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 is described as 1-Deoxy-1-(methylamino)-D-glucito[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 molecular formula of fosaprepitant dimeglumine is C23H22F7N4O6P • 2(C7H17NO5), and it has a molecular weight of 1004.83. The compound appears as a white to off-white 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 245.3 mg of fosaprepitant dimeglumine, equivalent to 150 mg of fosaprepitant free acid. 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

Fosaprepitant for injection should be administered as an intravenous infusion. The infusion must be completed approximately 30 minutes prior to the initiation of chemotherapy to ensure optimal efficacy.

For adult patients, the recommended dosage is 150 mg, which should be administered on Day 1 of the chemotherapy regimen. The intravenous infusion should be delivered over a period of 20 to 30 minutes. It is essential to monitor the patient during the infusion for any potential adverse reactions.

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. 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 may interact with warfarin, a substrate of CYP2C9, leading to a potential decrease in the International Normalized Ratio (INR) of prothrombin time. It is essential to monitor the INR during the two-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 a weak inhibitor of CYP3A4, while aprepitant, its active metabolite, serves as a substrate, inhibitor, and inducer of CYP3A4. Clinicians should refer to the Full Prescribing Information for comprehensive recommendations regarding contraindications, potential adverse reactions, and necessary dosage adjustments for fosaprepitant and any concomitant medications.

In summary, monitoring of INR is crucial during the specified timeframe after initiating fosaprepitant therapy to ensure patient safety and effective management of anticoagulation therapy.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions observed 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. In the event of such symptoms, it is imperative to discontinue the drug immediately and not to reinitiate fosaprepitant if similar symptoms have occurred with previous use.

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 advised to avoid infusing the drug into small veins. Should a severe reaction develop, the infusion should be discontinued, and appropriate treatment should be administered.

Additional considerations include known hypersensitivity to any component of the drug and the concurrent use with pimozide, which is contraindicated. There is also a risk of decreased INR of prothrombin time; therefore, monitoring of INR is recommended 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; thus, the use of effective alternative or backup methods of contraception is advised.

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.

It is essential to evaluate the pharmacodynamic and pharmacokinetic interactions that may arise when co-administering this medication with other drugs. Monitoring for adverse effects and therapeutic efficacy is recommended, and dosage adjustments may be necessary based on the specific interactions identified in the prescribing information.

For optimal patient safety and therapeutic outcomes, healthcare providers should remain vigilant and consider the implications of these interactions in their clinical decision-making.

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.

In juvenile animal studies, treatment with fosaprepitant in dogs revealed changes in reproductive organs, including decreased testicular weight and Leydig cell size in males, and increased uterine weight, hypertrophy of the uterus and cervix, and edema of vaginal tissues in females at doses of 6 mg/kg/day and 4 mg/kg/day, respectively. Additionally, juvenile rats treated with aprepitant showed slight changes in sexual maturation without any observed effects on reproduction, mating, fertility, embryonic-fetal survival, or the histomorphology of reproductive organs.

Neurobehavioral assessments in rats indicated no adverse effects on sensory function, motor function, learning, or memory following treatment with aprepitant at doses up to 1,000 mg/kg twice daily from postnatal day 10 to day 58, which corresponds to a developmental period from newborn to approximately 15 years of age.

While pediatric use information is approved for Emend (fosaprepitant) for injection, it is important to note that 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 their 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. In animal reproduction studies, 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.

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.

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. 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. Additionally, aprepitant crosses the placenta in both rats and rabbits.

Healthcare professionals should consider these findings when prescribing fosaprepitant to women of childbearing potential and weigh the potential benefits against any unknown risks.

Lactation

There are insufficient data on the use of fosaprepitant in lactating mothers to inform a drug-associated risk. Aprepitant has been shown to cross the placenta in animal studies conducted in rats and rabbits. However, data regarding the excretion of aprepitant in human breast milk and its effects on breastfed infants are not available. Therefore, caution is advised when considering the use of fosaprepitant in lactating mothers.

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 provide general supportive treatment and closely monitor the patient for any adverse effects.

Due to the antiemetic properties of fosaprepitant, it is important to note that drug-induced emesis may not be effective in managing symptoms associated with 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 management strategies in cases of significant overdose. Continuous assessment and supportive care remain the cornerstone of managing patients who have experienced an overdose of these agents.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. Oral administration of aprepitant did not impact 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 resulted in lower systemic levels in male rats compared to the recommended adult human dose of 150 mg, while female rats exhibited exposure levels approximately equivalent to those in adults.

Carcinogenicity studies were performed 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 (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, with the highest dose producing systemic exposure approximately twice that of the adult human exposure at the recommended human dose 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. No carcinogenicity studies were conducted with fosaprepitant.

Aprepitant and fosaprepitant were not found to be genotoxic in a series of 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.

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. These 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 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

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, can occur during or shortly after the infusion of fosaprepitant. Symptoms such as flushing, erythema, dyspnea, hypotension, and syncope have been reported. Additionally, infusion site reactions (ISRs) have been noted, particularly in conjunction with vesicant chemotherapy, where severe ISRs like thrombophlebitis and vasculitis were more common, especially with extravasation. Some patients experienced necrosis, and most ISRs occurred after the first three doses of fosaprepitant. In cases of severe ISR, it is crucial to discontinue the infusion and provide appropriate medical treatment, which may include surgical intervention.

FDA Insert (PDF)

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

View full prescribing information (PDF)