What is the role of Varubi (rolapitant) in managing chemotherapy-induced nausea and vomiting?

Varubi (Rolapitant) for Chemotherapy-Induced Nausea and Vomiting

Varubi (rolapitant) is a highly selective NK-1 receptor antagonist indicated in combination with a 5-HT3 receptor antagonist and dexamethasone for prevention of delayed nausea and vomiting in patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC), administered as a single 180 mg oral dose prior to chemotherapy. 1

Dosing and Administration

The standard regimen is rolapitant 180 mg orally as a single dose within 2 hours prior to chemotherapy initiation, combined with granisetron (or another 5-HT3 antagonist) and dexamethasone 20 mg on day 1. 1, 2

• For cisplatin-based HEC: Rolapitant 180 mg on day 1, plus dexamethasone 20 mg on day 1, then 8 mg twice daily on days 2-4, plus a 5-HT3 antagonist on day 1 1
• For MEC or anthracycline/cyclophosphamide regimens: Rolapitant 180 mg on day 1, plus dexamethasone 20 mg on day 1 (no additional dexamethasone on days 2-4), plus a 5-HT3 antagonist on days 1-2 1
• Rolapitant must not be administered at intervals less than 2 weeks due to its extended half-life of 180 hours 2, 1
• Unlike other NK-1 antagonists, rolapitant does not require dexamethasone dose adjustment because it does not interact with CYP3A4 1, 3

Clinical Efficacy

Rolapitant demonstrates superior efficacy compared to active control (5-HT3 antagonist plus dexamethasone alone) for preventing both delayed and overall CINV. 4

• In two phase 3 trials of cisplatin-based HEC, rolapitant achieved complete response rates of 71% versus 60% in the delayed phase (>24-120 hours) compared to active control (p=0.0001) 4
• For the overall phase (0-120 hours), rolapitant achieved 62.5% versus 46.7% complete response (p=0.032) 5
• The benefit extended across acute (0-24 hours), delayed (24-120 hours), and overall phases in patients receiving both HEC and MEC 2, 4
• Rolapitant significantly improved rates of no emesis and no significant nausea across all time periods 5, 4

Unique Pharmacologic Advantages

Rolapitant has a 180-hour half-life and does not inhibit or induce CYP3A4, distinguishing it from aprepitant and fosaprepitant. 3, 6

• The extended half-life provides prolonged protection throughout the entire at-risk period without requiring multiple doses 3
• Lack of CYP3A4 interaction eliminates the need for dexamethasone dose adjustments and reduces potential drug-drug interactions 1, 3
• This makes rolapitant particularly suitable for elderly patients or those with multiple comorbidities receiving numerous concomitant medications 3

Critical Safety Warnings

Rolapitant is contraindicated in patients taking CYP2D6 substrates with narrow therapeutic indices (thioridazine, pimozide) and in children under 2 years of age. 1

• Rolapitant is a moderate CYP2D6 inhibitor that increases exposure to CYP2D6 substrates approximately 3-fold, with inhibition persisting beyond 28 days after a single dose 1
• Combining rolapitant with thioridazine or pimozide can cause QT prolongation and Torsades de Pointes 1
• Before initiating rolapitant, assess whether patients require thioridazine or pimozide; if so, use an alternative antiemetic or substitute a non-CYP2D6-metabolized drug 1
• In pediatric patients under 2 years, rolapitant caused irreversible impairment of sexual development and fertility in animal studies at clinically relevant doses 1

Tolerability Profile

Rolapitant is well-tolerated with treatment-related adverse events occurring at similar rates to active control (7.0% versus 6.3%). 3, 4

• Most common treatment-related adverse events include headache, hiccups, constipation, and dyspepsia, each occurring in less than 1% of patients 4
• Grade 3-5 adverse events (neutropenia, anemia, leucopenia) were primarily related to chemotherapy rather than rolapitant 4
• No serious treatment-emergent adverse events were treatment-related, and no treatment-related deaths occurred 4

Guideline Recognition and Clinical Context

Major oncology guidelines recognize rolapitant as an emerging NK-1 receptor antagonist option for CINV prevention. 2

• The NCCN 2017 guidelines include rolapitant as an option for both HEC and MEC, noting its extended half-life and 2-week minimum dosing interval 2
• Rolapitant emerged alongside netupitant/palonosetron (NEPA) as part of recent advances in antiemetic therapy 2
• Despite guideline inclusion, real-world adoption has been minimal through 2016, with NK-1 antagonist use dominated by aprepitant and fosaprepitant 7

Clinical Pitfalls to Avoid

• Do not administer rolapitant more frequently than every 2 weeks, even for weekly chemotherapy regimens, due to prolonged CYP2D6 inhibition 1
• Screen all medications for CYP2D6 substrates before prescribing rolapitant, particularly those with narrow therapeutic indices 1
• Do not adjust dexamethasone doses when using rolapitant, unlike with aprepitant which requires dose reduction 1
• Rolapitant's efficacy in multiple-day chemotherapy regimens, high-dose chemotherapy with stem cell support, and specific patient populations requires further study 3