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  • CLASSES

    Peripheral Mu Opioid Receptor Antagonists for Constipation
    Peripheral Opioid Receptor Antagonists

    DEA CLASS

    Rx

    DESCRIPTION

    Opioid antagonist
    For the use of opioid induced constipation in adult patients with chronic non-cancer pain
    Not for use in patients with known or suspected gastrointestinal obstruction

    COMMON BRAND NAMES

    SYMPROIC

    HOW SUPPLIED

    Naldemedine/SYMPROIC Oral Tab: 0.2mg

    DOSAGE & INDICATIONS

    For the treatment of opiate agonist-induced constipation in patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.
    Oral dosage
    Adults

    0.2 mg PO once daily with or without food. Alteration of analgesic dosing regimen prior to initiating naldemedine is not required. Patients receiving opioids for less than 4 weeks may be less responsive to naldemedine. Discontinue naldemedine if the opioid pain medication is discontinued.

    MAXIMUM DOSAGE

    Adults

    0.2 mg PO once daily.

    Geriatric

    0.2 mg PO once daily.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Avoid use of naldemedine in patients with severe hepatic impairment, as the dosage in these patients has not been determined. No dosage adjustment is required for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naldemedine has not been evaluated.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Plasma concentrations of naldemedine in subjects with ESRD requiring hemodialysis were similar when naldemedine was administered either pre- or post-hemodialysis, indicating that naldemedine was not removed from the blood by hemodialysis.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    May be taken with or without food.
    Discontinue naldemedine therapy if treatment with the opioid pain medication is also discontinued.

    STORAGE

    SYMPROIC:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Abdominal pain, cholelithiasis, Crohn's disease, diarrhea, diverticulitis, fecal impaction, gastric cancer, GI disease, GI obstruction, GI perforation, inflammatory bowel disease, peptic ulcer disease

    Naldemedine is contraindicated in patients with known or suspected GI obstruction and in patients at increased risk of recurrent obstruction, due to the potential for GI perforation. Patients with current symptoms (e.g., severe, persistent or worsening abdominal pain) that may be suggestive of GI obstruction should be evaluated before using naldemedine. Common causes of obstruction include abdominal adhesions, hernias, tumors (gastric cancer, disseminated intraperitoneal cancer), foreign bodies (including gallstones, cholelithiasis), diverticulitis, inflammatory bowel disease (Crohn's disease), and fecal impaction. In addition, use naldemedine cautiously in patients with a GI disease that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (e.g.,  peptic ulcer disease, Ogilvie’s syndrome, diverticulitis, infiltrative GI tract malignancies or peritoneal metastases) as cases of GI perforation have been reported with use of another peripherally acting opioid antagonist in such patients. Take into account the overall risk-benefit profile when using naldemedine in patients with these conditions. Monitor for the development of severe, persistent or worsening abdominal pain and/or diarrhea.

    Acute opioid withdrawal

    Naldemedine is an antagonist of opioid binding at the mu-opioid receptor. When administered at recommended doses, naldemedine functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract; CNS penetration of naldemedine is expected to be negligible. Nevertheless, symptoms consistent with acute opioid withdrawal (e.g., hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning) have occurred in patients treated with naldemedine. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. Take into account the overall risk-benefit profile when using naldemedine in such patients; monitor for symptoms of opioid withdrawal.

    Hepatic disease

    Avoid use of naldemedine in patients with severe hepatic disease (Child-Pugh Class C) since the pharmacokinetics of naldemedine has not been evaluated and dosage in these patients has not been determined. No dosage adjustment is required for patients with mild or moderate hepatic impairment.

