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-[[[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), with an empirical formula of C23H22F7N4O6P ∙ 2(C7H17NO5) and a molecular weight of 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. The formulation includes inactive ingredients such as 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 use in adults and pediatric patients aged 6 months and older, 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. Additionally, it is indicated 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.

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, consisting of fosaprepitant for injection on Day 1, followed by aprepitant capsules or aprepitant for oral suspension 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

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 if hypersensitivity symptoms have been experienced 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 its active metabolite, aprepitant, acts 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.

To ensure patient safety, monitoring of INR is recommended within the two-week timeframe after starting fosaprepitant, particularly focusing on the 7 to 10-day mark.

Side Effects

Patients receiving fosaprepitant 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 similar symptoms have occurred with previous 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 infusion into small veins. Should a severe reaction develop, the infusion should be discontinued, and appropriate treatment should be administered.

Patients on warfarin, a CYP2C9 substrate, should be monitored for a potential decrease in INR of prothrombin time, particularly during the 2-week period following the initiation of fosaprepitant, with close attention at 7 to 10 days post-initiation.

Additionally, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the administration of fosaprepitant. It is recommended that patients use effective alternative or backup methods of contraception during this period.

Adverse reactions observed in pediatric patients are similar to those seen in adults, indicating a consistent safety profile across age groups.

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 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 use is supported by evidence from adequate and well-controlled studies of fosaprepitant for injection in adults, along with additional safety, efficacy, and pharmacokinetic data specific to pediatric patients within this age range.

Furthermore, efficacy and safety findings are reinforced by data from an adequate and well-controlled study of a 3-day oral aprepitant regimen in pediatric patients aged 6 months to 17 years. However, 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 responses between elderly and younger patients.

However, caution is advised when dosing geriatric patients due to the increased likelihood of decreased 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 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. 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 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, the induction of emesis may not be effective in managing overdose 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 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

Carcinogenesis 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 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 (RHD) of 150 mg. Treatment with aprepitant at doses of 5 to 1000 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 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 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. It is noteworthy that carcinogenicity studies were not conducted with fosaprepitant.

Aprepitant and fosaprepitant were evaluated for mutagenic potential 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.

Fertility studies involving fosaprepitant and aprepitant indicated that fosaprepitant, upon intravenous administration, is rapidly converted to aprepitant. The highest systemic exposures to aprepitant were observed following oral administration. Notably, 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 1000 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

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

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

Patients should be informed that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in individuals taking fosaprepitant. They should 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°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, 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 undergoing chronic warfarin therapy during the two weeks following the initiation of fosaprepitant, with particular attention to the 7 to 10 day mark after each chemotherapy cycle.

Patients are advised to utilize effective alternative or back-up methods of contraception during treatment with fosaprepitant and for one month after administration to ensure adequate contraceptive protection.

FDA Insert (PDF)

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

View full prescribing information (PDF)