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). The molecular formula of fosaprepitant is C23H22F7N4O6P ⋅2(C7H17NO5), and it has a molecular weight of 1004.83. The compound appears as a white to off-white powder or granular powder and is freely soluble in water. Each vial of fosaprepitant for injection 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 anhydrous (375 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, 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 a known hypersensitivity to any component of the formulation. Additionally, concurrent use with pimozide is contraindicated due to potential 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 has the potential to interact with warfarin, a substrate of CYP2C9, leading to a decreased International Normalized Ratio (INR) of prothrombin time. Therefore, it is essential to monitor INR levels during the two-week period following the initiation of fosaprepitant, with particular attention to measurements taken between 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 classified as a weak inhibitor of CYP3A4, while its active metabolite, aprepitant, serves as a substrate, inhibitor, and inducer of CYP3A4. For detailed recommendations regarding contraindications, potential adverse reactions, and necessary dosage adjustments of fosaprepitant in conjunction with other medications, refer to the Full Prescribing Information.

In the case of hypersensitivity symptoms, it is crucial to discontinue the drug and seek emergency medical assistance promptly. If any symptoms of hypersensitivity arise, patients should be instructed to stop taking fosaprepitant and contact their healthcare provider immediately.

Side Effects

Patients receiving this medication may experience a range of adverse reactions. The most common adverse reactions reported include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infections, and pain in the extremities.

Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or soon after infusion. If such symptoms arise, it is imperative to discontinue the drug immediately and not to reinitiate treatment if the patient has experienced similar symptoms with previous use.

Infusion site reactions have also been noted, including thrombophlebitis, necrosis, and vasculitis, particularly 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.

Additional considerations include known hypersensitivity to any component of this drug and the concurrent use with pimozide, which may pose further risks.

Drug Interactions

There are currently no documented drug interactions associated with 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. Additionally, the safety of the 3-day fosaprepitant for injection regimen was demonstrated in 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. 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 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 is known to cross 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 available data, 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 conducted in 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 administering fosaprepitant to lactating mothers.

Renal Impairment

There is no specific information available 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

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 the event of an overdose involving fosaprepitant or aprepitant, there is currently no specific antidote or treatment protocol established. Healthcare professionals are advised to provide general supportive care and continuous monitoring of the patient’s condition.

Discontinuation of Fosaprepitant In cases of overdose, fosaprepitant should be promptly discontinued. It is important to note that drug-induced emesis may not be effective due to the antiemetic properties of the drug, which could hinder the expulsion of the substance from the gastrointestinal tract.

Management of Aprepitant Overdose Aprepitant is not amenable to removal through hemodialysis, which limits the options for intervention in the event of an overdose. Supportive care remains the cornerstone of management, focusing on symptomatic relief and monitoring for any adverse effects.

Healthcare professionals should remain vigilant and provide appropriate care tailored to the individual patient's needs, ensuring that all supportive measures are employed effectively.

Nonclinical Toxicology

Carcinogenicity studies were conducted in Sprague-Dawley rats and CD-1 mice over a duration of 2 years. In the rat carcinogenicity 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, 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 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 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 exposure in female rats was approximately equivalent to the adult human exposure.

Postmarketing Experience

During post-approval use of fosaprepitant, the following adverse reactions have been identified. These reactions were reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders have included pruritus, rash, urticaria, and severe cases such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Immune system disorders have encompassed hypersensitivity reactions, including instances of anaphylaxis and anaphylactic shock. Additionally, nervous system disorders have been reported, specifically ifosfamide-induced neurotoxicity following the coadministration of fosaprepitant and ifosfamide.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) to understand the medication's use and potential risks.

Healthcare providers should inform patients about the risk of hypersensitivity reactions associated with fosaprepitant, which may include anaphylaxis and anaphylactic shock. Patients should be instructed to seek immediate medical attention if they experience any signs or symptoms of a hypersensitivity reaction, such as hives, rash and itching, skin peeling or sores, flushing, difficulty in breathing or swallowing, dizziness, rapid or weak heartbeat, or feeling faint.

It is important to discuss the possibility of infusion site reactions with patients. They should be advised to seek medical attention if they notice new or worsening signs or symptoms at or near the infusion site, including erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis.

Patients should be encouraged to discuss all medications they are currently taking, including prescription and non-prescription medications, as well as herbal products, to avoid potential drug interactions.

For patients on chronic warfarin therapy, healthcare providers should instruct them to follow specific guidelines regarding blood draws to monitor their INR during the 2-week period following the initiation of fosaprepitant with each chemotherapy cycle, particularly around 7 to 10 days post-initiation.

Lastly, patients should be made aware that the administration of fosaprepitant may reduce the efficacy of hormonal contraceptives. They should be instructed to use effective alternative or back-up methods of contraception, such as condoms and spermicides, during treatment with fosaprepitant 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 drug 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, particularly between 7 to 10 days after each chemotherapy cycle.

Fosaprepitant should not be infused into small veins or through a butterfly catheter. In the event of a severe infusion site reaction (ISR), the infusion should be discontinued, and appropriate medical treatment should be provided. Patients are advised to use effective alternative or back-up methods of contraception during treatment with fosaprepitant and for one month following its administration.

FDA Insert (PDF)

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

View full prescribing information (PDF)