Rolapitant (Monograph)

Brand name: Varubi
Drug class: Neurokinin-1 Receptor Antagonists
Chemical name: Monohydrochloride, monohydrate, (5S,8S)-7-diazaspiro[4.5]decan-2-one, 8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1
Molecular formula: C₂₅H₂₆F₆N₂O₂•HCl•H₂O
CAS number: CAS-914462-92-3; CAS-552292-08-7 [rolapitant]

Medically reviewed by Drugs.com on Jan 16, 2023. Written by ASHP.

Introduction

Antiemetic; a substance P/neurokinin-1 (NK₁) receptor antagonist.

Uses for Rolapitant

Cancer Chemotherapy-induced Nausea and Vomiting

Used 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.

In 2020, the American Society of Clinical Oncology (ASCO) issued updated guidelines for the use of prophylactic antiemetic therapy prior to emetogenic antineoplastic therapy.

To prevent chemotherapy-induced nausea and vomiting associated with highly emetogenic antineoplastic regimens that include cisplatin and other high-emetic-risk single agents, ASCO recommends a 4-drug antiemetic regimen consisting of an NK₁ receptor antagonist, a serotonin (5-HT₃) receptor antagonist, dexamethasone, and olanzapine on day 1 followed by continued dexamethasone and olanzapine therapy on days 2–4.

To prevent chemotherapy-induced nausea and vomiting associated with a highly emetogenic antineoplastic regimen that includes an anthracycline plus cyclophosphamide, ASCO currently recommends a 4-drug antiemetic regimen consisting of an NK₁ receptor antagonist, a 5-HT₃ receptor antagonist, dexamethasone, and olanzapine on day 1 followed by continued olanzapine therapy on days 2–4.

For patients receiving moderately emetogenic antineoplastic regimens that include carboplatin AUC ≥4 mg/mL/min, ASCO recommends a 3-drug combination consisting of an NK₁ receptor antagonist, a 5-HT₃ receptor antagonist, and dexamethasone on day 1.

Rolapitant Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.

Administer prior to initiation of each chemotherapy cycle, but at intervals of no less than 2-weeks. Administer within 2 hours prior to initiation of chemotherapy.

Dosage

Available as rolapitant hydrochloride; dosage expressed in terms of rolapitant.

Adults

Cancer Chemotherapy-induced Nausea and Vomiting

Administer as part of a regimen that includes a 5-HT₃ receptor antagonist and dexamethasone.

Cisplatin-based Highly Emetogenic Cancer Chemotherapy

Oral

Administer 180 mg of rolapitant within 2 hours before initiation of chemotherapy on day 1.

Administer 20 mg of dexamethasone 30 minutes prior to initiation of chemotherapy on day 1; administer the 5-HT₃ receptor antagonist on day 1 according to the prescribing information for the specific 5-HT₃ receptor antagonist. Administer dexamethasone 8 mg twice daily on days 2–4.

In clinical studies, the rolapitant regimen for prevention of delayed nausea and vomiting associated with cisplatin-based highly emetogenic chemotherapy included oral dexamethasone 20 mg and IV granisetron 10 mcg/kg on day 1, and oral dexamethasone 8 mg twice daily on days 2–4. Rolapitant 180 mg was administered 1–2 hours prior to chemotherapy, and dexamethasone and granisetron were administered 30 minutes prior to chemotherapy on day 1.

Moderately Emetogenic Cancer Chemotherapy and Combinations of Anthracycline and Cyclophosphamide

Oral

Administer 180 mg of rolapitant within 2 hours prior to initiation of chemotherapy on day 1.

Administer 20 mg of dexamethasone, 30 minutes prior to initiation of chemotherapy on day 1. Administer the 5-HT₃ receptor antagonist on days 1–4; refer to prescribing information for the specific 5-HT₃ receptor antagonist for appropriate dosage information.

