Aprepitant

1 INDICATIONS AND USAGE Aprepitant is a substance P/neurokinin 1 (NK 1 ) receptor antagonist. Aprepitant capsules are indicated in combination with other antiemetic agents, in patients 12 years of age and older for prevention of: acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin ( 1.1 ) 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. 1.1 Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) Aprepitant capsules, in combination with other antiemetic agents, are indicated in patients 12 years of age and older for the prevention of: acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin. nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). 1.2 Prevention of Postoperative Nausea and Vomiting (PONV) Aprepitant capsules are indicated in adults for the prevention of postoperative nausea and vomiting. 1.3 Limitations of Use Aprepitant has not been studied for the treatment of established nausea and vomiting. Chronic continuous administration of aprepitant is not recommended because it has not been studied, and because the drug interaction profile may change during chronic continuous use.

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. Administration ( 2.4 ) Aprepitant capsules can be administered with or without food. Swallow aprepitant capsules whole. 2.1 Recommended Dosage For 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-HT 3 antagonist Adults and Pediatric Patients 12 Years and Older See selected 5-HT 3 antagonist prescribing information for the recommended dosage none none none * Administer aprepitant capsules 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days 2 and 3, administer aprepitant capsules in the morning. † Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with aprepitant [see Clinical Pharmacology ( 12.3 )] . Table 2: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with MEC Population Day 1 Day 2 Day 3 Aprepitant capsules * Adults and Pediatric Patients 12 Years and Older 125 mg orally 80 mg orally 80 mg orally Dexamethasone Adults 12 mg orally none none 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-HT 3 antagonist Adults and Pediatric Patients 12 Years and Older See the selected 5-HT 3 antagonist prescribing information for recommended dosage none none * Administer aprepitant capsules 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days 2 and 3, administer aprepitant capsules in the morning. † Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with aprepitant [see Clinical Pharmacology ( 12.3 )]. 2.2 Recommended Dosage For Postoperative Nausea and Vomiting (PONV) The recommended oral dosage of aprepitant capsules in adults is 40 mg within 3 hours prior to induction of anesthesia. 2.4 Administration Instructions Aprepitant capsules can be administered with or without food. Aprepitant capsules Swallow capsules whole.

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 Drug Interactions 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 concentrations 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 Table 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 Pharmacology ( 12.3 )] . Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle, or following administration of a single 40 mg dose of aprepitant for the prevention of postoperative nausea and vomiting [see Drug Interactions ( 7.1 )] . 5.3 Risk of Reduced Efficacy of Hormonal Contraceptives Upon coadministration with aprepitant, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of aprepitant [see Clinical Pharmacology ( 12.3 )] . Advise patients to use effective alternative or back-up methods of contraception during treatment with aprepitant and for 1 month following the last dose of aprepitant [see Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.3 )] .

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 )

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 (125 mg/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 7: 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 dosage adjustment of oral dexamethasone needed Methylprednisolone Clinical Impact Increased methylprednisolone exposure [see Clinical Pharmacology ( 12.3 )]. Intervention 3-day aprepitant regimen Reduce the dose of intravenous methylprednisolone by approximately 25% Reduce the dose of oral methylprednisolone by approximately 50% Single 40 mg dose of aprepitant No dosage adjustment of methylprednisolone needed Chemotherapeutic agents that are metabolized by CYP3A4 Clinical Impact Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions [see Clinical Pharmacology ( 12.3 )] . Intervention Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents Monitor for chemotherapeutic-related adverse reactions. Etoposide, vinorelbine, paclitaxel, and docetaxel No dosage adjustment needed. Hormonal Contraceptives Clinical Impact Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of aprepitant [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.3 ), Clinical Pharmacology ( 12.3 )]. Intervention Effective alternative or back-up methods of contraception (such as condoms and spermicides) should be used during treatment with aprepitant and for 1 month following the last dose of aprepitant. Examples birth control pills, skin patches, implants, and certain IUDs CYP2C9 Substrates Warfarin Clinical Impact Decreased warfarin exposure and decreased prothrombin time (INR) [see Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.3 )]. Intervention In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day aprepitant regimen with each chemotherapy cycle, or following administration of a single 40 mg dose of aprepitant. Other 5-HT 3 Antagonists Clinical Impact No change in the exposure of the 5-HT 3 antagonist [see Clinical Pharmacology ( 12.3 )] . Intervention N…

