Varubi
(Rolapitant)Dosage & Administration
The recommended dosage of VARUBI in adults in combination with a 5-HT3 receptor antagonist and dexamethasone for the prevention of nausea and vomiting with emetogenic cancer chemotherapy is shown in
| Day 1 | Day 2 | Day 3 | Day 4 | |
Prevention of Nausea and Vomiting Associated with Cisplatin-Based Highly Emetogenic Cancer Chemotherapy | ||||
| VARUBI | 180 mg as a single dose orally within 2 hours prior to initiation of chemotherapy | None | ||
| Dexamethasone | 20 mg; 30 min prior to initiation of chemotherapy | 8 mg twice daily | 8 mg twice daily | 8 mg twice daily |
| 5-HT3receptor antagonist | See the prescribing information for the co-administered 5-HT3receptor antagonist for appropriate dosing information. | None | ||
Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Cancer Chemotherapy and Combinations of Anthracycline and Cyclophosphamide | ||||
| VARUBI | 180 mg as a single dose orally within 2 hours prior to initiation of chemotherapy | None | ||
| Dexamethasone | 20 mg; 30 min prior to initiation of chemotherapy | None | ||
| 5-HT3receptor antagonist | See the prescribing information for the co-administered 5-HT3receptor antagonist for appropriate dosing information. | See the prescribing information for the co-administered 5-HT3receptor antagonist for appropriate dosing information. | ||
Following a single oral dose administration of 180 mg VARUBI under fasting conditions to healthy subjects, rolapitant was measurable in plasma within 30 minutes and the peak plasma concentration (Cmax) for rolapitant which was reached in about 4 hours and mean Cmaxwas 968 ng/mL (%CV:28%).
Following multiple oral doses of 9 to 45 mg once daily of rolapitant (5% to 25% of the recommended dose) for 10 days, accumulation of rolapitant (ratio of AUC0-24hr) ranged from 5.0 to 5.3 fold.
The systemic exposures (Cmaxand AUC) to rolapitant increased in a dose-proportional manner when single oral doses of rolapitant increased from 4.5 mg to 180 mg. With 4 times the recommended clinical oral dose of 180 mg, the Cmaxand AUC of rolapitant increased 3.1 fold and 3.7 fold, respectively.
Concomitant administration of a high-fat meal did not significantly affect the pharmacokinetics of rolapitant after administration of 180 mg VARUBI
Rolapitant was highly protein bound to human plasma (99.8%). The apparent volume of distribution (Vd/F) following a single oral dose of 180 mg rolapitant was 460 L in healthy subjects. The large Vd indicated an extensive tissue distribution of rolapitant. In a population pharmacokinetic analysis of oral rolapitant, the Vd/F was 387 L in cancer patients.
Following single oral doses (4.5 to 180 mg) of rolapitant, the mean terminal half-life (t1/2) of rolapitant ranged from 169 to 183 hours (approximately 7 days), and was independent of dose. In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of oral rolapitant was 0.96 L/hour in cancer patients.
Rolapitant is metabolized primarily by CYP3A4 to form a major active metabolite, M19 (C4-pyrrolidine-hydroxylated rolapitant). In a mass balance study, the metabolite M19 was determined to be the major circulating metabolite. The rate of formation of M19 was relatively slow, resulting in the delayed median Tmaxof 120 hours (range: 24 to 168 hours) with Cmaxof 183 ng/mL. The mean half-life of M19 was 158 hours.
The exposure ratio of M19 to rolapitant was approximately 50% in plasma.
Rolapitant is eliminated primarily through the hepato/biliary route. Following administration of a single oral 180-mg dose of [14C]-rolapitant, on average 14.2% (range 9% to 20%) and 73% (range 52% to 89%) of the dose was recovered in the urine and feces, respectively over 6 weeks. In pooled samples collected over 2 weeks, 8.3% of the dose was recovered in the urine primarily as metabolites and 37.8% of the dose was recovered in the feces primarily as unchanged rolapitant. Unchanged rolapitant or M19 was not found in pooled urine sample.
Population pharmacokinetic analyses indicated that age, sex and race had no significant impact on the pharmacokinetics of rolapitant.
