Assistant Professor of Medicine; Director, Center for Gastrointestinal Motility Dartmouth-Hitchcock Medical Center Lebanon, NH
Eric D. Shah, MD, MBA1, Bruce H. Chamberlain, MD, CHMD2, Michelle Rhiner, DNP, GNP-BC, ACHPN3, Neal E. Slatkin, MD4, Nancy Stambler, DrPH5, Robert J. Israel, MD6; 1Dartmouth-Hitchcock Medical Center, Lebanon, NH; 2Genesis Healthcare, Davenport, IA; 3Loma Linda University Health, Loma Linda, CA; 4University of California Riverside, Salix Pharmaceuticals, Bridgewater, NJ; 5Progenics Pharmaceuticals, Inc., New York, NY; 6Bausch Health US, LLC, Bridgewater, NJ
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. Discussion: 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)
Disclosures: Eric Shah indicated no relevant financial relationships. Bruce Chamberlain indicated no relevant financial relationships. Michelle Rhiner: Salix Pharmaceuticals – Other Financial or Material Support, Travel expenses related to poster presentations at the 2018 World Congress on Regional Anesthesia & Pain Medicine and the 2018 Palliative and Supportive Care in Oncology meeting.. Wyeth Pharmaceuticals – Grant/Research Support. Neal Slatkin: Salix Pharmaceuticals, a subsidiary of Bausch Health US. – Employee. Nancy Stambler: Progenics Pharmaceuticals, Inc. – Employee. Robert Israel: Bausch Health US, LLC. – Employee.