Varubi Tablet
FDA Label NDC 70720-101

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 tablets and VARUBI injectable emulsion 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 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 tablets without regards to meals.

• VARUBI injectable emulsion is supplied as a single-dose vial for intravenous administration. The emulsion is homogeneous (no shaking required) and translucent white in appearance.
• Inspect VARUBI injectable emulsion for particulate matter and discoloration prior to administration; discard if present. Do not use if contamination is suspected.
• Use and maintain aseptic technique while handling VARUBI injectable emulsion.
• Do not add any diluents or other medications directly to the vial.
• Administer the dose by inserting a vented intravenous set through the septum of the vial. Once the stopper is punctured, use immediately. Do not dilute VARUBI injectable emulsion.
• Infuse 92.5 mL from the vial over 30 minutes.
• VARUBI injectable emulsion is compatible with the following other intravenous fluids through a Y-site connection:
  • Sodium Chloride 0.9% Injection, USP
  • Dextrose 5% Injection, USP
  • Dextrose 5% in Lactated Ringer's Injection, USP
  • Lactated Ringer's Injection, USP

VARUBI tablets: 90 mg rolapitant; film-coated capsule shaped, blue tablets, debossed with T0101 on one side and 100 on the other side.

VARUBI injectable emulsion: 166.5 mg/92.5 mL (1.8 mg/mL) rolapitant as a sterile, translucent white homogeneous liquid with some opalescence in a single-dose vial.

VARUBI is contraindicated in patients:

• who are hypersensitive to any component of the product (including soybean oil). Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported with VARUBI injectable emulsion [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Description (11)].
• 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 (5.2)].

Anaphylaxis, anaphylactic shock and other serious hypersensitivity reactions have been reported in the postmarketing setting, some requiring hospitalization [see Adverse Reactions (6.2)]. These reactions have occurred during or soon after the infusion of VARUBI 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.

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 VARUBI injectable emulsion [see Contraindications (4)].

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

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

• administration of VARUBI injectable emulsion should be stopped immediately.
• appropriate medical management (including epinephrine and or antihistamines) should be initiated, and
• VARUBI injectable emulsion should be permanently discontinued.

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 VARUBI [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Narrow Therapeutic Index Drugs (Thioridazine and Pimozide)

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 [see Contraindications (4)].

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.

Other Drugs

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 Tablets

In 4 controlled clinical trials in patients receiving emetogenic cancer chemotherapy, VARUBI tablets were given in combination with a 5-HT₃ receptor antagonist and dexamethasone. On Day 1 of Cycle 1 of chemotherapy, 1567 patients were treated with VARUBI tablets 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 tablets was four. VARUBI tablets 180 mg were administered to 1294 patients.

In Cycle 1 adverse reactions were reported in approximately 7% of patients treated with VARUBI tablets 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.

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.

VARUBI Injectable Emulsion

In healthy subjects receiving the recommended therapeutic dose of VARUBI injectable emulsion, infusion-related adverse reactions were reported in 2.6% (2/78) of subjects during the infusion and included sensation of warmth, abdominal pain, dizziness and paresthesia.

Since VARUBI injectable emulsion is the same active substance (rolapitant) as VARUBI tablets, adverse reactions associated with VARUBI tablets might also be expected to occur with VARUBI injectable emulsion.

Narrow Therapeutic Index Drugs (Thioridazine and Pimozide)

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 [see Contraindications (4), Warnings and Precautions (5.2)].

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.

Other Drugs

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 of CYP2D6 substrates to obtain further information about interactions with CYP2D6 inhibitors.

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 1.3 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 1.3 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.

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 [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VARUBI and any potential adverse effects on the breastfed infant from VARUBI or from the underlying maternal condition or the use of concomitant chemotherapy.

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.

Infertility

Females

In animal fertility studies, rolapitant impaired the fertility in females in a reversible fashion [see Nonclinical Toxicology (13.1)].

Juvenile Animal Toxicity Data

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.