Following administration of a single oral dose of 180 mg rolapitant to patients with mild hepatic impairment (Child-Pugh Class A), the pharmacokinetics of rolapitant were comparable with those of healthy subjects. In patients with moderate hepatic impairment (Child-Pugh Class B), the mean Cmaxwas 25% lower while mean AUC of rolapitant was similar compared to those of healthy subjects. The median Tmaxfor M19 was delayed to 204 hours in patients with mild or moderate hepatic impairment compared to 168 hours in healthy subjects. The pharmacokinetics of rolapitant were not studied in patients with severe hepatic impairment (Child-Pugh Class C)
In population pharmacokinetic analyses, rolapitant pharmacokinetics in cancer patients with mild (CLcr: 60 to 90 mL/min) or moderate (CLcr: 30 to 60 mL/min) renal impairment was comparable to cancer patients with normal kidney function. Information is insufficient for the effect of severe renal impairment. The pharmacokinetics of rolapitant was not studied in patients with end-stage renal disease requiring hemodialysis.
Rolapitant is a substrate for CYP3A4.
The effect of VARUBI on CYP450 enzymes and transporters is summarized below.
aA single oral dose of 180 mg rolapitant was administered on Day 1; the interacting drug (dextromethorphan 30 mg) was administered orally on Day 1 with rolapitant and alone on Day 8. | ||||||||||
bA single intravenous dose of 166.5 mg rolapitant was administered on Day 1; the interacting drug (dextromethorphan 30 mg) was administered orally on Day 1 with rolapitant and alone on Days 8, 15, 22, and 29. VARUBI is not approved for intravenous use. The AUC of rolapitant following single intravenous dose of 166.5 mg is similar to that following single oral dose of VARUBI 180 mg. | ||||||||||
↑ Denotes a mean increase in exposure by the percentage indicated. | ||||||||||
N/A: not applicable | ||||||||||
| Rolapitant Dose (route of administration) | % Change for Dextromethorphan | |||||||||
| Day 1 with Rolapitant | Day 8 without Rolapitant | Day 15 without Rolapitant | Day 22 without Rolapitant | Day 29 without Rolapitant | ||||||
| Change in Cmax | Change in AUC | Change in Cmax | Change in AUC | Change in Cmax | Change in AUC | Change in Cmax | Change in AUC | Change in Cmax | Change in AUC | |
| 180 mga(Oral) | 120% ↑ | 160% ↑ | 180% ↑ | 230% ↑ | N/A | |||||
| 166.5 mgb(Intavenous) | 75% ↑ | 110% ↑ | 140% ↑ | 220% ↑ | 170% ↑ | 220% ↑ | 120% ↑ | 180% ↑ | 96% ↑ | 130% ↑ |
Administer VARUBI prior to the initiation of each chemotherapy cycle, but at no less than 2 week intervals.
Administer VARUBI without regards to meals.
| Day 1 | Day 2 | Day 3 | Day 4 | |
Prevention of Nausea and Vomiting Associated with Cisplatin-Based Highly Emetogenic Cancer Chemotherapy | ||||
| VARUBI | 180 mg as a single dose orally within 2 hours prior to initiation of chemotherapy | None | ||
| Dexamethasone | 20 mg; 30 min prior to initiation of chemotherapy | 8 mg twice daily | 8 mg twice daily | 8 mg twice daily |
| 5-HT3 receptor antagonist | See the prescribing information for the co-administered 5-HT3 receptor antagonist for appropriate dosing information. | None | ||
Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Cancer Chemotherapy and Combinations of Anthracycline and Cyclophosphamide | ||||
| VARUBI | 180 mg as a single dose orally within 2 hours prior to initiation of chemotherapy | None | ||
| Dexamethasone | 20 mg; 30 min prior to initiation of chemotherapy | None | ||
| 5-HT3 receptor antagonist | See the prescribing information for the co-administered 5-HT3 receptor antagonist for appropriate dosing information. | See the prescribing information for the co-administered 5-HT3 receptor antagonist for appropriate dosing information. | ||
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Varubi Prescribing Information
Dosage and Administration (The recommended dosage of VARUBI in adults in combination with a 5-HT3receptor antagonist and dexamethasone for the prevention of nausea and vomiting with emetogenic cancer chemotherapy is shown in Table 1. There is no drug interaction between rolapitant and dexamethasone, so no dosage adjustment for dexamethasone is required. Administer a dexamethasone dose of 20 mg on Day 1 [see Clinical Pharmacology (12.3)] .Administer VARUBI prior to the initiation of each chemotherapy cycle, but at no less than 2 week intervals. Administer VARUBI without regards to meals.
