RELISTOR - RELISTOR - CT 5881 - English version

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Introduction RELISTOR 12 mg/0.6 ml solution for injection 1 vial (CIP: 387 365-1) 2 vials + 2 sterile syringes + 4 alcohol pads (CIP: 387 366-8) 7 vials + 7 sterile syringes + 14 alcohol pads (CIP: 387 367-4) Posted on Sep 22 2009 Active substance (DCI) methylnaltrexone (bromide) GASTRO-ENTEROLOGIE - NOUVEAU MEDICAMENT GASTRO-ENTEROLOGIE - NOUVEAU MEDICAMENT RELISTOR (bromure de méthylnaltrexone),antagoniste sélectif périphérique des récepteurs µ aux opioïdesProgrès thérapeutique mineur dans la prise en charge de la constipation liée aux opioïdes chez les patients en soins palliatifs, lorsque la réponse aux laxatifs habituels a été insuffisante. L’essentiel RELISTOR est le premier antagoniste sélectif périphérique des récepteurs µ aux opioïdes. Il est indiqué dans le traitement de la constipation liée aux opioïdes chez les patients présentant une pathologie à un stade avancé et relevant de soins palliatifs, lorsque la réponse aux laxatifs habituels a été insuffisante.RELISTOR a démontré un progrès thérapeutique mineur en termes de reprise du transit 4 heures après administration.La reprise du transit à 48 heures est un critère clinique plus pertinent. Néanmoins, l’ensemble des études n’a pas évalué ce critère.Stratégie thérapeutique Les soins palliatifs s’adressent aux patients atteints de maladies graves évolutives, mettant en jeu le pronostic vital ou en phase avancée. L’utilisation des antalgiques opioïdes fait souvent partie de ces soins et ces antalgiques peuvent être responsables de constipation.Chez les patients en soins palliatifs, la constipation induite par les opioïdes peut être aggravée par des facteurs liés à la pathologie sous-jacente, la présence d’affections associées (diabète, hypercalcémie, hypokaliémie, urémie, hypothyroïdie), la déshydratation, l’âge, la réduction de l’activité physique ou l’immobilité. Il est recommandé de surveiller régulièrement la présence de selles et leur facilité d’exonération. Le traitement sera guidé par l’inconfort et la douleur ainsi que par les difficultés d’exonération plus que par la fréquence des selles. Dans cette forme de constipation, les laxatifs proposés en première intention sont les laxatifs stimulants (anthracéniques ou bisacodyl) en association au sorbitol. En cas d’inefficacité, les laxatifs péristaltogènes intestinaux peuvent être utilisés.Dans les autres formes de constipation (où RELISTOR n’est pas indiqué), il est proposé d’utiliser en première intention soit les laxatifs de contact (docusate sodique ou poloxamere), soit les laxatifs osmotiques (en préférant le sorbitol en raison de sa meilleure tolérance). En cas d’efficacité insuffisante, les laxatifs de contact peuvent être associés à un laxatif stimulant anthracénique. L’utilisation des laxatifs de lest (son, mucilages) n’est pas recommandée car ils pourraient compléter une obstruction débutante et leur efficacité n’est pas démontrée dans les constipations sévères.Place de la spécialité dans la stratégie thérapeutique : L’efficacité de RELISTOR en association à un traitement de fond laxatif a été démontrée versus placebo dans la prise en charge de la constipation liée aux opioïdes chez les patients présentant une pathologie à un stade avancé et relevant de soins palliatifs, lorsque la réponse aux laxatifs habituels a été insuffisante.Données cliniques L’efficacité et la tolérance de RELISTOR ont été évaluées dans le cadre de deux études de phase III et de leur phase d’extension en ouvert (MNTX 301 et EXT, MNTX 302 et EXT) chez des patients relevant de soins palliatifs.Efficacité: Dans l’étude MNTX 301, le pourcentage de patients répondeurs 4 heures après une injection a été significativement plus important dans le groupe RELISTOR 0,15 mg/kg (61,7%) que dans le groupe placebo (13,5%), p<0,0001. Dans la phase de suivi en ouvert à 3 mois (MNTX 301 EXT) ayant inclus 72 des147 patients (49%), le pourcentage de patients répondeurs a été maintenu.Dans l’étude MNTX 302 :Après la première injection, le pourcentage de patients répondeurs a été significativement plus important dans le groupe RELISTOR 0,15 mg/kg (48,4%) que dans le groupe placebo (15,5%), p<0,0001.Après les quatre premières injections, le pourcentage de patients avec au moins deux émissions de selles 4 heures après l’injection a été significativement