Fosaprepitant

1 INDICATIONS AND USAGE Fosaprepitant for injection, in combination with other antiemetic agents, is indicated in adults and pediatric patients 6 months 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. • delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). Limitations of Use • Fosaprepitant for injection has not been studied for the treatment of established nausea and vomiting. Fosaprepitant for injection is a substance P/neurokinin-1 (NK 1 ) receptor antagonist, indicated in adults and pediatric patients 6 months of age and older, in combination with other antiemetic agents, for the prevention of (1 ): acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin. delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). Limitations of Use ( 1 ) Fosaprepitant for injection has not been studied for treatment of established nausea and vomiting.

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosage (2.1) Fosaprepitant for injection 150 mg on Day 1 as an intravenous infusion over 20 to 30 minutes. ( 2.1 ) Complete the infusion approximately 30 minutes prior to chemotherapy. Recommended Dosage for Pediatric Patients (6 months to 17 years) Weighing at Least 6 kg ( 2.2 ) See Full Prescribing Information for pediatric dosage regimens by age. For single dose chemotherapy regimens: single dose of fosaprepitant for injection on Day 1. For single or multi-day chemotherapy regimens: 3-day fosaprepitant for injection regimen of fosaprepitant for injection on Days 1, 2, and 3. Aprepitant capsules or fosaprepitant for oral suspension may be used as an alternative on Days 2 and 3. Administer fosaprepitant for injection through a central venous catheter as an intravenous infusion over 30 minutes (12 years to 17 years) or 60 minutes (6 months to less than 12 years). Complete the infusion approximately 30 minutes prior to chemotherapy. Concomitant Antiemetics See Full Prescribing Information for additional information. ( 2.1 , 2.2 ) 2.1 Prevention of Nausea and Vomiting Associated with HEC and MEC in Adult Patients The recommended dosage of fosaprepitant for injection, dexamethasone, and a 5-HT 3 antagonist for the prevention of nausea and vomiting associated with administration of HEC or MEC in adults is shown in Table 1 or Table 2, respectively. Administer fosaprepitant for injection as an intravenous infusion on Day 1 over 20 to 30 minutes, completing the infusion approximately 30 minutes prior to chemotherapy. Table 1 Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with HEC Day 1 Day 2 Day 3 Day 4 Fosaprepitant for injection 150 mg intravenously over 20 to 30 minutes none none none Dexamethasone * 12 mg orally 8 mg orally 8 mg orally twice daily 8 mg orally twice daily 5-HT 3 antagonist See selected 5-HT 3 antagonist prescribing information for the recommended dosage none none none * Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. Also administer dexamethasone in the evenings on Days 3 and 4. A 50% dosage reduction of dexamethasone on Days 1 and 2 is recommended to account for a drug interaction with fosaprepitant for injection [see Clinical Pharmacology (12.3 )] . Table 2 Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with MEC Day 1 Fosaprepitant for injection 150 mg intravenously over 20 to 30 minutes Dexamethasone * 12 mg orally 5-HT 3 antagonist See selected 5-HT 3 antagonist prescribing information for the recommended dosage * 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 fosaprepitant for injection [ see Clinical Pharmacology (12.3)]. 2.2 Prevention of Nausea and Vomiting Associated with HEC and MEC in Pediatric Patients The recommended pediatric dosage regimens of fosaprepitant for injection, to be administered with a 5-HT3 antagonist, with or without a corticosteroid, for the prevention of nausea and vomiting associated with administration of single or multi-day chemotherapy regimens of HEC or MEC, are shown in Tables 3 and 4. Single-day chemotherapy regimens include regimens in which HEC or MEC is administered for a single day only. Multi-day chemotherapy regimens include chemotherapy regimens in which HEC or MEC is administered for 2 or more days. Fosaprepitant for injection Dosage Regimens for Use with Single-Day Chemotherapy Regimens For pediatric patients weighing at least 6 kg receiving single-day HEC or MEC, fosaprepitant for injection may be administered as: a single dose regimen of fosaprepitant for injection infused through a central venous catheter on Day 1, as shown in Table 3; or as a 3-day fosaprepitant for injection regimen consisting of fosaprepitant for injection as an intravenous infusion through a central venous catheter on Days 1, 2, and 