Safety Of Naldemedine Research Articles

Effect of add-on naldemedine treatment in patients with cancer and opioid-induced constipation insufficiently responding to magnesium oxide: a pooled, subgroup analysis of two randomized controlled trials.

To evaluate the additive effect of naldemedine tosylate (naldemedine) on opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment. 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. 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 21.3h, respectively) than in the placebo group (27.7 and 211.7h, 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. 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.

Efficacy and safety of Naldemedine in the long-term treatment of opioid-induced constipation in patients on methadone agonist therapy monitored for three consecutive months

Efficacy and safety of Naldemedine in the long-term treatment of opioid-induced constipation in patients on methadone agonist therapy monitored for three consecutive months

Update on the role of naldemedine in opioid-induced constipation in patients with chronic noncancer pain.

Chronic noncancer pain (CNCP) affects up to 20% of adults and can interfere with activities of daily living. Up to 4% of adults in the United States receive chronic opioid therapy and up to 57% of patients on long-term opioids for CNCP report opioid-induced constipation (OIC). OIC is essentially constipation occurring after starting opioid treatment. While laxatives are traditionally the first-line therapy for OIC, 81% of patients taking daily laxatives and opioids still reported OIC and considered that it negatively affected their quality of life. Naldemedine is a peripherally acting µ-opioid receptor antagonists (PAMORA) approved for the treatment of OIC in patients with CNCP. This article reviews the mechanism of action, efficacy, and safety of naldemedine in CNCP patients. Naldemedine improves OIC in patients with CNCP by acting as an opioid receptor antagonist in the gastrointestinal tract. It does not interfere with the analgesic properties of opioids or cause withdrawal symptoms since these effects are centrally mediated, and naldemedine does not cross the blood brain barrier. Naldemedine showed significant and sustained improvement in frequency of bowel movements, quality of life, and constipation-related symptoms. It is generally well tolerated with a higher incidence of gastrointestinal adverse events of mild or moderate severity such as diarrhea, abdominal pain, or vomiting compared to placebo. While there are no randomized, controlled trials that compare head-to-head pharmacological therapies used for treatment of OIC, network meta-analysis shows that naldemedine has an overall good benefit-risk profile compared to the other approved medications.

Naldemedine is effective in the treatment of opioid-induced constipation in patients with chronic non-cancer pain who had a poor response to laxatives.

Background:Two studies demonstrated the efficacy and safety of naldemedine in adult patients with chronic non-cancer pain and opioid-induced constipation (OIC). However, no studies have compared the efficacy of peripherally acting µ-opioid receptor antagonists in patients with adequate and inadequate responses to prior OIC therapy with laxatives. This post hoc analysis of integrated data from the two previous studies compared the efficacy of naldemedine in patients who were unsuccessfully treated with laxatives [poor laxative responders (PLRs)] with those who either did not receive laxatives >30 days prior to screening or those who only received rescue laxative at or after screening (non-PLRs).Methods:Patients with OIC were randomized to once-daily treatment with naldemedine 0.2 mg or placebo. The primary efficacy endpoint was the proportion of responders [⩾3 spontaneous bowel movements (SBMs)/week and an increase from baseline of ⩾1 SBM/week for ⩾9 weeks of the 12-week treatment period and ⩾3 weeks of the final 4 weeks of the 12-week treatment period]. Additional endpoints included change in SBM frequency, change in frequency of SBMs without straining, proportion of complete SBM (CSBM) responders, change in CSBM frequency, and time to first SBM. Treatment-emergent adverse events (TEAEs) were assessed.Results:The analysis included 538 (317 PLRs, 221 non-PLRs) and 537 (311 PLRs, 226 non-PLRs) patients in the naldemedine and placebo arms, respectively. There were significantly more responders in the naldemedine PLR (46.4%; p < 0.0001) and non-PLR (54.3%; p = 0.0009) subgroups versus the placebo groups (30.2% and 38.9%, respectively). In both the PLR and non-PLR subgroups, naldemedine treatment was superior to placebo on all additional endpoints. Overall incidence of TEAEs in the PLR subgroups treated with naldemedine or placebo was similar.Conclusion:This integrated analysis further supports the efficacy and tolerability of naldemedine in the treatment of OIC and demonstrates a consistent effect in both PLR and non-PLR subgroups.[ClinicalTrials.gov identifier: NCT01965158 and NCT01993940]

