Long-term use of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: a randomized, double-blind, placebo-controlled phase 3 study

Webster, Lynn R.; Nalamachu, Srinivas; Morlion, Bart; Reddy, Jyotsna; Baba, Yoshitaka; Yamada, Tadaaki; Ferreira, Juan Camilo Arjona

doi:10.1097/j.pain.0000000000001174

Cited by 72 publications

(97 citation statements)

References 32 publications

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“…Data to support naldemedine use come from 4 randomized double-blind trials comparing naldemedine against placebo including 1 phase 2b trial (Webster et al 46 ) and 3 phase 3 trials (COMPOSE 1, 2, and 3 47,48 ), including >2400 patients in total. The primary end point for 3 of these studies (Webster et al and COMPOSE 1 and 2 trials) was the ability to achieve at least 3 spontaneous bowel movements (SBM) per week.…”

Section: Peripherally Acting M-opioid Receptor Antagonistsmentioning

confidence: 99%

“…Naldemedine is also the only prescription agent evaluated in this guideline, for which long-term (52-week) safety data are available. 48 The overall quality of evidence supporting use of naldemedine for management of OIC was considered high. The AGA issued a strong recommendation for use of naldemedine vs no treatment in patients with OIC refractory to laxatives.…”

Section: Peripherally Acting M-opioid Receptor Antagonistsmentioning

confidence: 99%

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American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation

et al. 2019

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Section: Peripherally Acting M-opioid Receptor Antagonistsmentioning

confidence: 99%

Section: Peripherally Acting M-opioid Receptor Antagonistsmentioning

confidence: 99%

American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation

et al. 2019

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“…A new oral PAMORA, naldemedine, which has also demonstrated good efficacy and tolerability in a large clinical trial program [33][34][35], has recently been approved by the FDA and is currently undergoing licensing application at the EMA.…”

Section: Secretagoguesmentioning

confidence: 99%

Medical Therapy of Constipation: Current Standards and Beyond

Andresen

Layer²

2018

Visc Med

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Chronic constipation is a very common medical problem with relevant impact on the patients' quality of life. Modern definitions recognize constipation as a polysymptomatic disorder, including various aspects of disturbed defecation. Current guidelines recommend a stepwise approach in the management of chronic constipation. Isolated or concomitant evacuation disorders should be identified and may need differential/additional treatment. Baseline measures include lifestyle components and bulking agents. The next step recommends treatment with conventional laxatives. In refractory patients, modern medical therapies, such as the prokinetic prucalopride or the secretagogues linalotide or lubiprostone, may be used effectively. For patients with opioid-induced constipation, the modern concept of peripherally acting µ-opioid antagonists has shown to successfully improve this increasing medical problem and even to potentially increase survival time in terminally ill patients on opioid therapy. Prolonged-released oral naloxone (in fixed combination with oxycodone), oral naloxegol or naldemedine, and subcutaneous methylnaltrexone have all demonstrated good efficacy and tolerability in the treatment of opioid-induced constipation. To adequately apply stepwise treatment algorithms, a simple tool to identify treatment failure may improve patient care.

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“…[14][15][16] Additionally, 0.2 mg naldemedine is the approved therapeutic dose in the United States. The renal and hepatic impairment studies were designed in accordance with US FDA Guidance for Industry (Pharmacokinetics in Patients With Impaired Renal Function and Pharmacokinetics in Patients With Impaired Hepatic Function, respectively) as described below.…”

Section: Methodsmentioning

confidence: 99%

“…12,13 A 0.2-mg dose of naldemedine was selected for these studies based on results from prior phase 2 and phase 3 studies, which demonstrated that 0.2 mg naldemedine administered once daily was a well-tolerated dose with efficacy for the treatment of opioid-induced constipation. [14][15][16] Additionally, 0.2 mg naldemedine is the approved therapeutic dose in the United States. 8 The renal impairment study consisted of 5 cohorts categorized as healthy subjects with normal renal function and subjects with mild renal impairment, moderate renal impairment, severe renal impairment, or end-stage renal disease (ESRD) requiring hemodialysis.…”

Section: Methodsmentioning

confidence: 99%

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine

Fukumura

Yamada

Yokota

et al. 2019

Clinical Pharm in Drug Dev

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Naldemedine is a peripherally acting μ-opioid-receptor antagonist for the treatment of opioid-induced constipation. Two phase 1 single-dose studies investigated the pharmacokinetics and safety of a 0.2-mg oral dose of naldemedine in subjects with renal impairment (mild, n = 9; moderate, n = 9; severe, n = 6; and end-stage renal disease, n = 8) or hepatic impairment (mild or moderate, n = 8 each) and demographically matched healthy subjects with normal renal and hepatic function (n = 8, both studies). Pharmacokinetic assessments indicate that dose adjustments for naldemedine are not necessary for subjects with any degree of renal impairment or for subjects with mild or moderate hepatic impairment. In subjects with renal impairment compared with healthy subjects with normal renal function, the geometric mean ratios of naldemedine area under the concentration-time curve (AUC 0-inf ) ranged from 82.8% (90%CI 69.5% to 98.6%) to 137.8% (90%CI 114.0% to 166.5%). Renal clearance decreased with reduced renal function (normal function 1.3 L/h; mild impairment 1.1 L/h; moderate impairment 1.0 L/h; severe impairment 0.5 L/h), and only 2.7% of naldemedine was removed by hemodialysis. In subjects with hepatic impairment compared with healthy subjects with normal hepatic function, the geometric mean ratio of AUC 0-inf ranged from 82.8% (90%CI 65.7% to 104.5%) to 105.2% (90%CI 83.4% to 132.6%). Naldemedine was well tolerated in both healthy subjects and subjects with renal or hepatic impairment, and reported adverse events were generally consistent with the known safety profile.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Long-term use of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: a randomized, double-blind, placebo-controlled phase 3 study

Abstract: Supplemental Digital Content is Available in the Text.Naldemedine treatment of opioid-induced constipation was well tolerated for 52 weeks, did not precipitate opioid withdrawal, and increased bowel movements and quality of life.

Cited by 72 publications

References 32 publications

American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation

American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation

Medical Therapy of Constipation: Current Standards and Beyond

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine

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