Fosaprepitant dimeglumine

Description

Fosaprepitant for injection is a sterile, lyophilized formulation containing fosaprepitant dimeglumine, a prodrug of aprepitant, which acts as a substance P/neurokinin-1 (NK1) receptor antagonist and serves as an antiemetic agent. The chemical structure is described as 1-Deoxy-1-(methylamino)-D-glucito[3-[[[2R,3S)-2-[(1R)-1-3,5-bis(trifluoromethyl)phenylethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonate(2:1) (salt). The empirical formula is C23H22F7N4O6P·2(C7H17NO5), and the molecular weight is 1004.83.

Fosaprepitant dimeglumine appears as a white to off-white powder. It is freely soluble in water, soluble in N,N-Dimethylsulfoxide, and insoluble in n-hexane. Each vial of fosaprepitant for injection is intended for intravenous infusion and contains 245.3 mg of fosaprepitant dimeglumine, which is equivalent to 150 mg of fosaprepitant free acid. Inactive ingredients include edetate disodium (5.4 mg), lactose anhydrous (375 mg), polysorbate 80 (75 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.

Uses and Indications

Fosaprepitant for injection is indicated in adults, in combination with other antiemetic agents, 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. Additionally, it is indicated for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Fosaprepitant for injection has not been studied for the treatment of established nausea and vomiting.

Dosage and Administration

Fosaprepitant for injection is to be administered as an intravenous infusion. For adult patients, the recommended dosage is 150 mg on Day 1. The infusion should be delivered over a period of 20 to 30 minutes, ensuring that it is completed approximately 30 minutes prior to the initiation of chemotherapy.

Contraindications

Use of this drug is contraindicated in patients with a known hypersensitivity to any component of the formulation. Additionally, concurrent use with pimozide is contraindicated due to the potential for serious interactions.

Warnings and Precautions

Fosaprepitant is associated with several important warnings and precautions that healthcare professionals must consider to ensure safe administration and patient management.

CYP3A4 Interactions Fosaprepitant acts as a weak inhibitor of CYP3A4, while its active metabolite, aprepitant, serves as a substrate, inhibitor, and inducer of this enzyme. It is crucial to consult the Full Prescribing Information for detailed recommendations regarding contraindications, potential adverse reactions, and necessary dosage adjustments for fosaprepitant and any concomitant medications.

Hypersensitivity Reactions Patients may experience hypersensitivity reactions, including anaphylaxis and anaphylactic shock, during or shortly after the infusion of fosaprepitant. Should any symptoms of hypersensitivity arise, the infusion must be discontinued immediately. It is imperative not to reinitiate fosaprepitant in patients who have experienced such reactions with prior use.

Infusion Site Reactions Infusion site reactions, such as thrombophlebitis, necrosis, and vasculitis, have been predominantly reported in patients receiving vesicant chemotherapy. To minimize the risk of these reactions, it is advised to avoid infusing fosaprepitant into small veins. In the event of a severe reaction, the infusion should be stopped, and appropriate treatment should be administered.

Warfarin Interaction Fosaprepitant may lead to a decreased International Normalized Ratio (INR) in patients taking warfarin, a CYP2C9 substrate. It is essential to monitor the INR closely during the two-week period following the initiation of fosaprepitant, with particular attention to the 7 to 10-day mark.

Hormonal Contraceptives The efficacy of hormonal contraceptives may be diminished during treatment with fosaprepitant and for up to 28 days following its administration. Healthcare providers should advise patients to utilize effective alternative or backup contraceptive methods during this period to prevent unintended pregnancy.

Laboratory Tests Monitoring of INR is recommended within the two-week timeframe after starting fosaprepitant, especially focusing on the 7 to 10-day interval to ensure patient safety and effective anticoagulation management.

Side Effects

Patients receiving fosaprepitant may experience a range of adverse reactions. Common adverse reactions reported include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infections, and pain in extremities.

Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or soon after infusion. If such symptoms arise, the drug should be discontinued immediately, and it is advised not to reinitiate fosaprepitant in patients with a history of these reactions.