Safety and efficacy of naldemedine in cancer patients with opioid-induced constipation: a pooled, subgroup analysis of two randomised controlled studies

ObjectiveThis post hoc, pooled, subgroup analysis of two randomised studies evaluated baseline characteristics that may influence the efficacy and safety of naldemedine in patients with opioid-induced constipation (OIC) and cancer.MethodsData for patients who received 0.2 mg naldemedine or placebo were pooled from randomised, placebo-controlled, phase IIb and phase III studies. Proportions of spontaneous bowel movement (SBM) responders and patients with diarrhoea were assessed for each treatment group. For the patient subgroups with or without possible blood–brain barrier (BBB) disruptions, changes in Numerical Rating Scale (NRS) and Clinical Opioid Withdrawal Scale (COWS) scores were assessed.ResultsA total of 307 patients were included in this analysis (naldemedine: n=155; placebo: n=152). The pooled proportion of SBM responders was 73.5% with naldemedine versus 35.5% with placebo. There was a significant increase in the proportion of SBM responders with naldemedine versus placebo (38.0% (95% CI 27.6% to 48.4%); p<0.0001). Greater proportions of SBM responders and patients who experienced diarrhoea were observed with naldemedine versus placebo in all subgroups. Changes from baseline in NRS and COWS scores were similar with naldemedine or placebo in patients with or without brain metastases.ConclusionsAlthough not powered to detect statistically significant differences in treatment effect among subgroups, this study demonstrated that naldemedine appeared to benefit patients with OIC and cancer, irrespective of baseline characteristics, and did not seem to affect analgesia or withdrawal–even in patients with potential BBB disruptions. Baseline characteristics did not appear to affect the incidence of diarrhoea in patients who received naldemedine.Trial registration numbersJapicCTI-111510 and JapicCTI-132340.

PGI3 INDIRECT TREATMENT COMPARISONS AND NETWORK META-ANALYSES OF NALDEMEDINE FOR THE TREATMENT OF OPIOID-INDUCED CONSTIPATION

Opioid treatment often leads to opioid-induced constipation (OIC). We compared the efficacy and safety of naldemedine 0.2mg (NLD), a peripherally-acting mu-opioid receptor antagonist, to alternative OIC treatments. A systematic literature review identified phase III/IV randomized controlled trials (RCTs) of EU-licensed OIC-indicated treatments in adults via searches of MEDLINE, Embase and the Cochrane Library from database inception to 14-Jun-2017, and of congresses, reference lists and grey literature. Outcomes at 12 and 52 weeks were assessed using indirect treatment comparisons (ITCs) or network meta-analyses (NMAs). Of 26 identified placebo/usual care-controlled RCTs, six reported 12-week outcomes (three NLD; two naloxegol 12.5mg [NLX12.5]-vs-naloxegol 25mg [NLX25]; one oxycodone/naloxone). NMAs suggest that NLD was generally comparable to other treatments at 12 weeks for response rate, mean change from baseline in spontaneous bowel movements (SBMs), patient assessment of constipation-symptoms (PAC-SYM) questionnaire, all-cause discontinuation (ACD) and discontinuation due to adverse events (AEs), except that there was a lower risk of discontinuation due to AEs for oxycodone/naloxone over NLD (risk ratio [RR]: 0.22; 95% credible interval [95%CrI]: 0.07, 0.60), and NMAs of SBMs and PAC-SYM favored NLD over NLX12.5 (SBMs: difference -0.82; 95%CrI: -1.33, -0.32; PAC-SYM: difference 0.16; 95%CrI: 0.01, 0.30). ITCs of the two studies reporting 52-week outcomes showed NLD had a lower risk of total AEs (RR: 0.84; 95% confidence interval [95%CI]: 0.75, 0.94), discontinuation due to AEs (RR: 0.19; 95%CI: 0.07, 0.52) and flatulence (RR: 0.10; 95%CI: 0.03, 0.41) versus NLX25; no statistically significant differences were observed in abdominal pain, ACD, serious AEs, deaths, diarrhea, nausea, vomiting or major adverse cardiac events. Efficacy of NLD and NLX25 was similar for OIC treatment, with an improved longer-term safety profile for NLD versus NLX25. 12-week comparisons suggest NLD is superior to NLX12.5 for the treatment of OIC in terms of SBMs and PAC-SYM.

Efficacy of naldemedine for the treatment of opioid-induced constipation: A meta-analysis.

