Naldemedine 200microgram tablets

BACKGROUND: Opioid-induced constipation (OIC) is a pervasive and distressing side effect of chronic opioid therapy in patients with cancer pain, significantly impacting their quality of life. Peripherally acting μ-opioid receptor antagonists (PAMORAS) were developed for treatment-resistant OIC but most studies were conducted with non-cancer patients. OBJECTIVE: to discuss two oral formulations of PAMORAs, naldemedine and naloxegol, and to review available evidence of the effectiveness of these drugs for OIC in cancer patients. METHODS: a comprehensive search to identify primary literature for either naldemedine or naloxegol for OIC in cancer patients. RESULTS: Only three prospective randomized, double-blind, placebo-controlled clinical trials for naldemedine enrolling cancer patients were identified; the results of a subgroup analysis of two of those studies and two non-interventional post marketing surveillance studies of these trials are also reported here. For naloxegol, only two randomized controlled trials were identified; both were unsuccessful in enrolling sufficient patients. An additional four prospective non-interventional observational studies with naloxegol were found that enrolled cancer patients. There were significantly higher rates of responders in the PAMORA groups than in the placebo groups. The most common side effect for both PAMORAs was diarrhea. LIMITATIONS: All studies were industry-funded, and given that only three trials were randomized controlled studies, the overall quality of the studies was lacking. CONCLUSION: Naldemedine or naloxegol appeared safe and useful in the treatment of OIC in cancer patients and may improve their quality of life. Larger-scale randomized placebo-controlled studies of PAMORAs in cancer patients would strengthen existing evidence.

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PURPOSE Opioid-induced constipation is the most frequent and non–self-limiting adverse effect of opioid analgesia, reducing adherence and interfering with pain relief. This clinical trial aimed to clarify the preventive effect of naldemedine versus placebo for constipation in patients with cancer starting regularly dosed strong opioids therapy. METHODS This multicenter, double-blinded, randomized, placebo-controlled, confirmatory trial was conducted between July 2021 and May 2023 at four academic hospitals in Japan (Japan Registry of Clinical Trials identifier: jRCTs031200397). Patients with cancer starting a first-time regularly dosed strong opioid for cancer pain and age 20+ years were included. Eligible patients were randomly assigned to the naldemedine (Symproic 0.2 mg) or placebo group in a 1:1 ratio for 14 days with protocol treatment. The primary end point was the proportion of patients with a Bowel Function Index (BFI) of <28.8 on day 14. The secondary end points included frequency of spontaneous bowel movements (SBM), quality of life (QOL), and frequency of opioid-induced nausea and vomiting (OINV). RESULTS Of the 103 patients assessed for eligibility, 99 received either naldemedine (n = 49) or placebo (n = 50). A BFI of <28.8 on day 14 was significantly more likely to occur in the naldemedine group (64.6%; 95% CI, 51.1 to 78.1) versus placebo (17.0%; 95% CI, 6.3 to 27.8), and the difference between groups was 47.6% (95% CI, 30.3 to 64.8; P < .0001). The frequency of SBM, QOL, and the severity of OINV were nominally significant in the naldemedine group than in the control group. CONCLUSION Naldemedine prevented constipation and improved constipation-related QOL, with possible preventive effect on OINV in patients with cancer starting regularly dosed opioids therapy.

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BACKGROUND: Acute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression. METHODS: The study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis. DISCUSSION: This study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes. TRIAL REGISTRATION: EudraCT no. 2021-000069-34. CLINICALTRIALS: gov NCT04966559. Registered on July 8, 2021.

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OBJECTIVE: To evaluate the additive effect of naldemedine tosylate (naldemedine) on opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment. METHODS: We combined two randomized, double-blind, placebo-controlled, phase IIb and III trials of naldemedine and conducted a post hoc subgroup analysis. We evaluated the effect and safety of naldemedine in 116 patients who received naldemedine in addition to magnesium oxide (naldemedine group) and 117 patients who received placebo in addition to magnesium oxide (placebo group). Both groups included patients insufficiently responding to magnesium oxide for opioid-induced constipation. Effect was assessed using spontaneous bowel movement responder rate, complete spontaneous bowel movement responder rate, changes in spontaneous bowel movements and complete spontaneous bowel movements. Safety was also assessed. RESULTS: During the 2-week treatment period, the responder rates for spontaneous bowel movement and complete spontaneous bowel movement were 73.3 and 43.1% in naldemedine group, respectively, which were significantly higher (P < 0.0001) than 41.9 and 14.5% in placebo group, respectively. Median time to first spontaneous bowel movement and first complete spontaneous bowel movement was significantly shorter (P < 0.0001) in the naldemedine group (4.0 and 21.3 h, respectively) than in the placebo group (27.7 and 211.7 h, respectively). The incidence of adverse events and diarrhoea was significantly higher (P < 0.05) in the naldemedine group than in the placebo group, while the incidence of serious adverse events and severe diarrhoea was not significantly different between the naldemedine and placebo groups. CONCLUSION: The study suggested the addition of naldemedine as an effective treatment option for opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment.

