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 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), with an empirical formula of C23H22F7N4O6P·2(C7H17NO5) and a molecular weight of 1004.83.

Fosaprepitant dimeglumine appears as a white to off-white powder and 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. The formulation includes inactive ingredients such as edetatedisodium (18.8 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

The recommended dosage for adults is 150 mg, to be administered on Day 1. Fosaprepitant for injection should be given 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.

Administration should be performed via intravenous route, ensuring that the infusion is delivered within the specified time frame to optimize therapeutic efficacy.

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. Reinitiation of fosaprepitant is contraindicated 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 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 weeks following the initiation of fosaprepitant, with particular attention to the period between 7 to 10 days post-initiation.

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

Side Effects

Patients receiving fosaprepitant may experience a range of adverse reactions. Common adverse reactions observed in clinical trials 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. 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 International Normalized Ratio (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 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 are 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 avoid the use of 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 co-administered drugs. Dosage adjustments may be necessary based on the specific interaction and the clinical context.

Healthcare providers should remain vigilant and consider both the pharmacodynamic and pharmacokinetic profiles of concomitant medications to ensure safe and effective therapy.

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. While pediatric use information is approved for Emend (fosaprepitant) for injection by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., the drug product is not labeled with this pediatric information due to the company's marketing exclusivity rights.

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.

In embryofetal development studies, aprepitant was administered to pregnant rats and rabbits during the period of organogenesis at oral doses up to 1,000 mg/kg twice daily and up to the maximum tolerated dose of 25 mg/kg/day, respectively. No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats at 1,000 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

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

Lactating mothers should be advised that the efficacy of hormonal contraceptives may be reduced upon administration of fosaprepitant. It is recommended that females of reproductive potential using hormonal contraceptives employ 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 available 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 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.

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

Additionally, it should be recognized that aprepitant is not removed from the body through hemodialysis, which may influence management decisions in cases of significant overdose. Continuous assessment and supportive care remain critical in the management of patients experiencing 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 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 humans or less than that of male humans at the recommended human dose (RHD) 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 adult humans at the RHD of 150 mg. Aprepitant treatment 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 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. 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 1,000 mg/kg twice daily, providing exposure in male rats lower than that at the recommended adult human dose of 150 mg and exposure in female rats 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. 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. Such symptoms 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 a period of 24 hours when kept at ambient room temperature, defined as at or below 25°C (77°F). Proper handling and storage conditions are crucial to maintain 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)