Opioid induced constipation (OIC) is the most common side effect of opioid therapy. It can lead to a decreased quality of life. Naldemedine is a peripherally acting μ-opioid receptor antagonist that has been recently studied in randomized controlled trials (RCTs) for the management of OIC. The aim of this study is to perform a meta-analysis of existing clinical trials to estimate the efficacy and safety of naldemedine in opioid-induced constipation. A systematic search of PubMed, CINAHL, Scopus, Cochrane database of systematic reviews, and ClinicalTrials.gov registry was performed in March 2018. Two independent reviewers systematically identified prospective RCTs published in the English language that compared the effect of oral naldemedine versus placebo in adults with OIC. Meta-analysis was performed using a random effects model to assess the primary outcome: spontaneous bowel movement (SBM) responder rates. Assessed secondary outcomes were: a change in SBM frequency per week from baseline during the treatment period, change from baseline in the frequency of complete SBM and incidence of treatment-emergent adverse events. Review Manager 5.3 software program was utilized for statistical analysis. Six RCTs met the inclusion criteria. A total of 2,762 patients were included in the meta-analysis. The proportion of SBM responders was significantly higher in the naldemedine group compared to the placebo group (56.4%, vs. 34.7%, p<0.00001). There was no statistically significant difference in treatment-emergent adverse events between naldemedine group and placebo group (mean odds ratio=1.18, p = 0.25, 95% CI: 0.89-1.55). Change in SBM frequency was higher in the naldemedine group versus placebo group (p<0.00001), as well as the change in complete SBM frequency. Naldemedine 0.2 mg daily significantly improved symptoms in patients with opioid-induced constipation and was generally well tolerated. These results support the use of naldemedine for the treatment of opioid-induced constipation.

Randomized phase III and extension studies: efficacy and impacts on quality of life of naldemedine in subjects with opioid-induced constipation and cancer

BackgroundThe efficacy and safety of naldemedine (a peripherally acting µ-opioid receptor antagonist) for opioid-induced constipation (OIC) in subjects with cancer was demonstrated in the primary report of a phase III, double-blind study (COMPOSE-4) and its open-label extension (COMPOSE-5). The primary end point, the proportion of spontaneous bowel movement (SBM) responders, was met. Here, we report results from secondary end points, including quality of life (QOL) assessments from these studies. Patients and methodsIn COMPOSE-4, eligible adults with OIC and cancer were randomly assigned 1:1 to receive once-daily oral naldemedine 0.2 mg (n = 97) or placebo (n = 96) for 2 weeks, and those who continued on to COMPOSE-5 received naldemedine for 12 weeks (n = 131). Secondary assessments in COMPOSE-4 included the proportion of complete SBM (CSBM) responders, SBM or CSBM responders by week, and subjects with ≥1 SBM or CSBM within 24 h postinitial dose. Changes from baseline in the frequency of SBMs or CSBMs per week were assessed at weeks 1 and 2. Time to the first SBM or CSBM postinitial dose was also evaluated. In both studies, QOL impact was evaluated by Patient Assessment of Constipation-Symptoms (PAC-SYM) and PAC-QOL questionnaires. ResultsNaldemedine improved bowel function for all secondary efficacy assessments versus placebo (all P ≤ 0.0002). The timely onset of naldemedine activity versus placebo was evidenced by median time to the first SBM (4.7 h versus 26.6 h) and CSBM (24.0 h versus 218.5 h) postinitial dose (all P < 0.0001). In COMPOSE-4, significant differences between groups were observed with the PAC-SYM stool domain (P = 0.045) and PAC-QOL dissatisfaction domain (P = 0.015). In COMPOSE-5, significant improvements from baseline were observed for overall and individual domain scores of PAC-SYM and PAC-QOL. ConclusionsNaldemedine provided effective and timely symptomatic relief from OIC and improved the QOL of subjects with OIC and cancer. Trial registration IDwww.ClinicalTrials.jp: JAPIC-CTI-132340 (COMPOSE-4) and JAPIC-CTI-132342 (COMPOSE-5).

