3.1. ATC Classification (2011) R Respiratory system R03 Drugs for obstructive airway diseases R03B Other drugs for obstructive airway diseases, inhalants R03BB Anticholinergics R03BB04 Tiotropium bromide  
3.2. Medicines in the same therapeutic category 3.2.1. Strictly comparable medicines SPIRIVA 18 µg and SPIRIVA RESPIMAT 2.5 µg/dose are the only medicines containing a long-acting anticholinergic bronchodilator indicated in COPD.  3.2.2. Medicines that are not strictly comparable  Inhaled long-acting beta2agonist bronchodilators indicated in the continuous treatment of COPD: Formoterol: FORADIL 12 µg per dose  FORMOAIR 12 µg per dose  ASMELOR NOVOLIZER 12 µg per dose  ATIMOS 12 µg per dose (not marketed)  OXIS TURBUHALER 12 µg per dose (not marketed) (Substantial AB)  
 
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  Indacaterol: HIROBRIZ BREEZHALER ONBREZ BREEZHALER  OSLIF BREEZHALER (Substantial AB)  These three proprietary medicinal products are not currently reimbursable but were the subject of an Opinion in which the Transparency Committee recommended inclusion on the lists of medicines refundable by National Health Insurance and approved for use by hospitals of 15 December 2010.  Salmeterol: SEREVENT 25 µg per dose  SEREVENT DISKUS 50 µg per dose (Substantial AB)  bronchodilators in several doses a day:  Short-acting Ipratropium: ATROVENT 20 µg per dose(substantial AB in the continuous symptomatic treatment of reversible COPD bronchospasm) Ipratropium + salbutamol: COMBIVENT 100/20 µg per dose(substantial AB) Ipratropium + fenoterol: BRONCHODUAL 100/40 µg per dose(substantial AB in the continuous symptomatic treatment of reversible COPD bronchospasm)   Long-acting beta2agonist bronchodilators combined with a corticosteroid: Budesonide + formoterol: SYMBICORT TURBUHALER 200/6 and 400/12 µg per dose (Moderate AB) Fluticasone + salmeterol: SERETIDE DISKUS 500/50 µg/dose   (Moderate AB)  These proprietary medicinal products are reserved for severe cases of COPD in patients with a history of repeated exacerbations and significant symptoms despite continuous treatment with a long-acting bronchodilator.   
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3.3. Medicines with a similar therapeutic a These are the other bronchodilator treatments: -short-acting beta2agonists, - theophylline and derivatives.   
 
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UPDATE ON DATA AVAILABLE SINCE THE PREVIOUS OPINION
4.1. Efficacy The company supplied two post-MA randomised clinical studies, one of them long-term versus placebo (the UPLIFT study) under conditions close to actual prescribing practice (no restriction on the coprescribing of other bronchodilators alone or in combination with inhaled corticosteroids), the other lasting one year versus salmeterol (the POET study).    Long-term study (four years) versus placebo: UPLIFT study  Main objective of tiotropium on the decline in FEV1 versus placeboTo evaluate the effect  
Method Inclusion criteria 
Main non-inclusion criteria 
Treatment groups 
Concomitant treatments Study schedule 
 
