Naldemedine

Indications

Naldemedine is used for: Opioid-induced Constipation

Adult Dose

Opioid-induced Constipation Indicated for opioid-induced constipation (OIC) in adults with chronic noncancer pain 0.2 mg PO qDay Hepatic impairment Mild or moderate (Child-Pugh A or B): No dose adjustment required Severe (Child-Pugh C): Avoid use

Child Dose

Renal Dose

Administration

May take with or without food Alteration of analgesic dosing regimen before initiating naldemedine is not required Patients receiving opioids for <4 weeks may be less responsive to naldemedine Discontinue naldemedine if treatment with opioids is also discontinued

Contra Indications

Known or suspected GI obstruction and patients at increased risk of recurrent obstruction, owing to the potential for GI perforation History of hypersensitivity to naldemedine; bronchospasm and rash reported

Precautions

Gastrointestinal perforation GI perforation reported with use of another PAMORA in patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (eg, peptic ulcer disease, Ogilvie syndrome, diverticular disease, infiltrative GI tract malignancies, peritoneal metastases) Consider risk with use in patients with these conditions or other conditions that might result in impaired integrity of the GI tract wall (eg, Crohn disease) Monitor for severe, persistent, or worsening abdominal pain and discontinue naldemedine in patients who develop this symptom Opioid withdrawal Clusters of symptoms consistent with opioid withdrawal include hyperhidrosis, chills, increased lacrimation, hot flush/flushing, pyrexia, sneezing, feeling cold, abdominal pain, diarrhea, nausea, and vomiting Patients with blood-brain barrier disruption may be at increased risk for opioid withdrawal or reduced analgesia Take into account the overall risk-benefit profile when prescribing naldemedine in such patients Monitor for symptoms of opioid withdrawal

Pregnancy-Lactation

Pregnancy Fetal/neonatal clinical considerations Naldemedine crosses the placenta and may precipitate opioid withdrawal in a fetus or newborn, owing to the immature fetal blood-brain barrier There are no available data with naldemedine in pregnant women to inform a drug-associated risk of major birth defects and miscarriage Lactation Unknown if distributed in human breast milk Naldemedine was present in the milk of rats Because of the potential for serious adverse reactions, including opioid withdrawal in breastfed infants, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother If drug is discontinued in order to minimize drug exposure to a breastfed infant, advise women that breastfeeding may be resumed 3 days after the final dose

Interactions

Substrate of CYP3A4 (major), P-gp, and UGT1A3 (minor) Opioid antagonists: Avoid use with another opioid antagonist Strong CYP3A4 inducers: Avoid coadministration, owing to potential for decreased efficacy of naldemedine Moderate or strong CYP3A4 inhibitors: Monitor for potential naldemedine adverse effects, owing to increased plasma concentrations P-gp inhibitors: Monitor for potential naldemedine adverse effects, owing to increased plasma concentrations

Side Effects

Side effects of Naldemedine : >10% Abdominal pain (8-11%) 1-10% Diarrhea (7%) Nausea (4-6%) Vomiting (3%) Gastroenteritis (2-3%) Opioid withdrawal (1-3%)

Mode of Action

Opioid antagonist with binding affinities for mu-, delta-, and kappa-opioid receptors Functions as a peripherally acting mu-opioid receptor antagonist (PAMORA) in tissues such as the GI tract, thereby decreasing the constipating effects of opioids Derivative of naltrexone to which a side chain has been added that increases the molecular weight and the polar surface area, thereby reducing its ability to cross the blood-brain barrier