Fosaprepitant dimeglumine

Description

Fosaprepitant for injection is a sterile, white to off-white lyophilized cake or powder 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 of fosaprepitant dimeglumine 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). Its molecular formula is C23H22F7N4O6P • 2(C7H17NO5), and it has a molecular weight of 1,004.83. Fosaprepitant dimeglumine is characterized 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), polysorbate 80 (75 mg), lactose anhydrous (375 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

Fosaprepitant for injection is recommended for adult patients at a dosage of 150 mg, administered as an intravenous infusion. The infusion should be delivered 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 the potential for adverse interactions.

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 has the potential to interact with warfarin, a substrate of CYP2C9, leading to a decreased International Normalized Ratio (INR) of prothrombin time. Therefore, it is essential to monitor the INR during a 2-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 classified as a weak inhibitor of CYP3A4, while its active metabolite, aprepitant, 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.

In the event of hypersensitivity symptoms, patients should discontinue the drug and seek emergency medical assistance. If hypersensitivity reactions occur, it is essential to stop taking fosaprepitant and contact a healthcare provider for further evaluation and management.

Regular monitoring of INR is recommended during the specified timeframe to ensure patient safety and effective management of anticoagulation therapy.

Side Effects

Patients receiving fosaprepitant may experience a range of adverse reactions. The most common adverse reactions reported in clinical trials involving adults (≥2%) 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 soon 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 hypersensitivity reactions to the drug.

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 recommended to avoid infusion 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 drug interactions to consider. When fosaprepitant is used concurrently with warfarin, a CYP2C9 substrate, there is a risk of decreased INR of prothrombin time. It is essential to monitor INR closely 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, the use of effective alternative or back-up methods of contraception is recommended.

Patients with known hypersensitivity to any component of this drug should not use fosaprepitant. Concurrent use with pimozide is also contraindicated.

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, including their mechanisms and clinical effects.

It is essential to evaluate the need for dosage adjustments or enhanced monitoring based on the specific interactions outlined in the prescribing information. This ensures optimal therapeutic outcomes while minimizing the risk of adverse effects associated with concurrent medication use.

Packaging & NDC

The table below lists all NDC Code configurations of 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 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 1,649 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. While the clinical experience with fosaprepitant has not identified significant differences in responses between elderly and younger patients, caution is advised when dosing this population.

Elderly patients often exhibit a higher frequency of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Therefore, healthcare providers should closely monitor these patients for potential adverse effects and consider dose adjustments as necessary to ensure safety and efficacy.

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

There are insufficient data on the use of fosaprepitant in nursing mothers to inform a drug-associated risk. Aprepitant, the active metabolite of fosaprepitant, is excreted in human breast milk. The effects of fosaprepitant on a nursing infant are unknown. Caution should be exercised when administering fosaprepitant to a nursing woman.

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

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 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 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 systemic exposure that was approximately twice that of the adult human exposure at the RHD 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 evaluated for genotoxicity and 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 1,000 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 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, reports of infusion site reactions have been noted. Patients should seek medical attention if they observe new or worsening signs or symptoms at or near the infusion site, such as erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly to understand the medication's use and potential risks.

Patients should be informed that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in individuals taking fosaprepitant. They 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, healthcare providers should counsel patients 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 at a temperature range of 2° to 8°C (36° to 46°F). 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). Any unused portion of the reconstituted solution should be discarded.

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 Dimeglumine as submitted by Eugia US LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)