Randomised double-blind study lasting four years 
-Age40 years  - Moderate to severe COPD with post-bronchodilator FEV1 < 70% of predicted and a post-bronchodilator FEV1/FVC ratio of70% - Stabilised respiratory treatment for at least six weeks before randomisation -Former or current smoker > 10 pack-years 
- Diseases other than COPD which can put the patient at risk or influence the results of the study, such as asthma, cystic fibrosis, active tuberculosis, interstitial lung disease, or thromboembolic lung disease - Recent history of myocardial infarction (less than six months ago), cardiac arrhythmia (unstable or life-threatening) or hospitalisation on account of heart failure (NYHA III or IV) in the previous year - History of exacerbation of the COPD or respiratory infection within four weeks before the selection visit (V1) or during the run-in period (between V1 and V2) - History of lung transplantation or surgical reduction in lung volume -Angle-closure glaucoma; symptomatic benign prostatic hypertrophy or obstruction of the bladder neck (well-controlled patients can be included) - Known moderate to severe renal impairment - Oral corticosteroid treatment with nonstable doses or > 10 mg of prednisone equivalent per day -Need for daily oxygen therapy (more than 12 hours/day) Tiotropium 18 µg (inhalation powder)  Placebo  Administration 1x/day Patients continued to take their usual treatment during the study. 
- Prerandomisation (two weeks); smoking cessation offered to patients -Randomisation: treatment for 4 years -of treatment. In place of theirOpen follow-up for 30 days after the end treatment, patients received two inhalations four times a day of ipratropium to maintain the effect in patients who received the active treatment and the
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placebo. 
Primary efficacyendpoints: annual decline in the pre-dose and post-dose FEV1.Two joint 1 endpoints Measured between D30 and D1440 (four years). Only patients with three measurements in the spirometric tests from D30 onwards were included in the analysis. Main secondary Exacerbations:2 endpoints  time to the onset of the first exacerbation,  frequency of exacerbations per patient per year,  time to the onset of the first exacerbation leading to hospitalisation,  Lung function: annual decline in pre-dose and apacit (FVC)1  ypost-dose forced vital c  Quality of life: annual decline in the total SGRQ score3 and proportion of responders    Results: A total of 5992 patients were included in the study, 2986 in the tiotropium group and 3006 in the placebo group. The characteristics of the patients on inclusion were the same in the two groups. Three quarters of the patients were male, mean age about 65 years, and had had COPD for nearly 10 years. Most patients were in a moderate to severe stage of the disease, with about 45% in stage II and 44% in stage III. About 30% of the patients were still smokers. They had a smoking history of an average of 49 pack-years. The pre-dose FEV1 for the bronchodilator was 1101 ml in the tiotropium group and 1092 ml in the placebo group. The post-dose FEV1 for the bronchodilator was 1328 ml in the tiotropium group and 1315 ml in the placebo group. The patients had moderate impairment of their quality of life, with a mean total SGRQ score of about 45/100. The concomitant treatments, both on randomisation and during the study, were similar in the two treatment groups: 72% of the patients had been treated with long-acting bronchodilators, 74% with inhaled corticosteroid and 48% with a combination of long-acting beta2agonist and inhaled corticosteroid. The percentage of patients who dropped out of the study was 36.8% in the tiotropium group and 45.2% in the placebo group, mainly on account of adverse events (24.8% in the tiotropium group and 21.0% in the placebo group). About half the cases involved an aggravation of the disease. There were also a large number of dropouts for administrative reasons: 18.4% in the tiotropium group and 13.8% in the placebo group. 
                                            1 Measured 90 minutes after successive inhalations of the study treatment, ipratropium and salbutamol 2 exacerbation is defined as the appearance or aggravation of at least one of the followingAn respiratory symptoms: cough, expectoration, purulent sputum, shortness of breath, sibilant rhonchi, lasting for at least three days and requiring treatment with antibiotics and/or corticosteroids (oral, intramuscular or intravenous. They are broken down into three categories: “mild”: treated at the patient’s home, without recourse to a healthcare professional; “moderate”: necessitates a visit by a healthcare professional, without hospitalisation, and “severe”: leads to hospitalisation for more than24 hours). 3 SGRQ: quality of life questionnaire for patients with chronic impairment of the airways. Three categories are evaluated: “Symptoms” (particularlytheir frequency and severity), “Activity” (cause or consequence of the dyspnoea) and “Impact on everyday life” (mainly about working life). Each category is rated independently with a score from 0 to 100 and the sum total leads to the total score, which is also from 0 to 100 (a score of 0 means no impairment of the quality of life).  
 
