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,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 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 the prevention of acute and delayed nausea and vomiting in adults and pediatric patients aged 6 months and older, when used in combination with other antiemetic agents. This drug is specifically indicated for the prevention of nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), including high-dose cisplatin, as well as for delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Limitations of use include that fosaprepitant for injection has not been studied for the treatment of established nausea and vomiting. There are no teratogenic or nonteratogenic effects reported for this medication.

Dosage and Administration

Fosaprepitant for injection is administered intravenously. For adult patients, the recommended dosage is 150 mg on Day 1, infused over a period of 20 to 30 minutes. It is essential to complete the infusion approximately 30 minutes prior to the initiation of chemotherapy.

For pediatric patients aged 6 months to 17 years, weighing at least 6 kg, dosing regimens vary by age and should be referenced in the Full Prescribing Information. For single-dose chemotherapy regimens, a single dose of fosaprepitant for injection is administered on Day 1. In cases of single or multi-day chemotherapy regimens, a 3-day fosaprepitant regimen is recommended, consisting of fosaprepitant for injection on Day 1, followed by fosaprepitant capsules or fosaprepitant for oral suspension on Days 2 and 3.

When administering fosaprepitant for injection to pediatric patients, the infusion should be delivered through a central venous catheter. The infusion duration is 30 minutes for patients aged 12 years to 17 years and 60 minutes for those aged 6 months to less than 12 years. Similar to adult patients, the infusion must be completed approximately 30 minutes prior to 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 drug must be discontinued immediately. It is imperative not to reinitiate fosaprepitant in patients who have previously experienced such reactions.

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 decrease the International Normalized Ratio (INR) of prothrombin time in patients taking warfarin, a CYP2C9 substrate. It is essential to monitor INR levels 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 time to prevent unintended pregnancy.

Laboratory Monitoring Regular monitoring of INR is recommended within the two-week period after starting fosaprepitant, especially around 7 to 10 days post-initiation, to ensure safe management of patients on anticoagulant therapy.

In summary, careful consideration of these warnings and precautions is essential for the safe use of fosaprepitant, and healthcare professionals should remain vigilant in monitoring patients for any adverse effects or interactions.

Side Effects

Patients receiving fosaprepitant may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

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

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 treatment in patients with a history of hypersensitivity to fosaprepitant or any of its components.

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.

Additional important considerations include the potential for decreased INR of prothrombin time in patients taking warfarin, a CYP2C9 substrate. Monitoring of INR is recommended during the two-week period following the initiation of fosaprepitant, especially 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 during this time.

Concurrent use of fosaprepitant with pimozide is contraindicated due to potential interactions.

Drug Interactions

Clinically significant drug interactions may occur with the use of this medication. It is essential to refer to the Full Prescribing Information for a comprehensive list of these interactions, which includes details on mechanisms and clinical effects.

Healthcare professionals are advised to monitor patients closely for potential interactions and consider dosage adjustments as necessary based on the specific interactions identified.

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 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 the pediatric population within this age range.

Efficacy and safety findings are further corroborated by data from an adequate and well-controlled study involving a 3-day oral regimen of aprepitant 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, with 5% of patients aged 75 and over. Clinical experience with fosaprepitant has not identified significant differences in therapeutic 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 functional capacity.

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. Aprepitant, the active metabolite of fosaprepitant, crosses the placenta in both rats and rabbits.

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.

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. Healthcare professionals should consider these factors when prescribing fosaprepitant to women of childbearing potential.

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 and any potential adverse effects on the breastfed infant from fosaprepitant or from the underlying maternal condition.

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.

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

Carcinogenicity studies were conducted in Sprague-Dawley rats and CD-1 mice over a duration of 2 years. In the rat carcinogenicity 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 that of female rats or less than that of male rats when compared to 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. The highest dose produced systemic exposure that was 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. It is noteworthy that carcinogenicity studies were not conducted with fosaprepitant.

Aprepitant and fosaprepitant 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. Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant.

In fertility studies involving fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were observed following oral administration. 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. This exposure in male rats was lower than that at the recommended adult human dose of 150 mg, while in female rats, it was approximately equivalent to the adult human exposure.

Postmarketing Experience

Hypersensitivity reactions, including 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, 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 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.

Healthcare providers should inform patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in individuals receiving fosaprepitant for injection. Patients must 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 possibility of infusion site reactions. They should be encouraged to seek medical attention if they notice new or worsening signs or symptoms at or near the infusion site, such as erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis.

Storage and Handling

Fosaprepitant for injection is supplied in vials that must be stored under refrigeration 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 at ambient room temperature, which is defined as at or below 25°C (77°F). It is important to discard any unused portion of the reconstituted solution to ensure safety and efficacy.

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 Camber Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)