plus important dans le groupe RELISTOR 0,15 mg/kg (51,6%) que dans le groupe placebo (8,5%), p<0,0001.A l’analyse des courbes de temps de reprise du transit, le pourcentage de patients avec reprise du transit à 48 heures (critère secondaire) a été de 67,7% sous RELISTOR versus 45,1% sous placebo (p=0,0087).Dans la phase ouverte de suivi en ouvert à 3 mois ayant inclus 89 des 133 patients, le pourcentage de patients répondeurs a été maintenu.Selon les experts, l’efficacité de RELISTOR ne peut être évaluée sur le seul critère « pourcentage de patients avec reprise du transit sans recours à un autre laxatif dans les 4 heures », critère principal des deux études présentées. Le critère « reprise du transit à 48 heures » qui permet d’évaluer la préservation du transit et le confort abdominal est cliniquement plus pertinent. Seule une des deux études a pris en compte ce critère et il a été choisi comme critère secondaire. Aucune évaluation de la qualité de vie par échelles validées n’a été réalisée. Aucune donnée comparative versus « prise en charge optimisée par laxatifs » n’est disponible.Tolérance: Les événements indésirables les plus fréquemment observés au cours de ces études (>10%) ont été: douleur abdominale (17,5% et 32% des patients selon les études), flatulences, nausées, vomissements.Intérêt du médicament Le service médical rendu* par RELISTOR est important.RELISTOR apporte une amélioration du service médical rendu mineure (ASMR IV)** dans la prise en charge de la constipation liée aux opioïdes chez les patients présentant une pathologie à un stade avancé et relevant de soins palliatifs, lorsque la réponse aux laxatifs habituels a été insuffisante.Avis favorable au remboursement en ville et à la prise en charge à l’hôpital.* Le service médical rendu par un médicament (SMR) correspond à son intérêt en fonction notamment de ses performances cliniques et de la gravité de la maladie traitée. La Commission de la Transparence de la HAS évalue le SMR, qui peut être important, modéré, faible, ou insuffisant pour que le médicament soit pris en charge par la solidarité nationale.** L'amélioration du service médical rendu (ASMR) correspond au progrès thérapeutique apporté par un médicament par rapport aux traitements existants. La Commission de la transparence de la HAS évalue le niveau d'ASMR, cotée de I, majeure, à IV, mineure. Une ASMR de niveau V (équivalent de « pas d'ASMR ») signifie « absence de progrès thérapeutique ». Progrès thérapeutique mineur dans la prise en charge de la constipation liée aux opioïdes chez les patients en soins palliatifs, lorsque la réponse aux laxatifs habituels a été insuffisante. RELISTOR est le premier antagoniste sélectif périphérique des récepteurs µ aux opioïdes. Il est indiqué dans le traitement de la constipation liée aux opioïdes chez les patients présentant une pathologie à un stade avancé et relevant de soins palliatifs, lorsque la réponse aux laxatifs habituels a été insuffisante.RELISTOR a démontré un progrès thérapeutique mineur en termes de reprise du transit 4 heures après administration.La reprise du transit à 48 heures est un critère clinique plus pertinent. Néanmoins, l’ensemble des études n’a pas évalué ce critère.Pour en savoir plus, téléchargez la synthèse ou l'avis complet ci-dessous Progrès thérapeutique mineur dans la prise en charge de la constipation liée aux opioïdes chez les patients en soins palliatifs, lorsque la réponse aux laxatifs habituels a été insuffisante. RELISTOR est le premier antagoniste sélectif périphérique des récepteurs µ aux opioïdes. Il est indiqué dans le traitement de la constipation liée aux opioïdes chez les patients présentant une pathologie à un stade avancé et relevant de soins palliatifs, lorsque la réponse aux laxatifs habituels a été insuffisante.RELISTOR a démontré un progrès thérapeutique mineur en termes de reprise du transit 4 heures après administration.La reprise du transit à 48 heures est un critère clinique plus pertinent. Néanmoins, l’ensemble des études n’a pas évalué ce critère.Pour en savoir plus, téléchargez la synthèse ou l'avis complet ci-dessous Laboratory / Manufacturer WYETH PHARMACEUTICALS FRANCE RELISTOR 12 mg/0.6 ml solution for injection 1 vial (CIP: 387 365-1) 2 vials + 2 sterile syringes + 4 alcohol pads (CIP: 387 366-8) 7 vials + 7 sterile syringes + 14 alcohol pads (CIP: 387 367-4) Posted on Sep 22 2009

