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Rolapitant

Class: Neurokinin-1 Receptor Antagonists
Chemical Name: (5S,8S) - 8 - [[(1R) - 1 - [3,5 - bis(trifluoromethyl)phenyl]ethoxy]methyl] - 8 - phenyl - 1,9 - diazaspiro[4.5]decan - 2 - one
Molecular Formula: C25H26F6N2O2
CAS Number: 552292-08-7
Brands: Varubi

Introduction

Rolapitant is a neurokinin-1 receptor antagonist antiemetic.

Uses for Rolapitant

Rolapitant has the following uses:

Rolapitant is a substance P/neurokinin 1 (NK1) receptor antagonist indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.1

Rolapitant Dosage and Administration

General

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

Tablets: 90 mg of rolapitant.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:

  • The recommended dosage is 180 mg rolapitant administered approximately 1 to 2 hours prior to the start of chemotherapy.1

  • Administer in combination with dexamethasone and a 5-HT3 receptor antagonist; see full prescribing information for dosing information.1

  • No dosage adjustment for dexamethasone is required.1

Cautions for Rolapitant

Contraindications

Concurrent use with thioridazine, a CYP2D6 substrate.1

Warnings/Precautions

Interaction with CYP2D6 Substrates with a Narrow Therapeutic Index

The inhibitory effect of rolapitant on CYP2D6 lasts at least 7 days and may last longer after a single dose administration of rolapitant. Avoid use of rolapitant in patients who are receiving pimozide, a CYP2D6 substrate. An increase in plasma concentrations of pimozide may result in QT prolongation. Monitor for adverse reactions if concomitant use of rolapitant and other CYP2D6 substrates with a narrow therapeutic index cannot be avoided.1

Specific Populations

Pregnancy

Risk Summary: There are no available data on rolapitant use in pregnant women to inform any drug-associated risks. In animal reproduction studies, there were no teratogenic or embryo-fetal effects observed with oral administration of rolapitant hydrochloride in rats and rabbits during the period of organogenesis at doses up to 1.2 times and 2.9 times, respectively, the maximum recommended human dose (MRHD). 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

Animal Data: The potential embryo-fetal toxicity of rolapitant hydrochloride was assessed in pregnant rats administered oral doses equivalent to up to 22.5 mg/kg per day rolapitant free base throughout organogenesis. Rats administered doses equivalent to 13.5 or 22.5 mg/kg per day rolapitant free base exhibited evidence of maternal toxicity including decreased body weight gain and/or body weight loss and a concomitant decrease in food consumption during the first week of dosing. No teratogenic or embryo-fetal effects were observed at doses equivalent to up to 22.5 mg/kg per day rolapitant free base (approximately 1.2 times the recommended human dose on a body surface area basis). In rabbits administered rolapitant hydrochloride throughout the period of organogenesis, oral doses equivalent to up to 27 mg/kg per day rolapitant free base (approximately 2.9 times the recommended human dose on a body surface area basis) were without effects on the developing fetus.1

The pre- and postnatal developmental effects of rolapitant hydrochloride were assessed in rats administered oral doses equivalent to 2.25, 9, or 22.5 mg/kg per day rolapitant free base during the periods of organogenesis and lactation. Maternal toxicity was evident based on mortality/moribund condition, decreased body weight and food consumption, total litter loss, prolonged parturition, decreased length of gestation, and increased number of unaccounted for implantation sites at a dose equivalent to 22.5 mg/kg per day free base (approximately 1.2 times the recommended human dose on a body surface area basis). Effects on offspring at this dose included decreased postnatal survival, and decreased body weights and body weight gain, and may be related to the maternal toxicity observed. At a maternal dose equivalent to 9 mg/kg per day rolapitant free base (approximately 0.5 times the recommended human dose on a body surface area basis), there was a decrease in memory in female pups in a maze test and a decrease in pup body weight.1

Lactation

There are no data on the presence of rolapitant in human milk, the effects of rolapitant in the breastfed infant, or the effects of rolapitant on milk production. Rolapitant hydrochloride administered orally to lactating female rats was present in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for rolapitant and any potential adverse effects on the breastfed infant from rolapitant or from the underlying maternal condition or the use of concomitant chemotherapy.1

Radioactivity from labeled [14C] rolapitant hydrochloride was transferred into milk of lactating rats following a single oral dose equivalent to 22.5 mg/kg rolapitant free base, and the maximum radioactivity in milk was observed at 12 hours post-dose. The mean milk/plasma radioactivity concentration ratios in dams at 1 to 48 hours post-dose ranged from 1.24 to 3.25. Based on average daily consumption of milk (2 mL/day) and the maximum milk radioactivity determined, pup exposure is expected to be 0.32% of the orally administered dose.1

Pediatric Use

Safety and efficacy of rolapitant have not been established in pediatric patients.1

Geriatric Use

Of the 1294 subjects treated with rolapitant, 25% were 65 years and over, while 5% were 75 and over. No overall differences in safety or efficacy were reported between the elderly subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.1

Hepatic Impairment

No dosage adjustment is needed in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh Class C). Avoid use of rolapitant in patients with severe hepatic impairment. If use cannot be avoided, monitor patients for adverse reactions related to rolapitant.1

Common Adverse Effects

Most common adverse reactions (≥ 5%) are:1

  • Cisplatin Based Highly Emetogenic Chemotherapy: neutropenia and hiccups1

  • Moderately Emetogenic Chemotherapy and Combinations of Anthracycline and Cyclophosphamide: decreased appetite, neutropenia and dizziness1

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:

  • BCRP and P-gp Substrates with a Narrow Therapeutic Index: inhibition of BCRP and P-gp by rolapitant can increase plasma concentrations of the concomitant drug and potential for adverse reactions. See full prescribing information for specific examples.1

  • Strong CYP3A4 Inducers (e.g., rifampin): significantly reduced plasma concentrations of rolapitant can decrease the efficacy of rolapitant; avoid use of rolapitant in patients who require chronic administration of such drugs.1

Actions

Mechanism of Action

Rolapitant is a selective and competitive antagonist of human substance P/NK1 receptors. Rolapitant does not have significant affinity for the NK2 or NK3 receptors or for a battery of other receptors, transporters, enzymes and ion channels. Rolapitant is also active in animal models of chemotherapy-induced emesis.1

Advice to Patients

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling.1

Advise patients to tell their healthcare provider when they start or stop taking any concomitant medications. Rolapitant is a moderate CYP2D6 inhibitor and can increase plasma concentrations of CYP2D6 substrates if they are co-administered. The inhibitory effect of rolapitant on CYP2D6 lasts at least 7 days and may last longer than 7 days after a single 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.

Rolapitant

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

90 mg rolapitant

Varubi

Tesaro Inc.

AHFS Drug Information. © Copyright 2016, Selected Revisions September 14, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Tesaro, Inc.. Varubi (rolapitant) ORAL prescribing information. 2015 Sep.

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