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Naldemedine Tosylate

Class: GI Drugs, Miscellaneous
Chemical Name: 17-(Cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy-3,6,14-trihydroxy-N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]morphinan-7-carboxamide 4-methylbenzenesulfonic acid
Molecular Formula: C32H34N4O6
CAS Number: 916072-89-4
Brands: Symproic

Introduction

Naldemedine tosylate, an opioid antagonist, is a GI drug.1

Uses for Naldemedine Tosylate

Naldemedine tosylate has the following uses:

Naldemedine tosylate is an opioid antagonist indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain.1

Naldemedine Tosylate Dosage and Administration

General

Naldemedine tosylate is available in the following dosage form(s) and strength(s):

Tablets: 0.2 mg of naldemedine.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

    Administration
  • Alteration of analgesic dosing regimen prior to initiating naldemedine tosylate is not required.1

  • Patients receiving opioids for less than 4 weeks may be less responsive to naldemedine tosylate.1

  • Discontinue naldemedine tosylate if treatment with the opioid pain medication is also discontinued.1

    Dosage
  • In adults, the recommended dosage is 0.2 mg once daily with or without food.1

Cautions for Naldemedine Tosylate

Contraindications

  • Patients with known or suspected gastrointestinal obstruction or at increased risk of recurrent obstruction.1

  • Patients with a history of a hypersensitivity reaction to naldemedine.1

Warnings/Precautions

Gastrointestinal Perforation

Cases of gastrointestinal perforation have been reported with use of another peripherally acting opioid antagonist in patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies, or peritoneal metastases). Take into account the overall risk-benefit profile when using naldemedine tosylate in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue naldemedine tosylate in patients who develop this symptom.1

Opioid Withdrawal

Clusters of symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, increased lacrimation, hot flush/flushing, pyrexia, sneezing, feeling cold, abdominal pain, diarrhea, nausea, and vomiting have occurred in patients treated with naldemedine tosylate.1

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 tosylate in such patients. Monitor for symptoms of opioid withdrawal in such patients.1

Specific Populations

Pregnancy

Risk Summary: There are no available data with naldemedine in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. There is a potential for opioid withdrawal in a fetus when naldemedine tosylate is used in pregnant women. Naldemedine tosylate should be used during pregnancy only if the potential benefit justifies the potential risk.1

In a rat embryo-fetal development study following oral administration of naldemedine during the period of organogenesis at doses resulting in systemic exposure approximately 23,000 times the human area under the plasma-concentration time curve (AUC) at the recommended human dose of 0.2 mg/day, no developmental abnormalities were observed. In rabbits, there were no adverse effects on embryo-fetal development following oral administration of naldemedine during the period of organogenesis at doses resulting in systemic exposure approximately 226 times the human AUC at the recommended human dose of 0.2 mg/day. No effects on pre- and postnatal development were observed in rats at exposures 12 times human exposures at the recommended human dose.1

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.1

Fetal/Neonatal Adverse Reactions: Naldemedine crosses the placenta, and may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier.1

Animal Data: In rats, there were no adverse effects on embryo-fetal development following oral administration of naldemedine during the period of organogenesis at doses up to 1000 mg/kg/day (approximately 23,000 times the human exposures [AUC] at the recommended human dose). In rabbits, there were no adverse effects on embryo-fetal development following oral administration of naldemedine during the period of organogenesis at doses up to 100 mg/kg/day (approximately 226 times the human exposures [AUC] at the recommended human dose). At 400 mg/kg/day (approximately 844 times the human exposures [AUC] at the recommended human dose), effects in maternal animals included body weight loss/decreased body weight gain and food consumption, fetal loss, and premature delivery. Decreased fetal body weights at this dose may be related to the maternal toxicity observed.1

In the pre- and postnatal development study, pregnant rats were administered naldemedine at oral doses up to 1000 mg/kg/day from gestation day 7 through lactation day 20. No effects on pre- and postnatal development were observed in rats at 1 mg/kg/day (approximately 12 times the human exposures [AUC] at the recommended human dose). A single dam died at parturition at 1000 mg/kg/day, and decreased body weights/body weight gain and food consumption, poor nursing, and total litter loss were noted at 30 and 1000 mg/kg/day (approximately 626 and 17,000 times the human exposures [AUC] at the recommended human dose, respectively). Decreases in the offspring viability index on Day 4 after birth were noted at 30 and 1000 mg/kg/day, and low body weights and delayed pinna unfolding in pups were noted at 1000 mg/kg/day.1

Lactation

There is no information regarding the presence of naldemedine in human milk, the effects on the breastfed infant, or the effects on milk production. 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 the 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 of naldemedine tosylate.1

Drug-related radioactivity was transferred into milk of lactating rats following a single oral dose of 1 mg/kg [carbonyl-14C]-naldemedine.1

Pediatric Use

The safety and effectiveness of naldemedine tosylate have not been established in pediatric patients.1

Geriatric Use

Of 1163 patients in clinical studies exposed to naldemedine tosylate, 183 (16%) were 65 years of age and over, while 37 (3%) were 75 years and over. No overall differences in safety or effectiveness between these and younger patients were observed, but greater sensitivity of some older individuals cannot be ruled out. In a population pharmacokinetic analysis, no age-related alterations in the pharmacokinetics of naldemedine were observed.1

Hepatic Impairment

The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naldemedine has not been evaluated. Avoid use of naldemedine tosylate in patients with severe hepatic impairment. No dose adjustment of naldemedine tosylate is required in patients with mild or moderate hepatic impairment.1

Common Adverse Effects

Most common adverse reactions (≥2%) are: abdominal pain, diarrhea, and nausea.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Strong CYP3A inducers (e.g., rifampin): Decreased naldemedine concentrations; avoid concomitant use.1

  • Other opioid antagonists: Potential for additive effect and increased risk of opioid withdrawal; avoid concomitant use.1

  • Moderate (e.g., fluconazole) and strong (e.g., itraconazole) CYP3A4 inhibitors: Increased naldemedine concentrations; monitor for adverse reactions.1

  • P-glycoprotein (P-gp) inhibitors (e.g., cyclosporine): Monitor for adverse reactions.1

Actions

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.1

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).1

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.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).1

Administration

Advise patients to discontinue naldemedine tosylate if treatment with the opioid pain medication is also discontinued.1

Gastrointestinal Perforation

Advise patients to discontinue naldemedine tosylate and to promptly seek medical attention if they develop unusually severe, persistent or worsening abdominal pain.1

Opioid Withdrawal

Advise patients that clusters of symptoms consistent with opioid withdrawal may occur while taking naldemedine tosylate and to contact their healthcare provider if these symptoms occur.1

Pregnancy

Advise females of reproductive potential, who become pregnant or are planning to become pregnant, that the use of naldemedine tosylate during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood-brain barrier.1

Lactation

Advise women that breastfeeding is not recommended during treatment with naldemedine tosylate and for 3 days after the final dose.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Naldemedine tosylate is subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug.

Naldemedine Tosylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

0.2 mg (of naldemedine)

Symproic (C-II)

Purdue Pharma LP

AHFS Drug Information. © Copyright 2017, Selected Revisions April 12, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Purdue Pharma LP. Symproic (naldemedine) oral prescribing information. 2017 Mar.

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