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-HT3 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…

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 clinic…

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 )

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-HT3 antagonist [see Clinical Pharmacology ( 12.3 )]. Intervention No dosage adjustmen…

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 Amneal Pharmaceuticals at 1-877-835-5472 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 Re…