TRANSPARENCY COMMITTEE OPINION. 10 December 2008

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 10 December 2008 RELISTOR 12 mg/0.6 ml solution for injection 1 vial (CIP: ) 2 vials + 2 sterile syringes + 4 alcohol pads (CIP: ) 7 vials + 7 sterile syringes + 14 alcohol pads (CIP: ) Applicant: WYETH PHARMACEUTICALS FRANCE Methylnaltrexone (bromide) ATC Code: Currently unavailable Date of MA: July 2, 2008 (centralised procedure) Reason for request: Inclusion on the list of medicines reimbursed by National Insurance and approved for use by hospitals. Medical, Economic and Public Health Assessment Division

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Methylnaltrexone bromide 1.2. Background RELISTOR is the first selective peripheral µ-opioid receptor antagonist indicated for the treatment of constipation Indication Treatment of opioid-related constipation in patients suffering from an advanced stage disease and receiving palliative care, when the response to usual laxatives is insufficient Dosage For adults only RELISTOR should be given to enable patients to regain good digestion fast when they are not responding sufficiently to usual laxatives. The recommended dosage for methylnaltrexone bromide is 8 mg (0.4 ml RELISTOR) (for patients weighing 38 to 61 kg) or 12 mg (0.6 ml RELISTOR) (for patients weighing 62 to 114 kg). The recommended administration is one dose, once every two days. Doses can also be taken further apart, according to clinical needs. Patients may only be given two consecutive doses 24 hours apart in case of the first dose has had no effect (good digestion not regained). Patients whose weight lies outside the specified ranges must be given a dose of 0.15 mg/kg. For these patients, the volume injected should be calculated as follows: Dose (ml) = patient s weight (kg) x Renal impairment: In patients presenting with severe renal impairment (creatinine clearance < 30 ml/min), the dose of methylnaltrexone bromide must be reduced from 12 mg to 8 mg (0.4 ml RELISTOR) for those weighing between 62 and 114 kg, or from 0.15 mg/kg to mg/kg for those weighing less than 62 kg or more than 114 kg. In the absence of available data, RELISTOR is not recommended for patients with end-stage renal impairment requiring dialysis. Hepatic impairment: No dosage adjustment is necessary for patients suffering from mild to moderate hepatic impairment. In the absence of available data, RELISTOR is not recommended for patients suffering from severe hepatic impairment (Child-Pugh score C). Children: In the absence of available data and pending further data, RELISTOR is not recommended for children under the age of 18. Elderly: No age-related dose adjustments are recommended. Administration: RELISTOR is administered subcutaneously. It is advisable to alternate injection sites and not to inject into areas where the skin is thinner, bruised, red or indurated. Scarred areas and stretch marks should also be avoided. The three recommended injection areas are the thighs, the abdomen and the upper arms. RELISTOR may be injected either at or between mealtimes.

3 2 SIMILAR MEDICINAL PRODUCTS 2.1. Current ATC Classification Currently unavailable 2.2. Medicines in the same therapeutic category There is no other selective peripheral µ-opioid receptor antagonist indicated for the treatment of constipation in patients suffering from an advanced stage disease, receiving palliative care, and not responding sufficiently to usual laxatives Medicines with a similar therapeutic aim All laxatives available on the market: Bulk laxatives: - mucilage: NORMACOL, PSYLIA, SPAGULAX, TRANSILANE. Lubrifying laxatives: - paraffin oil: LUBENTYL, MELAXOSE, PARAPSYLLIUM, TRANSULOSE. Osmotic laxatives: - polyethylene glycol: FORLAX, MOVICOL, TRANSIPEG. - lactitol: IMPORTAL. - lactose: DUPHALAC, LACTULOSE, oral solution and its generics, TRANSULOSE. Stimulant laxatives: not reimbursed. Rectal laxatives: EDUCTYL, NORMACOL enema.