Mo1571 - Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Subjects with Chronic Non-Cancer Pain Receiving Opioid Therapy: Results of Three Global Phase 3 Clinical Trials

Mo1571 - Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Subjects with Chronic Non-Cancer Pain Receiving Opioid Therapy: Results of Three Global Phase 3 Clinical Trials

Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials

Opioid-induced constipation is a frequent side-effect of opioid treatment, and standard interventions have limited or inconsistent efficacy. This study assessed the efficacy and safety of naldemedine, a peripherally acting μ-opioid receptor antagonist, for the treatment of opioid-induced constipation in patients with chronic non-cancer pain. We report two double-blind, randomised, placebo-controlled trials in adults with chronic non-cancer pain and opioid-induced constipation. The first (COMPOSE-1) was done in 68 outpatient sites in seven countries and the second (COMPOSE-2) at 69 outpatient sites in six countries; both studies were done in Europe and the USA. Eligible patients were aged 18-80 years, did not use laxatives, and had a stable opioid regimen for treatment of chronic non-cancer pain with a total daily dose averaging at least 30 mg (morphine equivalent) for at least 1 month before screening. Patients were randomly assigned (1:1) to receive either oral naldemedine 0·2 mg or matching placebo once a day for 12 weeks. Randomisation was stratified by average total daily opioid dose (30-100 mg and >100 mg equivalents of oral morphine sulphate). The primary endpoint was proportion of responders. A responder had at least three spontaneous bowel movements (SBMs) per week with an increase from baseline of at least one SBM per week for at least 9 weeks of the 12-week treatment period including at least three of the last 4 weeks. Efficacy endpoints were analysed by intention to treat and the safety population included all patients who received at least one dose of study drug. These trials have both been completed and are registered with ClinicalTrials.gov, numbers NCT01965158 and NCT01993940. In COMPOSE-1, 547 patients were recruited between Aug 29, 2013, and Jan 22, 2015, and were randomly assigned to receive naldemedine (n=274) or placebo (n=273). Patients for COMPOSE-2 were recruited between Nov 4, 2013, and June 9, 2015; 553 patients were randomly assigned to receive naldemedine (n=277) or placebo (n=276). Five patients were enrolled at more than one site, so were excluded from the intention-to-treat population (COMPOSE-1: one per group; COMPOSE-2: one in the naldemedine group, two from the placebo group), with intention-to-treat group sizes of 273 in the naldemedine group and 272 in the placebo group in COMPOSE-1, and 276 in the naldemedine group and 274 in the placebo group in COMPOSE-2. The proportion of responders in both trials was significantly higher with naldemedine than with placebo in COMPOSE-1 (130 responders [47·6%] of 273 in the naldemedine group vs 94 responders [34·6%] of 272 in the placebo group, difference 13·0% [95% CI 4·8-21·3]; p=0·002) and in COMPOSE-2 (145 [52·5%] of 276 vs 92 [33·6%] of 274, difference 18·9% [10·8-27·0]; p<0·0001). Incidence of adverse events with naldemedine was similar to placebo (COMPOSE-1: 132 [49%] of 271 in the naldemedine group vs 123 [45%] of 272 in the placebo group; COMPOSE-2: 136 [50%] of 271 vs 132 [48%] of 274). Treatment-related adverse events were noted in 59 (22%) of 271 patients in the naldemedine group and 45 (17%) of 272 in the placebo group in COMOPOSE-1, and in 54 (20%) of 271 patients in the naldemedine group and 31 (11%) of 274 in the placebo group of COMPOSE-2; the between-group differences were largely due to gastrointestinal disorders, which were more common with naldemedine than placebo (COMPOSE-1: 40 [15%] patients in the naldemedine group vs 18 [7%] in the placebo group; COMPOSE-2: 42 [16%] vs 20 [7%]). Naldemedine treatment led to a significantly higher responder rate than did placebo and was generally well tolerated. These results support that naldemedine could be a new option for the treatment of opioid-induced constipation in patients with chronic non-cancer pain. Shionogi & Co, Ltd.

Phase 3 study to evaluate the efficacy and safety of naldemedine for the treatment of opioid-induced constipation (OIC) in cancer patients.

10016Background: While opioid analgesics play a central role in managing cancer pain, opioid-induced constipation (OIC) is one of the most common side effects. Naldemedine (NAL) is a peripherally-a...

598 Efficacy and Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Subjects With Chronic Non-Cancer Pain Receiving Opioid Therapy: Results From Two Phase 3 Clinical Trials

598 Efficacy and Safety of Naldemedine for the Treatment of Opioid-Induced Constipation in Subjects With Chronic Non-Cancer Pain Receiving Opioid Therapy: Results From Two Phase 3 Clinical Trials