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-glucito[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-1 H-1,2,4-triazol-1-yl]phosphonate(2:1) (salt).

The molecular formula is C23 H22 F7 N4 O6 P • 2(C7 H17 NO5), 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 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 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 regimen is recommended, consisting of fosaprepitant for injection on Day 1, followed by aprepitant capsules or fosaprepitant 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 in patients who have experienced hypersensitivity reactions 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 a 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, serves as a substrate, inhibitor, and inducer of CYP3A4. Clinicians should refer to the Full Prescribing Information for comprehensive recommendations regarding contraindications, potential adverse reactions, and necessary dosage adjustments for fosaprepitant and any concomitant medications.

In summary, careful monitoring of INR and awareness of potential drug interactions are critical for the safe use of fosaprepitant. Immediate discontinuation of the drug is warranted in the event of hypersensitivity reactions.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions observed in adults, occurring in 2% or more of participants, include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infections, and pain in extremities. Adverse reactions in pediatric populations are similar to those observed in adults.

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, 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 infusions 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. It is particularly important to monitor INR during the 2-week period following the initiation of fosaprepitant, especially 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 potential for known hypersensitivity to any component of this drug and the concurrent use with pimozide, which should be avoided.

Drug Interactions

Clinically significant drug interactions are detailed in the Full Prescribing Information, specifically in Sections 4, 5.1, 5.4, 5.5, 7.1, and 7.2. Healthcare professionals are advised to consult these sections for comprehensive information regarding potential interactions, including their mechanisms and clinical effects.

It is essential to consider dosage adjustments or enhanced monitoring protocols when co-administering with other medications, as outlined in the prescribing information. This ensures optimal therapeutic outcomes while minimizing the risk of adverse effects.

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 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 were further corroborated by an adequate and well-controlled study of a 3-day oral aprepitant regimen in pediatric patients within the same age range. However, the safety and effectiveness of fosaprepitant dimeglumine for preventing nausea and vomiting associated with HEC or MEC have not been established in patients younger than 6 months of age.

Toxicity studies in juvenile dogs treated with fosaprepitant from postnatal day 14 to day 42 revealed adverse effects, including decreased testicular weight and Leydig cell size in males at a dosage of 6 mg/kg/day, and increased uterine weight, hypertrophy of the uterus and cervix, and edema of vaginal tissues in females at 4 mg/kg/day. Additionally, a study in young rats assessed the effects of aprepitant on growth, neurobehavioral, and sexual development from postnatal day 10 through postnatal day 58, which corresponds to developmental stages from newborn to approximately 15 years 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 at oral doses up to 1000 mg/kg twice daily and to pregnant rabbits at the maximum tolerated dose of 25 mg/kg/day. 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

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 involving 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 outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution and consider the overall clinical context when prescribing this medication to patients with hepatic impairment.

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, the induction of emesis may not be effective in managing fosaprepitant overdosage. Therefore, alternative supportive measures should be prioritized.

Additionally, it should be recognized that aprepitant is not removed from the body through hemodialysis, which may influence the management approach 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, hepatocellular adenomas were observed at doses of 5 to 1,000 mg/kg twice daily, while hepatocellular carcinomas and thyroid follicular cell adenomas were noted 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 approximately twice that of the adult human exposure at the RHD of 150 mg. Treatment with aprepitant resulted in the development of skin fibrosarcomas in male mice at doses of 125 and 500 mg/kg/day. It is important to note that carcinogenicity studies were not conducted with fosaprepitant.

Both aprepitant and fosaprepitant 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 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 indicative 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, infusion site reactions have been documented. Patients should also seek medical attention if they notice new or worsening signs or symptoms related to an infusion site reaction, such as 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 taking fosaprepitant. 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. 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, defined as at or below 25°C (77°F). Any unused portion of the reconstituted solution should be discarded to prevent potential safety risks.

Additional Clinical Information

Clinicians should monitor the International Normalized Ratio (INR) in patients on chronic warfarin therapy during the 2-week period following the initiation of fosaprepitant, particularly between 7 to 10 days after each chemotherapy cycle. It is important to avoid infusing fosaprepitant for injection into small veins or through a butterfly catheter to ensure proper administration.

Patients should be counseled to use effective alternative or back-up methods of contraception during treatment with fosaprepitant and for one month following its administration to prevent potential contraceptive failure.

FDA Insert (PDF)

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

View full prescribing information (PDF)