SINGULAIR - SINGULAIR - CT 3292 - English version
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Introduction SINGULAIR 5 mg, chewable tablet Box of 28 (CIP: 346 128-5) Box of 49 (CIP: 561 943-1) Posted on Jun 18 2009 Active substance (DCI) montelukast ATC Code R03DC03 Laboratory / Manufacturer MERCK SHARP & DOHME-CHIBRET SINGULAIR 5 mg, chewable tablet Box of 28 (CIP: 346 128-5) Box of 49 (CIP: 561 943-1) Posted on Jun 18 2009
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| Publié par | haute-autorite-sante-maladies-appareil-respiratoire |
| Publié le | 31 janvier 2007 |
| Nombre de lectures | 12 |
| Licence : |
En savoir + Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
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| Langue | English |
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The legally binding text is the original French version TRANSPARENCY COMMITTEE
OPINION 31 January 2007 SINGULAIR 5 mg, chewable tablet Box of 28 (CIP: 346 128-5) Box of 49 (CIP: 561 943-1) Applicant: MERCK SHARP & DOHME-CHIBRET montelukast ATC Code: R03DC03 List I Date of Marketing Authorisation : March 20, 1998, revision March 8, 2006 Reason for request: Inclusion on the list of medicines reimbursed by National Insurance and approved for use by hospitals and various public services in the extension of indication. “SINGULAIR may also provide an alternative to inhaled corticosteroids in small doses in patients with mild persistent asthma, without a recent history of severe asthma attacks, having justified treatment with oral corticosteroids and whose inability to comply with treatment using inhaled corticosteroids has been demonstrated. Health Technology Assessment Division
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CHARACTERISTICS OF THE MEDICINAL PRODUCT
1.1. Active ingredient montelukast
1.2. Indication (Latest modifications to SPC in bold) SINGULAIR is indicated in the treatment of asthma as add-on therapy in those patients with mild to moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom “as-needed short acting beta-2 adrenergic agonists provide inadequate clinical control of asthma SINGULAIR®is also indicated in the prophylaxis of exercise-induced asthma. SINGULAIR may also provide an alternative to small doses of inhaled corticosteroids in patients with mild persistent asthma, without recent history of severe asthma attacks, having justified treatment with oral corticosteroids and whose inability to comply with treatment using inhaled corticosteroids has been demonstrated.
1.3.Dosage and method of administration (Latest modifications to SPC in bold) The 5 mg form of SINGULAIR®is reserved for children aged between 6 and 14 years. A 10 mg form is indicated for adolescents from 15 years of age. The recommended dosage in children aged between 6 and 14 years is one 5 mg chewable tablet per day, to be taken in the evening. There should be a certain interval between taking the drug and mealtimes, with a gap of at least one hour before or two hours after consuming food. No dosage adjustment is required in this age group. General recommendations: the therapeutic effect of SINGULAIR on of the control of asthma symptoms are noticeable from the first day of treatment. Patients should be advised to continue their treatment even if their asthma is under control, as well as during periods of exacerbation of their symptoms. No dose adjustment is necessary in patients with renal impairment or mild to moderate hepatic impairment. No data is available on patients with severe hepatic impairment. The dosage is the same for both male and female patients. SINGULAIR is used as an alternative to treatment with small doses of inhaled corticosteroids for mild persistent asthma Montelukast is not recommended as monotherapy in patients with moderate persistent asthma. The use of montelukast as an alternative to inhaled corticosteroids in small doses must only be considered for children with mild persistent asthma, without any recent episodes of severe asthma attacks, having justified treatment with oral corticosteroids and whose inability to comply with treatment using inhaled corticosteroids has been demonstrated (see Section 4.1 of the SPC). Mild persistent asthma is characterised by daytime symptoms manifesting more than once a week, but less than once a day, with night symptoms occurring more than twice a month, but less than once a week, with normal pulmonary function between the attacks. If during the check-up the patient’s asthma is judged to be inadequately controlled (usually during the following month), treatment with an additional or different anti-
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inflammatory must be considered according to a gradual management scheme. Asthma control must be assessed regularly in these patients. When SINGULAIR is used as a treatment to supplement inhaled corticosteroids, it must not be substituted for inhaled corticosteroids (see Section 4.4. of the SPC).
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SIMILAR MEDICINAL PRODUCTS
2.1. ATC Classification (2006) R: Respiratory system R03: Drugs for obstructive airway diseases R03D: Other systemic drugs for obstructive airway diseases R03DC: Leukotriene receptor antagonists R03DC03: Montelukast
2.2. Medicines in the same therapeutic category SINGULAIR is the only representative in the leukotriene receptor antagonist category.
