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 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). Its empirical formula is C23H22F7N4O6P⋅ 2(C7H17NO5), and it has 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 (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 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 is recommended for adult patients at a dosage of 150 mg administered as an intravenous infusion. The infusion should be delivered over a period of 20 to 30 minutes. It is essential to complete the infusion approximately 30 minutes prior to the initiation of chemotherapy to ensure optimal efficacy.

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 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 within the two weeks following the initiation of fosaprepitant, especially around days 7 to 10, to ensure safe management of patients on anticoagulant therapy.

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

Side Effects

Patients receiving fosaprepitant may experience a range of adverse reactions. The most common adverse reactions reported in clinical trials among 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 adverse reactions may include hypersensitivity reactions, which can manifest as anaphylaxis or anaphylactic shock. These reactions may occur during or shortly after infusion. If such symptoms arise, the drug should be discontinued immediately, and it is advised not to reinitiate fosaprepitant in patients with a history of these reactions.

Infusion site reactions, including thrombophlebitis, necrosis, and vasculitis, have been predominantly reported in patients receiving vesicant chemotherapy. To minimize the risk of these reactions, it is recommended to avoid infusing fosaprepitant into small veins. In the event of a severe reaction, the infusion should be discontinued, and appropriate treatment should be administered.

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

Additionally, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the administration of fosaprepitant. Patients are advised to use effective alternative or back-up methods of contraception during this time.

Other important considerations include the risk of adverse reactions in patients with known hypersensitivity to any component of fosaprepitant and the concurrent use of pimozide, which is contraindicated.

Fosaprepitant is a weak inhibitor of CYP3A4, while aprepitant, its active moiety, acts as a substrate, inhibitor, and inducer of CYP3A4. Healthcare providers should refer to the Full Prescribing Information for detailed recommendations regarding contraindications, risk of adverse reactions, and dosage adjustments for fosaprepitant and concomitant medications.

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 the concomitant drugs. Dosage adjustments may be necessary based on the specific interaction and the clinical scenario.

Healthcare providers should remain vigilant and consider both the pharmacodynamic and pharmacokinetic profiles of all medications prescribed to ensure patient safety and therapeutic efficacy.

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 for injection 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. Caution is advised when considering the use of this medication in this age group.

Geriatric Use

Elderly patients, defined as those aged 65 and over, comprised 27% of the 1649 adult cancer patients treated with intravenous fosaprepitant for injection in high emetic risk (HEC) and moderate emetic risk (MEC) clinical studies, with 5% of patients aged 75 and over.

Clinical experience with fosaprepitant for injection has not identified significant differences in responses between elderly and younger patients. However, it is important to exercise caution when dosing geriatric patients due to their increased likelihood of having decreased hepatic, renal, or cardiac function, as well as the potential for concomitant diseases or other drug therapies.

Healthcare providers should closely monitor elderly patients for any adverse effects and consider individual patient factors when determining the appropriate dosage.

Pregnancy

There are insufficient data on the use of fosaprepitant for injection 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 available data, healthcare professionals should weigh the potential benefits and 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 lactating mother's clinical need for fosaprepitant for injection and any potential adverse effects on the breastfed infant from fosaprepitant for injection or from the underlying maternal condition.

Renal Impairment

In patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m²) and those with end-stage renal disease (ESRD) requiring hemodialysis, a single 240 mg oral dose of aprepitant was administered. Clinical findings indicate that in patients with severe renal impairment, the area under the curve (AUC₀-∞) of total aprepitant (both unbound and protein-bound) decreased by 21%, while the maximum concentration (Cmax) decreased by 32%, relative to healthy subjects with a creatinine clearance greater than 80 mL/min as estimated by the Cockcroft-Gault method.

In patients with ESRD undergoing hemodialysis, the AUC₀-∞ of total aprepitant decreased by 42%, with a similar 32% reduction in Cmax. Despite these changes, the modest decreases in protein binding of aprepitant in patients with renal disease did not significantly affect the AUC of the pharmacologically active unbound drug compared to healthy subjects. Furthermore, hemodialysis performed 4 or 48 hours after dosing had no significant impact on the pharmacokinetics of aprepitant, with less than 0.2% of the dose recovered in the dialysate.

Healthcare professionals should consider these pharmacokinetic alterations when prescribing aprepitant to patients with renal impairment and may need to monitor these patients closely.

Hepatic Impairment

Patients with hepatic impairment may not require dosage adjustments for fosaprepitant, as it is metabolized in various extrahepatic tissues. Consequently, hepatic impairment is not expected to significantly affect the conversion of fosaprepitant to aprepitant.

In clinical studies involving patients with mild hepatic impairment (Child-Pugh score 5 to 6), administration of a single 125 mg oral dose of aprepitant on Day 1 and 80 mg once daily on Days 2 and 3 resulted in an area under the curve (AUC0-24hr) of aprepitant that was 11% lower on Day 1 and 36% lower on Day 3 compared to healthy subjects receiving the same regimen. However, these differences in AUC0-24hr are not considered clinically meaningful.

For patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC0-24hr of aprepitant was observed to be 10% higher on Day 1 and 18% higher on Day 3 compared to healthy subjects. Similar to mild hepatic impairment, these variations are not deemed clinically significant.

Currently, there are no clinical or pharmacokinetic data available for patients with severe hepatic impairment (Child-Pugh score greater than 9). Therefore, caution is advised when considering the use of this medication in this population, and close monitoring may be warranted.

Overdosage

In the event of an overdose involving fosaprepitant or aprepitant, there is currently no specific information available regarding targeted treatment protocols. It is recommended that fosaprepitant for injection be discontinued immediately upon suspicion of an overdose.

General supportive treatment and close monitoring of the patient are essential components of management. Due to the antiemetic properties of fosaprepitant for injection, the induction of emesis may not be effective in cases of overdose, necessitating alternative supportive measures.

It is important to note that aprepitant is not removed from the body through hemodialysis, which should be taken into consideration when managing an overdose situation. Healthcare professionals should focus on symptomatic treatment and supportive care to ensure patient safety and comfort.

Nonclinical Toxicology

Carcinogenesis 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 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 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. The highest dose produced systemic exposure approximately two times 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, when administered intravenously, is rapidly converted to 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 1000 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 anaphylaxis and anaphylactic shock, have been reported in patients receiving fosaprepitant for injection. 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 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 receiving fosaprepitant for injection. 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 at a temperature range of 2° to 8°C (36° 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

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)