VARUBI (rolapitant) Tablets

Each tablet contains 90 mg rolapitant (equivalent to 100 mg rolapitant hydrochloride) and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch. The tablets are coated in non-functional blue and clear coats. The tablet coating comprises the following inactive ingredients: FD&C Blue No. 2-Indigo Carmine Lake, polyethylene glycol, polysorbate 80, polyvinyl alcohol, talc, and titanium dioxide.

VARUBI (rolapitant) Injectable Emulsion

Each single-dose vial of 92.5 mL sterile emulsion for intravenous use contains 166.5 mg rolapitant (equivalent to 185 mg of rolapitant hydrochloride) and the following inactive ingredients: dibasic sodium phosphate, anhydrous (2.8 mg/mL), medium chain triglycerides (11 mg/mL), polyoxyl 15 hydroxystearate (44 mg/mL), sodium chloride (6.2 mg/mL), soybean oil (6.6 mg/mL), water for injection and may contain hydrochloric acid and/or sodium hydroxide to adjust pH to 7.0 to 8.0. VARUBI injectable emulsion is a sterile, translucent white liquid and has some opalescence.

NK1 Receptor Occupancy

A human Positron Emission Tomography (PET) study with rolapitant demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK1 receptors. A dose-dependent increase in mean NK1 receptor occupancy was observed in the oral dose range from 4.5 mg to 180 mg of rolapitant. At the 180 mg oral dose of rolapitant, the mean NK1 receptor occupancy was 73% in the striatum at 120 hours after a single dose administration in healthy subjects. The relationship between NK1 receptor occupancy and the clinical efficacy of rolapitant has not been established.

Cardiac Electrophysiology

At an oral dose of 720 mg (4 times the recommended oral dose), VARUBI does not prolong the QT interval to any clinically relevant extent. The maximum rolapitant concentration after a single 720 mg dose of oral rolapitant was 30% to 50% higher than that achieved with the recommended dose of 166.5 mg of intravenous rolapitant.

Absorption

Oral tablet

Following a single oral dose administration of 180 mg VARUBI tablets under fasting conditions to healthy subjects, rolapitant was measurable in plasma between 30 minutes and the peak plasma concentration (C_max) for rolapitant which was reached in about 4 hours and mean C_max was 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 AUC_0-24hr) ranged from 5.0 to 5.3 fold.

The systemic exposures (C_max and 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 C_max and 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 tablets [see Dosage and Administration (2)].

Injectable emulsion

Following a 30-minute infusion of a single intravenous dose of 166.5 mg VARUBI injectable emulsion to healthy subjects, the mean C_max at the end of the infusion (30 min) was 1986 ng/mL (%CV:39%).

Following multiple intravenous doses of 18 to 54 mg once daily of rolapitant (approximately 10% to 33% of the recommended dose) for 10 days, accumulation of rolapitant (ratio of AUC_0-24hr) ranged from 4.3 fold to 5.4 fold.

The systemic exposures (C_max and AUC) to rolapitant increased in a dose-proportional manner when single intravenous doses of rolapitant increased from 18 mg to 180 mg. The C_max and AUC of rolapitant increased 11.6 fold and 10.1 fold, respectively.

At the recommended dose, the absolute bioavailability of rolapitant is 91%.

Distribution

Rolapitant was highly protein bound to human plasma (99.8%). The volume of distribution (Vd) was 392 L in healthy subjects following a single intravenous dose of 166.5 mg rolapitant. 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.

Elimination

Following single intravenous doses (18 to 180 mg) and single oral doses (4.5 to 180 mg) of rolapitant, the mean terminal half-life (t1/2) of rolapitant ranged from 138 to 205 hours and 169 to 183 hours (approximately 7 days), respectively, 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. The total clearance following intravenous administration of 166.5 mg rolapitant in healthy subjects was 1.65 L/hour.

Metabolism

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 the major circulating metabolite. The formation of M19 was significantly delayed with the median T_max of 120 hours (range: 24-168 hours) with C_max of 183 ng/mL. The mean half-life of M19 was 158 hours.

The exposure ratio of M19 to rolapitant was approximately 50% in plasma.