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Contraindications (VARUBI is contraindicated in patients taking CYP2D6 substrates with a narrow therapeutic index, such as thioridazine and pimozide. VARUBI can significantly increase the plasma concentrations of thioridazine and pimozide, which may result in QT prolongation and Torsades de Pointes [see Warnings and Precautions (5.1)] .VARUBI is contraindicated in pediatric patients less than 2 years of age because of irreversible impairment of sexual development and fertility observed in juvenile rats at clinically relevant dosages [see Use in Specific Populations (8.4)] .
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VARUBI® is 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.
The recommended dosage of VARUBI in adults in combination with a 5-HT3 receptor antagonist and dexamethasone for the prevention of nausea and vomiting with emetogenic cancer chemotherapy is shown in
| Day 1 | Day 2 | Day 3 | Day 4 | |
Prevention of Nausea and Vomiting Associated with Cisplatin-Based Highly Emetogenic Cancer Chemotherapy | ||||
| VARUBI | 180 mg as a single dose orally within 2 hours prior to initiation of chemotherapy | None | ||
| Dexamethasone | 20 mg; 30 min prior to initiation of chemotherapy | 8 mg twice daily | 8 mg twice daily | 8 mg twice daily |
| 5-HT3receptor antagonist | See the prescribing information for the co-administered 5-HT3receptor antagonist for appropriate dosing information. | None | ||
Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Cancer Chemotherapy and Combinations of Anthracycline and Cyclophosphamide | ||||
| VARUBI | 180 mg as a single dose orally within 2 hours prior to initiation of chemotherapy | None | ||
| Dexamethasone | 20 mg; 30 min prior to initiation of chemotherapy | None | ||
| 5-HT3receptor antagonist | See the prescribing information for the co-administered 5-HT3receptor antagonist for appropriate dosing information. | See the prescribing information for the co-administered 5-HT3receptor antagonist for appropriate dosing information. | ||
Following a single oral dose administration of 180 mg VARUBI under fasting conditions to healthy subjects, rolapitant was measurable in plasma within 30 minutes and the peak plasma concentration (Cmax) for rolapitant which was reached in about 4 hours and mean Cmaxwas 968 ng/mL (%CV:28%).
Following multiple oral doses of 9 to 45 mg once daily of rolapitant (5% to 25% of the recommended dose) for 10 days, accumulation of rolapitant (ratio of AUC0-24hr) ranged from 5.0 to 5.3 fold.
The systemic exposures (Cmaxand AUC) to rolapitant increased in a dose-proportional manner when single oral doses of rolapitant increased from 4.5 mg to 180 mg. With 4 times the recommended clinical oral dose of 180 mg, the Cmaxand AUC of rolapitant increased 3.1 fold and 3.7 fold, respectively.
Concomitant administration of a high-fat meal did not significantly affect the pharmacokinetics of rolapitant after administration of 180 mg VARUBI
Rolapitant was highly protein bound to human plasma (99.8%). The apparent volume of distribution (Vd/F) following a single oral dose of 180 mg rolapitant was 460 L in healthy subjects. The large Vd indicated an extensive tissue distribution of rolapitant. In a population pharmacokinetic analysis of oral rolapitant, the Vd/F was 387 L in cancer patients.
Following single oral doses (4.5 to 180 mg) of rolapitant, the mean terminal half-life (t1/2) of rolapitant ranged from 169 to 183 hours (approximately 7 days), and was independent of dose. In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of oral rolapitant was 0.96 L/hour in cancer patients.
Rolapitant is metabolized primarily by CYP3A4 to form a major active metabolite, M19 (C4-pyrrolidine-hydroxylated rolapitant). In a mass balance study, the metabolite M19 was determined to be the major circulating metabolite. The rate of formation of M19 was relatively slow, resulting in the delayed median Tmaxof 120 hours (range: 24 to 168 hours) with Cmaxof 183 ng/mL. The mean half-life of M19 was 158 hours.