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   endpoints Primary No statistically significant difference was observed between tiotropium and placebo in the annual decline in the pre- and post-dose FEV1 (see Table 1).  The pre-dose and post-dose FEV1 showed a larger increase with tiotropium than with placebo at the first measurement on D30 (p <0.0001); this difference was maintained for the four years of the study, with a mean difference over that period of 94 ml for the pre-dose FEV1 and 57 ml for the post-dose FEV1. However, these differences did not reach the level of clinical relevance which is usually set at 100 ml.  Table 1:post-dose FEV1 for the bronchodilator (UPLIFT study)Decline in the pre- and  
Tiotropium –  Placebo Tiotropium placebo 95% CI p difference FEV1 before bronchodilatation      Pre-dose[ml] 1097 ± 8 1188 ± 8    FEV1 on D30      Pre-doseFEV1 on D1470 [ml] 1091 ± 10 1083 ± 10     Decline in thepre-doseFEV1* [ml/year] -30 ± 1 -30 ± 1 0 ± 2 [-4; 4] 0.95 FEV1 after bronchodilatation FEV1 on D30 l 1330 ± 9 1377 ± 9      Pre-dose[m ]        Pre-doseFEV1 on D1470 [ml] 1273 ± 11 1276 ± 11     Decline in thepost-doseFEV1** [ml/year]  ± 2 ± 1 2-42 ± 1 -40 [-6; 2] 0.21 *Pre-dose = 2557FEV1: control group n = 2413 and tiotropium n *PostFEV1: control group n = 2410 and tiotropium = 2554 n   Secondary endpoints:  Exacerbations The median time to occurrence of the first exacerbation was significantly longer with tiotropium than with placebo: 16.7 months versus 12.5 months; RR = 0.86 (95% CI = [0.81; 0.91]); p < 0.0001. A statistically significant difference in favour of tiotropium was also observed for the median time to occurrence of the first exacerbation necessitating hospitalisation: 35.9 months versus 28.6 months; RR = 0.86 (95% CI = [0.78; 0.95]); p < 0.0024.  The frequency of moderate to severe exacerbations per patient-year was 0.73 with tiotropium and 0.85 with placebo (p < 0.0001). The difference between the groups is statistically significant but not clinically relevant (absolute difference of 0.12 exacerbation/patient-year, i.e. one exacerbation avoided every 8.3 years).  Forced vital capacity (FVC) No statistically significant difference was observed between tiotropium and placebo in the annual decline in the pre- or post-dose FVC. The pre-dose and post-dose FVC showed a larger increase with tiotropium than with placebo at the first measurement on D30 (p <0.0001); this difference was maintained for the four years of the study, with a mean difference over that period of 190 ml for the pre-dose FVC and 51 ml for the post-dose FVC.      
 
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 Quality of life (SGRQ score) No statistically significant difference was observed between tiotropium and placebo in the annual decline in the total SGRQ score. The mean total SGRQ score observed over the four years of the study was statistically higher in the tiotropium group without the difference between the groups reaching the level of clinical relevance (-4 points).     Study versus salmeterol: POET study  Main objective 
Method Inclusion criteria 
Main non-inclusion criteria 
Treatment groups 
Authorised concomitant treatments 
Primary efficacy endpoint Secondary endpoints included 
   
To compare the effect of tiotropium with that of salmeterol on the occurrence of exacerbations Randomised double-blind study lasting 12 months -Age 40 years  - Moderate to severe COPD with post-bronchodilator FEV170% of predicted and a post-short-acting-bronchodilator FEV1/FVC ratio of70% - History of at least one exacerbation in the preceding year which necessitated systemic antibiotic and/or corticosteroid treatment and/or hospitalisation -Former or current smoker³10 pack-years 
- Diseases other than COPD which can put the patient at risk or influence the results of the study, such as asthma, cystic fibrosis, active tuberculosis, life-threatening pulmonary obstruction - Recent history of myocardial infarction or hospitalisation for heart failure in the previous year, arrhythmia or cardiac disorders -Angle-closure glaucoma; symptomatic benign prostatic hypertrophy or obstruction of the bladder neck -Moderate to severe renal impairment - Exacerbation of COPD in the previous month - 10 mgOral corticosteroid treatment with nonstable doses or > of prednisone equivalent per day Tiotropium 18 µg (inhalation powder): 1x/day Salmeterol 50 µg: 2x/day Short-acting beta2agonists: if needed Inhaled corticosteroids Oral corticosteroids: if the patient is stabilised on a minimal dose Theophylline Mucolytics Time to occurrence of the first moderate to severe exacerbation4  Time to occurrence of the first exacerbation necessitating hospitalisation, Frequency of exacerbations Frequency of severe exacerbations 
                                            4 An exacerbation is defined as the appearance or aggravation of at least one of the following respiratory symptoms: cough, expectoration, purulent sputum, shortness of breath, sibilant rhonchi, lasting for at least three days and requiring treatment with antibiotics and/or corticosteroids (oral, intramuscular or intravenous). An exacerbation can be regarded as moderate or severe: - moderate: intensification or appearance of at least two of the above symptoms, with at least one symptom lasting at least three days and necessitating treatment with antibiotics but not requiring hospitalisation. - severe: the same criteria as those defining a moderate exacerbation and with a need to hospitalise the patient.
 
