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-glucitol [3-[[[2(R),3S)-2-(1(R)-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).

The empirical formula is C23H22F7N4O6P·2(C7H17NO5), and the molecular weight is 1004.83. Fosaprepitant dimeglumine appears as a white or whitish hygroscopic powder, which is freely soluble in water and methanol, but practically insoluble in absolute ethanol. Each vial for intravenous infusion contains 150 mg of fosaprepitant, equivalent to 245.3 mg of fosaprepitant dimeglumine, along with inactive ingredients including edetate disodium (5.4 mg), polysorbate 80 (75 mg), lactose anhydrous (375 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 should be administered as an intravenous infusion, with the infusion completed approximately 30 minutes prior to the initiation of chemotherapy.

For adult patients, the recommended dosage is 150 mg, to be administered on Day 1. The intravenous infusion should be delivered over a period of 20 to 30 minutes. It is essential to ensure that the infusion is prepared and administered in accordance with established guidelines for intravenous medications to maintain safety and efficacy.

Contraindications

Use of this drug is contraindicated in patients with known hypersensitivity to any component of the formulation. Additionally, concurrent use with pimozide is contraindicated due to potential drug interactions that may exacerbate adverse effects.

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 essential to consult the Full Prescribing Information for detailed recommendations regarding contraindications, potential adverse reactions, and necessary dosage adjustments for fosaprepitant for injection when used in conjunction with other medications.

Hypersensitivity Reactions Patients may experience hypersensitivity reactions during or shortly after the infusion of fosaprepitant. Should any symptoms arise, the infusion must be discontinued immediately. It is critical to avoid reinitiating treatment with fosaprepitant for injection in patients who have previously exhibited hypersensitivity reactions.

Infusion Site Reactions Infusion site reactions, including thrombophlebitis, necrosis, and vasculitis, have been predominantly reported in patients receiving vesicant chemotherapy. To minimize the risk of such 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 medical treatment should be administered.

Warfarin Interaction Fosaprepitant may lead to a decreased International Normalized Ratio (INR) in patients taking warfarin, a substrate of CYP2C9. It is recommended to monitor INR closely during the two weeks following the initiation of fosaprepitant for injection, with particular attention to the period between 7 to 10 days post-administration.

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

Side Effects

Patients receiving fosaprepitant for injection 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 shortly after infusion. In the event of such symptoms, it is imperative to discontinue the drug immediately and not to reinitiate treatment if similar symptoms have occurred with previous use.

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 advised to avoid infusing into small veins. Should a severe reaction develop, the infusion should be discontinued, and appropriate treatment should be administered.

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

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

Drug Interactions

Clinically significant drug interactions are detailed in the Full Prescribing Information, specifically in Sections 4, 5.1, 5.4, 5.5, 7.1, and 7.2. Healthcare professionals are advised to consult these sections for comprehensive information regarding potential interactions, including their mechanisms and clinical effects.

It is essential to consider dosage adjustments or enhanced monitoring protocols when co-administering with other medications, as outlined in the prescribing information. This ensures optimal therapeutic outcomes while minimizing the risk of adverse effects.

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 for injection in 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 juvenile animal studies, fosaprepitant has shown effects on reproductive organs. Specifically, in juvenile dogs treated with fosaprepitant, changes in reproductive organ morphology were observed. In juvenile rats, slight changes in sexual maturation were noted following treatment with aprepitant; however, these changes did not impact reproduction, mating, or fertility. Additionally, no adverse effects on neurobehavior, sensory and motor function, or learning and memory were observed in these studies.

A toxicity study in juvenile dogs, treated from postnatal day 14 (equivalent to a newborn human) to day 42 (approximately equivalent to a 2-year-old human), revealed decreased testicular weight and Leydig cell size in males at a dose of 6 mg/kg/day, while females exhibited increased uterine weight, hypertrophy of the uterus and cervix, and edema of vaginal tissues at a dose of 4 mg/kg/day.

Furthermore, a study in young rats evaluated the effects of aprepitant on growth and neurobehavioral and sexual development from Postnatal Day 10 (equivalent to a newborn human) through Postnatal Day 58 (approximately equivalent to a 15-year-old human). This study also indicated slight changes in the onset of sexual maturation in both male and female rats, but again, no effects were observed on mating, fertility, embryonic-fetal survival, or the histomorphology of reproductive organs.

While pediatric use information is approved for Emend (fosaprepitant) for injection, it is important to note that 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 for injection in high emetic risk (HEC) and moderate emetic risk (MEC) clinical studies, with 5% of patients aged 75 and over.

