Fosaprepitant dimeglumine

Uses and Indications

Fosaprepitant for injection is indicated in adults and pediatric patients 6 months of age 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.

• Delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Focinvez is similarly indicated in adults and pediatric patients 6 months of age and older, in combination with other antiemetic agents, for the same prevention of nausea and vomiting associated with HEC and MEC.

Limitations of Use:Fosaprepitant and Focinvez have not been studied for the treatment of established nausea and vomiting.

Teratogenic and Nonteratogenic Effects:No teratogenic or nonteratogenic effects have been mentioned for either Fosaprepitant or Focinvez.

Dosage and Administration

Fosaprepitant is administered as an intravenous infusion. The recommended adult dosage is 150 mg on Day 1, infused over 20 to 30 minutes, and the infusion should be completed approximately 30 minutes prior to the start of chemotherapy.

For pediatric patients aged 6 months to 17 years weighing at least 6 kg, the dosing regimen varies by age and specific chemotherapy protocol. For single-dose chemotherapy regimens, a single dose of fosaprepitant for injection is given on Day 1. For single or multi-day chemotherapy regimens, a 3-day regimen is recommended, consisting of fosaprepitant for injection on Day 1, followed by aprepitant capsules or aprepitant for oral suspension on Days 2 and 3.

Administration for pediatric patients should be through a central venous catheter, with the infusion duration as follows: 30 minutes for patients aged 12 years to 17 years, and 60 minutes for those aged 6 months to less than 12 years. The infusion should also be completed approximately 30 minutes prior to chemotherapy.

For preparation, fosaprepitant for injection should be reconstituted with 5 mL of 0.9% sodium chloride and added to an infusion bag containing 145 mL of 0.9% sodium chloride to achieve a final concentration of 1 mg/mL.

Contraindications

Known hypersensitivity to any component of this drug is a contraindication for use. Additionally, concurrent use with pimozide is not recommended due to potential interactions.

Warnings and Precautions

Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or soon after infusion. If symptoms occur, the drug should be discontinued immediately. Reinitiation of fosaprepitant is not recommended if symptoms occurred with previous use.

Infusion Site Reactions Infusion site reactions, such as thrombophlebitis, necrosis, and vasculitis, have been reported, particularly in patients receiving vesicant chemotherapy. Infusion into small veins should be avoided. If a severe reaction develops, the infusion should be discontinued, and appropriate treatment should be administered.

Warfarin Interaction Fosaprepitant is a weak inhibitor of CYP2C9 and may decrease the INR of prothrombin time in patients taking warfarin. INR should be monitored during a 2-week period, particularly at 7 to 10 days following the initiation of fosaprepitant.

Hormonal Contraceptives The efficacy of hormonal contraceptives may be reduced during treatment with fosaprepitant and for 28 days following administration. Effective alternative or backup methods of contraception should be used.

CYP3A4 Interactions Fosaprepitant is a weak inhibitor of CYP3A4, and aprepitant, the active moiety, is a substrate, inhibitor, and inducer of CYP3A4. Refer to the Full Prescribing Information for recommendations regarding contraindications, risk of adverse reactions, and dosage adjustments of fosaprepitant and concomitant drugs.

Laboratory Tests INR should be monitored in a 2-week period, particularly at 7 to 10 days following the initiation of fosaprepitant.

Emergency Medical Help If symptoms of hypersensitivity occur, the drug should be discontinued, and emergency medical help should be sought.

Discontinuation Instructions Patients should discontinue the drug if hypersensitivity reactions occur.

Side Effects

Most common adverse reactions reported in adults (≥2%) include:

• Fatigue

• Diarrhea

• Neutropenia

• Asthenia

• Anemia

• Peripheral neuropathy

• Leukopenia

• Dyspepsia

• Urinary tract infection

• Pain in extremity

Serious Adverse Reactions

Hypersensitivity Reactions

• Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or soon after infusion. If symptoms occur, the drug should be discontinued, and it should not be reinitiated if symptoms occurred with previous use.