    Pregnancy

    There are no well-controlled studies in pregnant women. The use of naldemedine during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. In animal studies, no effects on embryo-fetal development were observed following administration of naldemedine in pregnant rats or rabbits during the period of organogenesis at doses resulting in systemic exposure approximately 23,000 and 226 times (respectively) the human AUC at the maximum recommended human dose. According to the manufacturer, naldemedine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Breast-feeding

    It is not known whether naldemedine is present in human milk; however, naldemedine is present in rat milk. Because of the potential for serious adverse reactions, including opioid withdrawal in breast-feeding infants, the manufacturer recommends that a decision be made to discontinue nursing 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 breast-feeding may be resumed 3 days after the final dose of naldemedine. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    GI perforation / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known

    Moderate

    sinus tachycardia / Rapid / Incidence not known

    Mild

    abdominal pain / Early / 8.0-11.0
    diarrhea / Early / 7.0-11.0
    nausea / Early / 4.0-8.0
    vomiting / Early / 3.0-3.0
    flushing / Rapid / Incidence not known
    anxiety / Delayed / Incidence not known
    rash / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    rhinorrhea / Early / Incidence not known
    lacrimation / Early / Incidence not known
    sneezing / Early / Incidence not known
    irritability / Delayed / Incidence not known
    agitation / Early / Incidence not known
    tremor / Early / Incidence not known
    fever / Early / Incidence not known
    chills / Rapid / Incidence not known
    yawning / Early / Incidence not known

