DESERNIL - DESERNIL - CT 12062 - English version

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Introduction DESERNIL 1.65 mg, tablet B/20 (CIP: 302 982-0) Posted on Mar 19 2013 Active substance (DCI) methysergide (maleate) ATC Code N02CA04 Laboratory / Manufacturer CENTRE SPECIALITÉS PHARMACEUTIQUES DESERNIL 1.65 mg, tablet B/20 (CIP: 302 982-0) Posted on Mar 19 2013

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• Publié par: haute-autorite-sante-maladies-systeme-nerveux
• Publié le: 23 mai 2012
• Nombre de lectures: 18
• Licence : En savoir +
  Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
• Langue: English

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    The legally binding text is the original French version     TRANSPARENCY COMMITTEE   OPINION   23 May 2012       DESERNIL 1.65 mg, tablet B/20 (CIP: 302 982-0)     Applicant: CENTRE SPECIALITÉS PHARMACEUTIQUES   Methysergide (maleate) ATC code: N02CA04 (ergot alkaloid)   List II   Date of Marketing Authorisation (national procedure): 6 September 1994     Reason for request: Re-assessment of Actual Benefit of proprietary medicinal products based dihydroergotamine, in accordance with Article R 163-21 of the social security code. 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   Methysergide (maleate)  

1.2. Indications   “Preventative treatment for migraine and cluster headache”.  

1.3. Dosage   This proprietary medicinal product is reserved for adults.   Administration should be gradual: the starting dose is half a tablet, with the evening meal, for a few days. This daily dose should be increased to 2 or 3 tablets per day, at mealtimes. After a few weeks of treatment, gradually reducing the dose will enable an effective maintenance dose to be found.   Continuous administration should not exceed 6 months.     2 SIMILAR MEDICINAL PRODUCTS  

2.1.   N 02 C A 04  

ATC Classification (2011)

         

: Nervous system : Analgesics : Antimigraine preparations : Ergot alkaloids : Methysergide

2.2. Medicines in the same therapeutic category   Preventative treatment for migraine: The products in question are the dihydroergotamine-based rye ergot derivatives DIHYDROERGOTAMINE AMDIPHARM 3 mg, tablet DIHYDROERGOTAMINE AMDIPHARM 2 mg/ml, oral solution in drops IKARAN LP 5 mg, tablets IKARAN Ge 2 mg/ml, oral solution in drops (generic) SEGLOR 5 mg, hard capsule SEGLOR LYOC 5 mg, oral lyophilisate TAMIK Ge 3 mg, soft capsule (generic)   Cluster headache: There are no other proprietary medicinal products in the same class having the same indication.  

 

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2.3. Medicines with a similar therapeutic aim   Beta-blockers:   - metoprolol (LOPRESSOR, SELOKEN) - propranolol (AVLOCARDYL). Propranolol is also indicated in the preventative treatment of cluster headache   Antidepressant: amitriptyline (LAROXYL)   Anticonvulsant: topiramate (EPITOMAX)   Other products indicated in the preventative treatment of migraine: flunarizine (SIBELIUM), indoramine (VIDORA), oxetorone (NOCERTONE), pizotifen (SANMIGRAN).     3 ANALYSIS OF AVAILABLE DATA

    Prescribing data: According to IMS data (moving annual total November 2011), 6000 prescriptions were issued for DESERNIL. The small number of prescriptions is insufficient to allow a qualitative analysis of the data.   This proprietary medicinal product has been on the world market since 1948, and in France since 1962.    Efficacy This proprietary medicinal product has been on the market since 1948. The efficacy data available at the present time are incomplete.   A literature review 1 published in 1998 reports on 11 comparative double-blind clinical studies (versus placebo or active comparator [pizotifen, lisuride, propranolol or flunarizine]). These studies were conducted between 1964 and 1986. The results were analysed in 596 migraine patients (70%) out of a total of 849 subjects. The exact inclusion criteria are not recorded. The dose administered varied between 3 and 6 mg/day. The methysergide dosage according to the Marketing Authorisation is from 3.3 mg/day to 4.95 mg/day. The endpoints are not clearly described. No primary endpoints are indicated, and neither is a statistical test for each of the studies. Given the methodological shortcomings, the results cannot be taken into account.   One study 2  1986 evaluated the efficacy of methysergide versus 5-hydroxytryptophane in in migraine subjects. There are no proprietary medicinal products in France based on this active ingredient indicated in the preventative treatment of migraine. In the absence of a placebo group, the magnitude of the methysergide effect in the preventative treatment for migraine cannot be established.  