The exposure ratio of M19 to rolapitant was approximately 50% in plasma.
Rolapitant is eliminated primarily through the hepato/biliary route. Following administration of a single oral 180-mg dose of [14C]-rolapitant, on average 14.2% (range 9% to 20%) and 73% (range 52% to 89%) of the dose was recovered in the urine and feces, respectively over 6 weeks. In pooled samples collected over 2 weeks, 8.3% of the dose was recovered in the urine primarily as metabolites and 37.8% of the dose was recovered in the feces primarily as unchanged rolapitant. Unchanged rolapitant or M19 was not found in pooled urine sample.
Population pharmacokinetic analyses indicated that age, sex and race had no significant impact on the pharmacokinetics of rolapitant.
Following administration of a single oral dose of 180 mg rolapitant to patients with mild hepatic impairment (Child-Pugh Class A), the pharmacokinetics of rolapitant were comparable with those of healthy subjects. In patients with moderate hepatic impairment (Child-Pugh Class B), the mean Cmaxwas 25% lower while mean AUC of rolapitant was similar compared to those of healthy subjects. The median Tmaxfor M19 was delayed to 204 hours in patients with mild or moderate hepatic impairment compared to 168 hours in healthy subjects. The pharmacokinetics of rolapitant were not studied in patients with severe hepatic impairment (Child-Pugh Class C)
In population pharmacokinetic analyses, rolapitant pharmacokinetics in cancer patients with mild (CLcr: 60 to 90 mL/min) or moderate (CLcr: 30 to 60 mL/min) renal impairment was comparable to cancer patients with normal kidney function. Information is insufficient for the effect of severe renal impairment. The pharmacokinetics of rolapitant was not studied in patients with end-stage renal disease requiring hemodialysis.
Rolapitant is a substrate for CYP3A4.
- CYP3A4 inducers
When 600 mg rifampin was administered once daily for 7 days before and 7 days after administration of a single oral dose of 180 mg rolapitant, the mean Cmaxof rolapitant was reduced by 30% and the mean AUC was reduced by 85% compared to administration of rolapitant alone. The mean half-life of rolapitant decreased from 176 hours without rifampin to 41 hours with concurrent rifampin [see Drug Interactions (7)].
- CYP3A4 inhibitors
Concurrent administration of 400 mg ketoconazole, a strong CYP3A4 inhibitor, once daily for 21 days following a single 90 mg oral dose of rolapitant, did not affect the Cmaxof rolapitant while the AUC increased by 21%. These pharmacokinetic differences are not clinically significant.
The effect of VARUBI on CYP450 enzymes and transporters is summarized below.
- CYP3A4 substrates
Rolapitant is neither an inhibitor nor an inducer of CYP3A4. Midazolam: A single oral dose of 180 mg rolapitant had no significant effects on the pharmacokinetics of midazolam when oral midazolam 3 mg was co-administered on Day 1 and administered alone on Days 6 and 9. Ondansetron: Rolapitant had no significant effects on the pharmacokinetics of intravenous ondansetron when concomitantly administered with a single 180 mg oral dose of rolapitant on the same day. Dexamethasone: Rolapitant had no significant effects on the pharmacokinetics of dexamethasone when oral dexamethasone was administered on Days 1 to 3 after a single 180 mg oral dose of rolapitant was co-administered on Day 1 [see Dosage and Administration (2)].
- CYP2D6 substrates
Rolapitant is a moderate inhibitor of CYP2D6 [see Contraindications (4), Warnings and Precautions (5.1),andDrug Interactions (7)].Following a single dose of oral rolapitant, the AUC of dextromethorphan (CYP2D6 substrate) increased 2.6-fold on Day 1 and 3.3-fold on Day 8 and was similar to that following a single dose of intravenous rolapitant (VARUBI is not approved for intravenous use). Following intravenous rolapitant, inhibition of CYP2D6 continued with approximately a 3-fold increase in the AUC of dextromethorphan on Days 15 and 22 and attenuated to a 2.3-fold increase from Day 22 to Day 28, the last time point measured. See Table 6for the summary of effects of oral and intravenous rolapitant on dextromethorphan.
