FOCINVEZ

1 INDICATIONS AND USAGE FOCINVEZ, 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 FOCINVEZ has not been studied for the treatment of established nausea and vomiting. FOCINVEZ 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) FOCINVEZ has not been studied for treatment of established nausea and vomiting.

2 DOSAGE AND ADMINISTRATION Recommended Adult Dosage ( 2.1 ) FOCINVEZ 150 mg on Day 1 as an intravenous infusion over 20 to 30 minutes; 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. single dose chemotherapy regimens: single dose of FOCINVEZ on Day 1. single or multi-day chemotherapy regimens: 3-day regimen of FOCINVEZ on Day 1 and aprepitant capsules or aprepitant for oral suspension on Days 2 and 3. Administer FOCINVEZ through a central venous catheter on Day 1 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 Recommended Dosage for the Prevention of Nausea and Vomiting Associated with HEC and MEC in Adult Patients The recommended dosage of FOCINVEZ, 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 FOCINVEZ 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 Dosage for the Prevention of Nausea and Vomiting Associated with HEC Day 1 Day 2 Day 3 Day 4 FOCINVEZ a 150 mg intravenously over 20 to 30 minutes none none none Dexamethasone b 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 a The concentration of FOCINVEZ is 3 mg/mL b 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 FOCINVEZ [see Clinical Pharmacology ( 12.3 )] . Table 2 Recommended Adult Dosage for the Prevention of Nausea and Vomiting Associated with MEC Day 1 FOCINVEZ a 150 mg intravenously over 20 to 30 minutes Dexamethasone b 12 mg orally 5-HT 3 antagonist See selected 5-HT 3 antagonist prescribing information for the recommended dosage a The concentration of FOCINVEZ is 3 mg/mL. b 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 FOCINVEZ [see Clinical Pharmacology ( 12.3 )] . 2.2 Recommended Dosage for the Prevention of Nausea and Vomiting Associated with HEC and MEC in Pediatric Patients The recommended pediatric dosage regimens of FOCINVEZ, to be administered with a 5-HT 3 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 those 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. FOCINVEZ Dosage Regimens for Use with Single-Day Chemotherapy Regimens For pediatric patients weighing at least 6 kg receiving single-day HEC or MEC, FOCINVEZ may be administered as: a single dose regimen of FOCINVEZ infused through a central venous catheter on Day 1, as shown in Table 3; or as a 3-day fosaprepitant/aprepitant regimen consisting of FOCINVEZ as an intravenous infusion through a central venous catheter on Day 1 and aprepitant capsules or aprepitant for oral suspension on Days 2 and 3, as shown in Table 4. Administer FOCINVEZ 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 FOCINVEZ Single Dose Regimen for the Prevention of Nausea and Vomiting Associated with Single-Day Regimens of HEC or MEC in Pediatric Patients 6 Months a to 17 Years Drug Age Regimen FOCINVEZ b 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 c 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-HT 3 antagonist prescribing information for the recommended dosage a Dosing in pediatric patients less than 6 kg is not recommended b The concentration of FOCINVEZ is 3mg/mL. c Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 FOCINVEZ 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 FOCINVEZ as an intravenous infusion through a central venous catheter on Day 1 and aprepitant capsules or aprepitant for oral suspension on Days 2 and 3, as shown in Table 4. Administer FOCINVEZ 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/Aprepitant Dosage Regimen for Prevention of Nausea and Vomiting Associated with Single or Multi-day Regimens of HEC or MEC in Pediatric Patients 6 Months a to 17 Years Age Group Drug Day 1 Day 2 Day 3 12 Years to 17 Years FOCINVEZ b 115 mg intravenously over 30 minutes - - Aprepitant capsules c - 80 mg orally 80 mg orally 6 Months to Less than 12 Years FOCINVEZ 3 mg/kg (maximum dose 115 mg) intravenously over 60 minutes - - Aprepitant for oral suspension d - 2 mg/kg orally (maximum 80 mg) 2 mg/kg orally (maximum 80 mg) 6 Months to 17 Years Dexamethasone e If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 6 Months to 17 Years 5-HT 3 antagonist See selected 5-HT 3 antagonist prescribing information for the recommended dosage a Dosing in pediatric patients less than 6 kg is not recommended b The concentration of FOCINVEZ is 3 mg/mL. c For patients 12 years to 17 years who cannot swallow oral capsules, aprepitant for oral suspension can be used instead. d 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 on Days 2 and 