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 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. Fosaprepitant dimeglumine 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 (5.4 mg), polysorbate 80 (75 mg), lactose monohydrate (395 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 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 the 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, acts 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 as specified. If any symptoms of hypersensitivity reactions arise, the drug should be discontinued, and emergency medical assistance should be sought immediately.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions reported in adults (≥2%) include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, and pain in extremities. In pediatric populations, adverse reactions are similar to those observed in adults.

Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, 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, 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. Should a severe reaction develop, the infusion should be discontinued, and appropriate treatment should be administered.

Patients on warfarin, a CYP2C9 substrate, may experience a risk of decreased INR of prothrombin time. It is essential to monitor INR levels 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 known hypersensitivity to any component of this drug and the concurrent use of pimozide, which may pose additional 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 (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 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 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 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. Notably, 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. Additionally, 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. 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 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 and any potential adverse effects on the breastfed infant from fosaprepitant or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment may not have specific information regarding dosage adjustments, special monitoring, or safety considerations outlined in the prescribing information. Therefore, healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment and individualized patient assessment. Regular monitoring of renal function is advisable to ensure patient safety and therapeutic 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 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 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.

Due to the antiemetic properties of fosaprepitant, it is important to note that drug-induced emesis may not be effective in managing overdosage situations. Therefore, alternative supportive measures should be considered.

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 significant overdose. Continuous assessment and supportive care remain the cornerstone of management in such scenarios.

Nonclinical Toxicology

Carcinogenesis

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 1000 mg/kg twice daily. The highest dose resulted in systemic exposures to aprepitant that were approximately equivalent to the adult human exposure at the recommended human dose (RHD) of 150 mg, with female rats experiencing exposures at or below this level. 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. Carcinogenicity studies were not conducted with fosaprepitant.

Mutagenesis

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.

Impairment of Fertility

Fosaprepitant, upon intravenous administration, is rapidly converted to aprepitant. In fertility studies involving both 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 resulted in lower systemic levels in male rats compared to the recommended adult human dose of 150 mg, while female rats experienced exposures approximately equivalent to that of adult humans.

Postmarketing Experience

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in patients receiving fosaprepitant. Severe skin reactions, which may manifest as rash, skin peeling, or sores, have also been observed. Infusion site reactions (ISR) at or near the infusion site have occurred with fosaprepitant for injection, particularly in conjunction with certain chemotherapy agents known to cause skin damage, such as vesicants. These severe ISRs may present with symptoms including pain, swelling, and redness, and in some cases, necrosis of skin tissue has been reported.

Most ISRs can occur after the first, second, or third dose of fosaprepitant, with some lasting up to two weeks or longer. In adults, the most frequently reported side effects associated with fosaprepitant for injection include fatigue, weakness or numbness in the extremities, diarrhea, decreased white and red blood cell counts, dyspepsia, weakness, urinary tract infections, and pain in the arms and legs. In pediatric patients aged 6 months to 17 years, common side effects include low red blood cell count, low platelet count, and low white blood cell count accompanied by fever.

Healthcare professionals are advised to monitor for these adverse events and report any side effects to the FDA at 1-800-FDA-1088.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) thoroughly. It is important to inform patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in individuals taking fosaprepitant. Patients should 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.

Healthcare providers should instruct patients to seek medical attention if they notice new or worsening signs or symptoms of an infusion site reaction, which may include erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis at or near the infusion site. 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, it is crucial to follow the healthcare provider's instructions regarding blood draws to monitor their INR during the two-week period, particularly around 7 to 10 days after the initiation of fosaprepitant with each chemotherapy cycle. Patients should also be informed that the administration of fosaprepitant may reduce the efficacy of hormonal contraceptives. Therefore, they should 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.

Before receiving fosaprepitant for injection, patients should inform their healthcare provider if they have liver problems. Additionally, patients who are pregnant or planning to become pregnant should disclose this information, as it is not known whether fosaprepitant for injection can harm an unborn baby. Women using hormonal birth control should also be advised to use a backup method of contraception that does not contain hormones during treatment with fosaprepitant and for one month after receiving the injection.

Patients who are breastfeeding or planning to breastfeed should inform 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 obtaining a new medication. This is vital, as fosaprepitant for injection may affect the efficacy of other medications, and vice versa, potentially leading to serious side effects.

Storage and Handling

Fosaprepitant for injection is supplied in vials that must be stored under refrigeration at a temperature range of 2°C to 8°C (36°F to 46°F). It is important to ensure that the vials are kept within this temperature range to maintain the integrity of the product.

Once reconstituted, the final drug solution remains stable for 24 hours when stored at ambient room temperature, defined as at or below 25°C (77°F). Any unused portion of the reconstituted solution should be discarded to ensure patient safety and product efficacy.

Additional Clinical Information

Clinicians should monitor the International Normalized Ratio (INR) in patients on chronic warfarin therapy during the two weeks following the initiation of fosaprepitant, particularly around days 7 to 10, with each chemotherapy cycle. It is important to avoid infusing fosaprepitant for injection into small veins or through a butterfly catheter to minimize complications.

Patients should be counseled to use effective alternative or back-up methods of contraception during treatment with fosaprepitant and for one month after administration. Postmarketing experience has indicated that serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or shortly after the infusion of fosaprepitant. Additionally, infusion site reactions (ISRs) have been reported, with severe cases requiring medical or surgical intervention.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Fosaprepitant as submitted by Chia Tai Tianqing Pharmaceutical Group Co. , Ltd.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)