In clinical studies, the rolapitant regimen for prevention of delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy and combinations of anthracycline and cyclophosphamide included oral dexamethasone 20 mg and oral granisetron 2 mg on day 1, and oral granisetron 2 mg once daily on days 2–3. Rolapitant 180 mg was administered 1–2 hours prior to chemotherapy, and dexamethasone and granisetron were administered 30 minutes prior to chemotherapy on day 1.

Special Populations

Hepatic Impairment

No dosage adjustment necessary with mild or moderate (Child-Pugh class A or B) hepatic impairment.

Avoid use in patients with severe (Child-Pugh class C) hepatic impairment. If use is unavoidable, monitor patients for rolapitant-associated adverse effects.

Renal Impairment

No special dosage recommendations at this time.

Geriatric Patients

No special dosage recommendations at this time.

Cautions for Rolapitant

Contraindications

• Concurrent therapy with CYP2D6 substrates with a narrow therapeutic index such as pimozide or thioridazine.

• Pediatric patients <2 years of age.

Warnings/Precautions

Interactions with CYP2D6 Substrates

Rolapitant is a moderate inhibitor of CYP2D6; the inhibitory effect of the drug is expected to persist for beyond 28 days.

Concomitant use of rolapitant and CYP2D6 substrates with a narrow therapeutic index such as pimozide or thioridazine is contraindicated. The resulting increase in plasma concentrations of pimozide or thioridazine may cause serious and/or life-threatening events of QT prolongation and torsades de pointes. If use of these drugs is required, use an alternative antiemetic to rolapitant or an alternative to thioridazine or pimozide.

Before starting treatment with rolapitant in patients receiving other CYP2D6 substrates, consult the manufacturer's prescribing information for the CYP2D6 substrate to obtain additional information about interactions.

Specific Populations

Pregnancy

Insufficient data to inform a drug-associated risk of adverse developmental outcomes when rolapitant is used in pregnant women. No teratogenic or embryofetal effects observed in animal reproduction studies.

Lactation

Not known whether rolapitant is distributed in human milk; distributes into milk of lactating rats. Not known whether rolapitant has any effects on the breastfed infant or on milk production. Consider benefits of breastfeeding along with the mother's clinical need for rolapitant and any potential adverse effects on the breastfed infant from the drug or underlying maternal condition or use of concomitant chemotherapy.

Pediatric Use

Safety and efficacy not established in pediatric patients. Rolapitant is contraindicated in pediatric patients <2 years of age.

In juvenile rat studies, abnormal ovarian and uterine development, early sexual development in female rats, delayed sexual development in male rats, and impaired fertility reported.

Geriatric Use

No overall differences in safety, efficacy, or pharmacokinetics between geriatric patients and younger adults, but increased sensitivity cannot be ruled out.

Hepatic Impairment

No pharmacokinetic changes in patients with mild hepatic impairment (Child-Pugh class A). In patients with moderate hepatic impairment (Child-Pugh class B), peak plasma concentrations were reduced by 25%, but AUC was unchanged. Median time to peak plasma concentration of a metabolite of rolapitant (M19) was 204 hours in patients with mild or moderate hepatic impairment, compared to 168 hours in healthy individuals.

Pharmacokinetics not studied in patients with severe hepatic impairment (Child-Pugh class C). Avoid use in patients with severe hepatic impairment. If use is unavoidable, monitor patients for adverse effects.

Renal Impairment

No substantial effect on rolapitant pharmacokinetics in patients with mild (Cl_cr 60–90 mL/minute) or moderate (Cl_cr 30–60 mL/minute) renal impairment. Insufficient data in patients with severe renal impairment. Pharmacokinetics not studied in patients with end-stage renal disease requiring hemodialysis.

Common Adverse Effects

Cisplatin-based highly emetogenic chemotherapy: Adverse effects (≥3%): neutropenia, hiccups, abdominal pain.

Moderately emetogenic chemotherapy and combinations of anthracycline and cyclophosphamide: Adverse effects (≥3%): decreased appetite, neutropenia, dizziness, dyspepsia, urinary tract infection, stomatitis, anemia.

