The Scottish Medicines Consortium issued on 8th December, 2008 an advice on the recently approved opioid antagonist methylnaltrexone
ADVICE: following a full submissionMethylnaltrexone (Relistor) is accepted for restricted use within NHS Scotland for treatment of opioid-induced constipation in advanced illness patients who are receiving palliative care when response to usual laxative therapy has not been sufficient. It is restricted to use by physicians with expertise in palliative care.
Methylnaltrexone has been shown to be superior to placebo in achieving bowel movement in terminally ill patients with opioid-induced constipation already receiving a stable laxative regimen.
This is an excerpt of the detailed advice on methylnaltrexone:
Treatment of opioid-induced constipation in advanced illness patients who are receiving palliative care when response to usual laxative therapy has not been sufficient.
The recommended dose is 8 mg (0.4 ml) by subcutaneous injection (for patients weighing 38-61 kg) or 12 mg (0.6 ml) (for patients weighing 62-114 kg). Patients whose weight falls outside of these ranges should be dosed at 0.15 mg/kg.
The usual schedule is one single dose every other day. Doses may be given with longer intervals, as per clinical need. Patients may receive two consecutive doses 24 hours apart, only when there has been no response (bowel movement) to the dose on the preceding day.
Product availability date
08 July 2008
Summary of evidence on comparative efficacy
Methylnaltrexone bromide is a quaternary derivative of the non-selective opioid antagonist naltrexone. It has lower lipid solubility resulting in restricted access across the blood-brain barrier and therefore it is effective in reversing the peripherally mediated side effects of opioids, without interfering with the desired central analgesic effects. It selectively binds at the peripheral mu-opioid receptor with limited potency at the kappa receptor and much reduced activity at the delta opioid receptor.
There were two pivotal phase lll studies, both in patients with advanced medical illness and limited life expectancy, receiving a stable dose of opioid for at least three days prior to randomisation, on a stable laxative regimen for at least three days prior to treatment, and suffering from opioid-induced constipation (defined as no clinically significant bowel movement within 48 hours). Efficacy assessments were similar in both studies and included frequency, consistency, difficulty, and time to defaecation.
In a double-blind, single-dose study to evaluate the efficacy of methylnaltrexone, 154 patients with a life expectancy of between one and six months were randomised to a single administration of either subcutaneous methylnaltrexone 0.15mg/kg (n=47) or 0.30mg/kg (n=55) or placebo (n=52), followed by a 4-month open-label extension period. Treatment with additional laxatives was permitted during the study as clinically indicated, although not permitted within four hours before or after administration of the double-blind dose.
The primary outcome was the proportion of patients with defaecation (without a rescue intervention) within four hours of the first dose. In the methylnaltrexone 0.15mg/kg group, 29 patients (62% (95% confidence interval (CI): 48 to 76)) had a bowel movement within four hours compared with 32 (58% (95% CI: 45 to 71)) methylnaltrexone 0.30mg/kg patients and seven (13% (95% CI: 4 to 23)) placebo patients.
Secondary outcomes included the median time to defaecation and defaecation (without rescue intervention) within 24 hours. The median time to bowel movement for patients in both methylnaltrexone groups was significantly shorter than placebo (1.1 hours and 0.8 hours for the 0.15mg/kg and 0.3mg/kg doses respectively, compared with >24 hours for placebo). Significantly more patients had bowel movement within 24 hours of receiving methylnaltrexone compared with placebo patients (68% and 64% for 0.15 and 0.3mg/kg doses respectively versus 27% for placebo).
In the other, multicentre, double-blind, placebo-controlled study, 134 patients with a life expectancy of at least one month were recruited from nursing homes, palliative care sites or hospices. Patients were randomised to two weeks of double-blind treatment with either methylnaltrexone 0.15mg/kg (n=62) on alternate days (titrating to 0.3mg/kg if required) or placebo (n=71), followed by a 3-month open-label phase. Missing values were imputed from the last observation carried forward.