3. e Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. Additional pediatric use information is approved for Merck Sharp & Dohme LLCs EMEND (fosaprepitant) for injection. However, due to Merck Sharp & Dohme LLCs marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Preparation and Administration of FOCINVEZ FOCINVEZ is ready-to-use for intravenous infusion. The concentration of FOCINVEZ is 3 mg/mL . Determine the volume to be administered from the injection vial directly based on the recommended dose [see Dosage and Administration ( 2.1 , 2.2 )]. Adults The entire volume of the vial (50 mL) should be administered. Pediatrics In patients 12 years and older, the volume to be administered is calculated as follows: Volume to administer (mL) = the recommended dose (mg) / 3 (mg/mL)* In patients 6 months to less than 12 years, the volume to be administered is calculated as follows: Volume to administer (mL) = the recommended dose (mg/kg) x weight (kg) / 3 (mg/mL) * Note: Do not exceed the maximum dose [see Dosage and Administration ( 2.2 )] In pediatric patients, the entire volume in vial may NOT be required. Discard the unused portion. * The recommended dose of FOCINVEZ is based on the patient’s age and weight. The concentration of FOCINVEZ is 3 mg/mL. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if solution is cloudy, contains precipitates, or if the red flip top cap is not intact. Allow FOCINVEZ to come to room temperature before use if the injection is NOT stored at room temperature. Use a vented infusion set when FOCINVEZ is infused from the bottle. The vial hanger can be separated from the vial label. Gently invert the bottle and hang the bottle using the attached hanger and start infusion. FOCINVEZ is compatible with 0.9% Sodium Chloride Injection. Caution: Do not mix FOCINVEZ with solutions for which physical and chemical compatibility have not been established. FOCINVEZ is incompatible with any solutions containing divalent cations (e.g., Ca 2+ , Mg 2+ ), including Lactated Ringer’s Solution and Hartmann's Solution. Following administration of FOCINVEZ, flush the IV set with a sufficient volume of 0.9% Sodium Chloride Injection to ensure the full length of the tubing and catheter lumen is completely cleared of residual medication to prevent precipitation. Proceed with the administration of other medications through the same line only after the line has been completely flushed.

4 CONTRAINDICATIONS FOCINVEZ is contraindicated in patients: who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions, flushing, erythema, and dyspnea have been reported [see Warnings and Precautions (5.2 ), and Adverse Reactions ( 6.2 )] . taking pimozide. Inhibition of CYP3A4 by aprepitant, the active moiety, 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 , 5.2 ) Concurrent use with pimozide. ( 4 )

5 WARNINGS AND PRECAUTIONS CYP3A4 Interactions: Fosaprepitant is a weak inhibitor of CYP3A4, and aprepitant, the active moiety, is a substrate, inhibitor, and inducer of CYP3A4; see Full Prescribing Information for recommendations regarding contraindications, risk of adverse reactions, and dosage adjustment of FOCINVEZ and concomitant drugs. ( 4 , 5.1 , 7.1 , 7.2 ) Hypersensitivity Reactions (including anaphylaxis and anaphylactic shock) : May occur during or soon after infusion. If symptoms occur, discontinue the drug. Do not reinitiate FOCINVEZ if symptoms occur with previous use. ( 4 , 5.2 ) I nfusion Site Reactions (including thrombophlebitis, necrosis, and vasculitis) : Majority of reactions reported in patients receiving vesicant chemotherapy. Avoid infusion into small veins. Discontinue infusion and administer treatment if a severe reaction develops. ( 5.3 ) 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 FOCINVEZ. ( 5.4 , 7.1 ) Hormonal Contraceptives: Efficacy of contraceptives may be reduced during treatment and for 1 month following administration of the last dose of either fosaprepitant or oral aprepitant. Use effective alternative or back-up methods of contraception. ( 5.5 , 7.1 , 8.3 ) 5.1 Clinically Significant CYP3A4 Drug Interactions Fosaprepitant, a prodrug of aprepitant, is a weak inhibitor of CYP3A4, and aprepitant is a substrate, inhibitor, and inducer of CYP3A4. Use of FOCINVEZ with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug. Use of pimozide with FOCINVEZ 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 FOCINVEZ 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 FOCINVEZ. Use of FOCINVEZ with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of FOCINVEZ. See Table 7 and Table 8 for a listing of potentially significant drug interactions [see Drug Interactions ( 7.1 , 7.2 )] . 