    DRUG INTERACTIONS

    Abrocitinib: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with abrocitinib. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a P-gp substrate; abrocitinib is a P-gp inhibitor.
    Alvimopan: (Major) Avoid coadministration of alvimopan and other opiate antagonists, like naldemedine. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
    Amiodarone: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with amiodarone. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; amiodarone is a moderate P-gp inhibitor and a moderate CYP3A4 inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with clarithromycin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; clarithromycin is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Apalutamide: (Major) Avoid coadministration of naldemedine with apalutamide due to a significant decrease in naldemedine plasma concentrations which may reduce efficacy. Naldemedine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naldemedine exposure by 83%.
    Aprepitant, Fosaprepitant: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with aprepitant. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak,
    Atazanavir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with atazanavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; atazanavir is a CYP3A4 inhibitor.
    Atazanavir; Cobicistat: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with atazanavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; atazanavir is a CYP3A4 inhibitor. (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with cobicistat. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a moderate P-gp inhibitor and strong CYP3A4 inhibitor.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as phenobarbital, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Berotralstat: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with berotralstat. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-gp substrate; berotralstat is a P-gp and moderate CYP3A4 inhibitor.
    Brigatinib: (Moderate) Monitor for an increase in naldemedine-related adverse reactions if coadministration with brigatinib is necessary. Naldemedine is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Buprenorphine; Naloxone: (Major) Avoid concomitant use of naldemedine with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Bupropion; Naltrexone: (Major) Avoid concomitant use of naldemedine with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Cabozantinib: (Minor) Monitor for an increase in naldemedine-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of naldemedine may be necessary. Naldemedine is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Cannabidiol: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with cannabidiol. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a P-gp substrate; cannabidiol is a P-gp inhibitor.
    Capmatinib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with capmatinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; capmatinib is a P-gp inhibitor.
    Carbamazepine: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as carbamazepine, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Ceritinib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with ceritinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor.
    Chloramphenicol: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with chloramphenicol. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor.
    Ciprofloxacin: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with ciprofloxacin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; ciprofloxacin is a moderate CYP3A4 inhibitor.
    Clarithromycin: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with clarithromycin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; clarithromycin is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Cobicistat: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with cobicistat. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a moderate P-gp inhibitor and strong CYP3A4 inhibitor.
    Conivaptan: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with conivaptan. The plasma concentrations of naldemedine may be increased during concomitant use. Naldemedine is a CYP3A and P-gp substrate; conivaptan is a moderate CYP3A and P-gp inhibitor.
    Crizotinib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with crizotinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor.
    Cyclosporine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with cyclosporine. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; cyclosporine is a moderate P-gp inhibitor and a moderate CYP3A4 inhibitor.
    Daclatasvir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with daclatasvir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; daclatasvir is a moderate P-gp inhibitor.
    Danazol: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with danazol. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor.
    Darunavir: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with darunavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4; darunavir is a strong CYP3A4 inhibitor.
    Darunavir; Cobicistat: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with cobicistat. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a moderate P-gp inhibitor and strong CYP3A4 inhibitor. (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with darunavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4; darunavir is a strong CYP3A4 inhibitor.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with cobicistat. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a moderate P-gp inhibitor and strong CYP3A4 inhibitor. (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with darunavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4; darunavir is a strong CYP3A4 inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with ritonavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; ritonavir is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Delavirdine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with delavirdine. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor.
    Diltiazem: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with diltiazem. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4; diltiazem is a moderate CYP3A4 inhibitor.
    Dronedarone: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with dronedarone. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; dronedarone is a weak P-gp inhibitor and a moderate CYP3A4 inhibitor.
    Duvelisib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with duvelisib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor.
    Eliglustat: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with eliglustat. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; eliglustat is a moderate P-gp inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with cobicistat. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a moderate P-gp inhibitor and strong CYP3A4 inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with cobicistat. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a moderate P-gp inhibitor and strong CYP3A4 inhibitor.
    Enasidenib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with enasidenib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; enasidenib is a P-gp inhibitor.
    Enzalutamide: (Major) Avoid coadministration of naldemedine with enzalutamide due to a significant decrease in naldemedine plasma concentrations which may reduce efficacy. Naldemedine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naldemedine exposure by 83%.
    Erythromycin: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with erythromycin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; erythromycin is a moderate P-gp inhibitor and a moderate CYP3A4 inhibitor.
    Erythromycin; Sulfisoxazole: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with erythromycin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; erythromycin is a moderate P-gp inhibitor and a moderate CYP3A4 inhibitor.
    Ethotoin: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as hydantoins, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Fedratinib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with fedratinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor.
    Fluconazole: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with fluconazole. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor.
    Fluvoxamine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with fluvoxamine. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor.
    Fosamprenavir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with fosamprenavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor.
    Fosphenytoin: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as hydantoins, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Fostamatinib: (Moderate) Monitor for naldemedine toxicities that may require naldemedine dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a P-gp substrate may increase the concentration of the P-gp substrate. Fostamatinib is a P-gp inhibitor; naldemedine is a substrate for P-gp. Coadministration of fostamatinib with another P-gp substrate increased the P-gp substrate AUC by 37% and Cmax by 70%.
    Gilteritinib: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with gilteritinib. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    Glecaprevir; Pibrentasvir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with glecaprevir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; glecaprevir is a moderate P-gp inhibitor.
    Grapefruit juice: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with grapefruit. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; grapefruit is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Hydantoins: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as hydantoins, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Idelalisib: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with idelalisib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor.
    Indinavir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with indinavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor.
    Isavuconazonium: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with isavuconazonium. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; isavuconazonium is a weak P-gp inhibitor and a moderate CYP3A4 inhibitor.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as rifampin, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as rifampin, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Istradefylline: (Moderate) Monitor for an increase in naldemedine-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase naldemedine exposure. Naldemedine is a P-gp substrate and istradefylline is a P-gp inhibitor.
    Itraconazole: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with itraconazole. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; itraconazole is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Ketoconazole: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with ketoconazole. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; ketoconazole is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with clarithromycin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; clarithromycin is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Lapatinib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with lapatinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; lapatinib is a P-gp inhibitor.
