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. Fosaprepitant dimeglumine appears as a white or 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 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 following conditions:

• Prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), including high-dose cisplatin.

• 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 as an intravenous infusion. For patients receiving a single dose chemotherapy regimen, a single dose of 150 mg should be administered 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.

In cases of single or multi-day chemotherapy regimens, a 3-day regimen is recommended. Fosaprepitant for injection should be administered on Days 1, 2, and 3. On Days 2 and 3, aprepitant capsules or aprepitant for oral suspension may be utilized as an alternative.

For pediatric patients aged 12 years to 17 years, fosaprepitant for injection should be administered through a central venous catheter over 30 minutes. For patients aged 6 months to less than 12 years, the infusion should be extended to 60 minutes. As with 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 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 occurred with previous 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 the INR during a 2-week period, particularly between 7 to 10 days following the initiation of fosaprepitant.

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 the case of hypersensitivity symptoms, it is crucial to discontinue the drug and seek emergency medical assistance. If hypersensitivity reactions occur, patients should be instructed to stop taking the medication and contact their healthcare provider immediately.

Side Effects

Most common adverse reactions observed in adult patients (≥2%) include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, and pain in extremity.

Hypersensitivity reactions, which may include anaphylaxis and anaphylactic shock, can occur during or shortly after infusion. In the event that such symptoms arise, it is imperative to discontinue the drug immediately and not to reinitiate fosaprepitant for injection if similar symptoms have occurred with previous use.

Infusion site reactions, including thrombophlebitis, necrosis, and vasculitis, have been predominantly reported in patients receiving vesicant chemotherapy. To mitigate 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.

Patients taking warfarin, a CYP2C9 substrate, may experience a risk of decreased INR of prothrombin time. It is recommended to monitor INR closely during the two-week period following the initiation of fosaprepitant for injection, particularly around days 7 to 10.

The efficacy of hormonal contraceptives may be reduced during and for 28 days following the administration of fosaprepitant for injection. Patients are advised to use effective alternative or back-up methods of contraception during this time.

Adverse reactions in pediatric patients are reported to be similar to those observed in adults.

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 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 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 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 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. Additionally, 5% of these patients were aged 75 and over.

Clinical experience with fosaprepitant for injection has not revealed 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 prevalence of decreased hepatic, renal, or cardiac function, as well as concomitant diseases or other drug therapies that may influence drug metabolism and clearance.

Healthcare providers should carefully monitor elderly patients for potential adverse effects and consider dose adjustments as necessary to ensure safety and efficacy in this demographic.

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 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 of these patients.

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 information available regarding targeted treatment protocols. It is recommended that fosaprepitant for injection be discontinued immediately upon suspicion of an overdose.

General supportive treatment and close monitoring of the patient are essential in managing the situation. Due to the antiemetic properties of fosaprepitant for injection, the induction of emesis may not be effective in cases of overdose, which necessitates alternative supportive measures.

It is important to note that aprepitant is not removed from the body through hemodialysis, which may influence the management approach in cases of significant overdose. Healthcare professionals should remain vigilant and provide comprehensive care tailored to the individual patient's needs during such incidents.

Nonclinical Toxicology

Carcinogenesis 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 (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. 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 is rapidly converted to aprepitant when administered intravenously. In fertility studies involving both 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 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 anaphylaxis and anaphylactic shock, have been reported in patients receiving fosaprepitant for injection. 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 the most severe cases associated with certain chemotherapy agents known to cause skin damage, such as vesicants. These severe reactions may include pain, swelling, redness, and, in some instances, necrosis of the skin tissue.

Most ISR can occur following 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 include fatigue, weakness or numbness in the extremities, diarrhea, decreased white and red blood cell counts, dyspepsia, urinary tract infections, and limb pain. In pediatric patients aged 6 months to 17 years, common side effects consist of low red blood cell counts, low platelet counts, and low white blood cell counts, sometimes accompanied by fever.

Patients are advised to consult their healthcare provider for medical advice regarding side effects. Side effects may also be reported to the FDA at 1-800-FDA-1088.

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 advised 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, instruct them to follow their healthcare provider's guidance regarding blood draws to monitor their INR during the two-week period, particularly around 7 to 10 days after initiating fosaprepitant for injection with each chemotherapy cycle. 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. They should also disclose if they are pregnant, plan to become pregnant, or are breastfeeding, as it is not known whether fosaprepitant for injection can harm an unborn baby or if it passes into breast milk. Women using hormonal birth control methods should be advised to use a backup method of contraception that does not contain hormones during treatment and for one month after receiving fosaprepitant for injection.

Lastly, patients should be encouraged to maintain an updated 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 new medications. This is crucial 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. 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 after this period to ensure patient safety and product efficacy.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)