Fosaprepitant

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 dimeglumine 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. The compound appears as a white to off-white amorphous 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 (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

The recommended dosage for adults is 150 mg of Fosaprepitant for Injection, administered on Day 1. The administration should be conducted as an intravenous infusion 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 for Injection when used in conjunction with other 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 infusion must be discontinued immediately. It is imperative that Fosaprepitant for Injection is not reinitiated 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 essential to monitor the INR closely during the two-week period following the initiation of Fosaprepitant for Injection, 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 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 recommended within a two-week timeframe, especially between 7 to 10 days after the initiation of Fosaprepitant for Injection, to ensure safe management of patients on anticoagulant therapy.

In summary, careful consideration of these warnings and precautions is essential for the safe use of Fosaprepitant for Injection, and healthcare professionals should remain vigilant in monitoring patients for any adverse effects.

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 Fosaprepitant for Injection in patients with a history of these 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 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.

Fosaprepitant is a weak inhibitor of CYP3A4, while its active metabolite, aprepitant, acts as a substrate, inhibitor, and inducer of CYP3A4. Clinicians should refer to the Full Prescribing Information for guidance on contraindications, potential adverse reactions, and necessary dosage adjustments for Fosaprepitant for Injection and any concomitant medications.

Patients taking warfarin, a CYP2C9 substrate, should be monitored for a risk of decreased INR of prothrombin time, particularly during the 2-week period following the initiation of Fosaprepitant for Injection, with close attention to INR levels 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 for Injection. It is recommended that patients 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

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 (fosaprepitant dimeglumine), 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 in 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.

In a juvenile toxicity study involving dogs treated with fosaprepitant from postnatal day 14 to day 42, findings included decreased testicular weight and Leydig cell size in males at a dose of 6 mg/kg/day, and increased uterine weight, hypertrophy of the uterus and cervix, and edema of vaginal tissues in females at a dose of 4 mg/kg/day.

Additionally, a study in young rats assessed the effects of aprepitant on growth, neurobehavioral, and sexual development. Rats received oral doses up to 1000 mg/kg twice daily from postnatal day 10 through postnatal day 58. While slight changes in the onset of sexual maturation were noted in both sexes, there were no observed effects on mating, fertility, embryonic-fetal survival, or the histomorphology of reproductive organs. Neurobehavioral assessments of sensory function, motor function, and learning and memory showed no adverse effects.

Although pediatric use information is approved for this product, it is not included in the labeling due to marketing exclusivity rights held by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

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, caution is advised when dosing geriatric patients due to their increased likelihood of diminished hepatic, renal, or cardiac function, as well as the potential for concomitant diseases or other drug therapies. It is essential for healthcare providers to monitor these patients closely and consider dose modifications as necessary to ensure safety and efficacy.

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 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 the event of an overdose involving Fosaprepitant for Injection or Aprepitant, there is currently no specific information available regarding targeted treatment protocols. It is recommended that healthcare professionals discontinue the administration of Fosaprepitant for Injection immediately and provide general supportive care along with appropriate monitoring of the patient.

Due to the antiemetic properties of Fosaprepitant for Injection, it is important to note that drug-induced emesis may not be effective in managing overdose situations. Therefore, alternative supportive measures should be prioritized.

Additionally, it is crucial to understand that Aprepitant is not removed from the body through hemodialysis, which may influence the management approach in cases of overdose. Continuous assessment and supportive care remain the cornerstone of managing patients who have experienced an overdose of these agents.

Nonclinical Toxicology

Oral administration of aprepitant did not 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 the exposure at the recommended adult human dose of 150 mg, while in female rats, it was approximately equivalent to the adult human exposure.

Carcinogenicity studies were conducted in Sprague-Dawley rats and CD-1 mice over a period 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 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 a systemic exposure approximately two times that of the adult human exposure at the recommended human dose 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 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 of aprepitant.

Postmarketing Experience

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in patients receiving Fosaprepitant for Injection. Additionally, severe skin reactions, which may manifest as rash, skin peeling, or sores, have been observed. Infusion site reactions (ISR) at or near the infusion site have also occurred with Fosaprepitant for Injection. The most severe ISRs have been associated with certain chemotherapy agents known to cause skin damage, such as vesicants, which can lead to side effects including pain, swelling, and redness. In some cases, necrosis of skin tissue has been reported in individuals undergoing treatment with these chemotherapy agents. Most ISRs can occur after the first, second, or third dose of Fosaprepitant, with some reactions lasting up to two weeks or longer.

Patient Counseling

Advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly to understand the medication's use and potential risks. 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, such as hives, rash and itching, skin peeling or sores, flushing, difficulty in breathing or swallowing, dizziness, rapid or weak heartbeat, or feelings of faintness.

Patients should also be made aware of the possibility of new or worsening signs or symptoms of an infusion site reaction, including erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis at or near the infusion site, and should seek medical attention if these occur. It is essential for patients to discuss all medications they are currently taking, including prescription and non-prescription medications as well as herbal products, with their healthcare provider.

For patients on chronic warfarin therapy, instruct them to adhere to their healthcare provider's guidance regarding blood draws to monitor their INR during the two-week period following the initiation of Fosaprepitant for Injection with each chemotherapy cycle, particularly around days 7 to 10. Additionally, inform patients that the administration of Fosaprepitant for Injection may reduce the efficacy of hormonal contraceptives. Patients should be advised to use effective alternative or back-up methods of contraception, such as condoms and spermicides, during treatment and for one month following the administration of Fosaprepitant for Injection.

Before receiving Fosaprepitant for Injection, patients should inform their healthcare provider if they have liver problems. Pregnant patients or those planning to become pregnant should also notify their healthcare provider, as it is not known whether Fosaprepitant for Injection can harm an unborn baby. Women using hormonal birth control should be advised to use a non-hormonal backup method during treatment and for one month after receiving Fosaprepitant for Injection.

Patients who are breastfeeding or planning to breastfeed should discuss this with their healthcare provider, as it is not known if Fosaprepitant for Injection passes into breast milk. It is important for patients to keep a comprehensive list of all medications they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements, to share with their healthcare provider or pharmacist when receiving new medications, as Fosaprepitant for Injection may interact with other medicines, potentially leading to serious side effects.

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 when kept at ambient room temperature, which is defined as at or below 25°C (77°F). Proper handling and storage conditions are crucial to preserve the efficacy and safety of the medication.

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 Baxter Healthcare Corporation. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)