The C_max and AUC of M19 following single intravenous administration of 166.5 mg of rolapitant were 149 ng/mL and 68,600 ng∙h/mL, respectively. The median T_max was 168 hours. The mean half-life was 182 hours.

Excretion

Rolapitant is eliminated primarily through the hepatic/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 were not found in pooled urine sample.

Specific Populations

Age, Male and Female Patients and Racial or Ethnic Groups

Population pharmacokinetic analyses indicated that age, sex and race had no significant impact on the pharmacokinetics of rolapitant.

Patients with Hepatic Impairment

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 C_max was 25% lower while mean AUC of rolapitant was similar compared to those of healthy subjects. The median T_max for 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) [see Use in Specific Populations (8.6)].

Patients with Renal Impairment

In population pharmacokinetic analyses, creatinine clearance (CLcr) at baseline did not show a significant effect on rolapitant pharmacokinetics in cancer patients with mild (CLcr: 60 to 90 mL/min) or moderate (CLcr: 30 to 60 mL/min) renal impairment compared 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.

Drug Interaction Studies

Effect of Other Drugs on Rolapitant

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 C_max of 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 (7.2)].

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 C_max of rolapitant while the AUC increased by 21%. These pharmacokinetic differences are not clinically significant.

Effect of Rolapitant on Other Drugs

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. A single intravenous dose of 166.5 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 Day 8.

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 (5.2), and Drug Interactions (7.1)]. See Table 4 and Table 5 for a summary of the effects of VARUBI on the pharmacokinetics of co-administered dextromethorphan, a CYP2D6 substrate.

BCRP transporter

In vitro, rolapitant is a BCRP transporter inhibitor.

When sulfasalazine (BCRP substrate) was administered with a single intravenous dose of 166.5 mg rolapitant on Day 1 and without rolapitant on Day 11, no effect on C_max and AUC of sulfasalazine 500 mg was observed on Day 1, an 18% decrease in C_max and an 11% decrease in AUC were observed on Day 11. These differences in systemic exposures are not clinically significant.

When sulfasalazine was administered with a single oral dose of 180 mg rolapitant on Day 1 and without rolapitant on Day 8, a 140% increase in C_max and a 130% increase in AUC of sulfasalazine 500 mg was observed on Day 1, a 17% increase in C_max and a 32% increase in AUC was observed on Day 8 [see Drug Interactions (7.3)].

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 C_max and a 30% increase in AUC of digoxin 0.5 mg were observed [see Drug Interactions (7.4)].

When digoxin was administered with a single intravenous dose of 166.5 mg rolapitant, no effect on AUC and a 21% increase in the C_max of digoxin 0.5 mg was observed [see Drug Interactions (7.4)].

Warfarin

When warfarin was administered with a single intravenous dose of 166.5 mg rolapitant, 3% and 18% increases in C_max and AUC of S-warfarin were observed on Day 1, respectively. On Day 8, the increases were 3% for C_max and 21% for AUC. The effect on INR or prothrombin time was not measured [see Drug Interactions (7.5)].

Substrates for other CYP enzymes

In vitro studies suggest that rolapitant is not an inhibitor of CYP1A2 and CYP2E1. In vitro studies 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 intravenous dose of 166.5 mg rolapitant on Day 1 and without rolapitant on Day 8: caffeine (CYP1A2 substrate; no effect on caffeine 200 mg on Days 1 and 8), and omeprazole (CYP2C19 substrate; 14% increase in C_max and no effect on AUC of omeprazole 40 mg on Day 1; on Day 8: 15% increase in C_max and no effect on AUC).

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 C_max and AUC, respectively), efavirenz (CYP2B6 substrate; 18% decrease in C_max and no effect on AUC of efavirenz 600 mg on Day 1; on Day 8: no effect on C_max and 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 C_max and 23% increase in AUC of omeprazole 40 mg on Day 1; on Day 8: 37% and 15% increase in C_max and AUC, respectively).

Substrates for other transporters

In vitro studies 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.