Infusion Site Reactions

• Infusion site reactions, including thrombophlebitis, necrosis, and vasculitis, have been reported, particularly in patients receiving vesicant chemotherapy. Infusion into small veins should be avoided. If a severe reaction develops, the infusion should be discontinued, and appropriate treatment administered.

Drug Interactions

• Warfarin (a CYP2C9 substrate): There is a risk of decreased INR of prothrombin time; INR should be monitored during a 2-week period, particularly at 7 to 10 days following initiation of treatment.

• Hormonal Contraceptives: The efficacy of hormonal contraceptives may be reduced during treatment and for 28 days following administration. Effective alternative or back-up methods of contraception should be used.

Additional Notes

• Known hypersensitivity to any component of the drug is a contraindication.

• Concurrent use with pimozide is not recommended.

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

Drug Interactions

Fosaprepitant, available in forms such as injection, powder, and lyophilized solution, has clinically significant drug interactions that are detailed in the full prescribing information. Healthcare professionals are advised to consult Sections 4, 5.1, 5.4, 5.5, 7.1, 7.2 of the prescribing information for a comprehensive list of these interactions.

Focinvez, also provided as an injection, does not have any specific drug interactions or laboratory test interactions documented in its labeling. However, it is recommended to refer to the full prescribing information for any potential clinically significant interactions.

In summary, while Fosaprepitant has documented interactions that require careful consideration, Focinvez currently lacks specific interaction data. It is essential for healthcare providers to review the full prescribing information for both medications to ensure safe and effective use.

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 initial and repeat courses of highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC). This conclusion is supported by evidence from adequate and well-controlled studies of fosaprepitant in adults, along with additional safety, efficacy, and pharmacokinetic data in the pediatric population.

Efficacy and safety were further corroborated by data from an adequate and well-controlled study of a 3-day oral aprepitant regimen in pediatric patients within the same age range. The safety of the 3-day fosaprepitant for injection regimen was also supported by an open-label study involving 100 pediatric patients receiving HEC or MEC.

However, 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.

In toxicity studies involving juvenile dogs and rats, changes in reproductive organs and slight alterations in sexual maturation were observed, but no effects on mating, fertility, embryonic-fetal survival, or neurobehavioral functions were noted. These findings highlight the need for caution when considering the use of fosaprepitant in very young patients.

Pediatric use information is approved for Merck Sharp & Dohme Corp.'s Emend (fosaprepitant) for injection; however, due to marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Geriatric Use

In clinical studies involving 1,649 adult cancer patients treated with intravenous fosaprepitant, 27% were aged 65 and over, and 5% were aged 75 and over. Clinical experience has not identified significant differences in responses to fosaprepitant between elderly patients and younger adults. However, caution is advised when dosing elderly patients due to a higher prevalence of decreased hepatic, renal, or cardiac function, as well as the potential for concomitant diseases or other drug therapies. Regular monitoring of these patients is recommended to ensure safety and efficacy.

Pregnancy

There are insufficient data on the use of fosaprepitant in pregnant patients to inform a drug-associated risk. In animal reproduction studies, 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. 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.

In embryofetal development studies, aprepitant was administered during the period of organogenesis at oral doses up to 1,000 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. Aprepitant crosses the placenta in both rats and rabbits.

Due to the lack of data on the presence of aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production, caution is advised when considering the use of fosaprepitant in breastfeeding patients. Aprepitant is present in rat milk, suggesting that it may also be present in human milk. The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for fosaprepitant and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Lactation

Lactation studies have not been conducted to assess the presence of aprepitant in human milk, nor have the effects on breastfed infants or milk production been evaluated. However, aprepitant is known to be present in rat milk, suggesting that it may also be excreted in human milk. Given the lack of data, caution should be exercised when administering fosaprepitant to lactating mothers.

The developmental and health benefits of breastfeeding should be carefully weighed against the mother's clinical need for fosaprepitant and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition. The effects of fosaprepitant on nursing infants remain unknown, and there are insufficient data to inform a drug-associated risk in this population.