4 3 ANALYSIS OF AVAILABLE DATA 3.1. Efficacy The safety and efficacy of RELISTOR have been evaluated in two phase III clinical studies and their extension phase: - Study MNTX 301, the aim of which was to compare the efficacy of a single injection of RELISTOR (0.15 mg/kg and 0.30 mg/kg) with the placebo in terms of the rate of patients responding after 4 hours, plus open-label monitoring for 4 weeks. An openlabel extension (study MNTX 301 EXT) to 3 months was also conducted. - Study MNTX 302, the aim of which was to compare the efficacy of a single injection of RELISTOR (0.15 mg/kg and 0.30 mg/kg) with the placebo in terms of the rate of patients responding after 4 hours, plus double-blind monitoring for 2 weeks. An openlabel extension (study MNTX 302 EXT) to 3 months was also conducted Study MNTX 301 Method: Phase III randomised placebo-controlled study, including a double-blind period of one day and an open-label monitoring period of 4 weeks, including 147 patients suffering from an advanced stage disease, and receiving palliative care, with opioid-related constipation not responding sufficiently to usual laxatives. Inclusion criteria: Patients aged over 18 years with: - an advanced stage disease (end-stage cancer, AIDS, etc.) and an estimated life expectancy of 1 to 6 months, - opioid treatment stable for more than 3 days, - laxative treatment stable for at least 3 days, - no stools during the 48 hours preceding the first injection. Treatment: - RELISTOR 0.15 mg/kg, subcutaneous injection n=47, - RELISTOR 0.30 mg/kg, subcutaneous injection n=55 (non-ma dosage), - Placebo n = 52 - In the open-label monitoring phases to 4 weeks and 3 months, all the patients were given an initial injection of RELISTOR 0.15 mg/kg; this dosage was then adjusted (0.075 mg/kg to 0.30 mg/kg) according to the patients laxative response. All patients continued their current laxative treatment throughout the study. Primary endpoint: percentage of responsive patients defined as good digestion regained without using another laxative within 4 hours of an injection. RESULTS: analysis on ITT basis (see table 1) Overall, baseline patient characteristics were similar in both groups. Around 80% of the patients included had cancer. However, the mean doses of morphine equivalent administered (mg/day) before inclusion were different: 3,289.8, 1,220.4 and respectively in the RELISTOR 0.15 mg/kg, RELISTOR 0.30 mg/kg and placebo groups (no statistical test).

5 Table 1: Percentage of patients responsive 4 hours after injection. RELISTOR 0.15 mg/kg n=47 RELISTOR 0.30 mg/kg n=55 Placebo n=52 Percentage of 61.7% 58.2% 13.5% responsive patients [ ] [ ] [ ] [95% CI] Number of responsive n=29 n=32 n=7 patients p versus placebo < < After an injection, the percentage of patients responsive 4 hours after the first injection was significantly higher (p<0.0001) in the RELISTOR 0.15 mg/kg and 0.30 mg/kg groups (61.7% and 58.2% respectively) than in the placebo group (13.5%). In the open-label 4-week (MNTX 301 study) and 3-month (MNTX 301 EXT study) monitoring phases, all the patients were given an initial injection of RELISTOR 0.15 mg/kg; this dosage was then adjusted (0.075 mg/kg to 0.30 mg/kg) according to the patient s laxative response. 72/147 patients (49%) were monitored over 3 months. Over this period, the rate of responsive patients was maintained Study MNTX 302 Method: Phase III randomised, double-blind placebo-controlled study, involving 133 patients suffering from an advanced stage disease, and given palliative care, with opioid-related constipation not responding sufficiently to usual laxatives, monitored for 2 weeks. Inclusion criteria: Patients aged over 18 years with: - an advanced stage disease (end-stage cancer, AIDS, etc.) and an estimated life expectancy of over 1 month, - opioid treatment given for at least 2 weeks and stable for more than 3 days, - laxative treatment stable for at least 3 days, - opioid-related constipation defined as: o less than 3 bowel movements over the week preceding inclusion and no stools during the 24 hours preceding the first injection, o or no stools during the 48 hours preceding the first injection. Treatment: - RELISTOR 0.15 mg/kg, subcutaneous injection n=62, - Placebo n = 71 Patients were given an initial injection on day 1 then once every 2 days (D3, D5 D13) for two weeks. All patients also continued their current laxative treatment throughout the study. Primary endpoints: - percentage of responsive patients defined as gastro-intestinal transit regained without using another laxative within 4 hours of the first injection on D1, - percentage of patients with at least two bowel movements within 4 hours of the first four injections. Secondary endpoints, in particular: percentage of patients regaining gastro-intestinal transit within 48 hours following the first injection. RESULTS: analysis on ITT basis (see table 2) Overall, baseline patient characteristics were all similar. Around 60% of the patients included had cancer.

