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1 INDICATIONS AND USAGE Aprepitant is a substance P/neurokinin 1 (NK1) receptor antagonist. Aprepitant capsules are indicated • in combination with other antiemetic agents, in patients 12 years of age and older for prevention of: o acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin ( 1.1 ) o nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) ( 1.1 ) • for prevention of postoperative nausea and vomiting (PONV) in adults ( 1.2 ) Limitations of Use : ( 1.3 ) • Aprepitant has not been studied for treatment of established nausea and vomiting. • Chronic continuous administration of aprepitant is not recommended.

2 DOSAGE AND ADMINISTRATION Recommended Dosage for Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) ( 2.1 ) •Aprepitant capsules in adults and pediatric patients 12 years of age and older: is 125 mg on Day 1 and 80 mg on Days 2 and 3. • Administer aprepitant 1 hour prior to chemotherapy on Days 1, 2, and 3. If no chemotherapy is given on Days 2 and 3, administer aprepitant in morning. See Full Prescribing Information for recommended dosages of concomitant dexamethasone and 5-HT 3 antagonist for HEC and MEC. Recommended Dosage for PONV ( 2.2 ) • Adults: 40 mg Aprepitant capsules within 3 hours prior to induction of anesthesia. Preparation and Administration ( 2.3 ) • Aprepitant capsules can be administered with or without food. • Swallow aprepitant capsules whole. • For details on preparation see Full Prescribing Information. 2.1 Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) Adults and Pediatric Patients 12 Years of Age and Older The recommended oral dosage of aprepitant capsules, dexamethasone, and a 5-HT 3 antagonist in adults and pediatric patients 12 years of age and older who can swallow oral capsules, for the prevention of nausea and vomiting associated with administration of HEC or MEC is shown in Table 1 or Table 2, respectively. Table 1: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with HEC Population Day 1 Day 2 Day 3 Day 4 Aprepitant capsules* Adults and Pediatric Patients 12 Years and Older 125 mg orally 80 mg orally 80 mg orally none Dexamethasone Adults 12 mg orally 8 mg orally 8 mg orally 8 mg orally Pediatric Patients 12 Years and Older If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 [see Clinical Studies ( 14.3 )].† 5-HT3 antagonist Adults and Pediatric Patients 12 Years and Older See selected 5-HT3 antagonist prescribing information for the recommended dosage none none none Table 2: Recommended Dosing for…

12.2 PHARMACODYNAMICS NK 1 Receptor Occupancy In two single-blind, multiple-dose, randomized, and placebo-controlled studies, healthy young men received oral aprepitant doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily (0.08, 0.24, 0.8, and 2.4 times the maximum recommended single dose, respectively) for 14 days with 2 or 3 subjects on placebo. Both plasma aprepitant concentration and NK 1 receptor occupancy in the corpus striatum by positron emission tomography were evaluated, at predose and 24 hours after the last dose. At aprepitant plasma concentrations of approximately 10 ng/mL and 100 ng/mL, the NK 1 receptor occupancies were approximately 50% and 90%, respectively. The oral aprepitant regimen for CINV produced mean trough plasma aprepitant concentrations greater than 500 ng/mL in adults, which would be expected to, based on the fitted curve with the Hill equation, result in greater than 95% brain NK 1 receptor occupancy. However, the receptor occupancy for either CINV or PONV dosing regimen has not been determined. In addition, the relationship between NK 1 receptor occupancy and the clinical efficacy of aprepitant has not been established. Cardiac Electrophysiology In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mg dose of fosaprepitant had no effect on the QTc interval. Maximum aprepitant concentrations after a single 200-mg dose of fosaprepitant were 4- and 9-fold higher than that achieved with oral aprepitant 125 mg and 40 mg, respectively. QT prolongation with the recommended oral aprepitant dosing regimens for CINV and PONV is not expected.