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, during or soon after infusion of fosaprepitant have occurred. Symptoms including flushing, erythema, dyspnea, hypotension and syncope have been reported [see Adverse Reactions ( 6.2 )] . Monitor patients during and after infusion. If hypersensitivity reactions occur, discontinue the infusion and administer appropriate medical therapy. Do not reinitiate FOCINVEZ in patients who experience these symptoms with previous use [see Contraindications ( 4 )] . 5.3 Infusion Site Reactions Infusion site reactions (ISRs) have been reported with the use of intravenous fosaprepitant [see Adverse Reactions ( 6.1 )] . The majority of severe ISRs, including thrombophlebitis and vasculitis, were reported with concomitant vesicant (anthracycline-based) chemotherapy administration, particularly when associated with extravasation. Necrosis was also reported in some patients with concomitant vesicant chemotherapy. Most ISRs occurred with the first, second or third exposure to single doses of intravenous fosaprepitant and in some cases, reactions persisted for two weeks or longer. Treatment of severe ISRs consisted of medical, and in some cases surgical, intervention. Avoid infusion of FOCINVEZ into small veins or through a butterfly catheter. If a severe ISR develops during infusion, discontinue the infusion and administer appropriate medical treatment. 5.4 Decrease in INR with Concomitant Warfarin Coadministration of fosaprepitant with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in the 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 FOCINVEZ with each chemotherapy cycle [see Drug Interactions ( 7.1 )] . 5.5 Risk of Reduced Efficacy of Hormonal Contraceptives Upon coadministration with fosaprepitant, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of fosaprepitant [see Clinical Pharmacology ( 12.3 )] . Advise patients to use effective alternative or back-up methods of contraception during treatment with FOCINVEZ and for 1 month following administration of the last dose of fosaprepitant or oral aprepitant [see Drug Interactions ( 7.1 ), and Use in Specific Populations ( 8.3 )] .

7 DRUG INTERACTIONS See Full Prescribing Information for a list of clinically significant drug interactions. ( 4 , 5.1 , 5.4 , 5.5 , 7.1 , 7.2 ) Additional pediatric use information is approved for Merck Sharp & Dohme LLC’s EMEND (fosaprepitant) for injection. However, due to Merck Sharp & Dohme LLC’s marketing exclusivity rights, this drug product is not labeled with that information. 7.1 Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs When administered intravenously, fosaprepitant, a prodrug of aprepitant, is converted to aprepitant within 30 minutes. Therefore, drug interactions following administration of FOCINVEZ are likely to occur with drugs that interact with oral aprepitant. Fosaprepitant, given as a single 150-mg dose, is a weak inhibitor of CYP3A4, and the weak inhibition of CYP3A4 continues for 2 days after single dose administration. Single dose fosaprepitant does not induce CYP3A4. Aprepitant is a substrate, an inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9 [see Clinical Pharmacology ( 12.3 )] . Some substrates of CYP3A4 are contraindicated with FOCINVEZ [see Contraindications ( 4 )] . Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 7. Table 7 Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs CYP3A4 Substrates Pimozide Clinical Impact Increased pimozide exposure Intervention FOCINVEZ 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 Monitor for benzodiazepine-related adverse reactions. Dexamethasone Clinical Impact Increased dexamethasone exposure [see Clinical Pharmacology ( 12.3 )] . Intervention Reduce the dose of oral dexamethasone by approximately 50% [see Dosage and Administration ( 2.1 )]. Methylprednisolone Clinical Impact Increased methylprednisolone exposure [see Clinical Pharmacology ( 12.3 )]. Intervention Reduce the dose of oral methylprednisolone by approximately 50% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC. Reduce the dose of intravenous methylprednisolone by 25% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC. 