Drug Interactions

Metabolized by CYP3A4. Does not inhibit or induce CYP3A4. Moderate inhibitor of CYP2D6, inhibitor of P-glycoprotein (P-gp), and inhibitor of breast cancer resistance protein (BCRP).

In vitro studies suggest rolapitant is not an inhibitor of CYP1A2 or CYP2E1. Inhibits CYP2A6; however, clinically meaningful interaction via inhibition of CYP2A6 unlikely.

Oral rolapitant is unlikely to inhibit organic anion transporting polypeptides (OATP) 1B1 and 1B3, organic anion transporters (OAT1 and OAT3), organic cation transporter (OCT2), and multidrug and toxin extrusion proteins (MATE1 and MATE2K).

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

CYP2D6 substrates with narrow therapeutic index:Increased plasma concentrations and adverse effects of the CYP2D6 substrate. Inhibitory effect of rolapitant may persist beyond 28 days. When coadministered with a CYP2D6 substrate with a narrow therapeutic index (e.g., pimozide, thioridazine), increased concentrations of the substrate may cause serious and/or life-threatening events such as QT prolongation and torsades de pointes. Concomitant use contraindicated. If use of these drugs is required, use an alternative antiemetic to rolapitant or an alternative to thioridazine or pimozide.

Other CYP2D6 substrates:Potential for increased plasma concentrations and adverse effects of the CYP2D6 substrate. Inhibitory effect of rolapitant may persist beyond 28 days. Before starting treatment of rolapitant, consult prescribing information of the CYP2D6 substrate to obtain further information about interactions.

Strong CYP3A4 inducers: Substantial reduction in systemic exposure and possible decrease in efficacy of rolapitant when coadministered with a strong CYP3A4 inducer (e.g., rifampin). Avoid concomitant use in patients requiring chronic administration of a CYP3A4 inducer.

BCRP Substrates with Narrow Therapeutic Index

Increased plasma concentration of the BCRP substrate when rolapitant is coadministered with BCRP substrates with narrow therapeutic indices (e.g., methotrexate, topotecan, or irinotecan). May potentially result in adverse effects. If concomitant use cannot be avoided, monitor patient for adverse effects.

P-gp Substrates with Narrow Therapeutic Index

Increased plasma concentration of the P-gp substrate when rolapitant is coadministered with P-gp substrates with narrow therapeutic indices (e.g., digoxin). May potentially result in adverse effects. If concomitant use cannot be avoided, monitor patients for increased concentrations of the P-gp substrate and for adverse effects.

Specific Drugs

Rolapitant Pharmacokinetics

Absorption

Bioavailability

>90%.

Peak plasma concentration is attained approximately 4 hours following single-dose oral administration under fasting conditions in healthy individuals.

Approximately 5-fold accumulation following multiple oral doses of 9–45 mg once daily.

Systemic exposure increases in a dose-proportional manner over dose range of 4.5 to 180 mg.

Special Populations

Mean peak plasma concentrations decreased by 25% in patients with moderate hepatic impairment (Child-Pugh class B).

Distribution

Extent

Distributed into milk in rats; crosses blood-brain barrier in humans.

Plasma Protein Binding

99.8%.

Elimination

Metabolism

Metabolized principally by CYP3A4 to a major active metabolite (M19).

Elimination Route

Following a single oral radiolabeled dose of rolapitant, 14.2% and 73% is recovered in urine and feces, respectively.

In pooled samples collected over 2 weeks, 8.3% of dose recovered in urine principally as metabolites; 37.8% of dose recovered in feces principally as unchanged drug.

Half-life

Ranges from 169–183 hours and is independent of dose.

Mean half-life of major metabolite (M19) is 158 hours.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted to 15–30°C).

Actions

• Selective and competitive antagonist at human substance P/neurokinin-1 (NK₁) receptors.

• No substantial affinity for NK₂ or NK₃ receptors or for a battery of other receptors, transporters, enzymes, and ion channels.

• Crosses the blood-brain barrier and occupies NK₁ receptors in the brain.

Advice to Patients

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

• 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.

• Advise females of reproductive potential that rolapitant may impair fertility. Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Advise patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

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