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• Publié par: haute-autorite-sante-maladies-appareil-digestif
• Publié le: 10 décembre 2008
• Nombre de lectures: 32
• Licence : En savoir +
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• Langue: English

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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: 387 365-1) 2 vials + 2 sterile syringes + 4 alcohol pads (CIP: 387 366-8) 7 vials + 7 sterile syringes + 14 alcohol pads (CIP: 387 367-4)     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

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.   1.3. 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.”   1.4. 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 0.0075   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 0.075 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: dosage adjustment is necessary for patients suffering from mild to No 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: the absence of available data and pending further data, RELISTOR is not In 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.”  

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.     2.3. 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.  

 

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 open- label 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 open- label extension (study MNTX 302 EXT) to 3 months was also conducted.   3.1.1. 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 617.3 respectively in the RELISTOR 0.15 mg/kg, RELISTOR 0.30 mg/kg and placebo groups (no statistical test).        

Table 1:Percentage of patients responsive 4 hours after injection.  RELISTOR 0.15 mg/kg RELISTOR 0.30 mg/kg Placebo n=47 n=55 n=52 Percentage of 61.7% 58.2% 13.5% responsive patients [47.8 – 75.6] [45.1 – 71.2] [4.2 – 22.7] [95% CI] Number of responsive n=29 n=32 n=7 patients p versus placebo < 0.0001 < 0.0001   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.     3.1.2. 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.     

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 Placebo n=62 n=71 Percentage of patients responsive 4 hours     after first injection (D1) 48.4% 15.5% - [95% CI], [35.9 – 60.8] [7.1 – 23.9] -  n=11Number of patients n=30 - p versus placebo p<0.0001 Percentage of patients with at least two     bowel movements within 4 hours of the first   four injections 51.6% 8.5% - [95% CI], [39.2 – 64.1] [2.0 – 14.9] -  n=32Number of patients n=6 - p versus placebo p<0.0001   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<0.0001.   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<0.0001.   89/133 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).     3.2. 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%).

    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<0.0001. 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<0.0001. - 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”.

   

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.     4.2. 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.  

  4.3. Therapeutic use 1, 2, 3, 4    Palliative care is designed for patients suffering from serious evolutive diseases that are life- threatening 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.     4.4. 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 2002. 2 EPAR Relistor, July 2008. 3  “Standards, options et recommandations 2002 pour les traitements antalgiques médicamenteux des douleurs cancéreuses par excès de nociception chez l’adulte”FNCL dat mber 2002. 4 ahc  egrsirpne ensdaa  lnilie qunotspitad  ealc aitementet le trn ioRe “ pu CCetpeS de a prur lue catiqnaadocmm sopitno chronique de l’adulte”, Société Nationale Françaisede Gastroentérologie, Gastroenterol Clin Biol 2007;31:125- 135.

The size of this population can be estimated based on the following data: - according to data from the palliative care development plan 2008-2012, around 107,000 palliative care stays (PMSI MCO) were handled in 2007. 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.     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 indications and at the dosage in the MA.   Packaging: Appropriate for prescription requirements.   Reimbursement rate: 65%