There were two co-primary endpoints during the double-blind phase: the proportion of patients who had defaecation (without a rescue intervention) within four hours of the first dose and the proportion of patients who had defaecation within four hours after two or more of the first four doses (the first week of double-blind treatment). In the methylnaltrexone group, 30 patients (48% (95%CI: 36 to 61)) had bowel movement within four hours compared with 11 placebo patients (16% (95%CI: 7 to 24)). For the second primary endpoint, 32 methylnaltrexone patients (52% (95% CI: 39 to 64)) compared with six placebo patients (8% (95%CI: 2 to 15)) had bowel movement after two or more doses in the first week of treatment.
Secondary and tertiary outcomes included the proportion of patients with defaecation within four hours after four or more of the seven doses, the proportion of patients with defaecation within four to 24 hours after each dose, the time to bowel movement, overall pain scores and symptoms of opioid withdrawal. These endpoints in general supported the results of the primary outcomes. There were no differences between the groups in pain scores over the study period, indicating that methylnaltrexone did not cause clinically relevant opioid withdrawal symptoms.
There were no defined primary outcomes for the open-label extension and it mainly provided information on the long-term safety of methylnaltrexone. However it did show that the time to defaecation remained fairly constant over time. In an additional analysis, when the outcomes of the first dose of the two studies was combined, age and gender were found not to influence the outcome.
Summary of evidence on comparative safety
The overall rate of adverse events was similar in the methylnaltrexone (81%) and placebo groups (80%). In the methylnaltrexone group, the most commonly reported treatment-emergent adverse events were abdominal pain (17%), flatulence (13%), vomiting (13%), nausea (11%), and malignant neoplasm progression (11%). Most treatment-emergent adverse events were rated as mild or moderate by the investigators. In a majority of the patients in both treatment groups, the treatment-emergent adverse events were not related or were unlikely to be related to study drug.
Serious adverse events occurred in 18% of methylnaltrexone patients and 28% of placebo patients, none were deemed by the investigators to be related to study drug.
Discontinuations due to adverse events occurred in 6% and 7% of patients in the methylnaltrexone and placebo groups, respectively.
Summary of clinical effectiveness issues
Methylnaltrexone has been shown to be superior to placebo in achieving defaecation (without the need foe rescue intervention) in terminally ill patients with opioid-induced constipation, who were already being treated with a stable laxative regimen. A re-analysis of responders requested by the Committee for Medicinal Products for Human Use (CHMP) found that the more severe the constipation, the higher the response with methylnaltrexone.
The side effect profile was as expected. However the studies had small patient numbers and the double-blind assessment period was of short duration.
Just over half of patients achieved bowel movement within four hours of the initial dose and this may be due to a number of confounding factors including use of other concomitant medications, the disease process, diet, immobility and lack of fluid intake. In addition, opioids cause decreased gastric emptying and prolonged oral-caecal transit time through a centrally mediated action. These effects would not be inhibited by the peripheral action of methylnaltrexone.
The European Public Assessment Report (EPAR) noted that a reduction in overall ‘usual laxative medication’ was not convincingly shown. There was a significant difference in the proportion of patients who achieved a ‘satisfactory’ weekly bowel movement frequency in the first week but there was no significant difference in this outcome in the second week which might suggest that methylnaltrexone has a similar efficacy to standard and rescue laxative treatment combined.
The primary outcome in the clinical studies investigated methylnaltrexone used as an add-on treatment to already stable laxative therapy, so more of a rescue treatment rather than continuous treatment of constipation aimed at normalisation of bowel movement. Therefore, the single-dose study followed by as needed administration may better reflect the use of methylnaltrexone in clinical practice. For the patients in whom the drug shows efficacy it offers an alternative to the discomfort of an enema or the indignity of a manual evacuation.
Subcutaneous administration rather than an oral formulation and a requirement to rotate the injection site may be potential disadvantages, especially in patients who may already be receiving a number of injections. At present no compatibility studies have been done and therefore methynaltrexone should not be mixed with other drugs. Most of the patients in the studies were WHO performance status 3 or 4, therefore should represent the patients in whom this will be used in practice. However in the two-week double-blind study, all the recruited patients were in care and therefore may not represent the situation for those patients wishing to self-administer.
The European Medicines Agency (EMEA) has emphasised that methylnaltrexone should not be used in indications outwith its marketing authorisation.