2.3. Medicines with a similar therapeutic aim This includes all anti-asthma drugs (short and long-term action beta-2 agonist bronchodilators, anticholinergic bronchodilators, theophylline and its derivatives, inhaled corticosteroids).
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ANALYSIS OF AVAILABLE DATA
3.1. Efficacy The laboratory submitted a pivotal study (MOSAIC study1), which compared SINGULAIR 5 mg administered as monotherapy to an inhaled corticosteroid, fluticasone, among 6 to 14 year-old children with mild persistent asthma. This was a 12-month, double-placebo, randomised, double-blind, non-inferiority study. Inclusion criteria: · Children aged 6 to 14 years. ·Mild persistent asthma corresponding to step 2 of the GINA recommendations (1998) (asthma symptoms in the three months prior to the visit a least once a week, but not daily).
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Active treatment including a short-acting beta-2 agonist or a primary treatment combined with a short-acting beta-2 agonist.
The patient had to meet the following 4 conditions during the pre-randomisation visit: A history of at least 12 months of symptoms, including (but not limited to), dyspnoea, wheezing, bronchoconstriction, coughing or expectoration.
FEV1 A³80% of the predictive value (measurement taken pre-bronchodilator and at least 6 hours since the last dose of short-acting beta-2 agonist was taken), measured at least twice during the selection placebo period (visits 1, 2 or 3), and a FEV1 or peak expiratory flow³ of the predictive value on 70% pre-randomisation visit 3. A diagnosis of mild persistent asthma defined on the basis of:
- Anincrease in FEV1 or a peak expiratory flow³12% (absolute value), 20 to 30 minutes after an inhaled short-acting beta-2 agonist has been administered at the 3 pre-randomisation visits. - A positive provocative test for methacoline or histamine at a concentration causing a 20% reduction in FEV1 (corresponding to a reduction in FEV1≤8 mg/mL).
- reduction in FEV1 A³15% after an exercise test. Presence of symptoms requiring short-acting beta-2 agonists to be taken between 2 and 6 days a week during the 2 weeks prior to visit 3. Furthermore, patients had to be in good health, apart from having asthma, and capable of chewing a tablet. Treatment Phase 1: Four weeks prior to randomisation, patients discontinued their primary treatment and received single-blind a placebo of montelukast and fluticasone and a short-acting beta-2 agonist as needed.
1 Garcia M.L., Wahn U., Gilles L., Swern A., Tozzi C.A. and Polos P. : Montelukast, compared with fluticasone, for control of asthma among 6 to 14 years-old patients with mild asthma: the MOSAIC study.Pediatrics 2005, 116(2):360-69
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Phase 2 At the end of the selection period, the patients meeting the inclusion criteria were randomised to receive: - Eithermg oral daily dose of montelukast (10 mg if the patient turns 15 during the a 5 study) in the evening when going to bed (n=495) and the fluticasone placebo -µg twice a day of inhaled fluticasone (two 50 µg puffs morning and evening) or 100 (n=499) and the montelukast placebo. Primary efficacy endpoint: Percentage of days without any relief treatment asthma treatment (short-acting beta -2 agonist, systemic corticosteroid or any other relief treatment). A day without relief treatment was defined as a whole day during which a patient: -did not take any relief treatment - did not resort to unscheduled care linked to asthma (unscheduled visit to a doctor, relief treatment department or admission). Montelukast was considered to be non-inferior to fluticasone if the upper limit of the 95% confidence interval for the average of the least squares of the difference between treatments was greater than -7%, which corresponds to around 2 days without taking relief treatment a month. Results The analysis was carried out on a population of patients treated for at least 1 day. Seven data points (during the placebo and study periods) were necessary for the measurements to be included in the main analysis. The mean percentage of days without relief treatment asthma prior to randomisation was 61.4% in the montelukast group and 60.5% in the fluticasone group. After 1 year of treatment this rate increased in the two treatment groups: 84.0% in patients with montelukast and 86.7% with fluticasone. The difference in the means of the least squares was -2.8%, with a 95% confidence interval of [-4.7%; -0.9%]. As the lower limit of this interval was higher than the non-inferiority threshold of -7%, montelukast was considered to be non-inferior to fluticasone in terms of percentage of days without relief treatment.
3.2. Adverse events During the MOSAIC study the proportions of patients affected by adverse events attributable to the treatment were similar in the montelukast group (4.4%) and fluticasone group (3.2%). The most common adverse events occurring in over 0.5% of the patients were headaches (2.2% with montelukast and 1.0% with fluticasone) and bronchospasms (0.6% with montelukast and 0.4% with fluticasone). There were no severe adverse events attributable to the treatment during the study’s 12-month duration. The rate of growth after 12 months of treatment was 5.81 cm/year with fluticasone and 6.18 cm/year with montelukast. The SPC does not mention any other adverse effects observed specifically in children.
