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Naldemedine improves opioid-induced constipation in patients with cancer
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A 14-day treatment regimen with naldemedine improved opioid-induced constipation among patients with cancer, according to results of a phase 2b clinical trial.
“To our knowledge, this study is the first to successfully prospectively demonstrate the feasibility of using an oral [peripherally-acting µ-opioid receptor antagonist] to alleviate symptoms of [opioid-induced constipation] specifically in patients with cancer,” Nobuyuki Katakami, MD, PhD, from the Institute of Biomedical Research in Japan, and colleagues wrote.
The FDA in March approved naldemedine (Symproic; Shionogi, Purdue Pharma) for the treatment of opioid-induced constipation in adults with noncancer pain.
A phase 1 study among healthy Japanese volunteers showed the safety and tolerability of naldemedine, which was confirmed in a subsequent phase 2 trial in the United States. However, some patients who received 1 mg and 3 mg naldemedine experienced severe treatment-emergent adverse events.
To determine the recommended dose for phase 3 clinical trials, Katakami and colleagues randomly assigned 227 adults with cancer to 0.1 mg (n = 56), 0.2 mg (n = 58) or 0.4 mg (n = 56) naldemedine or placebo (n = 56) once daily for 14 days.
All patients received a stable regimen of opioid analgesics (mean, 54.9-85.5 mg per day) for at least 2 weeks, experienced at least one constipation symptom regardless of laxative use, and had no more than five spontaneous bowel movements during the previous 14 days.
Change in the number of spontaneous bowel movements per week from baseline during the treatment period served as the primary endpoint. Researchers assessed 225 patients for efficacy and 226 patients for safety.
Naldemedine at all doses conferred a higher change in spontaneous bowel movements than placebo (P < .05 for all comparisons).
Spontaneous bowel movement responder rates significantly improved compared with placebo (37.5%) in patients who received 0.1 mg naldemedine (56.4%; P = .0464), 0.2 mg naldemedine (77.6%; P < .001) and 0.4 mg naldemedine (82.1%; P < .001).
The change in spontaneous bowel movement frequency without straining significantly improved with 0.2 mg (P = .0021) and 0.4 mg (P < .001) naldemedine compared with placebo, but not with 0.1 mg naldemedine.
Patients who received any dose of naldemedine demonstrated a higher overall improvement rate for constipation by 2 weeks (P < .001 for all).
Patients treated with naldemedine experienced more treatment-emergent adverse events (0.1 mg: 66.1%; 0.2 mg: 67.2%; 0.4 mg: 78.6%) than patients assigned placebo (51.8%). The most common treatment-emergent adverse event was diarrhea. Severe adverse event occurrence remained low among all groups.
“Treatment with naldemedine for a 14-day period decreased the effects of [opioid-induced constipation] in patients with cancer in a significant, clinically meaningful, and generally well-tolerated manner, without abrogation of the centrally mediated analgesic effects of opioids,” the researchers wrote. “Naldemedine 0.2 mg was chosen as the dose for the phase 3 studies of naldemedine in patients with cancer and [opioid-induced constipation].” – by Melinda Stevens
Disclosures: Katakami reports speakers fees from AstraZeneca, Boehringer Ingelheim, Chugi Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Janssen, Novartis, Ono Pharmaceutical, Pfizer and Taiho Pharmaceutical; and institutional research funding from Amgen, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugi Pharma, Daiichi Sankyo, Eisai, Eli Lilly, Kyowa Hakko Kirin, Maruishi Pharma, Merck Serono, MSD, Ono Pharmaceutical, Shionogi and Taiho Pharmaceutical. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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