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 fosaprepitant [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.3 ), and Clinical Pharmacology ( 12.3 )] . Intervention Effective alternative or back-up methods of contraception (such as condoms and spermicides) should be used during treatment with FOCINVEZ and for 1 month following administration of the last dose of fosaprepitant or oral aprepitant. Examples birth control pills, transdermal systems, implants, and certain intrauterine systems CYP2C9 Substrates Warfarin Clinical Impact Decreased warfarin exposure and decreased prothrombin time (INR) [see Warnings and Precautions ( 5.4 ) and 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 administration of FOCINVEZ with each chemotherapy cycle. Other 5-HT 3 Antagonists Clinical Impact No change in the exposure of the 5-HT 3 antagonist [see Clinical Pharmacology ( 12.3 )]. Intervention No dosage adjustment needed Examples ondansetron, granisetron, dolasetron 7.2 Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant Aprepitant is a CYP3A4 substrate [see Clinical Pharmacology (12.3)] . Co-administration of FOCINVEZ with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of aprepitant, respectively, as shown in Table 8. Table 8 Effects of Other Drugs on Pharmacokinetics of Fosaprepitant / Aprepitant Moderate to Strong CYP3A4 Inhibitors Clinical Impact Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with FOCINVEZ [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)] . Intervention Avoid concomitant use of FOCINVEZ Examples Moderate inhibitor: diltiazem Strong inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir Strong CYP3A4 Inducers Clinical Impact Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of FOCINVEZ [see Clinical Pharmacology (12.3)] . Intervention Avoid concomitant use of FOCINVEZ Examples rifampin, carbamazepine, phenytoin

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 pediatric patients are similar to adults. To report SUSPECTED ADVERSE REACTIONS, contact Steriscience at 1-888-278-1784 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 safety of FOCINVEZ has been established from adequate and well-controlled studies of another intravenous formulation of fosaprepitant [see Clinical Studies ( 14 )] . Below is a display of the adverse reactions of fosaprepitant in these studies. The overall safety of intravenous fosaprepitant 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 intravenous fosaprepitant in combination with ondansetron and dexamethasone (intravenous fosaprepitant 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 a Intravenous fosaprepitant, ondansetron, and dexamethasone b (N=504) Ondansetron and dexamethasone c (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% a Reported in ≥2% of patients treated with the intravenous fosaprepitant regimen and at a greater incidence than standard therapy (ondansetron and dexamethasone alone). b Intravenous fosaprepitant regimen c Standard therapy Infusion-site reactions were reported in 2.2% of patients treated with the intravenous fosaprepitant 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 intravenous fosaprepitant 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 intravenous fosaprepitant 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 Intravenous Fosaprepitant Regimen The safety of a single dose of intravenous fosaprepitant 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 Intravenous Fosaprepitant/Oral Aprepitant/Oral Aprepitant Regimen In pediatric patients (12 to 17 years), the safety of the 3-day intravenous fosaprepitant/oral aprepitant/oral aprepitant 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 regimen was not directly evaluated. The safety of a single-dose of intravenous fosaprepitant (3 mg/kg) administered on day 1 of the 3-day regimen was evaluated in one active-controlled and one single-arm study including 48 patients who received a regimen of either HEC or MEC. In these clinical studies, pediatric patients also received ondansetron with or without dexamethasone. The adverse reaction profile was similar to adults and pediatric patients receiving a single dose of intravenous fosaprepitant. Because fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with intravenous fosaprepitant. See the full prescribing information for aprepitant capsules for complete safety information regarding studies performed with oral aprepitant. Additional pediatric use information is approved for Merck Sharp & Dohme LLC’s EMEND (fosaprepitant) for injection. However, due to Merck Sharp & Dohme LLC’s marketing exclusivity rights, this drug product is not labeled with that information. 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are insufficient data on use of fosaprepitant in pregnant women to identify a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. 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 equivalent to the exposure at the recommended human dose (RHD) of 150 mg (see Data ). The background risk of major birth defects and miscarriage for the indicated populations 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 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 (rats) and up to the maximum tolerated dose of 25 mg/kg/day (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 25 mg/kg/day were approximately equivalent to the exposure at the RHD of 150 mg. Aprepitant crosses the placenta in rats and rabbits. 