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 of fosaprepitant dimeglumine is described as 1-Deoxy-1-(methylamino)-D-glucitol[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 molecular formula is C23H22F7N4O6P × 2(C7H17NO5), and the molecular weight is 1004.83 g/mol. Fosaprepitant dimeglumine appears as a white to off-white amorphous powder, which 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 150 mg of fosaprepitant, 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 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. It is also indicated for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

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

Dosage and Administration

The recommended dosage of fosaprepitant for adults is 150 mg, to be administered on Day 1. The administration should be conducted as an intravenous infusion over a period of 20 to 30 minutes. It is essential to complete the infusion approximately 30 minutes prior to the initiation of chemotherapy to ensure optimal 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 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 Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or shortly after the infusion of fosaprepitant. Should any symptoms arise, the drug must be discontinued immediately. It is imperative not to reinitiate fosaprepitant in patients who have experienced hypersensitivity 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 discontinued, 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 a two-week timeframe after starting fosaprepitant, especially focusing on the 7 to 10-day interval to ensure patient safety and effective anticoagulation management.

In summary, healthcare professionals must remain vigilant regarding these warnings and precautions to optimize patient outcomes while using fosaprepitant.

Side Effects

Patients receiving fosaprepitant may experience a range of adverse reactions, which can be categorized into common adverse reactions, hypersensitivity reactions, infusion site reactions, and important drug interactions.

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 with varying frequencies among participants.

Hypersensitivity reactions may occur during or shortly after the infusion of fosaprepitant. In the event that such symptoms arise, it is recommended to discontinue the drug immediately and not to reinitiate treatment if similar symptoms have occurred with previous use.

Infusion site reactions, including 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 should be discontinued, and appropriate treatment should be administered.

Fosaprepitant is a weak inhibitor of CYP3A4, while its active metabolite, aprepitant, acts as a substrate, inhibitor, and inducer of CYP3A4. Healthcare providers should refer to the Full Prescribing Information for guidance on contraindications, potential adverse reactions, and necessary dosage adjustments for fosaprepitant and any concomitant medications.

Additionally, there is a risk of decreased International Normalized Ratio (INR) of prothrombin time when fosaprepitant is used concurrently with warfarin, a CYP2C9 substrate. It is essential to monitor INR levels during the two-week period following the initiation of fosaprepitant, particularly around days 7 to 10.

The efficacy of hormonal contraceptives may be reduced during and for 28 days following the administration of fosaprepitant. Patients are advised to use effective alternative or backup methods of contraception during this time.

Other important considerations include the potential for hypersensitivity to any component of the drug and the concurrent use of pimozide, which should be avoided.

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 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 (equivalent to a newborn human) to day 42 (approximately equivalent to a 2-year-old human), adverse effects were noted. Males exhibited decreased testicular weight and Leydig cell size at a dosage of 6 mg/kg/day, while females showed increased uterine weight, hypertrophy of the uterus and cervix, and edema of vaginal tissues at a dosage of 4 mg/kg/day.

Additionally, a study in young rats treated with oral doses up to 1000 mg/kg twice daily from postnatal day 10 (equivalent to a newborn human) through postnatal day 58 (approximately equivalent to a 15-year-old human) revealed slight changes in the onset of sexual maturation in both sexes. 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 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.

In embryofetal development studies, aprepitant was administered to rats at oral doses up to 1000 mg/kg twice daily and to rabbits at the maximum tolerated dose of 25 mg/kg/day during the period of organogenesis. 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 lack of human data and the findings from animal studies, healthcare professionals should weigh the potential benefits against the risks when considering the use of fosaprepitant in pregnant patients.

Lactation

Aprepitant crosses the placenta in rats and rabbits. There is no available data on the excretion of aprepitant or fosaprepitant in human breast milk. Therefore, the effects on breastfed infants are not well characterized.

Lactating mothers using hormonal contraceptives should be advised that the efficacy of these contraceptives may be reduced upon administration of fosaprepitant for injection. It is recommended that females of reproductive potential utilize an effective alternative or back-up non-hormonal contraceptive method, such as condoms and spermicides, during treatment with fosaprepitant and for 1 month following the last dose.

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 these patients to ensure safety and efficacy.

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 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, the induction of emesis may not be effective in managing overdose situations. Therefore, alternative supportive measures should be prioritized.

It is important to note 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 essential in the management of patients experiencing overdosage with 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 (in female rats) or less than (in male rats) the adult human exposure 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 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.

Aprepitant and fosaprepitant were not found to be genotoxic in several tests, 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 of aprepitant.

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. 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 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 BluePoint Laboratories. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)