3. Aprepitant capsules or fosaprepitant for oral suspension may be used on Days 2 and 3 instead of fosaprepitant for injection, as shown in Table 4. Administer fosaprepitant for injection on Day 1 over 30 minutes (12 years to 17 years) or 60 minutes (6 months to less than 12 years), completing the infusion approximately 30 minutes prior to chemotherapy. Table 3 Fosaprepitant for Injection Single Dose Regimen for the Prevention of Nausea and Vomiting Associated with Single- Day Regimens of HEC or MEC in Pediatric Patients 6 Months* to 17 Years Drug Age Regimen Fosaprepitant for injection 12 Years to 17 Years 150 mg intravenously over 30 minutes 2 Years to less than 12 Years 4 mg/kg (maximum dose 150 mg) intravenously over 60 minutes 6 Months to less than 2 Years 5 mg/kg (maximum dose 150 mg) intravenously over 60 minutes Dexamethasone† 6 Months to 17 Years If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 and 2. 5-HT 3 antagonist 6 Months to 17 Years See selected 5-HT3 antagonist prescribing information for the recommended dosage * Dosing in pediatric patients less than 6 kg is not recommended † Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 Fosaprepitant for injection Dosage Regimen for Use with Multi-Day Chemotherapy Regimens For pediatric patients weighing at least 6 kg receiving multi-day regimens of HEC or MEC, administer fosaprepitant for injection on Days 1, 2, and 3. Administer fosaprepitant for injection as an intravenous infusion through a central venous catheter on Days 1, 2, and 3. Aprepitant capsules or fosaprepitant for oral suspension may be used on Days 2 and 3 instead of fosaprepitant for injection, as shown in Table 4. Administer fosaprepitant for injection over 30 minutes (12 years to 17 years) or 60 minutes (6 months to less than 12 years), completing the infusion approximately 30 minutes prior to chemotherapy. Table 4 3-Day Fosaprepitant for Injection Dosage Regimen for Prevention of Nausea and Vomiting Associated with Single or Multi-day Regimens of HEC or MEC in Pediatric Patients 6 Months* to 17 Years Age of Pediatric Population Day 1 Day 2 Day 3 Fosaprepitant for injection * 12 years to 17 years 115 mg intravenously over 30 minutes 80 mg intravenously over 30 minutes OR 80 mg orally (aprepitant capsules) † 80 mg intravenously over 30 minutes OR 80 mg orally (aprepitant capsules) † 6 months to less than 12 years 3 mg/kg intravenously over 60 minutes (maximum dose 115 mg) 2 mg/kg intravenously over 60 minutes OR 2 mg/kg orally (Fosaprepitant for oral suspension) ‡ (maximum dose 80 mg) 2 mg/kg intravenously over 60 minutes OR 2 mg/kg orally (Fosaprepitant for oral suspension) ‡ (maximum dose 80 mg) Dexamethasone § 6 months to 17 years If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4. 5-HT3 antagonist 6 months to 17 years See selected 5-HT3 antagonist prescribing information for the recommended dosage. * Dosing in pediatric patients less than 6 kg is not recommended. † For patients 12 years to 17 years unable to swallow oral capsules, fosaprepitant for oral suspension can be used instead on Days 2 and 3 ‡ For patients less than 12 years of age who weigh at least 40 kg and who are able to swallow oral capsules, aprepitant capsules can be used instead on Days 2 and 3 § Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. 2.3 Preparation of Fosaprepitant for injection Table 5 Preparation Instructions for Fosaprepitant for Injection (150 mg) Step 1 Aseptically inject 5 mL 0.9% Sodium Chloride Injection, USP into the vial. Assure that 0.9% Sodium Chloride Injection, USP is added to the vial along the vial wall in order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting 0.9% Sodium Chloride Injection, USP into the vial. Step 2 Aseptically prepare an infusion bag filled with 145 mL of 0.9% Sodium Chloride Injection, USP. Step 3 Aseptically withdraw the entire volume from the vial and transfer it into the infusion bag containing 145 mL of 0.9% Sodium Chloride Injection, USP to yield a total volume of 150 mL and a final concentration of 1 mg/mL . Step 4 Gently invert the bag 2 to 3 times. Step 5 Determine the volume to be administered from this prepared infusion bag, based on the recommended dose [ see Dosage and Administration (2.1 , 2.2 )] . Adults The entire volume of the prepared infusion bag (150 mL) should be administered. Pediatrics In patients 12 years and older, the volume to be administered is calculated as follows: • Volume to administer (mL) equals the recommended dose (mg) In patients 6 months to less than 12 years, the volume to be administered is calculated as follows: • Volume to administer (mL) = recommended dose (mg/kg) x weight (kg) o Note: Do