8.2 Lactation Risk Summary There are no data on the presence of aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production. Aprepitant is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FOCINVEZ and any potential adverse effects on the breastfed infant from FOCINVEZ or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Upon administration of FOCINVEZ, the efficacy of hormonal contraceptives may be reduced. Advise females of reproductive potential using hormonal contraceptives to use an effective alternative or back-up non-hormonal contraceptive (such as condoms and spermicides) during treatment with FOCINVEZ and for 1 month following the last dose of fosaprepitant or oral aprepitant [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . 8.4 Pediatric Use The safety and effectiveness of a single dose regimen of FOCINVEZ and a 3-day intravenous fosaprepitant/oral aprepitant/oral aprepitant regimen have been established in pediatric patients 6 months to 17 years for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC and MEC. Use of FOCINVEZ in this age group is supported by evidence from adequate and well-controlled studies of intravenous fosaprepitant in adults, with additional safety, efficacy and pharmacokinetic data in pediatric patients 6 months to 17 years. Efficacy and safety were also supported by data from an adequate and well controlled study of a 3-day oral aprepitant regimen in pediatric patients 6 months to 17 years. See the full prescribing information for aprepitant capsules for complete clinical information regarding studies performed with oral aprepitant. Adverse reactions were similar to those reported in adult patients. [See Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 ), and Clinical Pharmacology ( 12.3 )] . The safety and effectiveness of FOCINVEZ for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients less than 6 months of age. Juvenile Animal Toxicity Data In juvenile dogs treated with fosaprepitant, changes in reproductive organs were observed. In juvenile rats treated with aprepitant, slight changes in sexual maturation were observed without an effect on reproduction. No effects on neurobehavior, sensory and motor function, or learning and memory were observed in rats. In a toxicity study in juvenile dogs treated with fosaprepitant from postnatal day 14 (equivalent to a newborn human) to day 42 (approximately equivalent to a 2 year old human), decreased testicular weight and Leydig cell size were seen in the males at 6 mg/kg/day and increased uterine weight, hypertrophy of the uterus and cervix, and edema of vaginal tissues were seen in females from 4 mg/kg/day. A study was also conducted in young rats to evaluate the effects of aprepitant on growth and on neurobehavioral and sexual development. Rats were treated at oral doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male and female rats lower than the exposure at the recommended pediatric human dose) from the early postnatal period (Postnatal Day 10 (equivalent to a newborn human) through Postnatal Day 58 (approximately equivalent to a 15 year old human)). Slight changes in the onset of sexual maturation were observed in female and male rats; however, there were no effects on mating, fertility, embryonic-fetal survival, or histomorphology of the reproductive organs. There were no effects in neurobehavioral tests of sensory function, motor function, and learning and memory. Additional pediatric use information is approved for Merck Sharp & Dohme LLC’s EMEND (fosaprepitant) for injection. However, due to Merck Sharp & Dohme LLC’s marketing exclusivity rights, this drug product is not labeled with that information. 8.5 Geriatric Use Of the 1649 adult cancer patients treated with intravenous fosaprepitant in HEC and MEC clinical studies, 27% were aged 65 and over, while 5% were aged 75 and over. Other reported clinical experience with fosaprepitant has not identified differences in responses between elderly and younger adult patients. No clinically meaningful differences in the pharmacokinetics of oral aprepitant were observed in healthy subjects 65 years of age and over compared to younger adult subjects [see Clinical Pharmacology ( 12.3 )]. 8.6 Patients with Hepatic Impairment The pharmacokinetics of aprepitant in patients with mild and moderate hepatic impairment were similar to those of healthy subjects with normal hepatic function. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9). Therefore, additional monitoring for adverse reactions in these patients may be warranted when FOCINVEZ is administered [see Clinical Pharmacology ( 12.3 )] .