Infusion site reactions, which may include thrombophlebitis, necrosis, and vasculitis, have been predominantly reported in patients receiving vesicant chemotherapy. To minimize the risk of these reactions, it is recommended to avoid infusing the drug into small veins. In the event of a severe reaction, the infusion should be discontinued, and appropriate treatment should be administered.

Additionally, there are important considerations regarding drug interactions. The use of fosaprepitant may lead to a decreased INR in patients taking warfarin, a CYP2C9 substrate. It is crucial to monitor INR levels during the two-week period following the initiation of fosaprepitant, particularly between days 7 to 10. Furthermore, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the administration of fosaprepitant; therefore, patients are advised to use effective alternative or back-up methods of contraception.

Patients with known hypersensitivity to any component of this drug or those concurrently using pimozide should not receive fosaprepitant.

Drug Interactions

Clinically significant drug interactions may occur with the use of this medication. It is essential for healthcare professionals to refer to the Full Prescribing Information for a comprehensive list of these interactions.

Pharmacodynamic interactions may lead to enhanced effects or increased toxicity when this medication is used concurrently with other agents. Careful monitoring of the patient’s clinical status is advised to mitigate potential adverse effects.

Pharmacokinetic interactions may alter the absorption, distribution, metabolism, or excretion of this medication or the concomitant drugs. Dosage adjustments may be necessary based on the specific interaction and the clinical scenario.

Healthcare providers should remain vigilant and consider both the pharmacodynamic and pharmacokinetic profiles of all medications prescribed to ensure patient safety and therapeutic efficacy.

Packaging & NDC

The table below lists all NDC Code configurations of Fosaprepitant, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of fosaprepitant dimeglumine for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) have not been established in pediatric patients less than 6 months of age.

In a juvenile toxicity study involving dogs treated with fosaprepitant from postnatal day 14 to day 42, findings included decreased testicular weight and Leydig cell size in male subjects at a dosage of 6 mg/kg/day, and increased uterine weight, hypertrophy of the uterus and cervix, and edema of vaginal tissues in female subjects at a dosage of 4 mg/kg/day.

Additionally, a study in young rats assessed the effects of aprepitant on growth, neurobehavioral, and sexual development. Rats received oral doses up to 1000 mg/kg twice daily from postnatal day 10 through postnatal day 58. The study noted slight changes in the onset of sexual maturation in both female and male rats; however, there were no observed effects on mating, fertility, embryonic-fetal survival, or the histomorphology of reproductive organs. Neurobehavioral assessments of sensory function, motor function, and learning and memory showed no adverse effects.

While pediatric use information is approved for Emend (fosaprepitant) for injection by Merck Sharp & Dohme Corp., due to marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Geriatric Use

Elderly patients, defined as those aged 65 and over, comprised 27% of the 1649 adult cancer patients treated with intravenous fosaprepitant in high emetic risk (HEC) and moderate emetic risk (MEC) clinical studies, with 5% of patients aged 75 and over. Clinical experience with fosaprepitant has not identified significant differences in responses between elderly and younger patients.

However, caution is advised when dosing geriatric patients due to the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. It is essential for healthcare providers to monitor these patients closely and consider potential dose adjustments based on individual health status and response to treatment.

Pregnancy

There are insufficient data on the use of fosaprepitant in pregnant patients to inform a drug-associated risk. Animal reproduction studies have shown that 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.

In embryofetal development studies, aprepitant was administered to pregnant rats at oral doses up to 1,000 mg/kg twice daily and to pregnant rabbits at the maximum tolerated dose of 25 mg/kg/day. No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats and rabbits at these doses were approximately equivalent to the exposure at the RHD of 150 mg. It is noted that aprepitant crosses the placenta in both rats and rabbits.

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 2 to 4% and 15 to 20%, respectively. Given the limited data available, healthcare professionals should weigh the potential benefits against the risks when considering the use of fosaprepitant in pregnant patients.