not exceed the maximum dose [ see Dosage and Administration (2.2) ] In pediatric patients, the entire volume in the infusion bag may not be required. Step 6 If necessary, for volumes less than 150 mL, the calculated volume can be transferred to an appropriate size bag or syringe prior to administration by infusion. Step 7 Before administration, inspect the bag for particulate matter and discoloration. Discard the bag if particulate and/or discoloration are observed. The recommended dose of fosaprepitant for injection is based on the patient’s age and weight. Caution: Do not mix or reconstitute fosaprepitant for injection with solutions for which physical and chemical compatibility have not been established. Fosaprepitant for injection is incompatible with any solutions containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringer’s Solution and Hartmann's Solution. Storage The reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below 25°C (77°F)]. Discard unused portion.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.2)] Infusion Site Reactions [see Warnings and Precautions (5.3)] Most common adverse reactions in adults (≥2%) are: fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, pain in extremity. (6.1) Adverse reactions in pediatrics are similar to adults. To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals Inc. at 1-855-668-2369 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 fosaprepitant for injection was evaluated in approximately 1800 adult and pediatric patients. Adverse Reactions in Adults for the Prevention of Nausea and Vomiting Associated with MEC In an active-controlled clinical trial in patients receiving MEC, safety was evaluated in 504 patients receiving a single dose of fosaprepitant for injection in combination with ondansetron and dexamethasone (fosaprepitant dimeglumine regimen) compared to 497 patients receiving ondansetron and dexamethasone alone (standard therapy). The most common adverse reactions are listed in Table 6. Table 6 Most Common Adverse Reactions in Patients Receiving MEC* Fosaprepitant for injection, ondansetron, and dexamethasone † (N=504) Ondansetron and dexamethasone ‡ (N=497) fatigue 15% 13% diarrhea 13% 11% neutropenia 8% 7% asthenia 4% 3% anemia 3% 2% peripheral neuropathy 3% 2% leukopenia 2% 1% dyspepsia 2% 1% urinary tract infection 2% 1% pain in extremity 2% 1% * Reported in ≥2% of patients treated with the fosaprepitant dimeglumine regimen and at a greater incidence than standard therapy. † Fosaprepitant dimeglumine regimen ‡ Standard therapy Infusion-site reactions were reported in 2.2% of patients treated with the fosaprepitant dimeglumine regimen compared to 0.6% of patients treated with standard therapy. The infusion-site reactions included: infusion-site pain (1.2%, 0.4%), injection-site irritation (0.2%, 0.0%), vessel puncture-site pain (0.2%, 0.0%), and infusion-site thrombophlebitis (0.6%, 0.0%), reported in the fosaprepitant dimeglumine regimen compared to standard therapy, respectively. Adverse Reactions in Adults for the Prevention of Nausea and Vomiting Associated with HEC In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1143 patients receiving a single dose of fosaprepitant for injection compared to 1169 patients receiving the 3-day regimen of oral aprepitant [ see Clinical Studies (14.1)]. The safety profile was generally similar to that seen in the MEC study with fosaprepitant and prior HEC studies with aprepitant. However, infusion- site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared to those in the aprepitant group (0.5%). The following additional infusion-site reactions occurred in the HEC study and were not reported in the MEC study described above: infusion-site erythema (0.5%, 0.1%), infusion-site pruritus (0.3%, 0.0%), and infusion-site induration (0.2%, 0.1%), reported in the fosaprepitant group compared to the aprepitant group, respectively. Adverse Reactions in Pediatric Patients 6 Months to 17 Years of Age for the Prevention of Nausea and Vomiting Associated with HEC or MEC Single Dose fosaprepitant for Injection Regimen The safety of a single dose of fosaprepitant for injection in pediatric patients (6 months to 17 years) was evaluated in two active-controlled and a single-arm clinical study in patients who received either HEC or MEC. Patients also received ondansetron with or without dexamethasone. The adverse reaction profile was similar to adults. The safety analysis included 69 pediatric patients who received the recommended dose. An additional 70 patients received a single, higher-than-recommended dose. The most common adverse reactions that occurred in >15% of patients who received the recommended dose were anemia, neutropenia, thrombocytopenia, and febrile neutropenia. 