Fosaprepitant

Description

11 DESCRIPTION Fosaprepitant for injection is a sterile, lyophilized 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-glucito[3-[[(2R,3S)-2-[(1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(4­ fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonate(2:1) (salt).Its empirical formula is C 23 H 22 F 7 N 4 O 6 P

What Is Fosaprepitant Used For?

1 INDICATIONS AND USAGE Fosaprepitant for injection, in combination with other antiemetic agents, is indicated in adults for the prevention of: acute and delayed nauseaand vomiting associated with initial and repeat coursesof 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. Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Fosaprepitant for injection is a substance P/neurokinin-1 (NK 1 ) receptor antagonist, indicated in adults, in combination with other antiemetic agents, for the prevention of ( 1 ): acute and delayed nausea and vomiting associated with initial and repeat coursesof 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.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Recommended Dosage ( 2.1 ) Administer fosaprepitant for injection as an intravenous infusion; complete the infusion approximately 30 minutes prior to chemotherapy. Adults: 150 mg on Day 1. Administer fosaprepitant for injection on Day 1 as an intravenous infusion over 20 to 30 minutes (adults). completing the infusion approximately 30 minutes prior to chemotherapy. See Full Prescribing Information for dosages of concomitantantiemetic(s). ( 2.1 ) 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 injectionas an intravenous infusion on Day 1 over 20 to 30 minutes, completing the infusion approximately 30 minutes priorto 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 approximately 30 minutes prior to chemotherapy 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 ClinicalPharmacology ( 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 approximately 30 minutes prior to chemotherapy 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 dimeglumine [see Clinical Pharmacology ( 12.3 )]. Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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...

Side Effects (Adverse Reactions)

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 ) To report SUSPECTED ADVERSE REACTIONS, Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 at 1-848-200-1906 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 1600 adult 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 patientsreceiving the 3-day regimen of oral aprepitant [see Clinical Studies (14.1) ] . The safety profile was generallysimilar to that seen in the MEC study with fosaprepitant and prior HEC studies with aprepitant. However,infusion- site reactionsoccurred at a higher incidence in patients in the fosaprepitant group (3.0%) comparedto those in the aprepitant group (0.5%). The following additional infusion-site reactions occurredin HEC study and were not reportedin the MEC study describedabove: 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.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. Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.,...

Drug Interactions

7 DRUG INTERACTIONS See Full Prescribing Information for a list of clinicallysignificant drug interactions. ( 4 , 5.1 , 5.4 , 5.5 , 7.1 , 7.2 ) Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric 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 fosaprepitant for injection 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 inducerof CYP2C9 [seeClinical Pharmacology (12.3) ] . Some substrates of CYP3A4 are contraindicated with fosaprepitant [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 Fosaprepitant 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 Reducethe dose of oral dexamethasone by approximately 50% [see Dosageand 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 agentmay increase the risk of adverse reactions [see Clinical Pharmacology (12.3) ] . Intervention Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agentsMonitor for chemotherapeutic-related adverse reactions.Etoposide, vinorelbine, paclitaxel, and docetaxelNo dosage adjustment needed. Hormonal Contraceptives Clinical Impact Decreased hormonal exposure...

Contraindications

4 CONTRAINDICATIONS Fosaprepitant is contraindicated in patients: who are hypersensitive to any component of the product Hypersensitivity reactions includinganaphylactic reactions, flushing, erythema, and dyspnea have been reported [see Warnings and Precautions ( 5.2 ), 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 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary There are insufficient data on use of fosaprepitant in pregnant women to inform a drug associated risk. In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic drug levels (AUC) approximately equivalent to the exposure at the recommended human dose (RHD) of 150 mg [seeData] . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of majorbirth 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 dosesup to 1,000 mg/kg twicedaily (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 eitherspecies. The exposures(AUC) in pregnantrats at 1,000 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.

8.3 Females and Males of Reproductive Potential Contraception Upon administration of fosaprepitant, 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 fosaprepitant and for 1 month following the last dose [see Drug Interactions (7.1) ,Clinical Pharmacology (12.3) ] .

Overdosage

10 OVERDOSAGE There is no specificinformation on the treatment of overdosage with fosaprepitant or aprepitant.In the event of overdose, fosaprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of fosaprepitant, drug-induced emesis may not be effective in cases of fosaprepitant overdosage.Aprepitant is not removedby hemodialysis.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING No.948 —Single-dose glass vial containing 150 mg of fosaprepitant as a white to off white lyophilized cake or powder for reconstitution. Supplied as follows: NDC43598-948-11 1 vial per carton. StorageFosaprepitant for injection vials must be refrigerated, store at 2°C - 8°C(36°F - 46°F).The reconstituted final drug solution is stable for 24 hours at ambient room temperature [at or below 25°C (77°F)].