                                             1 Silberstein SD. Methysergide. Cephalalgia. 1998; 18: 421-435. 2 the prophylaxis of migraine. Randomized clinical trial.Titus F et al. 5-Hydroxytryptophan versus methysergide in Eur Neurol. 1986; 25: 327-329.

 

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The efficacy of methysergide was evaluated in a study 3 in 130 migraine subjects. In view of the absence of a comparator group, the results of this study cannot be taken into account.   AFSSAPS data Following the pharmacovigilance survey of ergot derivatives, the Regional Pharmacovigilance Centres collected 13 cases associated with methysergide ingestion, consisting of 11 cases of retroperitoneal fibrosis and 2 cases of multiple valve disease, from the database from 1 January 1984 to 31 July 2011. The mean treatment duration was 52.5 months and the mean time to onset of adverse effects was 18.2 months. A therapeutic window involving a 1-month treatment suspension every 6 months is recommended.  According to the AFSSAPS data, it is estimated that the number of patients treated observing these recommendations (stopping treatment for 1 month every 6 months) was 1970, and the number of patients ignoring them was 1810. In other words, the recommendations for a therapeutic window are poorly observed in over half of cases.   The literature correlates cases of retroperitoneal fibrosis essentially with cases where prescription durations (> 6 months: 136 cases) are ignored, and less often with cases where prescription durations are heeded (< 6 months: 12 cases). Among the cases of retroperitoneal fibrosis identified by the Regional Pharmacovigilance Centres, the therapeutic window was observed in three cases, which means that observing therapeutic windows does not prevent the risk of onset of fibrosis.   Applicant’s pharmacovigilance data The applicant provided pharmacovigilance data covering the period from June 1968 to 31 October 2011. During this period, 325 adverse events involving fibrosis and affecting 256 patients were observed. Among these 325 adverse events, 80 (24.5%) were cases of valve disease, 148 (45.5%) of retroperitoneal fibrosis and 68 (20.1%) of pleural or pulmonary fibrosis (the other cases are unspecified).    In addition, the applicant provided pharmacovigilance data (Periodic Safety Update Reports) covering the period from 1 March 2006 to 28 February 2009. During this period, there were 175 adverse effects reported in 51 patients. Of these 175 effects, 91 were considered serious. The most common serious adverse effects are listed in the MedDRA classification according to the SOCs “nervous system disorders” (n= 17), “cardiac disorders” (n = 11), “general disorders and disorders related to the route of administration” (n = 12). There are data supplementing this Periodic Safety Update Report for the period from 1 March 2009 to 28 February 2011, during which three non-serious adverse effects and one case of retroperitoneal fibrosis were observed.

Conclusion  The efficacy data relating to methysergide are out of date and somewhat limited. The demonstration of the efficacy of methysergide in the preventative treatment of migraine offers a low level of evidence. As with all ergot derivatives, there are risks of retroperitoneal, pleuropulmonary, pericardial and cardiac valve fibrosis.  

                                             3  Drummondrelation to clinical features of migraine. Headache. 1985; 25: PD. Effectiveness of methysergide in 145-146.  

 

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TRANSPARENCY COMMITTEE CONCLUSIONS

4.1. Actual benefit   Migraine is a painful condition characterised by a marked deterioration in the quality of life. Cluster headache is a severe and disabling disease having a marked deleterious effect on patients’ quality of life.   This proprietary medicinal product is intended as a preventive therapy.   The efficacy/adverse effects ratio of this proprietary medicinal product in these indications is unfavourable.    There are treatment alternatives to this proprietary medicinal product with better evidence of efficacy and better safety, especially products based on propranolol and metoprolol.   The actual benefit of this proprietary medicinal product in its indicationsis insufficient.   

4.2. Transparency Committee recommendations   The transparency Committee does not recommend continued inclusion on the list of medicines refundable by National Health Insurance and on the list of medicines approved for hospital use and various public services.  

 

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