aA single oral dose of 180 mg rolapitant was administered on Day 1; the interacting drug (dextromethorphan 30 mg) was administered orally on Day 1 with rolapitant and alone on Day 8. | ||||||||||
bA single intravenous dose of 166.5 mg rolapitant was administered on Day 1; the interacting drug (dextromethorphan 30 mg) was administered orally on Day 1 with rolapitant and alone on Days 8, 15, 22, and 29. VARUBI is not approved for intravenous use. The AUC of rolapitant following single intravenous dose of 166.5 mg is similar to that following single oral dose of VARUBI 180 mg. | ||||||||||
↑ Denotes a mean increase in exposure by the percentage indicated. | ||||||||||
N/A: not applicable | ||||||||||
| Rolapitant Dose (route of administration) | % Change for Dextromethorphan | |||||||||
| Day 1 with Rolapitant | Day 8 without Rolapitant | Day 15 without Rolapitant | Day 22 without Rolapitant | Day 29 without Rolapitant | ||||||
| Change in Cmax | Change in AUC | Change in Cmax | Change in AUC | Change in Cmax | Change in AUC | Change in Cmax | Change in AUC | Change in Cmax | Change in AUC | |
| 180 mga(Oral) | 120% ↑ | 160% ↑ | 180% ↑ | 230% ↑ | N/A | |||||
| 166.5 mgb(Intavenous) | 75% ↑ | 110% ↑ | 140% ↑ | 220% ↑ | 170% ↑ | 220% ↑ | 120% ↑ | 180% ↑ | 96% ↑ | 130% ↑ |
- BCRP Transporter
- In vitro, rolapitant is a BCRP transporter inhibitor.
When sulfasalazine (BCRP substrate) was administered with a single oral dose of 180 mg rolapitant on Day 1 and without rolapitant on Day 8, a 140% increase in Cmaxand a 130% increase in AUC of sulfasalazine 500 mg was observed on Day 1, a 17% increase in Cmaxand a 32% increase in AUC was observed on Day 8 [see Drug Interactions (7)].
- P-glycoprotein substrates
- In vitro, rolapitant is a P-gp inhibitor.
When digoxin (P-gp substrate) was administered with a single oral dose of 180 mg rolapitant, a 70% increase in Cmaxand a 30% increase in AUC of digoxin 0.5 mg were observed [see Drug Interactions (7)].
- Warfarin
When warfarin was administered with a single intravenous dose of 166.5 mg rolapitant, 3% and 18% increases in Cmaxand AUC of S-warfarin were observed on Day 1, respectively. On Day 8, the increases were 3% for Cmaxand 21% for AUC. The effect on INR or prothrombin time was not measured. Of note, Cmaxwas greater with intravenous rolapitant when compared to oral VARUBI [see Drug Interactions (7)].
- Substrates for other CYP enzymes
- In vitrostudies suggest that rolapitant is not an inhibitor of CYP1A2 and CYP2E1.In vitrostudies suggest that rolapitant inhibits CYP2A6; however, a clinically meaningful drug interaction via an inhibition of CYP2A6 appears unlikely.
No clinically significant interaction was seen on the systemic exposures of the following drugs when administered with a single oral dose of 180 mg rolapitant on Day 1: repaglinide (CYP2C8 substrate; no effect on repaglinide 0.25 mg on Day 1; on Day 8: 29% and 24% increase in Cmaxand AUC, respectively), efavirenz (CYP2B6 substrate; 18% decrease in Cmaxand no effect on AUC of efavirenz 600 mg on Day 1; on Day 8: no effect on Cmaxand 28% increase in AUC), tolbutamide (CYP2C9 substrate; no effect on tolbutamide 500 mg on Day 1 and on Day 8), or omeprazole (CYP2C19 substrate; 44% increase in Cmaxand 23% increase in AUC of omeprazole 40 mg on Day 1; on Day 8: 37% and 15% increase in Cmaxand AUC, respectively).
- Substrates for other transporters
- In vitrostudies suggest that oral rolapitant is unlikely to inhibit organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), organic anion transporters 1 and 3 (OAT1 and OAT3), organic cation transporter 2 (OCT2), and multidrug and toxin extrusion proteins 1 and 2K (MATE1 and MATE2K)in vivo.
