Symproic (naldemedine tosylate)

Dosage of naldemedine tosylate is expressed in terms of naldemedine.

The recommended adult dosage of naldemedine for the management of opiate-induced constipation in patients with chronic non-cancer-related pain is 0.2 mg once daily.

Naldemedine tosylate is administered orally without regard to food.

No dosing information is available for this tab.

Naldemedine is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4), with minimal contribution from uridine diphosphate-glucuronosyltransferase (UGT) 1A3; naldemedine also is a substrate of P-glycoprotein (P-gp). Naldemedine did not inhibit CYP isoenzyme 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A11 in vitro at clinically relevant concentrations. The drug also did not substantially induce CYP isoenzyme 1A2, 2B6, or 3A4 or UGT 1A2, 1A6, or 2B7.

Naldemedine does not inhibit organic anion transport protein (OATP) 1B1 or 1B3, organic cation transporter (OCT) 1 or 2, organic anion transporter (OAT) 1 or 3, breast cancer resistance protein (BCRP), or P-gp.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Naldemedine/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of naldemedine.(1)

CLINICAL EFFECTS: Concurrent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of naldemedine.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US manufacturer recommends avoid concurrent use of a strong inducer of CYP3A4 with naldemedine.(1) The UK manufacturer states concurrent use of a strong inducer of CYP3A4 is not recommended.(2) If concurrent use is warranted, monitor patients for signs of decreased naldemedine effectiveness, such as constipation. Patients may require additional laxative therapy.

DISCUSSION: Rifampin (600 mg daily), a strong inducer of CYP3A4, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naldemedine by 38% and 83%, respectively.(1) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(1-4)

Naldemedine/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of naldemedine.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 may result in increased levels and potential risk of adverse reactions of naldemedine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer states concurrent use of a strong inhibitor of CYP3A4 should be avoided.(1) The US manufacturer recommends monitoring for potential naldemedine-related adverse reactions.(2) If concurrent use is unavoidable, monitor patients for signs of naldemedine adverse reactions, such as abdominal pain and opioid withdrawal.

DISCUSSION: Itraconazole, a strong inhibitor of CYP3A, increased exposure to naldemedine area-under-curve (AUC) by 2.9-fold which may result in an increased risk of adverse reactions.(1) Strong inhibitors of CYP3A include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(1-4)

There are no moderate interactions for this drug.

Because of the potential for GI perforation, naldemedine is contraindicated in patients with known or suspected GI obstruction and in patients at increased risk for recurrent GI obstruction. (See GI Perforation under Cautions: Warnings/Precautions.)

Naldemedine also is contraindicated in patients with known hypersensitivity to the drug.

• Gastrointestinal obstruction

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

Adverse effects reported in 2% or more of patients receiving naldemedine and at a greater incidence than that observed with placebo include abdominal pain, diarrhea, nausea, vomiting, and gastroenteritis.

Rare or Very Rare

• Bronchospastic pulmonary disease
• Gastrointestinal perforation

More Frequent

• Acute abdominal pain
• Diarrhea
• Gastroenteritis
• Nausea

Less Frequent

• Opioid withdrawal symptoms
• Vomiting

Rare or Very Rare

• Skin rash

No enhanced messaging available.

Safety and efficacy of naldemedine have not been established in pediatric patients.

Naldemedine should be used in pregnant women only if the potential benefits justify the potential risk to the fetus. There are no adequate and well-controlled studies of naldemedine in pregnant women. Naldemedine crosses the placenta; because of the immature fetal blood-brain barrier, use of naldemedine during pregnancy may precipitate opiate withdrawal in the fetus. No adverse effects of the drug on embryofetal development have been observed in animal reproduction studies.

It is not known whether naldemedine is distributed into human milk, affects milk production, or affects the breast-fed infant. Naldemedine is distributed into milk in rats. Because of the potential for serious adverse effects, including opiate withdrawal, in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. If naldemedine is discontinued, nursing may be resumed 3 days after the final dose of the drug.

In clinical studies, 16% of patients who received naldemedine were 65 years of age and older, while 3% were 75 years of age and older. Although no overall differences in safety and efficacy were observed between geriatric patients and younger adults, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. A population pharmacokinetic analysis revealed no age-related differences in the pharmacokinetics of naldemedine.