In vitro studies suggest that intravenous rolapitant is unlikely to inhibit OATP1B3, OAT1, OAT3, OCT2, and MATE2K in vivo. However, the potential for intravenous rolapitant to inhibit OATP1B1 or MATE1 in vivo cannot be ruled out.

Carcinogenesis

The carcinogenic potential of rolapitant was assessed in 2-year carcinogenicity studies in CD-1 mice and Sprague-Dawley rats. In mice, there were no drug-related neoplastic findings at doses up to 135 mg/kg per day (approximately 3.9 times the recommended intravenous human dose on a body surface area basis). In rats, there were no drug-related neoplastic findings at doses up to 90 mg/kg per day (approximately 5.2 times the recommended intravenous human dose on a body surface area basis).

Mutagenesis

Rolapitant was not genotoxic in an Ames test, a human peripheral blood lymphocyte chromosome aberration test, and a mouse micronucleus test.

Impairment of Fertility

In a fertility and early embryonic development study in female rats, rolapitant at an oral dose of 9 mg/kg per day (approximately 0.5 times the recommended intravenous human dose on a body surface area basis) caused a transient decrease in maternal body weight gain and increases in the incidence of pre- and post-implantation loss. At a rolapitant dose of 4.5 mg/kg per day (approximately 0.3 times the recommended intravenous human dose on a body surface area basis), there were slight decreases in the number of corpora lutea and implantation sites. Rolapitant did not affect the fertility or general reproductive performance of male rats at doses up to 90 mg/kg per day (approximately 5.2 times the recommended intravenous human dose on a body surface area basis). Reversibility in female rats was demonstrated in a follow-up study.

Cisplatin-Based Highly Emetogenic Chemotherapy (HEC)

In two multicenter, randomized, double-blind, parallel group, controlled clinical studies (Study 1 and Study 2), the VARUBI regimen (VARUBI tablets, granisetron and dexamethasone) was compared with control therapy (placebo, granisetron and dexamethasone) in patients receiving a chemotherapy regimen that included cisplatin >60 mg/m². See Table 6 for the treatment regimens.

Study 1

A total of 532 patients were randomized to either the VARUBI regimen (N=266) or control therapy (N=266). A total of 526 patients were included in the evaluation of efficacy. Of those randomized 42% were women, 58% men, 67% White, 23% Asian, 1% Black, and 9% multi­racial/other/unknown. The proportion of patients from North America was 16%. Patients in this clinical study ranged from 20 to 90 years of age, with a mean age of 57 years. In Study 1, 26% of patients were 65 years or older, with 3% of patients being 75 years or older. The mean cisplatin dose was 77 mg/m².

During this study, 82% of the patients received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common concomitant chemotherapeutic agents administered during Cycle 1 were: gemcitabine (17%), paclitaxel (12%), fluorouracil (11%), etoposide (10%), vinorelbine (9%), docetaxel (9%), pemetrexed (7%), doxorubicin (6%) and cyclophosphamide (5%).

Study 2

A total of 555 patients were randomized to either the VARUBI regimen (N=278) or control therapy (N=277). A total of 544 patients were included in the evaluation of efficacy. Of those randomized 32% were women, 68% men, 81% White, 14% Asian, 1% Black, and 5% multi­racial/other/unknown. The proportion of patients from North America was 7%. Patients in this clinical study ranged from 18 to 83 years of age, with a mean age of 58 years. In this study, 27% of patients were 65 years or older, with 3% of patients being 75 years or older. The mean cisplatin dose was 76 mg/m².

During this study, 85% of the patients received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common concomitant chemotherapeutic agents administered during Cycle 1 were: vinorelbine (16%), gemcitabine (15%), fluorouracil (12%), etoposide (11%), pemetrexed (9%), docetaxel (7%), paclitaxel (7%), epirubicin (5%) and capecitabine (4%).

The primary endpoint in both studies was complete response (defined as no emetic episodes and no rescue medication) in the delayed phase (25 to 120 hours) of chemotherapy-induced nausea and vomiting.

