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 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). The empirical formula is C23H22F7N4O6P ∙ 2(C7H17NO5), and the molecular weight is 1004.83 g/mol. Fosaprepitant dimeglumine appears as a white to off-white amorphous powder and is freely soluble in water. Each vial of EMEND for injection contains 150 mg of fosaprepitant, which is equivalent to 245.3 mg of fosaprepitant dimeglumine. Inactive ingredients in each vial 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

EMEND for injection is indicated for use in adults and pediatric patients aged 6 months and older, in conjunction with other antiemetic agents, for the prevention of acute and delayed nausea and vomiting. This includes prevention associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), such as high-dose cisplatin, as well as delayed nausea and vomiting related to initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).

Limitations of use include that EMEND has not been studied for the treatment of established nausea and vomiting. There are no reported teratogenic or nonteratogenic effects associated with EMEND.

Dosage and Administration

EMEND for injection is administered as an intravenous infusion. 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 who weigh at least 6 kg, dosing regimens vary by age and are detailed in the Full Prescribing Information. For single-dose chemotherapy regimens, a single dose of EMEND for injection is administered on Day 1. In cases of single- or multi-day chemotherapy regimens, a 3-day regimen is recommended, with EMEND for injection given on Days 1, 2, and 3. Alternatively, EMEND capsules or EMEND for oral suspension may be utilized on Days 2 and 3.

When administering EMEND 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

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. Reinitiation of EMEND is contraindicated 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 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 crucial to monitor the INR closely during the two-week period following the initiation of EMEND, with particular attention to values obtained between 7 to 10 days post-initiation.

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

Side Effects

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

In pediatric populations, adverse reactions are reported to be similar to those observed in adults, indicating a consistent safety profile across age groups.

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 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 infusion 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, particularly during the 2-week period following the initiation of EMEND, with particular attention 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 EMEND. It is recommended that patients use effective alternative or back-up methods of contraception during this time.

Other important considerations include the 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 are no known 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 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 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). Evidence supporting the use of EMEND in this age group includes data from adequate and well-controlled studies of EMEND for injection in adults, along with additional safety, efficacy, and pharmacokinetic data specific to pediatric patients.

Efficacy and safety were 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 EMEND for injection regimen was supported by an open-label study involving 100 pediatric patients receiving HEC or MEC.

It is important to note that the safety and effectiveness of EMEND 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 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 geriatric patients, as they may exhibit a higher frequency of decreased hepatic, renal, or cardiac function, as well as concomitant diseases or other drug therapies.

Healthcare providers should consider these factors when determining the appropriate dosage and monitoring requirements for elderly patients receiving EMEND.

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 occurred 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.

Aprepitant crosses the placenta in both rats and rabbits. 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 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 lack of human data and the unknown background risks, healthcare professionals should weigh the potential benefits and risks when considering the use of 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 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 EMEND (fosaprepitant or aprepitant), there is currently no specific information available regarding targeted treatment protocols. Healthcare professionals are advised to discontinue the administration of EMEND immediately upon suspicion of an overdose.

Supportive care and monitoring are essential components of management in such cases. Given the antiemetic properties of EMEND, it is important to note that drug-induced emesis may not be effective in mitigating the effects of an overdose. Therefore, alternative supportive measures should be employed to ensure patient safety and comfort.

Additionally, it is crucial to recognize that aprepitant is not removed from the body through hemodialysis, which may limit the effectiveness of this intervention in cases of overdose. Continuous assessment and supportive treatment remain the primary strategies for managing patients who have experienced an overdose of EMEND.

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 (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, when administered intravenously, 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 exposure at 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 EMEND. 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 EMEND for Injection, particularly in conjunction with certain chemotherapy agents known to cause skin damage (vesicants). These severe ISRs may present with symptoms such as pain, swelling, and redness, and in some cases, necrosis of skin tissue has been reported.

Most ISRs can occur following the first, second, or third dose of EMEND for Injection, 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, and urinary tract infections. 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) to understand the medication fully. It is important to inform patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in individuals taking EMEND. 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.

Healthcare providers should also counsel patients to seek medical attention if they notice new or worsening signs or symptoms of an infusion site reaction. These may include erythema, edema, pain, necrosis, vasculitis, or thrombophlebitis at or near the infusion site.

Patients must be encouraged to discuss all medications they are currently taking, including prescription medications, non-prescription medications, and herbal products, to ensure safe and effective use of EMEND. For patients on chronic warfarin therapy, it is essential to follow the healthcare provider's instructions regarding blood draws to monitor their INR during the 2-week period, particularly at 7 to 10 days after initiating EMEND with each chemotherapy cycle.

Additionally, patients should be made aware that the administration of EMEND may reduce the efficacy of hormonal contraceptives. They should be instructed to use effective alternative or back-up methods of contraception, such as condoms and spermicides, during treatment with EMEND and for one month following the administration of EMEND.

Storage and Handling

Emend 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 efficacy.

Additional Clinical Information

Patients receiving EMEND should be advised to utilize effective alternative or back-up methods of contraception during treatment and for one month following the administration of EMEND. No further information is available regarding laboratory tests, abuse potential, route, method, frequency of administration, or postmarketing experience.

FDA Insert (PDF)

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

View full prescribing information (PDF)