Fosaprepitant Drug Information

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

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. A 50% dosage reduction of dexamethasone on Days 1 and 2 is recommended to account for a drug interaction with fosaprepitant for injection. Table 2 Recommended Adult Dosing for the Prevention of Nausea and Vomiting Associated with MEC *Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1.

Prevention of Nausea and Vomiting Associated with HEC and MEC in Pediatric Patients The recommended pediatric dosage regimens of fosaprepitant for injection, to be administered with a 5-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 regimens in which HEC or MEC is administered for a single day only. Multi-day chemotherapy regimens include chemotherapy regimens in which HEC or MEC is administered for 2 or more days.

Fosaprepitant for Injection Dosage Regimens for Use with Single-Day Chemotherapy Regimens For pediatric patients weighing at least 6 kg receiving single-day HEC or MEC, fosaprepitant for injection may be administered as: a single dose regimen of fosaprepitant for injection infused through a central venous catheter on Day 1, as shown in Table 3; or as a 3-day fosaprepitant regimen consisting of fosaprepitant for injection as an intravenous infusion through a central venous catheter on Days 1, 2, and 3. Fosaprepitant capsules or fosaprepitant for oral suspension may be used on Days 2 and 3 instead of fosaprepitant for injection, as shown in Table 4. Table 4 3-Day Fosaprepitant Dosage Regimen for Prevention of Nausea and Vomiting Associated with Single or Multi-day Regimens of HEC or MEC in Pediatric Patients 6 Months* to 17 Years

Preparation of Fosaprepitant for Injection Table 5 Preparation Instructions for Fosaprepitant for Injection (150 mg) Determine the volume to be administered from this prepared infusion bag, based on the recommended dose. Pediatrics In patients 12 years and older, the volume to be administered is calculated as follows: Volume to administer (mL) equals the recommended dose (mg) In patients 6 months to less than 12 years, the volume to be administered is calculated as follows: Volume to administer (mL) = recommended dose (mg/kg) x weight (kg) o Note: Do not exceed the maximum dose In pediatric patients, the entire volume in the infusion bag may not be required. Step 6 If necessary, for volumes less than 150 mL, the calculated volume can be transferred to an appropriate size bag or syringe prior to administration by infusion.

Step 7 Before administration, inspect the bag for particulate matter and discoloration. The recommended dose of fosaprepitant for injection is based on the patient’s age and weight. Caution: Do not mix or reconstitute fosaprepitant for injection with solutions for which physical and chemical compatibility have not been established.

Fosaprepitant for injection is incompatible with any solutions containing divalent cations (e.g., Ca 2+, Mg 2+ ), including Lactated Ringer's Solution and Hartmann's Solution. Storage The reconstituted final drug solution is stable for 24 hours at ambient room temperature. Discard unused portion.

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 1,800 adult and pediatric patients. Adverse Reactions in Adults for the Prevention of Nausea and Vomiting Associated with MEC In an active-controlled clinical trial in patients receiving MEC, safety was evaluated in 504 patients receiving a single dose of fosaprepitant for injection in combination with ondansetron and dexamethasone (fosaprepitant 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 Infusion-site reactions were reported in 2.2% of patients treated with the fosaprepitant regimen compared to 0.6% of patients treated with standard therapy. 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 1,143 patients receiving a single dose of fosaprepitant for injection compared to 1,169 patients receiving the 3-day regimen of oral aprepitant.

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%). Adverse Reactions in Pediatric Patients 6 Months to 17 Years of Age for the Prevention of Nausea and Vomiting Associated with HEC or MEC Single-Dose fosaprepitant for Injection Regimen The safety of a single dose of fosaprepitant for injection in pediatric patients (6 months to 17 years) was evaluated in two active-controlled and a single-arm clinical study in patients who received either HEC or MEC.

Patients also received ondansetron with or without dexamethasone. The adverse reaction profile was similar to adults. The safety analysis included 69 pediatric patients who received the recommended dose.

An additional 70 patients received a single, higher-than-recommended dose. The most common adverse reactions that occurred in >15% of patients who received the recommended dose were anemia, neutropenia, thrombocytopenia, and febrile neutropenia. 3-Day Fosaprepitant Regimen In pediatric patients 12 to 17 years, the safety of the 3-day IV/oral/oral fosaprepitant regimen was evaluated in a single-arm clinical study including 12 patients who received a regimen of either HEC or MEC. In pediatric patients 6 months to 12 years of age, the safety of the 3-day IV/oral/oral fosaprepitant regimen was not directly evaluated.

The safety of the 3-day (IV/IV/IV) regimen of fosaprepitant for injection in pediatric patients (6 months to 17 years) was evaluated in a single-arm clinical study in 100 patients who received either HEC or MEC. The adverse reaction profile in pediatric patients was similar to the profile in adult patients receiving a single dose of fosaprepitant for injection. Because fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with fosaprepitant for injection.

See the full prescribing information for aprepitant capsules for complete safety information regarding studies performed with oral aprepitant.

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.

Immune system disorders: hypersensitivity reactions including anaphylaxis and anaphylactic shock. Nervous system disorders: ifosfamide-induced neurotoxicity reported after fosaprepitant and ifosfamide coadministration.

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 inducer of CYP2C9.

Some substrates of CYP3A4 are contraindicated with fosaprepitant. 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 Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions.

Intervention Monitor for benzodiazepine-related adverse reactions. Dexamethasone Clinical Impact Increased dexamethasone exposure. Intervention Reduce the dose of oral dexamethasone by approximately 50%.

Methylprednisolone Clinical Impact Increased methylprednisolone exposure. Chemotherapeutic agents that are metabolized by CYP3A4 Clinical Impact Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions. Intervention Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents Monitor for chemotherapeutic-related adverse reactions.

Hormonal Contraceptives Clinical Impact Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of fosaprepitant. Decreased warfarin exposure and decreased prothrombin time (INR). 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 fosaprepitant with each chemotherapy cycle.

Other 5-HT 3 Antagonists Clinical Impact No change in the exposure of the 5-HT 3 antagonist. Intervention No dosage adjustment needed Examples ondansetron, granisetron, dolasetron

Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant Aprepitant is a CYP3A4 substrate. Co-administration of fosaprepitant 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 ClinicalImpact Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with fosaprepitant.

Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of fosaprepitant. Intervention Avoid concomitant use of fosaprepitant Examples rifampin, carbamazepine, phenytoin

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. 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 major birth defects and miscarriage in clinically recognized pregnancies is 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 1,000 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 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.

Pediatric Use The safety and effectiveness of a single dose and a 3-day regimen of fosaprepitant 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 fosaprepitant in this age group is supported by evidence from adequate and well-controlled studies of fosaprepitant for injection 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.

The safety of the 3-day fosaprepitant for injection regimen in pediatric patients 6 months to 17 years of age was supported by an open-label study in 100 patients receiving HEC or MEC. See the full prescribing information for fosaprepitant capsules for complete clinical information regarding studies performed with oral aprepitant. Adverse reactions were similar to those reported in adult patients.

The safety and effectiveness of fosaprepitant 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 1,000 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.

Fosaprepitant 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. 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.

Known hypersensitivity to any component of this drug. Concurrent use with pimozide.

There is no specific information 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 removed by hemodialysis.