Fixed-Dose Subcutaneous Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation: Results of a Randomized, Placebo-Controlled Study and Open-Label Extension.

Janet Bull,William P Forbes,Craig Paterson,Charles V Wellman,Robert J Israel,Andrew C Barrett

doi:10.1089/jpm.2014.0362

Abstract

Background: Subcutaneous methylnaltrexone (MNTX), dosed based on body weight, is efficacious and well tolerated in inducing bowel movements in patients with advanced illness and opioid-induced constipation (OIC); however, fixed-dose administration of MNTX may improve ease of administration.Objective: The study objective was to assess safety and efficacy of fixed-dose MNTX in two phase 4 trials.Methods: In a double-blind, randomized, placebo-controlled trial (RCT), patients with advanced illness and OIC received MNTX (8 mg or 12 mg by body weight [38 kg to <62 kg or ≥62 kg, respectively]) or placebo every other day (QOD) for two weeks. Patients completing the RCT could enroll in an open-label extension (OLE) study with MNTX administered as needed (PRN). The primary endpoint was percentage of patients with a rescue-free bowel movement (RFBM) within four hours after ≥2 of the first 4 doses in the first week.Results: In the RCT, 116 and 114 patients received MNTX and placebo, respectively, and 149 patients continued to the OLE study. The percentage of patients achieving primary endpoint was 62.9% and 9.6% for MNTX and placebo groups, respectively (p<0.0001). Median time to RFBM after the first dose was 0.8 hour and 23.6 hours in MNTX and placebo groups, respectively (p<0.0001). Efficacy results during the OLE study were consistent with the RCT. MNTX demonstrated a favorable safety profile in the RCT and OLE study.Conclusion: Fixed-dose MNTX administered QOD in the RCT and PRN in the OLE study demonstrated robust efficacy and was well tolerated in treating OIC in patients with advanced illness.

Highlights

Opioids are often prescribed to treat moderate to severe pain and dyspnea in patients with advanced illness, and constipation is a common and often distressing adverse effect of chronic opioid therapy.[1]
In most cases opioid-induced constipation (OIC) is managed nonspecifically with stool softeners, osmotic agents, and stimulant laxatives.[6]. These approaches are often insufficient and burdensome, and there is no evidence of their efficacy for OIC in controlled clinical trials.[6,7,8]
Patients treated with MNTX or placebo who completed the treatment phase of this study could enroll in an open-label extension (OLE) study if they met eligibility criteria

Summary

Introduction

Opioids are often prescribed to treat moderate to severe pain and dyspnea in patients with advanced illness, and constipation is a common and often distressing adverse effect of chronic opioid therapy.[1]. Subcutaneous methylnaltrexone (MNTX), dosed based on body weight, is efficacious and well tolerated in inducing bowel movements in patients with advanced illness and opioid-induced constipation (OIC); fixed-dose administration of MNTX may improve ease of administration. Methods: In a double-blind, randomized, placebo-controlled trial (RCT), patients with advanced illness and OIC received MNTX (8 mg or 12 mg by body weight [38 kg to < 62 kg or ‡ 62 kg, respectively]) or placebo every other day (QOD) for two weeks. Results: In the RCT, 116 and 114 patients received MNTX and placebo, respectively, and 149 patients continued to the OLE study. Conclusion: Fixed-dose MNTX administered QOD in the RCT and PRN in the OLE study demonstrated robust efficacy and was well tolerated in treating OIC in patients with advanced illness

Objectives

Methods

Results