FOCINVEZ

FOCINVEZ (fosaprepitant injection) is a sterile, ready-to-use, clear and colorless solution formulation containing fosaprepitant dimeglumine, a prodrug of aprepitant, a substance P/neurokinin-1 (NK 1 ) receptor antagonist, an antiemetic agent, chemically described as 1-Deoxy-1-(methylamino)-D-glucitol[3-[[(2R,3S)-2-[(1R)-1-[3,5bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1 H -1,2,4triazol-1-yl]phosphonate (2:1) (salt). Its empirical formula is C 23 H 22 F 7 N 4 O 6 P ⋅ 2(C 7 H 17 NO 5 ) and its structural formula is: Fosaprepitant dimeglumine is a white to off-white amorphous powder with a molecular weight of 1004.83. It is freely soluble in water. Each 50 mL vial of FOCINVEZ for administration as an intravenous infusion contains 150 mg of fosaprepitant (equivalent to 245.3 mg of fosaprepitant dimeglumine) and the following inactive ingredients: Betadex sulfobutyl ether sodium (8 g), edetate disodium (5.4 mg), sodium hydroxide (for pH adjustment) in water for injection. structure

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.

Recommended Adult Dosage ( 2.1 ) FOCINVEZ 150mg 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-HT3 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 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. 2.3 Preparation 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. 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. FOCINVEZ is compatible with 0.9% Sodium Chloride Injection. Always flush the IV set with 0.9% sodium chloride to remove any residual medication. Utilization of IV set without flushing may cause precipitation.

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 )

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.

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