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. Fosaprepitant is chemically 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). Its empirical formula is C23H22F7N4O6P·2(C7H17NO5), and it has a molecular weight of 1004.83 g/mol. Fosaprepitant dimeglumine appears as a white or whitish hygroscopic powder, which is freely soluble in water and methanol, but practically insoluble in absolute ethanol. Each vial of fosaprepitant for injection contains 150 mg of fosaprepitant, equivalent to 245.3 mg of fosaprepitant dimeglumine. Inactive ingredients include edetate disodium (5.4 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 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, the dosing regimen varies based on the chemotherapy schedule. For single-dose chemotherapy regimens, a single dose of fosaprepitant for injection is administered on Day 1. For 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 an alternative for Days 2 and 3.

When administering fosaprepitant for injection to pediatric patients, the infusion 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 adults, 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 the potential for serious interactions.

Warnings and Precautions

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or shortly after the infusion of fosaprepitant for injection. In the event of such symptoms, it is imperative to discontinue the drug immediately. Reinitiation of fosaprepitant is contraindicated if hypersensitivity reactions have been observed 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 for injection 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 INR closely during the two-week period following the initiation of fosaprepitant, with particular attention to the 7 to 10-day mark.

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 aprepitant, its active metabolite, 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.

To ensure patient safety, it is crucial to monitor INR levels within the specified two-week timeframe, particularly focusing on the 7 to 10 days following the initiation of treatment.

In the event of hypersensitivity reactions, patients should be instructed to discontinue the drug and seek emergency medical assistance immediately.

Side Effects

Patients receiving fosaprepitant for injection may experience a range of adverse reactions. Common adverse reactions reported include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infections, and pain in extremities.

Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or soon after infusion. If such symptoms arise, the drug should be discontinued immediately, and it is advised not to reinitiate treatment with fosaprepitant for injection if similar symptoms have occurred with previous use.

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

Additional important considerations include the risk of known hypersensitivity to any component of the drug and the potential for interactions with other medications. Concurrent use with pimozide is contraindicated. Furthermore, there is a risk of decreased INR of prothrombin time in patients taking warfarin, a CYP2C9 substrate; therefore, monitoring of INR is essential during the two-week period following the initiation of fosaprepitant for injection, particularly around days 7 to 10. It is also important to note that the efficacy of hormonal contraceptives may be reduced during and for 28 days following administration of fosaprepitant for injection; thus, effective alternative or backup methods of contraception should be utilized.

Drug Interactions

There are currently no documented drug interactions associated with the use of this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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 in adults, along with additional safety, efficacy, and pharmacokinetic data specific to pediatric patients within this age range.

Efficacy and safety findings are further corroborated by an adequate and well-controlled study of a 3-day oral aprepitant regimen in pediatric patients aged 6 months to 17 years. The safety profile of the 3-day fosaprepitant for injection regimen in this population was also supported by an open-label study involving 100 patients receiving HEC or MEC.

It is important to note that the safety and effectiveness of fosaprepitant for injection 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 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 patients and their younger counterparts. However, it is important to exercise caution when dosing in this population. Elderly patients often exhibit a higher frequency of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

Healthcare providers should consider these factors when determining the appropriate dosage and monitoring requirements for geriatric patients receiving fosaprepitant for injection.

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 during the period of organogenesis at oral doses up to 1000 mg/kg twice daily in rats and up to the maximum tolerated dose of 25 mg/kg/day in rabbits. 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.

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

Patients with renal impairment have no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular monitoring of renal function may be warranted in patients with reduced kidney function to ensure safety and efficacy.

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 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 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 recognition of an overdose.

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

Additionally, it is important to note that aprepitant is not removed from the body through hemodialysis, which may influence the management approach in cases of overdose. Healthcare professionals should remain vigilant and provide appropriate supportive care as needed.

Nonclinical Toxicology

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 1000 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 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. The highest dose produced systemic exposure that was approximately twice that of the adult human exposure at the RHD of 150 mg. Treatment with aprepitant resulted in the development of skin fibrosarcomas at doses of 125 and 500 mg/kg/day in male mice. It is noteworthy that carcinogenicity studies were not conducted with fosaprepitant.

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. Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant.

In fertility studies involving fosaprepitant and 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 cases of 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, reports of new or worsening signs or symptoms of infusion site reactions have been documented. Patients should seek medical attention if they notice 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 fully. It is important to inform patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in individuals receiving fosaprepitant for injection. Patients 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.

Healthcare providers should also 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.

Patients should be encouraged to discuss all medications they are currently taking, including prescription medications, non-prescription medications, and herbal products, to ensure safe and effective use of fosaprepitant for injection. For patients on chronic warfarin therapy, it is essential to follow the healthcare provider's instructions regarding blood draws to monitor their INR during the 2-week period, particularly around 7 to 10 days after initiating fosaprepitant for injection with each chemotherapy cycle.

Additionally, patients should be informed that the administration of fosaprepitant for injection may reduce the efficacy of hormonal contraceptives. Therefore, it is crucial to instruct patients to use effective alternative or back-up methods of contraception, such as condoms and spermicides, during treatment with fosaprepitant for injection and for one month following its administration.

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 potential safety and efficacy issues.

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 for injection, particularly around days 7 to 10, with each chemotherapy cycle.

Patients are advised to use effective alternative or back-up methods of contraception during treatment with fosaprepitant for injection and for one month following its administration.

FDA Insert (PDF)

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

View full prescribing information (PDF)