naldemedine (Rx)

>10%

Abdominal pain (8-11%)

1-10%

Diarrhea (7%)

Nausea (4-6%)

Vomiting (3%)

Gastroenteritis (2-3%)

Opioid withdrawal (1-3%)

Frequency Not Defined

Bronchospasm

Rash

Contraindications

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

Cautions

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

Drug interaction overview

• 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

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

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism 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

Absorption

Peak plasma concentrations: 45 minutes (fasting); 2.5 hr (high-fat meal)

A high-fat meal decreased the rate, but not the extent of absorption

Distribution

Protein bound: 93-94%

Vd: 155 L

Metabolism

Primarily metabolized by CYP3A4 to nor-naldemedine, with minor contribution from UGT1A3 to form naldemedine 3-G

Nor-naldemedine and naldemedine 3-G have been shown to have antagonistic activity for opioid receptors, with less potent effect than naldemedine

Naldemedine also undergoes cleavage in the GI tract to form benzamidine and naldemedine carboxylic acid

Elimination

Half-life: 11 hr

Excretion: 57% urine; 35% feces

Oral 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

Storage

Store in light-resistant container at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)