6 However, the mean doses of morphine equivalent administered (mg/day) before inclusion were higher with RELISTOR 0.15 mg/kg (417) than with the placebo (338.8) (no statistical test). Table 2: Results for the two primary endpoints RELISTOR 0.15 mg/kg n=62 Percentage of patients responsive 4 hours after first injection (D1) - [95% CI], - Number of patients - p versus placebo Percentage of patients with at least two bowel movements within 4 hours of the first four injections - [95% CI], - Number of patients - p versus placebo 48.4% [ ] n=30 p< % [ ] n=32 p< Placebo n= % [ ] n=11 8.5% [ ] n=6 After the first injection, the percentage of patients responsive 4 hours after the injection was significantly higher in the RELISTOR 0.15 mg/kg group than in the placebo group: 48.4% versus 15.5%, p< The percentage of patients with at least two bowel movements within 4 hours following the first four injections was significantly higher in the RELISTOR 0.15 mg/kg group than in the placebo group: 51.6% versus 8.5%, p< /133 patients were included in the open-label 3-month monitoring phase. Over this period, the rate of responsive patients was maintained. The analysis of the time curves for regaining gastro-intestinal transit showed that 67.7% of patients regained gastro-intestinal transit after 48 hours (secondary endpoint) with RELISTOR versus 45.1% with the placebo (p=0.0087) Safety MNTX 301 and MNTX 301 EXT studies: During these studies, 103 of the 154 patients (66.9%) experienced at least one adverse effect: 34/47 patients (72.3%) in the RELISTOR 0.15 mg/kg group, 44/55 patients (80%) in the RELISTOR 0.30 mg/kg group and 25/52 patients (48.1%) in the placebo group. The most common adverse effects observed with RELISTOR 0.15 mg/kg, compared to placebo, were: - abdominal pain: 15/47 patients (32%) versus 3/52 (5.7%), - flatulence: 6/47 (12.8%) versus 2/52 (3.8), - asthenia: 4/47 (8.5%) versus 1/52 (1.9%). Study MNTX 302: During the two weeks of treatment, 108 of the 137 patients (78.8%) experienced at least one adverse effect: 51/63 (81%) of the RELISTOR 0.15 mg/kg group and 57/71 (80.3%) of the placebo group. The most common adverse effects observed with RELISTOR 0.15 mg/kg, compared to placebo, were: - abdominal pain: 11/63 patients (17.5%) versus 9/57 (12.7%), - flatulence: 8/63 (12.8%) versus 5/57 (7%), - nausea: 7/63 (11.1%) versus 5/57 (7%), - vomiting: 8/63 (12.7%) versus 9/57 (12.7%).

7 3.3. Conclusion The efficacy and safety of RELISTOR have been evaluated in two phase III studies and their open-label extension phase (MNTX 301 and EXT, MNTX 302 and EXT) in patients suffering from an advanced stage disease and receiveing palliative care, with opioid-related constipation responding insufficiently to laxatives. In study MNTX 301, after an injection, the percentage of patients responsive 4 hours after the injection was significantly higher in the RELISTOR 0.15 mg/kg group (61.7%) than in the placebo group (13.5%), p< In the open-label 3-month monitoring phase (MNTX 301 EXT), 72/147 patients (49%) were included and the percentage of responsive patients was maintained. In study MNTX 302: - after the first injection, the percentage of patients responsive was significantly higher in the RELISTOR 0.15 mg/kg group (48.4%) than in the placebo group (15.5%), p<0.0001, - after the first four injections, the percentage of patients with at least two bowel movements within 4 hours was significantly higher in the RELISTOR 0.15 mg/kg group (51.6%) than in the placebo group (8.5%), p< the analysis of the time curves for regaining gastro-intestinal transit showed that 67.7% of patients regained gastro-intestinal transit after 48 hours (secondary endpoint) with RELISTOR versus 45.1% with the placebo (p=0.0087). In the open-label 3-month monitoring phase, 89/133 patients were included and the percentage of responsive patients was maintained. According to experts, the efficacy of RELISTOR cannot be evaluated on the unique criterion percentage of patients regaining gastro-intestinal transit without the use of another laxative within 4 hours, which is the primary endpoint of both studies presented. The criterion regaining gastro-intestinal transit within 48 hours endpoint, which enables the preservation of good digestion and intestinal comfort to be evaluated, is clinically relevant. The Committee therefore finds it regrettable that only one of the studies took into account this criterion and that the latter was considered to be secondary. The changes in the severity of the constipation were assessed by the patient and the investigator on a 3-level qualitative scale. No evaluation of quality of life based on validated scales was performed. The most common adverse effects observed in these studies (> 10 %) were: abdominal pain (17.5% and 32% of patients, depending on the study), flatulence, nausea, and vomiting. There is no data available comparing to optimised management with laxatives.