3.3. Conclusion In the MOSAIC study (randomised, double-blind) carried out on children aged 6-14 years, with mild persistent asthma, montelukast was non-inferior to inhaled fluticasone in terms of percentage of days without emergency care (emergency medication or unscheduled care) after 1 year of treatment. The treatments were well tolerated in both groups. The most common adverse effects (>0.5%) were headaches and asthma.
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TRANSPARENCY COMMITTEE CONCLUSIONS
4.1. Actual benefit Asthma is characterised by the development of a disability and a deterioration in the quality of life. It may be life-threatening in exceptional cases. SINGULAIR 5 mg is part of the primary treatment for asthma patients. Public health benefit: The public health burden due to asthma is significant. Among the sub-population of patients likely to receive SINGULAIR 5 mg for this indication, the burden is low, in view of the small number of patients concerned. Improving the therapeutic management of asthma is a public health need. In spite of good tolerance and even though SINGULAIR 5 mg can provide a benefit in terms of improving compliance in children who are unable to comply with treatment using corticosteroids, it is not expected, at population level, to have an impact on reducing the morbidity associated with asthma. Consequently, SINGULAIR 5 mg is not expected to benefit public health in this indication. The efficacy/safety ratio for this product is high. This medicinal product is a second-line treatment for children (6-14 years) with mild persistent asthma, without a recent history of severe asthma attacks, having justified treatment with oral corticosteroids and whose inability to comply with treatment using inhaled corticosteroids has been demonstrated. There are alternative drugs available. The actual benefit of SINGULAIR 5 mg for this indication is substantial.
4.2. Improvement in actual benefit SINGULAIR 5 mg in chewable tablet form, as an alternative to inhaled corticosteroids in small doses, provides a minor improvement in actual benefit (IAB IV) in terms of efficacy and safety in managing patients with mild persistent asthma, without any recent history of severe asthma attacks, having justified treatment with oral corticosteroids and whose inability to comply with treatment using inhaled corticosteroids has been demonstrated.
4.3. Therapeutic use 4.3.1. Usual therapeutic strategy for treating asthma Given that patient follow-up is focused on asthma control, the therapeutic strategy is adapted to the level of asthma control and the primary care being administered. Where the level of control is acceptable or ideal, the minimum effective treatment should be sought. · for Treatmentintermittent asthma inhaled short-acting beta-2 agonists only in requires the case of respiratory discomfort. ·Treatment forpersistent asthmavaries according to the stage:
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The primary treatment is associated with the treatment of the symptoms (short-acting beta 2-agonists inhaled as needed). mild persistent asthma: Daily preventive treatment with anti-inflammatories using a small dose of inhaled corticosteroids.
moderate persistent asthma: - First of all, the dosage of inhaled corticosteroids must be increased in order to control the inflammatory component as well as possible. - Secondly, when short-acting beta-2 agonists are being taken several times daily or when there are night symptoms, it is recommended to also use a long-acting bronchodilator (long-acting inhaled beta-2 agonist or sustained-release oral beta-2 agonist). The recent recommendations from ANAES-AFSSAPS envisage the possibility of using straightaway a combination of an inhaled corticosteroid and a long-acting inhaled beta-2 agonist in the case of severe symptoms or impaired respiratory function. Anti-leukotrienes may be used as a supplementary treatment to inhaled corticosteroids as an alternative to long-acting beta-2 agonists. Sustained-release theophylline is an alternative to long-acting beta-2 agonists (which are prefererred), especially when there are night symptoms. but it poses a number of disadvantages, including the need for follow-up treatment due to its narrow therapeutic margin, its many adverse effects and numerous drug interactions. severe persistent asthma: This most often requires a combination of a high dose of inhaled corticosteroids, a long-acting bronchodilator (long-acting beta-2 agonists, sustained-release theophylline or anticholinergics) and oral corticosteroids. The aim of combining a high dose of inhaled corticosteroids and long-acting bronchodilators is to delay or reduce the use of long term oral corticosteroids. In patients with severe persistent allergic asthma (confirmed by the IgE dosage), which is poorly controlled using standard treatments such as a high dose of inhaled corticosteroids and a long-acting beta-2 agonist, supplementary treatment with omalizumab (anti-IgE) may be an alternative to treatment with oral corticosteroids.