8.1 Pregnancy Risk Summary There are insufficient data on use of aprepitant in pregnant women to inform a drug associated risk. In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic drug levels (AUC) approximately 1.5 times the adult human exposure at the 125 mg/80 mg/80 mg aprepitant regimen [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. 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 In embryofetal development studies in rats and rabbits, aprepitant was administered during the period of organogenesis at oral doses up to 1000 mg/kg twice daily in rats and up to the maximum tolerated dose of 25 mg/kg/day in rabbits. No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats at 1000 mg/kg twice daily and in pregnant rabbits at 125 mg/kg/day were approximately 1.5 times the adult exposure at the 125 mg/80 mg/80 mg aprepitant regimen. Aprepitant crosses the placenta in rats and rabbits.

6 ADVERSE REACTIONS Most common adverse reactions are ( 6.1 ): Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) Adults (≥3%): fatigue, diarrhea, asthenia, dyspepsia, abdominal pain, hiccups, white blood cell count decreased, dehydration, and alanine aminotransferase increased. Pediatrics (≥3%): neutropenia, headache, diarrhea, decreased appetite, cough, fatigue, hemoglobin decreased, dizziness, and hiccups. PONV Adults (≥3%): constipation and hypotension. To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 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 6800 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 ondansetron 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 1412 patients treated with the aprepitant regimen during Cycle 1 of chemotherapy and 1099 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. The most common adverse reactions reported in patients who received HEC and MEC in pooled Studies 1, 2, 3 and 4 are listed in Table 5. Table 3: Most Common Adverse Reactions in Patients Receiving HEC and MEC from a Pooled Analysis of HEC and MEC Studies * Aprepitant, ondansetron, and dexamethasone † (N=1412) Ondansetron and dexamethasone ‡ (N=1396) fatigue 13% 12% diarrhea 9% 8% asthenia 7% 6% dyspepsia 7% 5% abdominal pain 6% 5% hiccups 5% 3% white blood cell count decreased 4% 3% dehydration 3% 2% alanine aminotransferase increased 3% 2% * Reported in ≥ 3% of patients treated with the aprepitant regimen and at a greater incidence than standard therapy. † Aprepitant regimen ‡ Standard therapy In a pooled analysis of the HEC and MEC studies, less common adverse reactions reported in patients treated with the aprepitant regimen are listed in Table 6. Table 4: Less Common Adverse Reactions in Aprepitant-Treated Patients from a Pooled Analysis of HEC and MEC Studies * Infection and Infestations oral candidiasis, pharyngitis Blood and the Lymphatic System Disorders anemia, febrile neutropenia, neutropenia, thrombocytopenia Metabolism and Nutrition Disorders decreased appetite, hypokalemia Psychiatric Disorders anxiety Nervous System Disorders dizziness, dysgeusia, peripheral neuropathy Cardiac Disorders palpitations Vascular Disorders flushing, hot flush Respiratory, Thoracic and Mediastinal Disorders cough, dyspnea, oropharyngeal pain Gastrointestinal Disorders dry mouth, eructation, flatulence, gastritis, gastroesophageal reflux disease, nausea, vomiting Skin and Subcutaneous Tissue Disorders alopecia, hyperhidrosis, rash Musculoskeletal and Connective Tissue Disorders musculoskeletal pain General Disorders and Administration Site Condition edema peripheral, malaise Investigations aspartate aminotransferase increased, blood alkaline phosphatase increased, blood sodium decreased, blood ur…