S0493 Subcutaneous Methylnaltrexone in Cancer and Non-Cancer Patients for Rapid Relief of Opioid-Induced Constipation

INTRODUCTION: Rapid relief of opioid-induced constipation (OIC) is often necessary in acute care settings for patients with cancer and chronic noncancer pain. Methylnaltrexone (MNTX) is the only FDA approved peripherally acting µ-receptor antagonist with a subcutaneous (SC) formulation for OIC. We report the ability of MNTX SC to achieve early rescue-free laxation (RFL) in advanced-illness OIC patients with and without cancer. METHODS: Two multicenter, double-blind, randomized, placebo-controlled studies (study 302 [NCT00402038] and study 4000 [NCT00672477]) were conducted in adults with advanced illness and OIC (>98% of whom were laxative refractory). In study 302, patients from 27 sites (26 US; 1 Canada) were randomized 1:1 to receive MNTX SC 0.15 mg/kg or placebo every other day for 2 weeks. In study 4000, patients from 48 US and international sites were randomized 1:1 to receive MNTX SC based on body weight (8 or 12 mg) or placebo for ≤7 doses for 14 days. Endpoints included the proportion of patients achieving RFL within 4 hours after the first dose (co-primary endpoint for study 302; endpoint for study 4000); the proportion of patients with an RFL within 4 hours for ≥2 of the first 4 doses (co-primary endpoint for study 302; primary endpoint for study 4000); changes from baseline in pain scores; and safety. Patients were stratified by active cancer versus noncancer. RFL response was analyzed by chi-square tests; the nominal significance level was 0.05, with no multiplicity adjustment. RESULTS: Study 302 included 78 cancer patients (MNTX n = 37; placebo n = 41) and 56 noncancer patients (MNTX n = 26; placebo n = 30). Study 4000 included 152 cancer patients (MNTX n = 79; placebo n = 73) and 78 noncancer patients (MNTX n = 37; placebo n = 41). In both studies, significantly greater proportions of patients treated with MNTX versus placebo achieved an RFL within 4 hours after the first dose among cancer and noncancer patients (Figure 1). Repeat dosing with MNTX SC also maintained bowel symptom response within 4 hours in both cohorts (Figure 2). No significant changes in pain scores were observed between treatment groups in either study . The most common adverse events were abdominal pain, flatulence, and nausea. CONCLUSION: In two individual studies, MNTX use effectively reduced OIC within 4 hours of the first dose and maintained bowel symptom response with repeat dosing in cancer and noncancer patients without affecting central opioid receptor mediated analgesia.Figure 1.: Patients achieving a rescue-free laxation within 4 hours of the first dose.Figure 2.: Repeat dosing with MNTX SC (RFL within 4 hours for ≥2 of the first 4 injections) maintained bowel symptom response in cancer and noncancer patients (ITT population).

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