6 ADVERSE REACTIONS Most common adverse reactions (≥3%) are ( 6.1 ): Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) • Adults: fatigue, diarrhea, asthenia, dyspepsia, abdominal pain, hiccups, white blood cell count decreased, dehydration, and alanine aminotransferase increased. • Pediatrics: neutropenia, headache, diarrhea, decreased appetite, cough, fatigue, hemoglobin decreased, dizziness, and hiccups. PONV • Adults: constipation and hypotension. To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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. The overall safety of aprepitant was evaluated in approximately 6,800 individuals. Adverse Reactions in Adults in the Prevention of Nausea and Vomiting Associated with HEC and MEC In 2 active-controlled, double-blind clinical trials in patients receiving highly emetogenic chemotherapy (HEC) (Studies 1 and 2), aprepitant in combination with ondansetron and dexamethasone (aprepitant regimen) was compared to ondansetron and dexamethasone alone (standard therapy [see Clinical Studies ( 14.1 )]. In 2 active-controlled clinical trials in patients receiving moderately emetogenic chemotherapy (MEC) (Studies 3 and 4), aprepitant in combination with ondasetron and dexamethasone (aprepitant regimen) was compared to ondansetron and dexamethasone alone (standard therapy) [see Clinical Studies ( 14.2 )] . The most common adverse reaction reported in patients who received MEC in pooled Studies 3 and 4 was dyspepsia (6% versus 4%). Across these 4 studies there were 1,412 patients treated with the aprepitant regimen during Cycle 1 of chemotherapy and 1,099 of these patients continued into the…

4 CONTRAINDICATIONS Aprepitant is contraindicated in patients: • who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions have been reported [see Adverse Reactions ( 6.2 )] . • taking pimozide. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of this drug which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide [see Warnings and Precautions ( 5.1 )] . • Known hypersensitivity to any component of this drug. ( 4 ) • Concurrent use with pimozide. ( 4 )

5 WARNINGS AND PRECAUTIONS • CYP3A4 Interactions : Aprepitant is a substrate, weak-to-moderate inhibitor and inducer of CYP3A4; See Full Prescribing Information for recommendations regarding contraindications, risk of adverse reactions, and dosage adjustments of aprepitant and concomitant drugs. ( 4 , 5.1 , 7.1 , 7.2 ) • Warfarin (a CYP2C9 substrate) : Risk of decreased INR of prothrombin time; monitor INR in 2-week period, particularly at 7 to 10 days, following initiation of aprepitant. ( 5.2 , 7.1 ) • Hormonal Contraceptives : Efficacy of contraceptives may be reduced during administration of and for 28 days following the last dose of aprepitant. Use effective alternative or back-up methods of contraception. ( 5.3 , 7.1 , 8.3 ) 5.1 Clinically Significant CYP3A4 Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Use of aprepitant with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug. Use of pimozide with aprepitant is contraindicated due to the risk of significantly increased plasma concentrations of pimozide, potentially resulting in prolongation of the QT interval, a known adverse reaction of pimozide [see Contraindications ( 4 )] . Use of aprepitant with strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, diltiazem) may increase plasma conentrations of aprepitant and result in an increased risk of adverse reactions related to aprepitant. Use of aprepitant with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of aprepitant. See table 10 and 11 for a listing of potentially significant drug interactions [see Drug Interactions ( 7.1 , 7.2 )] . 5.2 Decrease in INR with Concomitant Warfarin Coadministration of aprepitant with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time [see Clinical…

7 DRUG INTERACTIONS See Full Prescribing Information for a list of clinically significant drug interactions. ( 4 , 5.1 , 5.2 , 5.3 , 7.1 , 7.2 ) 7.1 Effect of Aprepitant on the Pharmacokinetics of Other Drugs Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9 [see Clinical Pharmacology ( 12.3 )] . Aprepitant acts as a moderate inhibitor of CYP3A4 when administered as a 3-day regimen (125mg/80-mg/80-mg) and can increase plasma concentrations of concomitant drugs that are substrates for CYP3A4. Aprepitant acts as a weak inhibitor when administered as a single 40-mg dose and has not been shown to alter the plasma concentrations of concomitant drugs that are primarily metabolized through CYP3A4. Some substrates of CYP3A4 are contraindicated with aprepitant [see Contraindications ( 4 )] . Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 10. Table 10: Effects of Aprepitant on the Pharmacokinetics of Other Drugs CYP3A4 Substrates Pimozide Clinical Impact Increased pimozide exposure Intervention Aprepitant is contraindicated [see Contraindications ( 4 )] . Benzodiazepines Clinical Impact Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions [see Clinical Pharmacology ( 12.3 )]. Intervention 3-day aprepitant regimen Monitor for benzodiazepine-related adverse reactions. Depending on the clinical situation (e.g., elderly patients) and degree of monitoring available, reduce the dose of intravenous midazolam Single 40 mg dose of aprepitant No dosage adjustment of the benzodiazepine needed Dexamethasone Clinical Impact Increased dexamethasone exposure [see Clinical Pharmacology ( 12.3 )]. Intervention 3-day aprepitant regimen Reduce the dose of oral dexamethasone by approximately 50% [see Dosage and Administration ( 2.1 )]. Single 40 mg dose of aprepitant No…