Fosaprepitant

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 antiemetic agent. The chemical structure is described as 1-Deoxy-1-(methylamino)-D-glucitol[3-[[[2(R),3(S)-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) (salt). The empirical formula is C23H22F7N4O6P ⋅ 2(C7H17NO5), and the molecular weight is 1004.83.

Fosaprepitant dimeglumine appears as a white to light brown powder and is soluble in water and methanol. Each vial of fosaprepitant for injection is intended for intravenous infusion and contains 150 mg of fosaprepitant, which is equivalent to 245.3 mg of fosaprepitant dimeglumine. 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 for use in adults and pediatric patients aged 6 months and older, in conjunction 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. There are no specific teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

Fosaprepitant for injection is administered intravenously at a recommended dosage of 150 mg for adults on Day 1. The infusion should be delivered over a period of 20 to 30 minutes, with the completion of the infusion occurring approximately 30 minutes prior to the initiation of chemotherapy.

For pediatric patients aged 6 months to 17 years who weigh at least 6 kg, specific dosing information is not provided in the current excerpt. Healthcare professionals should refer to the appropriate guidelines or clinical resources for detailed dosing recommendations for this population.

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 potential drug interactions that may exacerbate adverse effects.

Warnings and Precautions

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or shortly after the infusion of fosaprepitant. In the event of such symptoms, it is imperative to discontinue the drug immediately. Reinitiation of fosaprepitant is contraindicated in patients who have experienced hypersensitivity reactions with prior use.

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. Should a severe reaction develop, the infusion must be discontinued, and appropriate treatment should be administered.

Fosaprepitant may interact with warfarin, a substrate of CYP2C9, leading to a potential decrease in the International Normalized Ratio (INR) of prothrombin time. It is essential to monitor the INR during a two-week period following the initiation of fosaprepitant, with particular attention to the values at 7 to 10 days post-initiation.

The efficacy of hormonal contraceptives may be diminished during treatment with fosaprepitant and for 28 days following its administration. Healthcare professionals should advise patients to utilize effective alternative or backup methods of contraception during this period.

Fosaprepitant is a weak inhibitor of CYP3A4, while aprepitant, its active metabolite, serves as a substrate, inhibitor, and inducer of CYP3A4. 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.

To ensure patient safety, monitoring of INR is recommended within the specified two-week timeframe, particularly focusing on the 7 to 10-day interval following the initiation of fosaprepitant.

Side Effects

Patients receiving fosaprepitant may experience a range of adverse reactions, which can be categorized into common and serious reactions.

Common adverse reactions reported in clinical trials include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infections, and pain in extremities. These reactions were observed among participants and may vary in frequency and severity.

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

Infusion site reactions have also been noted, including thrombophlebitis, necrosis, and vasculitis, particularly in patients receiving vesicant chemotherapy. To minimize the risk of these reactions, it is advised to avoid infusion 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 may lead to a decreased INR of prothrombin time in patients taking warfarin, a CYP2C9 substrate. It is recommended to monitor INR closely during the two weeks 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 the administration of fosaprepitant; therefore, patients should be advised to use effective alternative or backup 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 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.

It is essential to evaluate the pharmacodynamic and pharmacokinetic interactions that may arise when co-administering this medication with other drugs. Monitoring for adverse effects and therapeutic efficacy is recommended, and dosage adjustments may be necessary based on the specific interactions identified in the prescribing information.

For optimal patient safety and therapeutic outcomes, healthcare providers should remain vigilant and consider the implications of these interactions in their clinical decision-making.

Packaging & NDC

The table below lists all NDC Code configurations of Fosaprepitant (fosaprepitant dimeglumine), 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 have been established in pediatric patients aged 6 months to 17 years for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC). This use is supported by evidence from adequate and well-controlled studies in adults, along with additional safety, efficacy, and pharmacokinetic data specific to pediatric patients within this age range.

Efficacy and safety findings are further corroborated by data from an adequate and well-controlled study of a 3-day oral aprepitant regimen in pediatric patients aged 6 months to 17 years. However, the safety and effectiveness of fosaprepitant for injection have not been established in patients younger than 6 months of age.

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. Additionally, 5% of these patients were aged 75 and over.

Clinical experience with fosaprepitant 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 closely monitor elderly patients for any adverse effects and consider potential dose adjustments based on individual health status and organ function.

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 1000 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 at 1000 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. 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

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 mother's clinical need for fosaprepitant and any potential adverse effects on the breastfed infant from fosaprepitant or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment have no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular assessment of renal function may be warranted to ensure safe and effective use of the medication in patients with reduced kidney function.

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 provide general supportive treatment and closely monitor the patient for any adverse effects.

Due to the antiemetic properties of fosaprepitant, it is important to note that drug-induced emesis may not be effective in managing overdosage situations. 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 management strategies in cases of significant 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 1000 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 1000 mg/kg twice daily. The highest dose resulted in systemic exposures to aprepitant that were approximately equivalent to the adult human exposure in female rats and less than that in male rats at the recommended human dose 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. The highest dose produced systemic exposure that was 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 at doses of 125 and 500 mg/kg/day in male mice. It is noteworthy that carcinogenicity studies were not conducted with fosaprepitant.

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.

Patients should be instructed 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 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 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 at ambient room temperature, which is defined as at or below 25°C (77°F). Any unused portion of the reconstituted solution should be discarded to prevent potential safety and efficacy issues.

Additional Clinical Information

Clinicians should monitor the International Normalized Ratio (INR) in patients on chronic warfarin therapy during the two weeks following the initiation of fosaprepitant, particularly around days 7 to 10 of each chemotherapy cycle. It is important to avoid infusing fosaprepitant for injection into small veins or through a butterfly catheter to minimize complications.

Patients should be counseled to use effective alternative or back-up methods of contraception during treatment with fosaprepitant and for one month after administration. Postmarketing experience has indicated that serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or shortly after the infusion of fosaprepitant. Infusion site reactions (ISRs) have also been reported, particularly with initial doses, and in some cases, these reactions may persist for two weeks or longer, necessitating medical or surgical intervention for severe cases.

FDA Insert (PDF)

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

View full prescribing information (PDF)