3-Day fosaprepitant dimeglumine Regimen In pediatric patients 12 to 17 years, the safety of the 3-day IV/oral/oral fosaprepitant dimeglumine regimen was evaluated in a single-arm clinical study including 12 patients who received a regimen of either HEC or MEC. In pediatric patients 6 months to 12 years of age, the safety of the 3-day IV/oral/oral fosaprepitant dimeglumine regimen was not directly evaluated. The safety of a single dose of fosaprepitant for injection (3 mg/kg) administered on day 1 of the 3-day IV/oral/oral regimen was evaluated in one active-controlled and one single-arm study including 48 pediatric patients 6 months to 12 years of age who received a regimen of either HEC or MEC. The safety of the 3-day (IV/IV/IV) regimen of fosaprepitant for injection in pediatric patients (6 months to 17 years) was evaluated in a single-arm clinical study in 100 patients who received either HEC or MEC. In these clinical studies, pediatric patients also received ondansetron with or without dexamethasone. The adverse reaction profile in pediatric patients was similar to the profile in adult patients receiving a single dose of fosaprepitant for injection. Because fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with fosaprepitant for injection. See the full prescribing information for aprepitant capsules for complete safety information regarding studies performed with oral aprepitant. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of fosaprepitant. 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. Skin and subcutaneous tissue disorders : pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis [ see Warnings and Precautions (5.2)]. Immune system disorders : hypersensitivity reactions including anaphylaxis and anaphylactic shock [ see Contraindications (4), Warnings and Precautions (5.2)]. Nervous system disorders: ifosfamide-induced neurotoxicity reported after fosaprepitant and ifosfamide coadministration.

12.3 Pharmacokinetics Aprepitant after Fosaprepitant Administration Following administration of a single intravenous 150-mg dose of fosaprepitant, a prodrug of aprepitant administered as a 20-minute infusion to healthy subjects, the mean AUC 0-∞ of aprepitant was 37.4 (±14.8) mcg•hr/mL and the mean maximal aprepitant concentration (C max ) was 4.2 (±1.2) mcg/mL. Plasma concentrations of fosaprepitant are below the limits of quantification (10 ng/mL) within 30 minutes of the completion of infusion. Distribution Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vd ss ) was approximately 70 L in humans. Aprepitant crosses the blood brain barrier in humans [see Clinical Pharmacology (12.1) ]. Elimination Metabolism Fosaprepitant is converted to aprepitant in in vitro incubations with human liver preparations and in S9 preparations from multiple other human tissues including kidney, lung and ileum. Thus, it appears that the conversion of fosaprepitant to aprepitant can occur in multiple extrahepatic tissues in addition to the liver. Aprepitant undergoes extensive metabolism. In vitro studies using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the morpholine ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected. In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [ 14 C]-aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. Excretion Following administration of a single intravenous 100-mg dose of [ 14 C]-fosaprepitant to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces. Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent terminal half-life ranged from approximately 9 to 13 hours. Specific Populations Age: Geriatric Population Following oral administration of a single 125-mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5, the AUC 0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (65 years and older) relative to younger adults. The C max was 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful [see Use in Specific Populations (8.5) ]. Age: Pediatric Population Single Dose Fosaprepitant for Injection Regimen: Simulated systemic exposures of aprepitant in patients 2 years to less than 12 years and observed systemic exposures in patients 6 months to less than 2 years and 12 to 17 years are shown in Table 9, including AUC 0-24hr , peak plasma concentration (C max ) on Day 1 and concentrations at the end of Day 1 (C 24 ), Day 2 (C 48 ) and Day 3 (C 72 ). Table 9 Systemic Exposures of Aprepitant for Single Dose Fosaprepitant for Injection Regimen in Pediatric Patients Population Single Dose of Fosaprepitant for Injection Regimen Geometric Mean AUC 0-24hr . (mcg*hr/mL) C max (mcg/mL) C 24 (mcg/mL) C 48 (mcg/mL) C 72 (mcg/mL) 12 Years to 17 Years 150 mg 29.4 3.4 0.7 ND* ND* 6 Years to less than 12 Years 4 mg/kg 35.2 3.6 0.7 0.2 0.05 2 Years to less than 6 Years 28.2 3.1 0.4 0.1 0.02 6 Months to less than 2 Years 5 mg/kg 32.7 3.3 0.4 NE † ND * * ND = Not Determined. Pharmacokinetic samples were not collected to support the parameter value of interest. † NE = Not Estimated. The geometric mean could not be estimated due to values being below the limitation of quantification. 