Clinical experience with fosaprepitant for injection has not identified significant differences in responses between elderly and younger patients. However, it is important to exercise caution when dosing geriatric patients due to their increased likelihood of having decreased hepatic, renal, or cardiac function, as well as the potential for concomitant diseases or other drug therapies.

Healthcare providers should consider these factors when determining the appropriate dosage and monitoring requirements for elderly patients receiving fosaprepitant for injection.

Pregnancy

There are insufficient data on the use of fosaprepitant for injection 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 during the period of organogenesis at oral doses up to 1000 mg/kg twice daily in rats and up to the maximum tolerated dose of 25 mg/kg/day in rabbits. No embryofetal lethality or malformations were observed at any dose level in either species. 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. However, 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 available data, healthcare professionals should weigh the potential benefits against the unknown risks when considering the use of fosaprepitant in pregnant patients.

Lactation

Lactation studies have not been conducted to assess the presence of aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production. However, aprepitant is present in rat milk.

The developmental and health benefits of breastfeeding should be considered alongside the lactating mother's clinical need for fosaprepitant for injection and any potential adverse effects on the breastfed infant from fosaprepitant for injection or from the underlying maternal condition.

Renal Impairment

There is no specific information regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

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 outlined 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 the event of an overdose involving fosaprepitant or aprepitant, there is currently no specific information available regarding targeted treatment protocols. It is recommended that fosaprepitant for injection be discontinued immediately upon suspicion of an overdose.

General supportive treatment and close monitoring of the patient are essential components of management in such cases. Due to the antiemetic properties of fosaprepitant for injection, the induction of emesis may not be effective in mitigating the effects of an overdose.

Additionally, it is important to note that aprepitant is not removed from the body through hemodialysis, which may influence the management approach in cases of overdose. Healthcare professionals should remain vigilant and provide appropriate supportive care as needed.

Nonclinical Toxicology

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 1000 mg/kg twice daily. The highest dose resulted in systemic exposures to aprepitant that were approximately equivalent to (in female rats) or less than (in male rats) the adult human exposure at the recommended human dose (RHD) of 150 mg. Treatment with aprepitant at doses of 5 to 1000 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 1000 mg/kg twice daily, as well as hepatocellular carcinomas and thyroid follicular cell adenomas at doses of 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day, with the highest dose producing systemic exposure approximately twice that of the adult human exposure at the RHD of 150 mg. Treatment with aprepitant in male mice resulted in the development of skin fibrosarcomas at doses of 125 and 500 mg/kg/day. Carcinogenicity studies were not conducted with fosaprepitant.

Aprepitant and fosaprepitant were evaluated for genotoxicity and were found to be non-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.

In fertility studies involving fosaprepitant and aprepitant, it was observed that oral administration of aprepitant resulted in the highest systemic exposures to the active compound. Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. Oral 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 1000 mg/kg twice daily, with male rat exposure being lower than that at the recommended adult human dose of 150 mg, and female rat exposure being approximately equivalent to the adult human exposure.

Postmarketing Experience

Hypersensitivity reactions, including cases of anaphylaxis and anaphylactic shock, have been reported in patients receiving fosaprepitant for injection. 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, reports of new or worsening signs or symptoms of infusion site reactions have been documented. Patients should seek medical attention if they notice erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis at or near the infusion site.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) thoroughly to understand the medication's use and potential risks. It is important to inform patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in individuals receiving fosaprepitant for injection.

Healthcare providers should instruct patients to seek immediate medical attention if they experience any signs or symptoms of a hypersensitivity reaction. These 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 made aware of the importance of monitoring for new or worsening signs or symptoms of an infusion site reaction. They should be advised to seek medical attention if they notice erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis at or near the infusion site.

Storage and Handling

Fosaprepitant for injection is supplied in vials that require refrigeration. It should be stored at a temperature range of 2°C to 8°C (36°F to 46°F).

Once reconstituted, the final drug solution remains stable for 24 hours when kept at ambient room temperature, which is defined as at or below 25°C (77°F). Proper handling and storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Clinicians should monitor the International Normalized Ratio (INR) in patients undergoing chronic warfarin therapy during the two weeks following the initiation of fosaprepitant for injection, particularly around days 7 to 10 of each chemotherapy cycle.

Patients are advised to utilize effective alternative or back-up methods of contraception during treatment with fosaprepitant for injection and for one month after administration to ensure adequate contraceptive protection.

FDA Insert (PDF)

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

View full prescribing information (PDF)