8 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Constipation is a common adverse effect with opioid treatments, which results in a deterioration in the quality of life for patients suffering from an advanced stage disease and receiveing palliative care. This product is used as a form of symptomatic treatment. The efficacy/adverse effects ratio in this indication is high. This product is a second-line treatment for patients suffering from an advanced stage disease, and receiving palliative care, when response to usual laxatives is insufficient, in addition to diet and lifestyle changes. There are alternative treatments (optimised laxative treatments). Public health benefit: The public health burden of patients suffering from an advanced stage disease and receiving palliative care, and suffering from opioid-related constipation, can be considered moderate. The public health burden of patients suffering from constipation refractory to laxatives is minor due to the more limited numbers. The improved management of patients suffering from an advanced stage disease and receiving palliative care and particularly the improvement on their quality of life, constitutes a public health need identified as a priority (GTNDO* cancer management priority). Given the data available (little efficacy compared to placebo, low quality of demonstration), RELISTOR is not expected to have any impact in terms of morbidity and quality of life. RELISTOR is not expected to provide an additional solution as far as the identified public health need is concerned. For this reason, RELISTOR is not expected to benefit public health. * French Public Health objectives group The actual benefit of this product is substantial for patients suffering from an advanced stage disease and given palliative care Improvement in actual benefit RELISTOR provides a minor improvement in actual benefit (IAB IV) in the treatment of opioid-related constipation in patients suffering from an advanced stage disease, and receiving palliative care, when the response to usual laxatives is insufficient.

9 1, 2, 3, Therapeutic use Palliative care is designed for patients suffering from serious evolutive diseases that are lifethreatening or at an advanced stage. Decisions concerning the management of associated symptoms must be based on: - their intensity, regardless of the type of disease or stage, - the assessment of the patient s needs, - the benefit/risk ratio of each option in terms of the ability to relieve suffering and to preserve dignity and quality of life. Pain: Pain is the most common symptom among patients suffering from an evolutive or terminal disease, particularly with cancer patients. Strong opioids are used for moderate to strong pain. The most common adverse effects observed with these treatments are: constipation, abdominal pain, nausea, vomiting and urinary retention. Chronic constipation is observed in 40 to 70% of these patients. Constipation: In patients in palliative care, opioid-related constipation can be altered or worsened by factors relating to the underlying condition, the presence of comorbidities (diabetes, hypercalcaemia, hypokalaemia, uraemia, hypothyroidism), dehydration, age, reduced physical activity or immobility. It is advisable to regularly monitor the presence of stools and how easy they are passed. Treatment will be guided more by the discomfort or pain experienced by the patient and the difficulty passing stools than by the frequency of bowel movements. According to ANAES 2002 recommendations 1, in cases of opioid-related constipation, the first-line laxatives proposed are stimulant laxatives (anthracene or bisacodyl) combined with sorbitol. When ineffective, laxatives increasing intestinal peristalsis can be used. In other cases of constipation, suggested first-line treatment is either contact laxatives (docusate sodium or poloxamer) or osmotic laxatives (preferably sorbitol, which is safer). If this does not prove to be sufficiently effective, contact laxatives may be combined with a stimulant anthracene laxative. Bulk laxatives (bran, mucilage) are not recommended as they can worsen initial obstruction and their efficacy is not demonstrated in severe constipation. In studies MNTX 301 and 302 the efficacy of RELISTOR compared to placebo has been demonstrated in combination with constitutional laxative treatments in the treatment of opioid-related constipation in patients suffering from an advanced stage disease, and receiving palliative care, when the response to usual laxatives is insufficient Target population The target population of RELISTOR is comprised of adult patients suffering from an advanced stage disease, and given palliative care, and having opioid-related constipation, when the response to usual laxatives is insufficient. 1 Management of adult patients requiring palliative care ANAES recommendations, December EPAR Relistor, July Standards, options et recommandations 2002 pour les traitements antalgiques médicamenteux des douleurs cancéreuses par excès de nociception chez l adulte FNCLCC updated September Recommandations pour la pratique clinique dans la prise en charge et le traitement de la constipation chronique de l adulte, Société Nationale Française de Gastroentérologie, Gastroenterol Clin Biol 2007;31:

10 The size of this population can be estimated based on the following data: - according to data from the palliative care development plan , around 107,000 palliative care stays (PMSI MCO) were handled in According to data from the company, around 30,000 patients were recorded in the 2007 PMSI SSR, - 50 to 80% of these patients (expert opinion) are treated with strong opioids, - chronic constipation is observed in 40 to 70% of patients treated with opioids (EPAR 2008), - experts estimate the percentage of patients unresponsive to the usual laxatives at around 20%. The target population of RELISTOR is therefore estimated to be no more than 15,000 patients 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 indications and at the dosage in the MA. Packaging: Appropriate for prescription requirements. Reimbursement rate: 65%