    Lefamulin: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with oral lefamulin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin.
    Letermovir: (Moderate) Administering letermovir with naldemedine may increase naldemedine concentration and risk for adverse events. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Naldemedine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Levoketoconazole: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with ketoconazole. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; ketoconazole is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Lomitapide: (Major) Monitor for potential naldemedine-related adverse reactions and consider dose reduction of naldemedine if coadministered with lomitapide. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; lomitapide is a moderate P-gp inhibitor.
    Lonafarnib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with lonafarnib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-gp substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor.
    Lopinavir; Ritonavir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with ritonavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; ritonavir is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as lumacaftor, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as lumacaftor, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Maribavir: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with maribavir. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a P-gp substrate; maribavir is a P-gp inhibitor.
    Mefloquine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with mefloquine. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; mefloquine is a moderate P-gp inhibitor in vitro.
    Methylnaltrexone: (Major) Avoid coadministration of methylnaltrexone and other opiate antagonists, like naldemedine. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
    Mitapivat: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with mitapivat. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a P-gp substrate; mitapivat is a P-gp inhibitor.
    Mitotane: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as mitotane, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Nalmefene: (Major) Avoid concomitant use of naldemedine with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Naloxegol: (Major) Avoid concomitant use of naldemedine and naloxegol because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Naloxone: (Major) Avoid concomitant use of naldemedine with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Naltrexone: (Major) Avoid concomitant use of naldemedine with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Nefazodone: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with nefazodone. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor.
    Nelfinavir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with nelfinavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; nelfinavir is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Neratinib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with neratinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; neratinib is a P-gp inhibitor.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with netupitant. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor.
    Nicardipine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with nicardipine. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4; nicardipine is a CYP3A4 inhibitor.
    Nilotinib: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with nilotinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor.
    Nirmatrelvir; Ritonavir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with ritonavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; ritonavir is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Olanzapine; Samidorphan: (Major) Avoid concomitant use of naldemedine with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with ritonavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; ritonavir is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Osimertinib: (Moderate) Monitor for an increase in naldemedine-related adverse reactions if coadministration with osimertinib is necessary. Naldemedine is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Concomitant use may increase naldemedine exposure.
    Pacritinib: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with pacritinib. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a P-gp substrate; pacritinib is a P-gp inhibitor.
    Pentazocine; Naloxone: (Major) Avoid concomitant use of naldemedine with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Phenobarbital: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as phenobarbital, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as phenobarbital, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Phenytoin: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as hydantoins, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Posaconazole: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with posaconazole. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; posaconazole is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Primidone: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as primidone, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Quinine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with quinine. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; quinine is a moderate CYP3A4 inhibitor.
    Ranolazine: (Major) Monitor for potential naldemedine-related adverse reactions and consider dose reduction of naldemedine if coadministered with ranolazine. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; ranolazine is a moderate P-gp inhibitor in vitro.
    Ribociclib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with ribociclib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with ribociclib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor.
    Rifampin: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as rifampin, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Rifapentine: (Major) Avoid coadministration of naldemedine with rifapentine due to a significant decrease in naldemedine plasma concentrations which may reduce efficacy. Naldemedine is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naldemedine exposure by 83%.
    Ritonavir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with ritonavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; ritonavir is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Saquinavir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with saquinavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; saquinavir is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Simeprevir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with simeprevir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; simeprevir is a moderate P-gp inhibitor.
    Sofosbuvir; Velpatasvir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with velpatasvir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; velpatasvir is a moderate P-gp inhibitor.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with velpatasvir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; velpatasvir is a moderate P-gp inhibitor. (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with voxilaprevir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; voxilaprevir is a moderate P-gp inhibitor.
    Sorafenib: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with sorafenib. Naldemedine is a P-gp substrate; sorafenib is a P-gp inhibitor in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Sotorasib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with sotorasib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; sotorasib is a P-gp inhibitor.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as St. John's Wort, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
    Temsirolimus: (Moderate) Monitor for an increase in naldemedine-related adverse reactions if coadministration with temsirolimus is necessary. Naldemedine is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of naldemedine.
    Tepotinib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with tepotinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; tepotinib is a P-gp inhibitor.
    Tipranavir: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with tipranavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor.
    Trandolapril; Verapamil: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with verapamil. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; verapamil is a moderate P-gp inhibitor and a moderate CYP3A4 inhibitor.
    Tucatinib: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with tucatinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
    Verapamil: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with verapamil. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; verapamil is a moderate P-gp inhibitor and a moderate CYP3A4 inhibitor.
    Voclosporin: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with voclosporin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; voclosporin is a P-gp inhibitor.
    Vonoprazan; Amoxicillin; Clarithromycin: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with clarithromycin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; clarithromycin is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Voriconazole: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with voriconazole. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor.
    Voxelotor: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with voxelotor. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a CYP3A substrate; voxelotor is a moderate CYP3A inhibitor.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no well-controlled studies in pregnant women. The use of naldemedine during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. In animal studies, no effects on embryo-fetal development were observed following administration of naldemedine in pregnant rats or rabbits during the period of organogenesis at doses resulting in systemic exposure approximately 23,000 and 226 times (respectively) the human AUC at the maximum recommended human dose. According to the manufacturer, naldemedine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    It is not known whether naldemedine is present in human milk; however, naldemedine is present in rat milk. Because of the potential for serious adverse reactions, including opioid withdrawal in breast-feeding infants, the manufacturer recommends that a decision be made to discontinue nursing 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 breast-feeding may be resumed 3 days after the final dose of naldemedine. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Naldemedine is an opioid antagonist with binding affinities for mu-, delta-, and kappa-opioid receptors. Naldemedine functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids. Naldemedine is a 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 (BBB). Naldemedine is also a substrate of the P-glycoprotein (P-gp) efflux transporter. Based on these properties, the CNS penetration of naldemedine is expected to be negligible at the recommended dose levels, limiting the potential for interference with centrally-mediated opioid analgesia.