Lactation

There are insufficient data on the use of fosaprepitant in nursing mothers to inform a drug-associated risk. Aprepitant is excreted in human breast milk; however, the effects of fosaprepitant on the breastfed infant and on milk production are unknown. Caution should be exercised when administering fosaprepitant to a nursing woman.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring of these patients.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of overdosage with fosaprepitant or aprepitant, there is currently no specific information available regarding targeted treatment protocols. In the event of an overdose, it is recommended that fosaprepitant be discontinued immediately. Healthcare professionals should ensure that general supportive treatment and monitoring are provided to the patient.

Due to the antiemetic properties of fosaprepitant, it is important to note that drug-induced emesis may not be effective in managing fosaprepitant overdosage. Therefore, alternative supportive measures should be considered.

Additionally, it is crucial to understand that aprepitant is not removed from the body through hemodialysis, which may influence the management approach in cases of overdose. Continuous assessment and supportive care remain the cornerstone of managing patients who have experienced an overdose of these agents.

Nonclinical Toxicology

Oral administration of aprepitant did not adversely affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1,000 mg/kg twice daily. This exposure in male rats was lower than the exposure at the recommended adult human dose of 150 mg, while in female rats, it was approximately equivalent to the adult human exposure.

Carcinogenicity studies were conducted in Sprague-Dawley rats and CD-1 mice over a duration of 2 years. In the rat studies, animals received oral doses ranging from 0.05 to 1,000 mg/kg twice daily. The highest dose resulted in systemic exposures to aprepitant that were approximately equivalent to that of female rats or less than that of male rats at the recommended human dose of 150 mg. Treatment with aprepitant at doses of 5 to 1,000 mg/kg twice daily led to an increased incidence of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, the treatment resulted in hepatocellular adenomas at doses of 5 to 1,000 mg/kg twice daily, as well as hepatocellular carcinomas and thyroid follicular cell adenomas at doses of 125 to 1,000 mg/kg twice daily.

In the mouse carcinogenicity studies, animals were treated with oral doses ranging from 2.5 to 2,000 mg/kg/day, with the highest dose producing systemic exposure approximately twice that of the adult human exposure at the recommended human dose of 150 mg. Treatment with aprepitant resulted in the development of skin fibrosarcomas in male mice at doses of 125 and 500 mg/kg/day. It is noteworthy that carcinogenicity studies were not conducted with fosaprepitant.

Aprepitant and fosaprepitant were not found to be genotoxic in several assays, including the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test, and the mouse micronucleus test.

Postmarketing Experience

Hypersensitivity reactions, including cases of anaphylaxis and anaphylactic shock, have been reported in patients receiving fosaprepitant. Patients are advised to seek immediate medical attention if they experience signs or symptoms of a hypersensitivity reaction, which may include hives, rash and itching, skin peeling or sores, flushing, difficulty in breathing or swallowing, dizziness, rapid or weak heartbeat, or feelings of faintness.

Additionally, patients should seek medical attention for new or worsening signs or symptoms of an infusion site reaction. These may include erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis occurring at or near the infusion site.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) to understand the medication's proper use and potential risks.

Healthcare providers should inform patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in individuals taking fosaprepitant. Patients must be instructed to seek immediate medical attention if they experience any signs or symptoms of a hypersensitivity reaction, which may include hives, rash and itching, skin peeling or sores, flushing, difficulty in breathing or swallowing, dizziness, rapid or weak heartbeat, or feelings of faintness.

Additionally, patients should be counseled to seek medical attention if they notice new or worsening signs or symptoms of an infusion site reaction. These may include erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis at or near the infusion site.

Storage and Handling

Fosaprepitant for injection is supplied in vials that must be stored under refrigeration. It is essential to maintain a temperature range of 2°C to 8°C (36°F to 46°F) to ensure the integrity of the product.

Once reconstituted, the final drug solution remains stable for 24 hours when kept at ambient room temperature, defined as at or below 25°C (77°F). Care should be taken to adhere to these storage conditions to preserve the efficacy and safety of the medication.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Fosaprepitant as submitted by Dr. Reddy's Laboratories Inc. ,. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)