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 Results: A total of 7384 patients were included in the study, 7376 of whom received at least one dose of one of the treatments: 3707 in the tiotropium group and 3669 in the placebo group.  The characteristics of the patients on inclusion were the same in the 2 groups. The patients’ mean age was about 63 years and they had had COPD for 8 years. Most patients were in a moderate to severe stage of the disease, with about 48.7% in stage II and 42.6% in stage III. The percentage of smokers at the time of the study was 48%. They had a smoking history of an average of 38 pack-years. The mean FEV1 was 1.41 l (49.3% of predicted).  15.8% of the patients in the tiotropium group and 17.7% of those in the salmeterol group dropped out of the study, mainly on account of adverse events (7.1% in the tiotropium group and 8.0% in the salmeterol group), withdrawal of consent (5.2% in the tiotropium group and 5.7% in the salmeterol group).   Primary efficacy endpoint Since less than 50% of patients had an exacerbation during the study, the estimate of the time to occurrence of the first exacerbation is based on an analysis of the results in the 1st quartile (time at the end of which 25% of patients had had a first exacerbation). Under these conditions, the time to occurrence of the first moderate to severe exacerbation in the 1st quartile was 187 days (95% CI = 170; 203]) with tiotropium and 145 days (95% CI  [130; = 159]) with salmeterol with a hazard ratio of 0.83 (95% CI = [0.77; 0.90], p<0.0001).   Secondary endpoints: The time to occurrence of the first severe exacerbation was longer with tiotropium than with salmeterol with a hazard ratio of 0.72 (95% CI = [0.61; 0.85], p<0.0001, analysis in the 1st quartile). The study report does not give an absolute value for the time to occurrence of the first severe exacerbation which means that the clinical relevance of this result cannot be assessed.  The annual frequency of moderate to severe exacerbations was 0.64 exacerbation/patient-year with tiotropium and 0.72 exacerbation/patient-year with salmeterol. The difference between the treatments is statistically significant (RR = 0.89, 95% CI = [0.83; 0.96], p = 0.0017) but not clinically relevant (absolute difference of 0.08 exacerbation/patient-year, i.e. one exacerbation avoided every 12.5 years).  The annual frequency of severe exacerbations was 0.09 exacerbation/patient-year with tiotropium and 0.13 exacerbation/patient-year with salmeterol. The difference between the treatments is statistically significant (RR = 0.73, 95% CI = [0.66; 0.82], p < 0.0001) but not clinically relevant (absolute difference of 0.04 exacerbation/patient-year, i.e. one exacerbation avoided every 25 years).  
4.2. Adverse effects
4.2.1. Clinical studies  Long-term tolerance (4 years): UPLIFT study One or more adverse events were reported by about 92% of patients in the two groups, tiotropium and placebo.  The percentage of patients who had an adverse event linked to treatment was 10.2% in the tiotropium group and 7.8% in the placebo group, mainly due to dry mouth (4% versus 2%).  
 