Moderately Emetogenic Chemotherapy (MEC) and Combinations of Anthracycline and Cyclophosphamide Chemotherapy

Study 3

In Study 3, a multicenter, randomized, double-blind, parallel group, controlled clinical study in moderately emetogenic chemotherapy, the VARUBI regimen (VARUBI tablets, granisetron and dexamethasone) was compared with control therapy (placebo, granisetron and dexamethasone) in patients receiving a moderately emetogenic chemotherapy regimen that included at least 50% of patients receiving a combination of anthracycline and cyclophosphamide. The percentage of patients who received carboplatin in Cycle 1 was 30%. Treatment regimens for the VARUBI and control arms are summarized in Table 7.

A total of 1369 patients were randomized to either the VARUBI regimen (N=684) or control therapy (N=685). A total of 1332 patients were included in the evaluation of efficacy. Of those randomized 80% were women, 20% men, 77% White, 13% Asian, 4% Black, and 6% multi­racial/other/unknown. The proportion of patients from North America was 33%. Patients in this clinical study ranged from 22 to 88 years of age, with a mean age of 57 years. In this study, 28% of patients were 65 years or older, with 7% of patients being 75 years or older.

The primary endpoint was complete response (defined as no emetic episodes and no rescue medication) in the delayed phase (25 to 120 hours) of chemotherapy-induced nausea and vomiting.

A summary of the study results from HEC Studies 1 and 2 and for the MEC Study 3 is shown in Table 8.

Multiple-Cycle Extension: In Studies 1, 2, and 3, patients had the option of continuing into a multiple-cycle extension for up to 5 additional cycles of chemotherapy receiving the same treatment as assigned in cycle 1. At Day 6 to 8 following initiation of chemotherapy, patients were asked to recall whether they had any episode of vomiting or retching or nausea that interfered with normal daily life. The results are summarized by study and treatment group in Figure 1 below.

Figure 1: No Emesis and No Nausea Interfering with Daily Life over Cycles 2-6

VARUBI Tablets

VARUBI tablets are available as film-coated, capsule shaped, blue tablets, debossed with T0101 on one side and 100 on the other side. Each tablet contains 90 mg rolapitant. VARUBI tablets are packaged in an Aclar blister shell with aluminum foil backing and supplied as follows:

VARUBI Injectable Emulsion

VARUBI injectable emulsion is supplied as a sterile, translucent white homogeneous liquid that has some opalescence. Each stoppered vial delivers 166.5 mg/92.5 mL (1.8 mg/mL) rolapitant:

Anaphylaxis, Anaphylactic Shock and Other Serious Hypersensitivity Reactions

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

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 VARUBI injectable emulsion.

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 [see Contraindications (4) and Warnings and Precautions (5.1)].

Drug Interactions

Advise patients to tell their healthcare provider when they start or stop taking any concomitant medications. VARUBI is a moderate CYP2D6 inhibitor and can increase plasma concentrations of CYP2D6 substrates [see Contraindications (4), Warnings and Precautions (5.2), Drug Interactions (7.1)].

Infertility

Advise females of reproductive potential that VARUBI may impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Manufactured for: TerSera Therapeutics LLC, Lake Forest, IL 60045

©2018 TerSera Therapeutics LLC

119511

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Anaphylaxis, Anaphylactic Shock and Other Serious Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Interaction with CYP2D6 Substrates [see Contraindications (4) and Warnings and Precautions (5.2)]

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.

The following adverse reactions have been identified during post-approval use of VARUBI injectable emulsion. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In postmarketing experience, severe systemic reactions have occurred within minutes of the start of infusion with VARUBI injectable emulsion.

Immune system disorders: hypersensitivity reactions including anaphylaxis, anaphylactoid reactions and anaphylactic shock, including back pain and chest pain

Gastrointestinal disorders: abdominal pain

Skin and subcutaneous disorders: erythema

General disorders and administration site conditions: feeling hot

Vascular disorders: generalized flushing, dizziness

Rolapitant is a moderate CYP2D6 inhibitor. Exposure to dextromethorphan, 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 VARUBI [see Clinical Pharmacology (12.3)].

