Overdose
Single doses up to 500 times the recommended dose, as well as multiple doses up to 150 times the recommended dose for ten days, resulted in an increase of the mentioned side effects. Theses side effects were mild to moderate. Interactions
As naldemedine is mainly metabolized by the liver enzyme CYP3A4, inhibitors of this enzyme can increase its concentrations in the body and thus its potential for side effects. Examples include itraconazole (which increased naldemedine exposure 2.9-fold in a study), ketoconazole, clarithromycin and grapefruit juice. Conversely, CYP3A4 inducers such as rifampicin and St Johns wort decrease naldemedine concentrations; with rifampicin, the reduction was 83% in a study.Strong inhibitors of the pump P-glycoprotein such as ciclosporin may increase naldemedine concentrations in the blood plasma. Pharmacology
Mechanism of action
Naldemedine is a derivative of naltrexone and, like this substance, blocks opioid receptors of the types μ (mu), δ (delta) and κ (kappa). While naltrexone is able to cross the blood–brain barrier and can therefore be used to treat opioid dependence, the large hydrophilic side chain of naldemedine and its affinity to P-glycoprotein result in negligible concentrations in the central nervous system when recommended doses are applied. Instead, it acts mainly on μ-receptors in the gastrointestinal tract, where it counteracts the constipation inducing effects of opioid drugs. Pharmacokinetics
After oral intake, naldemedine has an absolute bioavailability in the range of 20% to 56% and reaches highest blood plasma levels after 0.75 hours when taken without food and 2.5 hours when taken with a high-fat meal.
Naldemedine (brand name Symproic in the US and Rizmoic in the European Union) is a medication that is used for the treatment of opioid-induced constipation in adults with chronic non-cancer pain. It is a peripherally acting μ-opioid receptor antagonist and was developed by Shionogi. Clinical studies have found it to possess statistically significant effectiveness for these indications and to be generally well tolerated, with predominantly mild to moderate gastrointestinal side effects. Effects indicative of central opioid withdrawal or impact on the analgesic or miotic effects of co-administered opioids have only been observed in a small number of patients. Medical uses
In the US, naldemedine is approved for the treatment of opioid induced constipation in adults with chronic non-cancer pain, including those who have chronic pain related to prior cancer or its treatment and do not need frequent opioid dosage escalation.In the European Union, naldemedine is also approved for the treatment of opioid induced constipation in adults, but as a second-line therapy after treatment with a laxative. Contraindications
The drug is contraindicated in patients with gastrointestinal obstruction or perforation, or those at risk for these problems. Side effects
Side effects in studies were abdominal pain (8–11% of patients as compared to 2–5% under placebo, depending on the study), diarrhea (7% versus 2–3%), nausea (4–6% versus 2–5%), vomiting (3% versus 2%), gastroenteritis (2–3% versus 1%), and opioid withdrawal syndrome (1.5–3.2% versus 0.5–1.5%). The latter was severe but manageable in one patient, and otherwise mild to moderate. Hypersensitivity reactions were rare; they occurred in two patients.