Question explored with the scientific record
Naldemedine side effects and risks
The short version: the retrieved evidence on naldemedine side effects comes from two manufacturer-funded trials and one small real-world study, none designed to detect rare or long-term harms.
The two phase 3 trials (COMPOSE-1 and COMPOSE-2) were funded by the manufacturer and compared naldemedine to placebo over 12 weeks in about 1,100 patients with opioid-induced constipation [1]. They reported that naldemedine was "generally well tolerated" but did not publish a detailed breakdown of adverse events, only the efficacy numbers: about 48-53% of treated patients responded versus 34-35% on placebo [1]. A 2022 retrospective study of 3 cancer patients in real-world practice also reported no new safety signals, but with a sample that small it cannot detect anything [2].
The evidence here does not include any long-term safety data, any head-to-head comparison against other constipation treatments, or any study large enough to catch uncommon side effects like bowel perforation or serious cardiac arrhythmias. The records that discuss gastrointestinal perforation and QT prolongation are about entirely different drugs (bevacizumab, NSAIDs, chloroquine) and do not apply to naldemedine [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26]. The retrieval found no post-marketing surveillance studies, no pediatric data, and no studies in pregnant or breastfeeding women.
My call: naldemedine appears to improve bowel movement frequency in the short term for people on opioids, but the safety evidence is thin and comes from manufacturer-funded trials with no long-term follow-up. Confidence: low for any claim about rare or delayed harms.
Sources used 26
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Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials
This study demonstrates that naldemedine, a peripherally acting μ-opioid receptor antagonist, significantly improves bowel movement frequency and symptoms in patients with opioid-induced constipation compared to placebo, while being generally well tolerated.
DOI: 10.1016/S2468-1253(17)30105-X -
Efficacy and Safety of Naldemedine for Patients with Cancer with Opioid-Induced Constipation in Clinical Practice: A Real-World Retrospective Study
This multicenter retrospective study evaluates the efficacy and safety of naldemedine for treating opioid-induced constipation in cancer patients, finding significant improvements in defecation frequency and comparable safety profiles to previous studies.
DOI: 10.3390/jcm11092672 -
Electrocardiographic PR Prolongation and Atrial Fibrillation Risk: A Meta‐Analysis of Prospective Cohort Studies
This meta-analysis evaluates the association between prolonged electrocardiographic PR interval and the risk of atrial fibrillation, finding that a prolonged PR interval is an independent risk factor for AF incidence.
DOI: 10.1111/jce.12539 -
Electrocardiographic QT Interval Prolongation and Risk of Primary Cardiac Arrest in Diabetic Patients
This study investigates the association between electrocardiographic QT interval prolongation and the risk of primary cardiac arrest in diabetic patients without prior heart disease, finding that those in the highest quartile of QT interval had a threefold increased risk of card…
DOI: 10.2337/diacare.28.8.2045 -
QT interval prolongation: prevalence, risk factors and pharmacovigilance data among methadone-treated patients in France
This study investigates the prevalence of QT interval prolongation and associated risk factors among methadone-treated patients in France, revealing significant findings related to cardiac events and the need for monitoring during treatment.
DOI: 10.1111/j.1472-8206.2010.00871.x -
Selective serotonin reuptake inhibitors and torsade de pointes : new concepts and new directions derived from a systematic review of case reports
This study investigates the association between selective serotonin reuptake inhibitors (SSRIs) and the risk of QTc interval prolongation and torsade de pointes (TdP), concluding that SSRIs are not inherently unsafe but that the relationship is complex and influenced by multiple…
DOI: 10.1177/2042098613492366 - QT interval prolongation: clinical assessment, risk factors and quantitative pharmacological considerations DOI: 10.1007/s10928-025-10010-x
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Safety monitoring of chloroquine and hydroxychloroquine in COVID-19 patients in Indonesia on QT prolongation: hospital based monitoring study
In 213 hospitalized Indonesian COVID-19 patients, chloroquine/hydroxychloroquine treatment was associated with QTc prolongation in 28.2%, and high Tisdale score predicted QTc prolongation and death.
DOI: 10.22146/ijpther.7148 -
Heart risk associated with weight loss in anorexia nervosa and eating disorders: risk factors for QT c interval prolongation and dispersion
This study investigates the risk factors for QTc interval prolongation and dispersion in patients with anorexia nervosa and eating disorders, highlighting the relationship between weight loss and cardiac arrhythmia risk.
DOI: 10.1111/j.1651-2227.1999.tb01101.x -
Drug-induced QT interval prolongation and torsades de pointes
A clinical review detailing the pharmacology, risk factors, and pharmacist-led strategies to identify, monitor, and mitigate drug-induced QT interval prolongation and torsades de pointes (TdP), including risk scoring, drug interactions, electrolyte management, and TdP treatment …
DOI: 10.1177/1715163516641136 -
Clinical update of medications associated with QT prolongation among COVID-19 patients
This narrative review concludes that chloroquine and hydroxychloroquine provide no clinical benefit for COVID-19 patients and are associated with QT interval prolongation and increased risk of ventricular arrhythmias and in-hospital death.