Administer VARUBI prior to the initiation of each chemotherapy cycle, but at no less than 2 week intervals.
Administer VARUBI without regards to meals.
| Day 1 | Day 2 | Day 3 | Day 4 | |
Prevention of Nausea and Vomiting Associated with Cisplatin-Based Highly Emetogenic Cancer Chemotherapy | ||||
| VARUBI | 180 mg as a single dose orally within 2 hours prior to initiation of chemotherapy | None | ||
| Dexamethasone | 20 mg; 30 min prior to initiation of chemotherapy | 8 mg twice daily | 8 mg twice daily | 8 mg twice daily |
| 5-HT3 receptor antagonist | See the prescribing information for the co-administered 5-HT3 receptor antagonist for appropriate dosing information. | None | ||
Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Cancer Chemotherapy and Combinations of Anthracycline and Cyclophosphamide | ||||
| VARUBI | 180 mg as a single dose orally within 2 hours prior to initiation of chemotherapy | None | ||
| Dexamethasone | 20 mg; 30 min prior to initiation of chemotherapy | None | ||
| 5-HT3 receptor antagonist | See the prescribing information for the co-administered 5-HT3 receptor antagonist for appropriate dosing information. | See the prescribing information for the co-administered 5-HT3 receptor antagonist for appropriate dosing information. | ||
Tablets: 90 mg rolapitant; film-coated, blue capsule shaped, debossed with T0101 on one side and 100 on the other side.
The limited data with VARUBI 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 1.2 times and 2.9-times, respectively, the maximum recommended human dose (MRHD)
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 1.2 times the recommended 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 2.9 times the recommended 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 1.2 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 of 9 mg/kg per day rolapitant (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.
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.
VARUBI is contraindicated in patients taking CYP2D6 substrates with a narrow therapeutic index, such as thioridazine and pimozide. VARUBI can significantly increase the plasma concentrations of thioridazine and pimozide, which may result in QT prolongation and Torsades de Pointes
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 (CYP2D6 substrate) 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 VARUBI
VARUBI 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
Before starting treatment with VARUBI, consider whether patients require treatment with thioridazine or pimozide. If patients require these drugs, use an alternative antiemetic to VARUBI or an alternative to thioridazine or pimozide that is not metabolized by CYP2D6.
VARUBI can also increase plasma concentrations of other CYP2D6 substrates for at least 28 days following administration of VARUBI and may result in adverse reactions.
Before starting treatment with VARUBI, consult the prescribing information for CYP2D6 substrates to obtain additional information about interactions with CYP2D6 inhibitors.
VARUBI is contraindicated in pediatric patients less than 2 years of age because of irreversible impairment of sexual development and fertility observed in juvenile rats at clinically relevant dosages
The safety and effectiveness of VARUBI have not been established in pediatric patients. VARUBI is contraindicated in pediatric patients less than 2 years of age
A toxicity study in juvenile rats at rolapitant doses approximately 1.2 and 2.5 times the approved adult body surface area (BSA)-based dose from postnatal day (PND) 7 through PND 70 (approximate human age equivalent of birth to 16 years) identified reproductive toxicity. A subsequent toxicity study in juvenile rats was conducted to identify the critical window of exposure for reproductive toxicity. A rolapitant dose of 50 mg/kg/day (approximately 2.7 times the approved adult BSA-based dose) was administered daily from PNDs 7 through 70, 7 to 21, 21 to 42 and 42 to 70 (approximate human age equivalent of birth to 16 years, birth to 2 years, 2 years to 12 years, and 12 years to 16 years, respectively). Female juvenile rats treated with rolapitant beginning on PND 7 developed adverse effects including partial or irreversible lower uterine weights that correlated with decreased endometrial glands of the uterus, decreases in the numbers of corpora lutea, implantation sites and live embryos and increases in pre- and post-implantation loss, and early resorptions. These adverse effects were observed in female juvenile rats administered rolapitant prior to PND 21 (approximate human age equivalent of 2 years). Additionally, juvenile rats treated with rolapitant beginning on either PND 7 or PND 21 developed slight changes in the onset of sexual maturation (including earlier attainment of vaginal opening in females and delay in preputial separation in males).