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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

Warning

Special Alerts:

[Posted 01/16/2018]

AUDIENCE: Pharmacy, Oncology, Nursing

ISSUE: Anaphylaxis, anaphylactic shock and other serious hypersensitivity reactions have been reported in the postmarketing setting, some requiring hospitalization. These reactions have occurred during or soon after the infusion of rolapitant injectable emulsion. Most reactions have occurred within the first few minutes of administration. Symptoms of anaphylaxis can include wheezing or difficulty breathing; swelling of the face or throat; hives or flushing; itching; abdominal cramping, abdominal pain or vomiting; back pain or chest pain; hypotension or shock.

See the Health Care Provider Letter, available at: , for important prescribing information to reflect the new safety information.

BACKGROUND: Rolapitant injectable emulsion is approved to prevent delayed phase chemotherapy-induced nausea and vomiting (emesis). Rolapitant is approved in adults in combination with other drugs (antiemetic agents) that prevent nausea and vomiting associated with initial and repeat courses of vomit-inducing (emetogenic and highly emetogenic) cancer chemotherapy.

RECOMMENDATION: Healthcare professionals must be vigilant for signs of hypersensitivity or anaphylaxis in all patients receiving rolapitant injectable emulsion, both during and following its administration. It is advised that Healthcare professionals consult with patients to determine if the patient is hypersensitive to any component of the product (including soybean oil). Furthermore, as cross reactions to other allergens is possible, patients with known allergies to legumes or other related allergens should be monitored closely. Patients with a potential hypersensitivity should not be administered rolapitant injectable emulsion.

Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during treatment with rolapitant injectable emulsion.

If anaphylaxis or any other serious hypersensitivity/infusion reaction occurs,

  • administration of rolapitant injectable emulsion should be stopped immediately.

  • appropriate medical management (including epinephrine and or antihistamines) should be initiated, and

  • Rolapitant injectable emulsion should be permanently discontinued.

For more information visit the FDA website at: and .

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

  • Injectable emulsion: 166.5 mg/92.5 mL (1.8 mg/mL) of rolapitant in a single-dose vial.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:

Adults

Dosage & Administration
  • 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

  • Administer rolapitant within 2 hours prior to the initiation of chemotherapy on Day 1.1

  • Tablets: The recommended dosage is 180 mg as a single dose.1

  • Injectable emulsion: The recommended dosage is 166.5 mg administered as an intravenous infusion over 30 minutes.1

Cautions for Rolapitant

Contraindications

  • Known hypersensitivity to any component of this drug, including soybean oil.1

  • CYP2D6 substrates with a narrow therapeutic index (e.g., thioridazine and pimozide).1

Warnings/Precautions

Anaphylaxis, Anaphylactic Shock, and Other Serious Hypersensitivity Reactions

Anaphylaxis, anaphylactic shock and other serious hypersensitivity reactions have been reported in the postmarketing setting, some requiring hospitalization. These reactions have occurred during or soon after the infusion of rolapitant injectable emulsion. Most reactions have occurred within the first few minutes of administration. Symptoms of anaphylaxis can include wheezing or difficulty breathing; swelling of the face or throat; hives or flushing; itching; abdominal cramping, abdominal pain or vomiting; back pain or chest pain; hypotension or shock.1

Consult with patients to determine if the patient is hypersensitive to any component of the product (including soybean oil). Furthermore, as cross reactions to other allergens are possible, patients with known allergies to legumes or other related allergens should be monitored closely. Patients with a potential hypersensitivity should not be administered rolapitant injectable emulsion.1

Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during treatment with rolapitant injectable emulsion.1

If anaphylaxis or any other serious hypersensitivity/infusion reaction occurs:1

  • administration of rolapitant injectable emulsion should be stopped immediately.1

  • appropriate medical management (including epinephrine and/or antihistamines) should be initiated, and1

  • rolapitant injectable emulsion should be permanently discontinued.1

Interaction with CYP2D6 Substrates

Rolapitant is a moderate inhibitor of CYP2D6. Exposure to dextromethorphan, a CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured. The inhibitory effect of rolapitant on CYP2D6 is expected to persist beyond 28 days for an unknown duration following administration of rolapitant.1

Narrow Therapeutic Index Drugs (Thioridazine and Pimozide)

Rolapitant is contraindicated in patients taking CYP2D6 substrates with a narrow therapeutic index such as thioridazine and pimozide. Increased plasma concentrations of thioridazine and pimozide are associated with serious and/or life-threatening events of QT prolongation and Torsades de Pointes.1

