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-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). Its empirical formula is C23H22F7N4O6P • 2(C7H17NO5), and it has a molecular weight of 1004.83. Fosaprepitant dimeglumine appears as a white to off-white amorphous powder that is freely soluble in water.

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. The formulation includes inactive ingredients such as edetate disodium (18.8 mg), meglumine (75 mg), povidone k12 (600 mg), and water for injection. Hydrochloric acid and/or meglumine may be added 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 for adults is 150 mg administered as an intravenous infusion on Day 1. The infusion should be delivered over a period of 20 to 30 minutes, ensuring that it is completed approximately 30 minutes prior to the initiation of chemotherapy.

Prior to administration, the medication must be reconstituted with 5 mL of 0.9% sodium chloride. Following reconstitution, the solution should be added to an infusion bag containing 145 mL of 0.9% sodium chloride, resulting in a final concentration of 1 mg/mL.

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 for Injection. In the event of such symptoms, it is imperative to discontinue the drug immediately. Reinitiation of Fosaprepitant for Injection is contraindicated if hypersensitivity reactions have occurred with previous 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 for Injection into small veins. Should a severe reaction develop, the infusion must be discontinued, and appropriate treatment should be administered.

Caution is warranted when administering Fosaprepitant for Injection to patients on warfarin, a CYP2C9 substrate, due to the potential risk of decreased INR of prothrombin time. It is essential to monitor INR levels during the two-week period following the initiation of Fosaprepitant for Injection, with particular attention to the 7 to 10-day mark.

The efficacy of hormonal contraceptives may be diminished during treatment with Fosaprepitant for Injection and for 28 days thereafter. 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 for Injection and any concomitant medications.

Healthcare professionals should instruct patients to seek emergency medical assistance if symptoms of hypersensitivity reactions occur. Additionally, patients should be advised to discontinue the drug and contact their healthcare provider if any hypersensitivity reactions manifest.

Regular monitoring of INR is recommended during the two-week period following the initiation of Fosaprepitant for Injection, particularly focusing on the 7 to 10-day interval to ensure patient safety and effective management of anticoagulation therapy.

Side Effects

Patients receiving Fosaprepitant for Injection may experience a range of adverse reactions. The most common adverse reactions, occurring in 2% or more of participants, include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, 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 Fosaprepitant for Injection if similar symptoms have occurred with previous 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 infusion into small veins. Should a severe reaction develop, the infusion should be discontinued, and appropriate treatment should be administered.

Patients on warfarin, a CYP2C9 substrate, should be monitored for a potential decrease in INR of prothrombin time. It is particularly important to monitor INR during the 2-week period following the initiation of Fosaprepitant for Injection, especially around days 7 to 10.

Additionally, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the administration of Fosaprepitant for Injection. Patients are advised to use effective alternative or back-up methods of contraception during this time.

Other important considerations include the risk of known hypersensitivity to any component of this drug and the concurrent use with 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:

• The potential for additive effects exists when this medication is used concurrently with other agents that have similar pharmacological effects. Close monitoring of the patient’s clinical status is advised to mitigate risks associated with increased effects.

Pharmacokinetic Interactions:

• Co-administration with drugs that are known to induce or inhibit metabolic pathways may alter the pharmacokinetics of this medication. Adjustments in dosage may be necessary based on the specific interacting agent and the clinical scenario. Regular monitoring of therapeutic levels and clinical response is recommended to ensure optimal therapeutic outcomes.

Healthcare providers should remain vigilant for any signs of interaction and adjust treatment regimens accordingly, ensuring patient safety and efficacy of 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

Fosaprepitant for Injection is not approved for use in pediatric patients. Therefore, there are no established age ranges, dosage recommendations, or safety and efficacy data available for children, infants, or adolescents. Healthcare professionals should consider this lack of approval when making treatment decisions for pediatric populations.

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 to date has not identified significant differences in responses to fosaprepitant between elderly and younger patients. However, it is important to exercise caution when dosing geriatric patients due to their increased likelihood of having diminished 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 individual patient factors when determining the appropriate dosage.

Pregnancy

There are no available data on the use of fosaprepitant in pregnant patients to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic exposures (AUC) approximately equivalent to the exposure at the recommended human dose (RHD) of 150 mg.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown; however, all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. 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.

In embryofetal development studies, aprepitant was administered during the period of organogenesis at oral doses up to 1,000 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. Aprepitant crosses the placenta in rats and rabbits, with exposures (AUC) in pregnant rats at 1,000 mg/kg twice daily and in pregnant rabbits at 25 mg/kg/day being approximately equivalent to the exposure at the RHD of 150 mg.

Healthcare professionals should consider the potential risks and benefits when prescribing fosaprepitant to women of childbearing potential.

Lactation

Aprepitant is known to cross into breast milk; however, there are no available data on the use of fosaprepitant in nursing mothers to inform a drug-associated risk of adverse developmental outcomes. The effects of fosaprepitant on a nursing infant are currently unknown. Therefore, caution should be exercised when administering fosaprepitant to a lactating mother.

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 of these patients.

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 with fosaprepitant or aprepitant, there is currently no specific information available regarding the treatment of such occurrences. It is recommended that Fosaprepitant for Injection be discontinued immediately. General supportive treatment and monitoring should be initiated to manage the patient's condition effectively.

Due to the antiemetic properties of Fosaprepitant for Injection, the induction of emesis may not be a viable option for addressing overdose situations. Therefore, healthcare professionals should be prepared to provide alternative supportive care as needed.

It is important to note that aprepitant is not removed from the body through hemodialysis, which may influence management strategies in cases of overdose. Continuous monitoring and supportive care remain the cornerstone of management in these situations.

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 1,000 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 period 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 (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 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. The highest dose produced a 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 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 indicative 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, infusion site reactions have been documented. Patients should also seek medical attention if they notice new or worsening signs or symptoms related to an infusion site reaction, such as 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) 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

The product is supplied in various package configurations, with specific NDC numbers available for identification. It is essential to store the product at a temperature range of 2° to 8°C (36° to 46°F) to maintain its efficacy and safety. Proper container requirements must be adhered to, ensuring that the product is kept in a suitable environment. Special handling needs should be observed to prevent any compromise to the product's integrity during storage and transportation.

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 for Injection, particularly around days 7 to 10 of each chemotherapy cycle.

Patients are advised to use effective alternative or back-up methods of contraception during treatment with Fosaprepitant for Injection 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. Symptoms such as flushing, erythema, dyspnea, hypotension, and syncope have been reported. Infusion site reactions (ISRs) have also been noted, particularly severe cases associated with concomitant vesicant chemotherapy, which may lead to complications such as thrombophlebitis, vasculitis, and necrosis. Most ISRs occurred after the first three exposures to Fosaprepitant, with some reactions lasting two weeks or longer. In cases of severe ISR, the infusion should be discontinued, and appropriate medical treatment should be administered. It is recommended to avoid infusing Fosaprepitant for Injection into small veins or through a butterfly catheter.

FDA Insert (PDF)

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

View full prescribing information (PDF)