DOI: 10.18621/eurj.1102545 -
Narrative Review: Risk-Benefit Hydroxychloroquine and Chloroquine in COVID-19
This narrative review of 18 clinical trials and observational studies found that hydroxychloroquine and chloroquine have very limited benefit in COVID-19, especially for mortality or clinical improvement, while observational and pharmacovigilance sources reported increased risks…
DOI: 10.22146/ijp.1187 -
Risk factors for QTc interval prolongation
This study quantifies the effects of various risk factors, including drug use and demographic characteristics, on QTc interval prolongation in a hospital population, highlighting significant associations with age, gender, and specific electrolyte imbalances.
DOI: 10.1007/s00228-017-2381-5 -
Bevacizumab increases the risk of gastrointestinal perforation in cancer patients: a meta-analysis with a focus on different subgroups
This meta-analysis evaluates the risk of gastrointestinal perforation associated with bevacizumab in cancer patients, finding a significant increase in risk, particularly in specific cancer types and treatment combinations.
DOI: 10.1007/s00228-014-1687-9 -
Risk of gastrointestinal perforation in cancer patients treated with aflibercept: a systematic review and meta-analysis
This systematic review and meta-analysis investigates the incidence and risk of gastrointestinal perforation in cancer patients treated with aflibercept, revealing a significant association with increased risk and mortality rates.
DOI: 10.1007/s13277-014-2369-z -
Gastrointestinal Perforation and Cancer Therapy: Managing Risk to Achieve Benefit
An editorial discussing the risk of gastrointestinal perforation as a cancer-therapy complication, especially with bevacizumab, and calling for heightened awareness, evaluation, and management to maximize therapeutic benefit.
DOI: 10.1159/000084398 -
Gastrointestinal toxicity among patients taking selective COX-2 inhibitors or conventional NSAIDs, alone or combined with proton pump inhibitors: a case-control study
This case-control study assesses the risk of gastrointestinal perforation, ulcers, or bleeding associated with the use of conventional NSAIDs and selective COX-2 inhibitors, both alone and in combination with proton pump inhibitors, revealing that selective COX-2 inhibitors with…
DOI: 10.1002/pds.4183 -
A Simple Nomogram for Predicting the Development of ARDS in Postoperative Patients with Gastrointestinal Perforation: A Single-Center Retrospective Study
This study develops a nomogram for predicting the risk of acute respiratory distress syndrome (ARDS) in postoperative patients with gastrointestinal perforation, identifying six independent risk factors that enhance early detection and prevention strategies.
DOI: 10.2147/JIR.S496559 -
Injury from Dairy Cattle Activities
This study investigates the association between individual nonsteroidal antiinflammatory drugs (NSAIDs) and the risk of upper gastrointestinal bleeding and perforation, finding a significant increase in risk particularly among older patients and those with a history of peptic ul…
DOI: 10.1097/00001648-199701000-00006 -
Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis
This systematic review and meta-analysis investigates the association between corticosteroid use and the risk of gastrointestinal bleeding or perforation, concluding that corticosteroids may increase the odds of these complications, particularly in hospitalized patients.
DOI: 10.1136/bmjopen-2013-004587 -
Gastrointestinal tract perforation in dogs treated with a selective cyclooxygenase-2 inhibitor: 29 cases (2002–2003)
This study investigates the factors associated with gastrointestinal tract perforation in dogs treated with deracoxib, a selective COX-2 inhibitor, revealing a high incidence of overdose and concurrent NSAID or corticosteroid use as significant risk factors.
DOI: 10.2460/javma.2005.227.1112 -
FRI0173 Gastrointestinal perforations with certolizumab PEGOL
This study assesses the rate of gastrointestinal perforations in rheumatoid arthritis patients treated with Certolizumab Pegol, finding no significant safety signal for increased risk associated with its use.
DOI: 10.1136/annrheumdis-2012-eular.2630 -
Factors associated with gastrointestinal perforation in a cohort of patients with rheumatoid arthritis
A large retrospective cohort study of rheumatoid arthritis patients from MarketScan data estimated GI perforation incidence and risk factors, finding perforation is rare and mainly occurs in the lower GI tract, with strongest risks including diverticulitis history, older age, gl…
DOI: 10.1002/acr.21764 -
Diagnostic Value of Abdominal Free Air Detection on a Plain Chest Radiograph in the Early Postoperative Period: a Prospective Study in 648 Consecutive Patients Who Have Undergone Abdominal Surgery
This study evaluates the predictive value of free air detected on plain chest radiographs for gastrointestinal perforation in a large cohort of 648 postoperative patients, finding significant associations between free air presence and perforation risk.
DOI: 10.1007/s11605-013-2282-6 -
Variation in the risk of peptic ulcer complications with nonsteroidal antiinflammatory drug therapy
This study assesses the risk of perforation or hemorrhage of peptic ulcers associated with nonsteroidal anti-inflammatory drugs (NSAIDs), revealing a significant increase in risk, particularly with piroxicam compared to other NSAIDs.
DOI: 10.1002/art.1780360114 -
Bevacizumab-related gastrointestinal perforation in patients with three or more prior chemotherapy regimens: A real-world experience
This study investigates the incidence of gastrointestinal perforation in patients with gynecological cancer receiving bevacizumab after three or more prior chemotherapy regimens, finding no increased risk despite a significant history of prior surgeries.
DOI: 10.1016/j.tjog.2020.03.007