    PHARMACOKINETICS

    Naldemedine is administered orally. Plasma protein binding of naldemedine in humans is 93% to 94%. The mean apparent volume of distribution during the terminal phase (Vz/F) is 155 L. The terminal elimination half-life of naldemedine is 11 hours. Naldemedine is primarily metabolized by CYP3A to nor-naldemedine, with minor contribution from UGT1A3 to form naldemedine 3-G. Although these metabolites have been shown to have antagonistic activity for opioid receptors, they are less potent than naldemedine. Following oral administration of radio-labelled naldemedine, the primary metabolite in plasma was nor-naldemedine, with a relative exposure compared to naldemedine of approximately 9% to 13%. Naldemedine 3-G was a minor metabolite in plasma, with a relative exposure to naldemedine of less than 3%. Naldemedine also undergoes cleavage in the GI tract to form benzamidine and naldemedine carboxylic acid. Following oral administration of radio-labelled naldemedine, the total amount of radioactivity excreted in the urine and feces was 57% and 35% of the administered dose of naldemedine, respectively. The amount of naldemedine excreted unchanged in the urine was approximately 16% to 18% of the administered dose. Benzamidine was the most predominant metabolite excreted in the urine and feces, representing approximately 32% and 20% of the administered dose of naldemedine, respectively. The percentage of unchanged drug in feces has not been estimated.
     
    Affected cytochrome P450 isoenzymes: CYP3A, UGT1A3, P-gp
    Naldemedine is primarily metabolized by CYP3A to nor-naldemedine, with minor contribution from UGT1A3 to form naldemedine 3-G. Naldemedine is a substrate of P-gp. In in vitro studies at clinically relevant concentrations, naldemedine did not inhibit the major CYP enzymes (including CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A11 isozymes) and is not an inhibitor of transporters (including OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, BCRP, or P-gp). Naldemedine did not cause significant induction of CYP1A2, CYP2B6, CYP3A4, UGT1A2, UGT1A6, or UGT2B7 isozymes.

    Oral Route

    Following oral administration, naldemedine is absorbed with the time to achieve peak concentrations (T) of approximately 0.75 hours in a fasted state. Across the range of doses evaluated, the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose-proportional or almost dose-proportional manner. Accumulation was minimal following multiple daily doses of naldemedine. A high-fat meal decreased the rate, but not the extent of naldemedine absorption. The Cmax was decreased by approximately 35% and time to achieve C was delayed from 0.75 hours in the fasted state to 2.5 hours in the fed state, whereas there was no meaningful change in the AUC in the fed state.