Before starting treatment with rolapitant, consider whether patients require treatment with thioridazine or pimozide. If patients require these drugs, use an alternative antiemetic to rolapitant or an alternative to thioridazine or pimozide that is not metabolized by CYP2D6.1

Other Drugs

Rolapitant can also increase plasma concentrations of other CYP2D6 substrates for at least 28 days following administration of rolapitant and may result in adverse reactions.1

Before starting treatment with rolapitant, consult the prescribing information for CYP2D6 substrates to obtain additional information about interactions with CYP2D6 inhibitors.1

Specific Populations

Pregnancy

Risk Summary: The limited data with rolapitant use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. In animal reproduction studies, there were no adverse developmental effects observed with oral administration of rolapitant in rats and rabbits during the period of organogenesis at doses up to 1.3 times and 2.9-times, respectively, the maximum recommended human dose (MRHD). 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

Animal Data: The potential embryo-fetal toxicity of rolapitant was assessed in pregnant rats administered oral doses up to 22.5 mg/kg per day throughout the period of organogenesis. Rats administered doses of 13.5 or 22.5 mg/kg per day rolapitant 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 adverse embryo-fetal developmental effects were observed at doses up to 22.5 mg/kg per day rolapitant (approximately 1.3 times the recommended intravenous human dose on a body surface area basis). In rabbits administered rolapitant throughout the period of organogenesis, oral doses up to 27 mg/kg per day (approximately 3 times the recommended intravenous human dose on a body surface area basis) were without effects on the developing fetus. The pre- and postnatal developmental effects of rolapitant were assessed in rats administered oral doses of 2.25, 9 or 22.5 mg/kg per day 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 of 22.5 mg/kg per day (approximately 1.3 times the recommended intravenous 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 of 9 mg/kg per day rolapitant (approximately 0.5 times the recommended intravenous 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

Risk Summary: 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 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

Data: Radioactivity from labeled [14C] rolapitant was transferred into milk of lactating rats following a single oral dose of 22.5 mg/kg, 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

Females and Males of Reproductive Potential

In animal fertility studies, rolapitant impaired the fertility in females in a reversible fashion.1

Pediatric Use

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

In non-clinical studies, sexual development and fertility of juvenile rats (human age equivalent of birth to 16 years) were affected following oral administration of rolapitant.1

In an oral juvenile toxicity study in rats, at rolapitant doses of 11.3, 22.5 and 45 mg/kg/day from postnatal (PND) Day 7 through PND 70 (equivalent human age of newborn to 16 years), there was a delay in the attainment of balanopreputial separation in males and an acceleration of the attainment of vaginal patency in females with rolapitant doses of 22.5 and 45 mg/kg/day (approximately 1.3 and 2.6 times, respectively, the recommended intravenous human dose on a body surface area basis). Treated males and females were mated following a 2-week wash-out period after the last dose. There were lower mean numbers of implantation sites, corpora lutea, and mean number of viable embryos at 22.5 and 45 mg/kg/day (approximately 1.3 and 2.6 times, respectively, the recommended intravenous human dose on a body surface area basis) when compared to control.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 hiccups.1

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

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

  • Warfarin: Monitor for increased INR or prothrombin time; adjust the dose of warfarin as needed.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

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Anaphylaxis, Anaphylactic Shock, and Other Serious Hypersensitivity Reactions

Advise patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in patients taking rolapitant injectable emulsion.1

Consult with patients to determine if the patient is hypersensitive to any component of the product (including soybean oil). Furthermore, as cross reactions to other allergens is possible, patients with known allergies to legumes or other related allergens should be monitored closely. Patients with a potential hypersensitivity should not be administered rolapitant injectable emulsion.1

Advise patients to seek immediate medical attention if they experience signs or symptoms of a hypersensitivity reaction, such as wheezing or difficulty breathing; swelling of the face or throat; hives or flushing; itching; abdominal cramping, abdominal pain or vomiting; back pain and chest pain; hypotension or shock.1

Drug Interactions

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.1

Infertility

Advise females of reproductive potential that rolapitant may impair fertility.1

Additional Information

AHFSfirstRelease. 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

Varubi

Tesaro Inc.

Parenteral

Injection, Emulsion

166.5 mg/92.5 mL (1.8 mg/mL)

Varubi

Tesaro Inc.

AHFS Drug Information. © Copyright 2018, Selected Revisions January 29, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Tesaro, Inc.. Varubi (rolapitant) tablets for oral use and injectable emulsion for intravenous use prescribing information. 2018 Jan.

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