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-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).

The molecular formula is C23H22F7N4O6P•2(C7H17NO5), and the molecular weight is 1004.83. Fosaprepitant dimeglumine 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 for the prevention of acute and delayed nausea and vomiting in adults and pediatric patients aged 6 months and older, when used in combination with other antiemetic agents. This drug is specifically indicated for the prevention of nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), including high-dose cisplatin, as well as for delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Limitations of use include that fosaprepitant for injection has not been studied for the treatment of established nausea and vomiting. There are no teratogenic or nonteratogenic effects reported for this medication.

Dosage and Administration

Fosaprepitant for injection is administered intravenously. For adult patients, the recommended dosage is 150 mg on Day 1, infused over a period of 20 to 30 minutes. It is essential to complete the infusion approximately 30 minutes prior to the initiation of chemotherapy.

For pediatric patients aged 6 months to 17 years, weighing at least 6 kg, dosing regimens vary by age and should be referenced in the Full Prescribing Information. For single-dose chemotherapy regimens, a single dose of fosaprepitant for injection is administered on Day 1. In cases of single or multi-day chemotherapy regimens, a 3-day fosaprepitant for injection regimen is recommended on Days 1, 2, and 3. Alternatively, aprepitant capsules or fosaprepitant for oral suspension may be utilized on Days 2 and 3.

When administering fosaprepitant for injection to pediatric patients, it should be delivered through a central venous catheter. The infusion should last 30 minutes for patients aged 12 years to 17 years, and 60 minutes for those aged 6 months to less than 12 years. As with adult patients, the infusion must be completed approximately 30 minutes prior to chemotherapy.

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.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions reported in adults, 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 if these 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 infusion 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 may occur with the use of this medication. It is essential to refer to the Full Prescribing Information for a comprehensive list of these interactions, which can be found in Sections 4, 5.1, 5.4, 5.5, 7.1, and 7.2.

Healthcare professionals are advised to evaluate the potential for drug interactions when prescribing this medication. Monitoring for adverse effects or therapeutic efficacy may be necessary, and dosage adjustments should be considered based on the specific interactions identified in the prescribing information.

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 have been established in pediatric patients aged 6 months to 17 years for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC). This is supported by data from adequate and well-controlled studies in adults, along with additional safety, efficacy, and pharmacokinetic data specific to the pediatric population.

Efficacy and safety findings are further corroborated by an adequate and well-controlled study of a 3-day oral aprepitant regimen in pediatric patients within the same age range. Additionally, the safety of the 3-day fosaprepitant for injection regimen was demonstrated in an open-label study involving 100 pediatric patients receiving HEC or MEC.

It is important to note that the safety and effectiveness of fosaprepitant dimeglumine for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients younger than 6 months of age.

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 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. 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 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 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 overdosage situations. 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 strategies in cases of significant overdose. Continuous assessment and supportive care remain critical in the management of patients experiencing overdosage with 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, with male rat exposure being lower than that at the recommended adult human dose of 150 mg and female rat exposure being approximately equivalent to the adult human exposure.

Postmarketing Experience

During post-approval use of fosaprepitant, the following adverse reactions have been identified. These reactions were reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders have included pruritus, rash, urticaria, and severe cases such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Immune system disorders have encompassed hypersensitivity reactions, including instances of anaphylaxis and anaphylactic shock. Additionally, nervous system disorders have been reported, specifically ifosfamide-induced neurotoxicity occurring after the coadministration of fosaprepitant and ifosfamide.

Patient Counseling

Healthcare providers should monitor patients closely during and after the infusion of fosaprepitant for any signs of hypersensitivity reactions. Symptoms to be vigilant for include flushing, erythema, dyspnea, hypotension, and syncope. In the event that hypersensitivity reactions occur, the infusion should be discontinued immediately, and appropriate medical therapy should be administered. It is important to advise patients that fosaprepitant should not be reinitiated in those who have experienced hypersensitivity symptoms with previous use.

Additionally, healthcare providers should counsel patients on the importance of using effective alternative or back-up methods of contraception during treatment with fosaprepitant and for one month following administration. This is crucial as the efficacy of hormonal contraceptives may be reduced during and after treatment.

Providers should also caution patients against infusing fosaprepitant into small veins or through a butterfly catheter to minimize the risk of infusion site reactions. If a severe infusion site reaction develops during the infusion, the infusion should be discontinued, and appropriate medical treatment should be provided.

Storage and Handling

Fosaprepitant for injection is supplied in vials that must be stored under refrigeration at a temperature range of 2°C to 8°C (36°F to 46°F).

Once reconstituted, the final drug solution remains stable for 24 hours when kept at ambient room temperature, which should not exceed 25°C (77°F). It is important to discard any unused portion of the reconstituted solution to ensure safety and efficacy.

Additional Clinical Information

Fosaprepitant for injection should be administered as an intravenous infusion on Day 1, with the infusion lasting 20 to 30 minutes, and completed approximately 30 minutes prior to chemotherapy. For patients aged 12 to 17 years, the infusion should take 30 minutes, while for those aged 6 months to less than 12 years, it should take 60 minutes.

Clinicians should counsel patients to utilize effective alternative or back-up methods of contraception during treatment with fosaprepitant and for one month following its administration. Postmarketing experience has revealed skin and subcutaneous tissue disorders such as pruritus, rash, urticaria, and severe conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis. Additionally, hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported. There is also a noted risk of ifosfamide-induced neurotoxicity when fosaprepitant is coadministered with ifosfamide.

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)