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4.3.2. Use of SINGULAIR 5 mg Montelukast is not intended to be used for treating asthma attacks. In the case of dyspnoea or an asthma attack, an immediate and short-acting inhaled beta-2 agonist must be used. SINGULAIR 5 mg is a primary treatment for mild to moderate persistent asthma, which is used: · Either as monotherapy as an alternative to inhaled corticosteroids in small doses in patients with mild persistent asthma, without a recent history of severe asthma attacks, having justified treatment with oral corticosteroids and whose inability to comply with treatment using inhaled corticosteroids has been demonstrated; ·supplementary treatment to treatment with inhaled corticosteroids in patients with as a Or mild to moderate asthma and whose asthma is inadequately controlled on inhaled corticosteroids, despite the use of short-acting beta-2 agonists. There is no data available at the moment making it possible to indicate exactly where SINGULAIR should be used in relation to long-acting beta-2 agonists as part of a supplementary treatment to inhaled corticosteroids in patients with moderate asthma, inadequately controlled by inhaled corticosteroids and taking short-acting beta-2 agonists (see detailed comments in the opinion of July 6, 2005).
In the preventive treatment of exercise-induced asthma, mainly in children, SINGULAIR 5 mg is a first-line treatment as an alternative to short-acting beta-2 agonists when the symptoms only appear during exercise or as a supplementary treatment to inhaled corticosteroids in the case of persistent symptoms during exercise, in spite of administering inhaled corticosteroids as primary treatment. SINGULAIR 5 mg is reserved for children aged between 6 and 14 years. Montelukast is of particular benefit in the case of managing asthma in children, particularly because it is taken orally once a day just before going to bed.
4.4. Target population The target population for SINGULAIR for the extension of indication is defined by patients with mild persistent asthma, without a recent history of severe asthma attacks, having justified treatment with oral corticosteroids and whose inability to comply with treatment using inhaled corticosteroids has been demonstrated. According to the data from the CREDES study2, the prevalence of mild persistent asthma is around 2% in children aged 6-14 years. Extrapolating this prevalence to the French population (INED 2005 data), the population of children aged 6 to 14 years with mild persistent asthma can be estimated at around 130,000. In view of the absence of any published epidemiological data making it possible to estimate the population of patients without any history of severe asthma attacks, having justified treatment with oral corticosteroids, the laboratory submitted a Thales study (retrospective study, annual mobile total, January 2006).
2Com-Ruelle L. et al. : L’asthme en France selon les stades de sévérité. CREDES 2000.
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According to this data, among patients aged 6 to 14 years, classified with mild persistent asthma, only 11% i.e. 14,300 patients had received treatment with inhaled corticosteroids in small doses (beclomethasone - daily dose of up to 200 µg, budesonide - daily dose up to 400 µg and fluticasone - daily dose up to 200 µg). Patients who received treatment with short-acting oral corticosteroids in the previous 6 months accounted for 22%. As a result, 88% of patients with mild persistent asthma did not have any recent history of a severe asthma attack, which corresponds to 12,584 patients. Note: these results must be considered with caution insofar as the diagnosis for mild persistent asthma was based on the clinical diagnosis (GINA 2005) or the drug treatment prescribed during the last prescription and both approaches were correlated in only 3.9% of cases. In the literature, four studies4,5,6,7the compliance with inhaled corticosteroids in examined children (from the age of 2) and adolescents, with one study even including young adults (up to the age of 21). Compliance varied in these studies between 30 and 60%. Non-compliance among children can therefore be estimated between 40 and 70%. On the basis of this compliance data, the target population of SINGULAIR in this extension of indication would be between 5,000 and 9,000 patients.
4.5. Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines reimbursed by National Insurance and on the list of medicines approved for use by hospitals and various public services in the Marketing Authorisation's extension of indication and dosage. 4.5.1. Packaging: Appropriate for the prescribing conditions
4.5.2. Reimbursement rate : 65%
4Patel P, Hutson A, Chesrown S, Hendeles L. Adherence to oral montelukast and inhaled fluticasone in children J, Sherman with persistent asthma.Pharmacotherapy 2001;21(12):1464-1467. 5 JA, Lozano P, Farber HJ, Miroshnik I, Lieu TA. Underuse of controller medications among medicaid-insured Finkelstein children with asthma.Arch pediatr adolesc med 2002;156:562-567. 6 Kelloway JS, Wyatt RA, Adlis SA. Comparison of patients’compliance with prescribed oral and inhaled asthma medications. Arch Inter Med 1994;154:1349-52. 7Non compliance and treatment failure in children with asthma.Milgrom H, Bender B, Ackerson L, et al. J. Allergy clin immunol, 1996, 98, n°6 : 1051-1056.
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