Co-administration of VARUBI with strong CYP3A4 inducers (e.g., rifampin) can significantly reduce the plasma concentrations of rolapitant and decrease the efficacy of VARUBI. Avoid the use of VARUBI in patients who require chronic administration of strong CYP3A4 inducers [see Clinical Pharmacology (12.3)].

Oral rolapitant is an inhibitor of Breast-Cancer-Resistance Protein (BCRP). Increased plasma concentrations of BCRP substrates (e.g., methotrexate, topotecan, or irinotecan) may result in potential adverse reactions. Monitor for adverse reactions related to the concomitant drug if use of VARUBI tablets cannot be avoided. Use the lowest effective dose of rosuvastatin (see prescribing information for additional information on recommended dosing) [see Clinical Pharmacology (12.3)].

Oral rolapitant is an inhibitor of p-glycoprotein (P-gp). Increased plasma concentrations of P-gp substrates (e.g., digoxin) may result in potential adverse reactions. 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 tablets with other P-gp substrates with a narrow therapeutic index cannot be avoided.

Although co-administration of intravenous 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. Monitor INR and prothrombin time and adjust the dosage of warfarin, as needed with concomitant use of VARUBI, to maintain the target INR range.

Rolapitant, given as a single intravenous or oral dose, is not an inhibitor or inducer of CYP3A4 [see Clinical Pharmacology (12.3)]. Therefore, no dosage adjustment for dexamethasone (CYP3A4 substrate) is needed when co-administered with VARUBI [see Dosage and Administration (2)].

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

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 VARUBI, as described below in Juvenile Animal Toxicity Data.

Of the 1294 subjects treated with VARUBI, 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.

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 VARUBI in patients with severe hepatic impairment. If use cannot be avoided, monitor patients for adverse reactions related to rolapitant [see Adverse Reactions (6.1)].

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.

VARUBI contains rolapitant, a substance P/neurokinin 1 (NK1) receptor antagonist. Rolapitant hydrochloride is chemically described as (5S,8S)-8- { [(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]}-8-phenyl-1,7-diazaspiro[4.5]decan-2-one hydrochloride. Its empirical formula is C₂₅H₂₆F₆N₂O₂. HCl.H₂O, and its structural formula is:

Rolapitant hydrochloride is a white to off-white powder, with a molecular weight of 554.95. Solubility of rolapitant hydrochloride in aqueous solution is pH-dependent and is more soluble at lower pH. Rolapitant has good solubility in common pharmaceutical solvents such as ethanol, propylene glycol and 40% hydroxypropyl beta-cyclodextrin.

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.

Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP Controlled Room Temperature].

Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP Controlled Room Temperature].

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

• VARUBI tablets are taken on Day 1 of chemotherapy. Take 2 VARUBI tablets by mouth within 2 hours before you receive your anti-cancer medicine (chemotherapy).
• VARUBI tablets can be taken with or without food.
• Do not take VARUBI more than 1 time every 14 days.
• If you take too much VARUBI, call your doctor or go to the nearest hospital emergency room right away.

• VARUBI injectable emulsion is given on Day 1 of chemotherapy. It will be given to you in your vein (intravenously) over 30 minutes, within 2 hours before you receive your anti-cancer medicine (chemotherapy).

NDC 70720-101-02

Single dose
180 mg total dose (2 x 90 mg tablets)

VARUBI^®
(rolapitant) tablets

90 mg* per tablet

Contains two 90 mg tablets
equal to a single dose of 180 mg

*(equivalent to 100 mg rolapitant hydrochloride)

Rx only

For oral use.

Keep this and all drugs out of the reach of
children. This package is child-resistant.

Store at 20°C - 25°C (68°F - 77°F);
excursions permitted to 15°C - 30°C
(59°F - 86°F) [see USP Controlled
Room Temperature].

TerSera^®
therapeutics

Manufactured for TerSera Therapeutics LLC
Lake Forest, IL 60045

See package insert for dosage information.