Naldemedine

Uses

Naldemedine is an opioid antagonist used to to treat opioid-induced constipation.

For the treatment of opioid-induced constipation [FDA Label].

Naldemedine is also used to associated treatment for these conditions: Opioid Induced Constipation (OIC)

How Naldemedine works

Naldemedine binds to and antagonizes mu-, delta-, and kappa-opioid receptors [FDA Label]. The binding of opioid agonists to peripheral mu-opioid receptors slows the transit of feces through the intestine resulting in constipation. By antagonizing mu-opioid receptors, naldemedine inhibits this effect.

Toxicity

The most common adverse effects of naldemedine are abdominal pain (11%), diarrhea (7%), nausea (6%), vomiting (3%), and gastroenteritis (3%) [FDA Label].

Food Interaction

• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of naldemedine.
• Take with or without food.

[Moderate] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of naldemedine.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

In pharmacokinetic studies, naldemedine systemic exposure (AUC) was increased approximately 90% by the moderate CYP450 3A4 inhibitor fluconazole and nearly 200% by the potent inhibitor itraconazole.

The interaction has not been studied with grapefruit juice.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased exposure to naldemedine may precipitate opioid withdrawal symptoms such as hyperhidrosis, lacrimation, rhinorrhea, chills, diarrhea, abdominal pain, anxiety, insomnia, irritability, restlessness, and yawning.

Food does not significantly affect the overall bioavailability of naldemedine.

When administered with a high-fat meal, the rate of naldemedine absorption was decreased, but not the extent.

Specifically, naldemedine peak plasma concentration (Cmax) was decreased by approximately 35% and time to achieve Cmax was delayed from 0.75 hours in the fasted state to 2.5 hours in the fed state, while naldemedine AUC was not significantly changed.

MANAGEMENT: Naldemedine may be taken with or without food.

Patients should avoid consumption of grapefruit and grapefruit juice during treatment with naldemedine.

Naldemedine Drug Interaction

Moderate: diltiazemUnknown: lactobacillus acidophilus, charcoal, aspirin, sulfamethoxazole / trimethoprim, ubiquinone, copper gluconate, ubiquinone, glucose, tamsulosin, fluticasone nasal, glycerin, heparin, sodium iodide, clonazepam, arginine, levocarnitine, metoprolol, acetaminophen, cholecalciferol

Naldemedine Disease Interaction

Major: hepatic impairment, intestinal obstructionModerate: hemodialysis

Volume of Distribution

The apparent volume of disribution during the terminal phase is 155 L [FDA Label]

Elimination Route

Tmax is 0.75 h [FDA Label]. Administration with a high-fat meal reduces Cmax by 35% and increases Tmax to 2.5 h.

Half Life

The terminal elimination half life is 11 h [FDA Label].

Elimination Route

57% of naldemedine is excreted in the urine with 16-18% as the parent compound and 35% is excreted in the feces [FDA Label].

Innovators Monograph

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