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BACKGROUND AND AIMS: No medications are currently approved for the prevention of recurrent acute pancreatitis. This trial evaluated whether naldemedine, a peripherally acting μ-opioid receptor antagonist, reduces the risk of acute pancreatitis in patients with recurrent acute pancreatitis. METHODS: This was a multicentre, double-blinded, placebo-controlled randomised trial conducted at four Danish pancreatitis referral centres. Participants aged 18-75 years with recurrent acute pancreatitis, both with and without a diagnosis of chronic pancreatitis, were randomised to receive naldemedine 0.2 mg or a matching placebo daily for up to 12 months. The primary outcome was acute pancreatitis recurrence, defined by the revised Atlanta Criteria. Secondary outcomes included pain flares, gastrointestinal symptoms, and quality of life. At the end of follow-up, the participant's global impression of change, safety and tolerability outcomes, new-onset diabetes and pancreatic exocrine insufficiency were assessed. RESULTS: 74 participants (mean age: 46 years; 41% female) were randomised to naldemedine (n = 36) or placebo (n = 38). During a median follow-up time of 365 days (IQR, 352-370), participants in the naldemedine group had a numerically lower risk of acute pancreatitis compared to placebo (HR 0.54; 95% CI, 0.29-1.01; p = 0.05). No differences were observed between the groups for secondary efficacy, safety, and tolerability outcomes. Participants treated with naldemedine for at least 1 year had a lower risk of acute pancreatitis (HR 0.49; 95% CI, 0.24-0.97; p = 0.04). CONCLUSIONS: Treatment with naldemedine was safe and well-tolerated and may reduce the risk of recurrent acute pancreatitis. A larger confirmatory trial is needed to verify these findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: PAMORA-RAP: NCT04966559.

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BACKGROUND: Gastrointestinal cancers are one of the most common cancer cases worldwide. Cancer treatment is multidisciplinary, which includes opioid pain management. Opioid analgesics cause opioid-induced constipation (OIC) with the onset of effect. Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in gastrointestinal cancers. METHODS: We retrospectively evaluated patients with gastrointestinal cancer treated with naldemedine at ten institutions in Japan from June 2017 to August 2019. Patients with gastrointestinal cancer who initiated treatment with opioids during hospitalization and were treated with naldemedine for the first time were included in the study. The gastrointestinal cancer types included were esophageal, gastric, small bowel, and colorectal cancers. We assessed the defecation frequency before and after the initiation of naldemedine use. Responders were defined as patients who defecated three or more times/week, with an increase from the baseline of one or more bowel movements/week over seven days after starting naldemedine. RESULTS: Thirty-three patients were observed for one week before and after starting naldemedine. Twenty-one patients had an increase in defecation frequency of at least three times per week or at least once per week above the baseline. The response rate was 63.6% [95% confidence interval (CI): 46.6-77.9%]. The median number of bowel movements for a week before and after the initiation of naldemedine treatment was 3 (range, 0-13) and 7 (range, 1-39), respectively, in the overall population (n=33), with a significant increase in defecation frequency following naldemedine administration (Wilcoxon signed rank test, P<0.005). Diarrhea was the predominant gastrointestinal symptom, with 13 (39.4%) patients experiencing grade 1 and none experiencing grade 3 or grade 4 adverse events. The frequency of other grade 1 adverse events was low abdominal pain in two patients, nausea in two patients, and anorexia in one patient, without any grade 2-4 adverse events. CONCLUSIONS: The results of the study suggest that naldemedine is effective and safe in clinical practice for gastrointestinal cancer treatment.

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