Varubi Drug Information

® 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. VARUBI 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In 4 controlled clinical trials in patients receiving emetogenic cancer chemotherapy, VARUBI was given in combination with a 5-HT 3 receptor antagonist and dexamethasone. On Day 1 of Cycle 1 of chemotherapy, 1567 patients were treated with VARUBI and 1198 of these patients continued into the optional multiple cycle extension for up to 6 cycles of chemotherapy.

The median number of cycles administered 180 mg of VARUBI was four. VARUBI 180 mg was administered to 1294 patients. In Cycle 1 adverse reactions were reported in approximately 7% of patients treated with VARUBI compared with approximately 6% of patients treated with control therapy.

The most common adverse reactions reported with an incidence of ≥3% and greater than control are listed in Table 2 and Table 3. Table 2: Most Common Adverse Reactions in Patients Receiving Cisplatin-Based Highly Emetogenic Chemotherapy (Cycle 1)* * all reactions occurring at ≥3% in the VARUBI group and for which the rate for VARUBI exceeds the rate for control VARUBI Regimen (VARUBI, Dexamethasone, and 5-HT 3 Receptor Antagonist) N = 624 Control (Placebo, Dexamethasone, and 5-HT 3 Receptor Antagonist) N = 627 Neutropenia 9% 8% Hiccups 5% 4% Abdominal Pain 3% 2% Table 3: Most Common Adverse Reactions in Patients Receiving Moderately Emetogenic Chemotherapy and Combinations of Anthracycline and Cyclophosphamide (Cycle 1)* *all reactions occurring at ≥3% in the VARUBI group and for which the rate for VARUBI exceeds the rate for control. VARUBI Regimen (VARUBI, Dexamethasone, and 5-HT 3 Receptor Antagonist) N = 670 Control (Placebo, Dexamethasone, and 5-HT 3 Receptor Antagonist) N = 674 Decreased appetite 9% 7% Neutropenia 7% 6% Dizziness 6% 4% Dyspepsia 4% 2% Urinary tract infection 4% 3% Stomatitis 4% 2% Anemia 3% 2% Adverse reactions in the multiple-cycle extensions of highly and moderately emetogenic chemotherapy studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1.

Rolapitant is a moderate CYP2D6 inhibitor. 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 VARUBI . Oral rolapitant is an inhibitor of Breast-Cancer-Resistance Protein (BCRP) and p-glycoprotein (P-gp). Rolapitant, given as a single oral dose, is not an inhibitor or inducer of CYP3A4 . Therefore, no dosage adjustment for dexamethasone (CYP3A4 substrate) is needed when co-administered with VARUBI . Table 4 and Table 5 include drugs with clinically important drug interactions when administered concomitantly with VARUBI and instructions for preventing or managing them.

Table 4: Clinically Relevant Interactions Affecting Drugs Co-Administered with VARUBI CYP2D6 Substrates Narrow Therapeutic Index Drugs (Thioridazine and Pimozide) Clinical Impact: Increased plasma concentrations of thioridazine and pimozide are associated with serious and/or life-threatening events of QT prolongation and Torsades de Pointes. Intervention: VARUBI is contraindicated in patients taking CYP2D6 substrates with a narrow therapeutic index such as thioridazine and 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. Other CYP2D6 Substrates Clinical Impact: VARUBI can 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 of CYP2D6 substrates to obtain further information about interactions with CYP2D6 inhibitors. Intervention: Before starting treatment with VARUBI consult the prescribing information of CYP2D6 substrates to obtain further information about interactions with CYP2D6 inhibitors. BCRP Substrates with a Narrow Therapeutic Index (e.g., methotrexate, topotecan, or irinotecan) Clinical Impact: Increased plasma concentrations of BCRP substrates (e.g., methotrexate, topotecan, or irinotecan) may result in potential adverse reactions.

Intervention: Monitor for adverse reactions related to the concomitant drug if use of VARUBI cannot be avoided. Use the lowest effective dose of rosuvastatin (see prescribing information for additional information on recommended dosing). P-gp Substrates with a Narrow Therapeutic Index (e.g. digoxin) Clinical Impact: Increased plasma concentrations of P-gp substrates (e.g., digoxin) may result in potential adverse reactions. Intervention: Monitor digoxin concentrations with concomitant use of VARUBI and adjust the dosage as needed to maintain therapeutic concentrations.

Monitor for adverse reactions if concomitant use of VARUBI with other P-gp substrates with a narrow therapeutic index cannot be avoided. Warfarin Clinical Impact: Although co-administration of intravenous rolapitant (VARBI is not approved for intravenous use), which has a higher C max than oral VARUBI, with warfarin did not substantially increase the systemic exposure to S-warfarin, the active enantiomer, the effects on INR and prothrombin time were not studied . Intervention: Monitor INR and prothrombin time and adjust the dosage of warfarin, as needed with concomitant use of VARUBI, to maintain the target INR range. Table 5: Clinically Relevant Interactions Affecting Rolapitant When Co-Administered with Other Drugs Strong CYP3A4 Inducers (e.g. rifampin) Clinical Impact: Co-administration of VARUBI with rifampin can significantly reduce the plasma concentrations of rolapitant and decrease the efficacy of VARUBI . Intervention: Avoid the use of VARUBI in patients who require chronic administration of strong CYP3A4 inducers.

Strong CYP3A4 Inducers (e.g., rifampin) : significantly reduced plasma concentrations of rolapitant can decrease the efficacy of VARUBI; avoid use of VARUBI in patients who require chronic administration of such drugs. BCRP and P-gp Substrates with a Narrow Therapeutic Index : Oral VARUBI 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.

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

Pregnancy Risk Summary 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) (see Data ). 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. Data 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 1.2 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.

Pediatric Use 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. Rolapitant administration in juvenile rats (human age equivalent of birth to 2 years) resulted in abnormal ovarian and uterine development, early sexual development in females, delayed sexual development in males, and impaired fertility.

Juvenile Animal Toxicity Data 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).

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 . 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 . CYP2D6 substrates with a narrow therapeutic index (e.g., thioridazine and pimozide) Pediatric patients less than 2 years of age because of irreversible impairment of sexual development and fertility in juvenile rats

There are no data on overdose with VARUBI. There is no antidote for VARUBI overdose. Discontinue VARUBI in the event of overdose, and institute general supportive measures and close observation.