3-Day IV/Oral/Oral Fosaprepitant Regimen: Simulated aprepitant systemic exposures in patients 6 months to less than 12 years and observed systemic exposures in patients 12 to 17 years are shown in Table 10, including AUC 0-24hr , peak plasma concentration (C max ) on Day 1 and concentrations at the end of Day 1 (C 24 ), Day 2 (C 48 ) and Day 3 (C 72 ). Table 10 Systemic Exposures of Aprepitant for 3-Day IV/Oral/Oral Regimen in Pediatric Patients Population 3-Day Dose of Fosaprepitant (IV/Oral/Oral*) Geometric Mean AUC 0-24hr . (mcg*hr/mL) C max (mcg/mL) C 24 (mcg/mL) C 48 (mcg/mL) C 72 (mcg/mL) 12 Years to 17 Years 115/80/80 mg 18.0 3.0 0.4 0.2 NE † 6 Years to less than 12 Years 3/2/2 mg/kg 25.7 2.7 0.5 0.3 0.3 2 Years to less than 6 Years 20.2 2.3 0.3 0.2 0.2 6 Months to less than 2 Years 16.6 1.9 0.2 0.1 0.1 *IV on Day 1, Oral on Day 2, and Oral on Day 3 † NE = Not Estimated. The geometric mean could not be estimated due to values being below the limitation of quantification. 3-Day IV/IV/IV fosaprepitant Regimen: Simulated aprepitant systemic exposures in patients 6 months to 17 years are shown in Table 11, including AUC 0-24hr , peak plasma concentration (C max ) on Day 1 and concentrations at the end of Day 1 (C 24 ), Day 2 (C 48 ) and Day 3 (C 72 ). Table 11 Systemic Exposures of Aprepitant for 3-Day IV/IV/IV Regimen in Pediatric Patients Population 3-Day Dose of Fosaprepitant (IV/IV/IV)* Geometric Mean AUC 0-24hr. (mcg*hr/mL) C max (mcg/mL) C 24 (mcg/mL) C 48 (mcg/mL) C 72 (mcg/mL) 12 Years to 17 Years 115/80/80 mg 21.1 2.5 0.4 0.4 0.4 6 Years to less than 12 Years 3/2/2 mg/kg 25.6 2.7 0.5 0.4 0.4 2 Years to less than 6 Years 20.3 2.3 0.3 0.2 0.2 6 Months to less than 2 Years 16.7 1.9 0.2 0.2 0.2 *IV on Day 1, Day 2, and Day 3 Plasma concentrations of fosaprepitant are negligible within 15 to 30 minutes after the completion of the infusion in pediatric patients. Sex Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC 0-24hr and C max are 9% and 17% higher in females as compared with males. The half-life of aprepitant is approximately 25% lower in females as compared with males and T max occurs at approximately the same time. These differences are not considered clinically meaningful.A population pharmacokinetic analysis of aprepitant in pediatric patients (6 months to 17 years) suggests that sex has no clinically meaningful effect on the pharmacokinetics of aprepitant. Race/Ethnicity Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC 0-24hr and C max are approximately 27% and 19% higher in Hispanics as compared with Caucasians. The AUC 0-24hr and C max were 74% and 47% higher in Asians as compared to Caucasians. There was no difference in AUC 0-24hr or C max between Caucasians and Blacks. These differences are not considered clinically meaningful.A population pharmacokinetic analysis of aprepitant in pediatric patients (6 months to 17 years) suggests that race has no clinically meaningful effect on the pharmacokinetics of aprepitant. Renal Impairment A single 240-mg oral dose of aprepitant was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m 2 as measured by 24-hour urinary creatinine clearance) and to patients with end stage renal disease (ESRD) requiring hemodialysis. In patients with severe renal impairment, the AUC 0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and C max decreased by 32%, relative to healthy subjects (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method). In patients with ESRD undergoing hemodialysis, the AUC 0-∞ of total aprepitant decreased by 42% and C max decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal impairment compared with healthy subjects. Hemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate. Hepatic Impairment Fosaprepitant is metabolized in various extrahepatic tissues; therefore hepatic impairment is not expected to alter the conversion of fosaprepitant to aprepitant. Following administration of a single 125-mg oral dose of aprepitant on Day 1 and 80 mg once daily on Days 2 and 3 to patients with mild hepatic impairment (Child-Pugh score 5 to 6), the AUC 0-24hr of aprepitant was 11% lower on Day 1 and 36% lower on Day 3, as compared with healthy subjects given the same regimen. In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC 0-24hr of aprepitant was 10% higher on Day 1 and 18% higher on Day 3, as compared with healthy subjects given the same regimen. These differences in AUC 0-24hr are not considered clinically meaningful. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9) [see Use in Specific Populations (8.6) ]. Body Mass Index (BMI) For every 5 kg/m 2 increase in BMI, AUC 0-24hr and C max of aprepitant decrease by 9% and 10%. BMI of subjects in the analysis ranged from 18 kg/m 2 to 36 kg/m 2 . This change is not considered clinically meaningful. Drug Interactions Studies Fosaprepitant, given as a single 150-mg dose, is a weak inhibitor of CYP3A4, with no evidence of inhibition or induction of CYP3A4 observed on Day 4. The weak inhibition of CYP3A4 continues for 2 days after single dose administration of fosaprepitant. Aprepitant is a substrate, an inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Fosaprepitant or aprepitant is unlikely to interact with drugs that are substrates for the P­-glycoprotein transporter. Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs CYP3A4 Substrates Midazolam: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC 0-∞ of midazolam by approximately 1.8-fold on Day 1 and had no effect on Day 4 when midazolam was coadministered as a single oral dose of 2 mg on Days 1 and 4 [see Drug Interactions (7.1) ]. Corticosteroids: Dexamethasone : Fosaprepitant administered as a single 150 mg intravenous dose on Day 1 increased the AUC 0-24hr of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2 [see Dosage and Administration (2.1), Drug Interactions (7.1) ]. Methylprednisolone: When oral aprepitant as a 3-day regimen (125-mg/80-mg/80-mg) was administered with intravenous methylprednisolone 125 mg on Day 1 and oral methylprednisolone 40 mg on Days 2 and 3, the AUC of methylprednisolone was increased by 1.34-fold on Day 1 and by 2.5-fold on Day 3 [see Drug Interactions (7.1)]. Chemotherapeutic agents: Docetaxel: In a pharmacokinetic study, oral aprepitant administered as a 3-day regimen (125­-mg/80-mg/80-mg) did not influence the pharmacokinetics of docetaxel. Vinorelbine: In a pharmacokinetic study, oral aprepitant administered as a 3-day regimen (125­-mg/80-mg/80-mg) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree. Oral contraceptives: When oral aprepitant was administered as a 3-day regimen (125-mg/80-mg/80­ mg) with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks post-treatment [see Drug Interactions (7.1)]. CYP2C9 substrates (Warfarin, Tolbutamide): Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with oral aprepitant [see Drug Interactions (7.1)]. Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. This effect was not considered clinically important. Other Drugs P-glycoprotein substrates: Aprepitant is unlikely to interact with drugs that are substrates for the P­-glycoprotein transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin in a clinical drug interaction study. 5-HT 3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant Rifampin: When a single 375-mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold [see Drug Interactions (7.2)]. Ketoconazole: When a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold [see Drug Interactions (7.2)]. Diltiazem: In a study in 10 patients with mild to moderate hypertension, administration of 100 mg of fosaprepitant as an intravenous infusion with 120 mg of diltiazem, a moderate CYP3A4 inhibitor administered three times daily, resulted in a 1.5-fold increase in the aprepitant AUC and a 1.4-fold increase in the diltiazem AUC. When fosaprepitant was administered with diltiazem, the mean maximum decrease in diastolic blood pressure was significantly greater than that observed with diltiazem alone [24.3 ± 10.2 mm Hg with fosaprepitant versus 15.6 ± 4.1 mm Hg without fosaprepitant]. The mean maximum decrease in systolic blood pressure was also greater after co-administration of diltiazem with fosaprepitant than administration of diltiazem alone [29.5 ± 7.9 mm Hg with fosaprepitant versus 23.8 ± 4.8 mm Hg without fosaprepitant]. Co-administration of fosaprepitant and diltiazem; however, did not result in any additional clinically significant changes in heart rate or PR interval, beyond those changes observed with diltiazem alone [see Drug Interactions (7.2)]. Paroxetine : Coadministration of once daily doses of oral aprepitant 170 mg, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and C max by approximately 20% of both aprepitant and paroxetine. This effect was not considered clinically important.