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 Among the serious adverse events reported in more than 1% of patients, differences were observed in the frequency of cardiovascular adverse events; however, these data must be used with care since patients had major comorbidities including myocardial infarction and it is not known what influence the severity of the disease or confounding factors such as smoking was on cardiovascular morbidity and mortality in patients treated with anticholinergics.  Mortality During the corresponding period of treatment (four years) + 30 days post-treatment, the incidence of mortality was 4.10 per 100 patient-years in the tiotropium group and 4.79 per 100 patient-years in the placebo group with a hazard ratio of 0.84 (ITT analysis). This result obtained from the analysis of a secondary tolerance endpoint suggests a reduction in mortality with tiotropium compared with placebo.  Tolerance compared with that of salmeterol: POET study In this study, only serious adverse events were recorded systematically: 16.5% with salmeterol and 14.7% with tiotropium. The percentage of adverse events regarded as linked to treatment was comparable in the two groups. The most common were: respiratory, thoracic and mediastinal disorders (1.2% with tiotropium versus 1.4% with salmeterol), cardiac disorders (0.3% versus 0.1%) and gastrointestinal disorders (0.2% in the two groups).  The frequency of occurrence of major cardiac adverse events, fatal major cardiac adverse events and cerebral vascular accidents was similar with tiotropium and salmeterol.  Summary of product characteristics Since its first examination by the Transparency Committee, the “Undesirable effects” section has been amended to take account in particular of data from the UPLIFT study. Among the undesirable effects mentioned, only dry mouth is regarded as a common undesirable effect which was observed in about 4% of the patients included who were treated with tiotropium in 26 clinical studies (9149 patients) in which dry mouth led 18 patients to discontinue treatment. The serious undesirable effects attributed to anticholinergic effects include: glaucoma, constipation and intestinal obstruction, including paralytic ileus, plus urinary retent on i .  Pharmacovigilance The pharmacovigilance data (PSUR for the period from October 2001 to October 2008) did not reveal any new tolerance signal.  
4.3. Conclusion In a randomised double-blind study lasting four years, tiotropium (18 µg 1x/day) was compared with placebo in 5992 patients with moderate to severe COPD. The patients continued to take their usual treatment (other bronchodilator alone or in combination with an inhaled corticosteroid) during the study. No statistically significant difference was observed between tiotropium and placebo in the annual decline in the pre- and post-dose FEV1 (joint primary efficacy nepdios)nt. The statistically significant increase in pre- and post-dose FEV1 observed at the first visit on D30 was maintained over time but is not clinically relevant (< 100 ml).     
 
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 The median time to occurrence of the first exacerbation was significantly longer with tiotropium than with placebo (16.7 months versus 12.5 months, p < 0.0001), as was the median time to occurrence of the first exacerbation necessitating hospitalisation (35.9 months versus 28.6 months, p = 0.0024). On the other hand, the difference observed in favour of tiotropium in the frequency of exacerbations/patient-year, although statistically significant, is not clinically relevant (0.73 with tiotropium versus 0.85 with placebo, i.e. one exacerbation avoided every 8.3 years). No statistically significant difference was observed in terms of quality of life (SGRQ score).  Tiotropium was compared with salmeterol in a randomised double-blind study lasting one year in 7376 patients with moderate to severe COPD. The time to occurrence of the first moderate to severe exacerbation was longer with tiotropium than with salmeterol (187 days versus 145 days, RR = 0.83, p<0.0001, analysis in the 1st quartile), as was the time to occurrence of the first severe exacerbation necessitating hospitalisation (absolute values not available, HR = 0.72). The differences observed in terms of the frequency of moderate to severe exacerbations (difference of 0.08 exacerbation/patient-year) or severe exacerbations (differences of 0.04 exacerbation/patient-year) were statistically significant but not clinically relevant: one moderate to severe exacerbation avoided every 12.5 years, one severe exacerbation avoided every 25 years.  The long-term tolerance data showed that the treatment-related adverse event most commonly observed with tiotropium was dry mouth (about 4% of patients versus 2% with placebo). The percentage of treatment-related adverse events was similar with tiotropium and salmeterol, in particular for cardiovascular adverse events. The pharmacovigilance data did not reveal any new tolerance signal.  In conclusion, these new data confirm the efficacy and long-term tolerance of tiotropium compared with placebo in terms of the improvement in FEV1; however, this effect is modest and the annual decline in FEV1 is not slowed down under the influence of tiotropium as compared with placebo. The comparative data versus salmeterol did not reveal any clinically relevant difference between tiotropium and salmeterol in terms of efficacy or tolerance.   
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DATA ON USE OF THE MEDICINE
  According to data from the IMS-DOREMA panel (rolling total as at November 2010), 1.23 million prescriptions were issued for SPIRIVA 18 µg. This proprietary medicinal product was prescribed mainly for chronic obstructive airway diseases (59%) and respiratory failure (8.7%). It should be noted that there was off-label prescription in asthma (8.9%).        
 
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