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-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). The empirical formula is C23H22F7N4O6P · 2(C7H17NO5), and the molecular weight is 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. Inactive ingredients include 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 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 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 as follows:

For adult patients, the recommended dosage is 150 mg administered as an intravenous infusion over a period of 20 to 30 minutes on Day 1. 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, the dosing regimen varies by age and should be referenced in the Full Prescribing Information. For single-dose chemotherapy regimens, a single dose of Fosaprepitant for injection is to be given on Day 1. For both single and multi-day chemotherapy regimens, a 3-day Fosaprepitant regimen is recommended, consisting of Fosaprepitant for injection on Day 1, followed by Aprepitant capsules or Aprepitant for oral suspension on Days 2 and 3.

Administration of Fosaprepitant for injection in pediatric patients should be performed through a central venous catheter. The infusion should be delivered over 30 minutes for patients aged 12 years to 17 years, and over 60 minutes for those aged 6 months to less than 12 years. Similar to 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.

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 recommended to monitor the INR closely during the two-week period following the initiation of fosaprepitant, with particular attention to the 7 to 10-day mark.

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 period to prevent unintended pregnancy.

Laboratory Tests Monitoring of INR is essential in patients receiving warfarin therapy, particularly within the first two weeks after starting fosaprepitant, with a focus on the 7 to 10-day interval for optimal management of anticoagulation therapy.

In summary, careful consideration of these warnings and precautions is vital for the safe use of fosaprepitant in clinical practice.

Side Effects

Most common adverse reactions observed in adult patients (≥2%) include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, and pain in extremity.

In clinical trials for the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy (MEC), the following adverse reactions were reported: fatigue (15%), diarrhea (13%), neutropenia (8%), asthenia (4%), anemia (3%), peripheral neuropathy (3%), leukopenia (2%), dyspepsia (2%), urinary tract infection (2%), and pain in extremity (2%). Additionally, infusion-site reactions occurred in 2.2% of participants, which included infusion-site pain (1.2%), injection-site irritation (0.2%), vessel puncture-site pain (0.2%), and infusion-site thrombophlebitis (0.6%).

For the prevention of nausea and vomiting associated with highly emetogenic chemotherapy (HEC), infusion-site reactions were reported in 3.0% of adult patients, with specific reactions including infusion-site erythema (0.5%), infusion-site pruritus (0.3%), and infusion-site induration (0.2%).

In pediatric patients aged 6 months to 17 years receiving treatment for the prevention of nausea and vomiting associated with HEC or MEC, adverse reactions included anemia, neutropenia, thrombocytopenia, and febrile neutropenia, with the latter being the most common adverse reaction occurring in more than 15% of patients who received the recommended dose.

Hypersensitivity reactions may occur during or soon after infusion. If such symptoms arise, the drug should be discontinued, and it is advised not to reinitiate fosaprepitant if symptoms have occurred with previous use. Infusion site reactions, including thrombophlebitis, necrosis, and vasculitis, have been reported, particularly in patients receiving vesicant chemotherapy. It is recommended to avoid infusion into small veins, and if a severe reaction develops, the infusion should be discontinued, and appropriate treatment administered.

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 that have similar mechanisms of action. Close monitoring of the patient’s clinical status is advised to mitigate potential adverse effects.

Pharmacokinetic interactions may arise due to alterations in the absorption, distribution, metabolism, or excretion of this medication when administered with other drugs. Dosage adjustments may be necessary based on the specific interacting agent and the patient's response. Regular monitoring of drug levels and clinical parameters is recommended to ensure therapeutic efficacy and safety.

Healthcare providers should remain vigilant for any signs of interaction and adjust treatment regimens accordingly to optimize patient outcomes.

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 a single dose and a 3-day regimen 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).

The use of Fosaprepitant in this age group is supported by evidence from adequate and well-controlled studies conducted in adults, along with additional safety, efficacy, and pharmacokinetic data specific to pediatric patients aged 6 months to 17 years. Furthermore, efficacy and safety were corroborated by data from an adequate and well-controlled study of a 3-day oral aprepitant regimen in the same pediatric population.

It is important to note that the safety and effectiveness of Fosaprepitant 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 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

Lactation studies have not been conducted to assess the presence of aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production. However, aprepitant is present in rat milk.

When considering the use of fosaprepitant in lactating mothers, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for fosaprepitant and any potential adverse effects on the breastfed infant from fosaprepitant or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

Hepatic Impairment

In patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9), the pharmacokinetics of aprepitant are similar to those observed in healthy subjects with normal hepatic function. Consequently, no dosage adjustment is necessary for this patient population.

However, there is a lack of clinical and pharmacokinetic data regarding the use of aprepitant in patients with severe hepatic impairment (Child-Pugh score greater than 9). Therefore, when fosaprepitant is administered to patients with severe hepatic impairment, additional monitoring for adverse reactions may be warranted to ensure patient safety.

Overdosage

In the event of an overdose involving fosaprepitant or aprepitant, there is currently no specific information available regarding targeted treatment protocols. The primary recommendation is to discontinue the administration of fosaprepitant immediately.

Supportive care and monitoring are essential components of management in cases of overdose. Healthcare professionals should ensure that the patient is closely observed for any adverse effects and provided with general supportive treatment as necessary.

It is important to note that due to the antiemetic properties of fosaprepitant, the induction of emesis may not be effective in managing overdose situations. Additionally, aprepitant is not amenable to removal through hemodialysis, which should be taken into consideration when planning further management strategies.

Overall, the focus should remain on supportive care and vigilant monitoring of the patient’s condition following an overdose of these agents.

Nonclinical Toxicology

Carcinogenesis

Carcinogenicity studies were conducted in Sprague-Dawley rats and CD-1 mice over a duration of two 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 (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 the adult human exposure at the RHD 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. Carcinogenicity studies were not conducted with fosaprepitant.

Mutagenesis

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.

Impairment of Fertility

Fosaprepitant is rapidly converted to aprepitant when administered intravenously. In fertility studies involving both fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were achieved 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 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, with patients encouraged to seek medical attention for new or worsening signs or symptoms. 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 ensure they are fully informed about the medication.

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. These 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. This includes symptoms such as 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°C to 8°C (36°F to 46°F). Once reconstituted, the final drug solution remains stable for 24 hours at ambient room temperature, which is defined as at or below 25°C (77°F). Any unused portion of the reconstituted solution should be discarded. It is important to note that the container closure is not made with natural rubber latex, ensuring compatibility for individuals with latex sensitivities.

Additional Clinical Information

Patients receiving fosaprepitant should be advised to utilize effective alternative or back-up methods of contraception during treatment and for one month following administration. No further information is available regarding laboratory tests, abuse potential, route, method, and frequency of administration, or postmarketing experience.

FDA Insert (PDF)

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

View full prescribing information (PDF)