Emend

Description

EMEND (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 antiemetic agent. The chemical structure of fosaprepitant dimeglumine is described as 1-Deoxy-1-(methylamino)-D-glucitol[3-[[[2(R),3(S)-2-[(1(R)-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 EMEND for injection is intended for intravenous infusion and contains 150 mg of fosaprepitant, which is equivalent to 245.3 mg of fosaprepitant dimeglumine. The formulation includes inactive ingredients such as 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

EMEND 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. 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: EMEND has not been studied for the treatment of established nausea and vomiting.

Dosage and Administration

The recommended dosage for adults is 150 mg, administered as an intravenous infusion over a period of 20 to 30 minutes, approximately 30 minutes prior to the initiation of chemotherapy.

Prior to administration, the medication must be reconstituted with 5 mL of 0.9% sodium chloride. Following reconstitution, the solution should be added to an infusion bag containing 145 mL of 0.9% sodium chloride, resulting in a final concentration of 1 mg/mL.

Healthcare professionals should refer to the Full Prescribing Information for guidance on the recommended dosages of concomitant dexamethasone and a 5-HT3 antagonist for the management of highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC).

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 essential to consult the Full Prescribing Information for detailed recommendations regarding contraindications, potential adverse reactions, and necessary dosage adjustments for EMEND and any concomitant medications.

Hypersensitivity Reactions Patients may experience hypersensitivity reactions, including anaphylaxis and anaphylactic shock, during or shortly after the infusion of EMEND. Should any symptoms of hypersensitivity arise, the drug must be discontinued immediately. It is critical not to reinitiate EMEND in patients who exhibit these symptoms upon first-time use.

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 EMEND into small veins. In the event of a severe reaction, the infusion should be discontinued, 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 recommended to monitor INR closely during the two-week period following the initiation of EMEND, with particular attention to the 7 to 10-day mark.

Hormonal Contraceptives The efficacy of hormonal contraceptives may be compromised during treatment with EMEND and for up to 28 days following its administration. Healthcare providers should advise patients to utilize effective alternative or backup methods of contraception during this period to prevent unintended pregnancy.

Side Effects

Patients receiving EMEND may experience a range of adverse reactions. The most common adverse reactions, occurring in 2% or more of participants, include fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, and pain in extremities.

Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during or shortly after infusion. In such cases, it is imperative to discontinue the drug immediately and not to reinitiate EMEND if symptoms arise with first-time use.

Infusion site reactions, such as thrombophlebitis, necrosis, and vasculitis, have been predominantly reported in patients undergoing vesicant chemotherapy. To minimize the risk of these reactions, it is advised to avoid infusing EMEND into small veins. If a severe reaction develops, the infusion should be discontinued, and appropriate treatment should be administered.

Patients on warfarin, a CYP2C9 substrate, should be monitored for a potential decrease in INR of prothrombin time. It is particularly important to monitor INR during the 2-week period following the initiation of EMEND, especially around days 7 to 10.

Additionally, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the administration of EMEND. 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 EMEND and the concurrent use of pimozide, which should be avoided.

Drug Interactions

Clinically significant drug interactions are detailed in the Full Prescribing Information. Healthcare professionals are advised to consult this resource for comprehensive information regarding potential interactions, including pharmacodynamic and pharmacokinetic considerations.

Monitoring and dosage adjustments may be necessary based on the specific interactions identified. It is essential to evaluate each patient's medication regimen to mitigate risks associated with these interactions.

Packaging & NDC

The table below lists all NDC Code configurations of Emend (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 EMEND for injection have not been established in pediatric patients. Therefore, caution should be exercised when considering its use in this population. Further studies are needed to determine appropriate dosing and outcomes in children and adolescents.

Geriatric Use

Elderly patients, defined as those aged 65 and over, comprised 27% of the 1649 adult cancer patients treated with intravenous EMEND in high emetogenic chemotherapy (HEC) and moderate emetogenic chemotherapy (MEC) clinical studies. Additionally, 5% of these patients were aged 75 and over.

Clinical experience with EMEND has not identified 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 frequency of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Therefore, careful monitoring and consideration of these factors are recommended to ensure the safe and effective use of EMEND in geriatric patients.

Pregnancy

There are insufficient data on the use of EMEND (aprepitant) 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 these 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, with no evidence of embryofetal lethality or malformations at any dose level in either species.

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 lack of human data and the potential for drug exposure, healthcare professionals should weigh the benefits and risks of using EMEND 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 EMEND and any potential adverse effects on the breastfed infant from EMEND 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 outlined 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 EMEND (fosaprepitant or aprepitant), there is currently no specific information available regarding the treatment of such overdosage. Healthcare professionals are advised to discontinue the administration of EMEND immediately and to provide general supportive treatment along with appropriate monitoring of the patient.

Due to the antiemetic properties of EMEND, the induction of emesis may not be effective in cases of overdose. Therefore, alternative supportive measures should be prioritized to manage the patient's condition.

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. Continuous assessment and supportive care remain critical in ensuring patient safety and recovery.

Nonclinical Toxicology

Carcinogenesis 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 that of female rats or less than that of male rats 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 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.

In terms of mutagenesis, both aprepitant and fosaprepitant 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.

Regarding impairment of fertility, fosaprepitant is rapidly converted to aprepitant upon intravenous administration. 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, with male rat exposure being lower than that at the RHD of 150 mg and female rat exposure being approximately equivalent to human exposure.

Postmarketing Experience

Hypersensitivity reactions, including cases of anaphylaxis and anaphylactic shock, have been reported in patients receiving EMEND. Patients are advised to seek immediate medical attention if they experience signs or symptoms indicative of a hypersensitivity reaction, which may include hives, rash and itching, skin peeling or sores, flushing, difficulty in breathing or swallowing, dizziness, rapid or weak heartbeat, or feelings of faintness.

Additionally, new or worsening signs or symptoms of infusion site reactions have been documented. These may include erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis occurring at or near the infusion site.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) to ensure they are fully informed about the medication.

Healthcare providers should inform patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in individuals taking EMEND. Patients must be instructed to seek immediate medical attention if they experience any signs or symptoms of a hypersensitivity reaction. These may include hives, rash and itching, skin peeling or sores, flushing, difficulty in breathing or swallowing, dizziness, rapid or weak heartbeat, or feelings of faintness.

Additionally, patients should be counseled to seek medical attention if they notice new or worsening signs or symptoms of an infusion site reaction. This includes symptoms such as erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis at or near the infusion site.

Storage and Handling

Emend for injection is supplied in vials that require refrigeration. It should be 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 when kept at ambient room temperature, which is defined as at or below 25°C (77°F). Proper handling and storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Emend as submitted by Merck Sharp & Dohme Corp.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)