Fosaprepitant

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),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). 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 (5.4 mg), polysorbate 80 (75 mg), lactose monohydrate (395 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 patients undergoing initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), including those receiving high-dose cisplatin, as well as for the prevention of 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 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 regimen is recommended, with administration on Days 1, 2, and 3. Aprepitant capsules or aprepitant for oral suspension may be utilized as alternatives on Days 2 and 3.

When administering fosaprepitant for injection to pediatric patients, it should be delivered through a central venous catheter. The infusion duration is 30 minutes for patients aged 12 years to 17 years, and 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 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 arise, the drug must be discontinued immediately. It is imperative not to reinitiate fosaprepitant 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 essential 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 time to prevent unintended pregnancy.

Laboratory Tests Regular monitoring of INR is recommended within the two-week period following the initiation of fosaprepitant, especially around 7 to 10 days post-administration, to ensure safe management of patients on anticoagulant therapy.

In summary, healthcare professionals must remain vigilant regarding these warnings and precautions when prescribing fosaprepitant, ensuring appropriate monitoring and patient education to mitigate risks associated with its use.

Side Effects

Patients receiving treatment may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Most commonly reported adverse reactions in adults (≥2%) include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, and pain in extremity. In clinical trials specifically focused on the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy (MEC), the following frequencies were observed: 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 were reported in 2.2% of participants, with specific manifestations including infusion-site pain (1.2%), injection-site irritation (0.2%), vessel puncture-site pain (0.2%), and infusion-site thrombophlebitis (0.6%).

For patients receiving treatment for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy (HEC), infusion-site reactions were noted at a frequency of 3.0%, 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 either HEC or MEC, adverse reactions included anemia, neutropenia, thrombocytopenia, and febrile neutropenia, which occurred in more than 15% of patients who received the recommended dose.

Serious adverse reactions may include hypersensitivity reactions, such as anaphylaxis and anaphylactic shock, which can occur during or soon after infusion. If such symptoms occur, it is advised to discontinue the drug and not to reinitiate fosaprepitant if similar symptoms have been experienced with previous use. Furthermore, 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 to discontinue the infusion and provide appropriate treatment if a severe reaction develops.

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. Careful monitoring of the patient's clinical status is advised to mitigate potential adverse effects.

Pharmacokinetic interactions may alter the absorption, distribution, metabolism, or excretion of this medication or co-administered drugs. Dosage adjustments may be necessary based on the specific interaction and the clinical context.

Healthcare providers should remain vigilant and consider both the pharmacodynamic and pharmacokinetic profiles of concomitant medications to ensure safe and effective therapy.

Packaging & NDC

The table below lists all NDC Code configurations of Fosaprepitant (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 have been established in pediatric patients aged 6 months to 17 years for the prevention of acute and delayed nausea and vomiting associated with 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.

In this age group, both a single dose and a 3-day regimen of fosaprepitant for injection have demonstrated efficacy and safety. Furthermore, a 3-day oral regimen of aprepitant has also shown supportive efficacy and safety data in pediatric patients aged 6 months to 17 years. The safety of the 3-day fosaprepitant for injection regimen was further corroborated by an open-label study involving 100 pediatric patients receiving HEC or MEC.

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. Despite this representation, other reported clinical experience with fosaprepitant has not identified significant differences in responses between elderly and younger patients.

It is important to exercise caution when dosing geriatric patients, as they may exhibit a higher frequency of decreased hepatic, renal, or cardiac function, as well as concomitant diseases or other drug therapies. Therefore, careful monitoring and consideration of individual patient factors are recommended to ensure safe and effective use of fosaprepitant in this population.

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 1000 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 1000 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.

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; however, 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.

The developmental and health benefits of breastfeeding should be considered alongside 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

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

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 or 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 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, inducing vomiting may not be effective in managing overdosage situations. Therefore, alternative supportive measures should be prioritized.

It is important to note 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

Oral aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 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 1000 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 1000 mg/kg twice daily led to an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, the treatment resulted in hepatocellular adenomas at doses of 5 to 1000 mg/kg twice daily, as well as hepatocellular carcinomas and thyroid follicular cell adenomas at doses of 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day, with the highest dose producing a systemic exposure approximately two times 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. 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 conducted with both fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were achieved 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 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, new or worsening signs or symptoms of infusion site reactions have been documented. 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 any 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. 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 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 to prevent waste and ensure patient safety.

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 administering fosaprepitant for injection into small veins or via a butterfly catheter to prevent complications.

Patients should be counseled to utilize effective alternative or back-up contraceptive methods during treatment with fosaprepitant and for one month after its administration. Postmarketing experience has indicated that serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or shortly after the infusion of fosaprepitant. Additionally, infusion site reactions (ISRs) have been reported, particularly with initial doses, and may persist for two weeks or longer. Management of severe ISRs may require medical or, in some cases, surgical intervention.

FDA Insert (PDF)

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

View full prescribing information (PDF)