Healthcare providers are advised to consider these factors when prescribing fosaprepitant to nursing women.

Renal Impairment

Patients with renal impairment may not require specific dosage adjustments or special monitoring when using Fosaprepitant or Fosaprepitant Dimeglumine, as no detailed information regarding these considerations is provided in the available labels.

However, it is noteworthy that in a study involving patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m²) and those with end-stage renal disease (ESRD) requiring hemodialysis, a single 240 mg oral dose of aprepitant was administered. The pharmacokinetic analysis revealed that the area under the curve (AUC₀-∞) of total aprepitant decreased by 21% in patients with severe renal impairment and by 42% in patients with ESRD, with a corresponding decrease in Cmax of 32% in both groups. Despite these reductions, the pharmacologically active unbound drug's AUC was not significantly affected compared to healthy subjects, indicating that the clinical implications of these changes may be minimal.

Additionally, hemodialysis performed 4 or 48 hours post-dosing did not significantly alter the pharmacokinetics of aprepitant, with less than 0.2% of the dose recovered in the dialysate.

Overall, while specific renal impairment considerations are not extensively detailed across the labels, the available data suggest that patients with renal impairment can be managed without significant alterations to dosing regimens, although clinical judgment should always be exercised.

Hepatic Impairment

Patients with hepatic impairment may require careful consideration when administering fosaprepitant. The pharmacokinetics of aprepitant in patients with mild (Child-Pugh score 5 to 6) and moderate (Child-Pugh score 7 to 9) hepatic impairment are similar to those of healthy subjects with normal hepatic function.

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. However, there are no clinical or pharmacokinetic data available for patients with severe hepatic impairment (Child-Pugh score greater than 9). Therefore, additional monitoring for adverse reactions may be warranted when fosaprepitant is administered to these patients.

It is important to note that fosaprepitant is metabolized in various extrahepatic tissues, suggesting that hepatic impairment is not expected to significantly alter the conversion of fosaprepitant to aprepitant.

Overdosage

In the event of an overdose involving fosaprepitant or aprepitant, it is essential to discontinue the administration of the drug immediately. General supportive treatment and monitoring should be provided to the patient. Due to the antiemetic properties of fosaprepitant, drug-induced emesis may not be effective in managing overdose situations.

It is important to note that aprepitant is not removed by hemodialysis, which may influence the management strategy in cases of overdose. Continuous monitoring of the patient's condition is recommended to address any potential complications that may arise.

Nonclinical Toxicology

Carcinogenesis

Carcinogenicity studies were conducted in Sprague-Dawley rats and CD-1 mice for a duration of 2 years. In the rat studies, animals were treated with 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 increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, hepatocellular adenomas were observed at doses of 5 to 1000 mg/kg twice daily, along with hepatocellular carcinomas and thyroid follicular cell adenomas at doses of 125 to 1000 mg/kg twice daily. In the mouse 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. Additionally, treatment with aprepitant resulted in the development of skin fibrosarcomas at doses of 125 and 500 mg/kg/day in male mice. 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, when administered intravenously, is rapidly converted to aprepitant. In fertility studies involving fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were achieved following oral administration of aprepitant. 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, which provided lower exposure in male rats than the exposure at the recommended adult human dose of 150 mg, and exposure in female rats that was approximately equivalent to the adult human exposure.

Storage and Handling

Fosaprepitant is supplied in the following forms: Injection, Powder, and Lyophilized for Solution. The vials must be refrigerated and stored at a temperature range of 2°C to 8°C (36°F to 46°F).

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). It is important to discard any unused portion of the reconstituted solution.

Focinvez is available as an Injection and should also be refrigerated at 2°C to 8°C (36°F to 46°F). When kept in the original carton, Focinvez vials can be stored at room temperature between 20°C to 25°C (68°F to 77°F) for a maximum of 90 days.

All handling should be conducted in accordance with standard medical protocols to ensure the integrity and safety of the products.