Emend Drug Information
Generic name: APREPITANT
Substance P/Neurokinin-1 Receptor Antagonist [EPC]
Uses of Emend
EMEND ® for oral suspension, in combination with other antiemetic agents, is indicated in patients 6 months of age and older 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. nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). EMEND ® is a substance P/neurokinin 1 (NK 1 ) receptor antagonist. Chronic continuous administration of EMEND is not recommended.
Limitations of Use EMEND has not been studied for the treatment of established nausea and vomiting.
Dosage & Administration of Emend
Recommended Dosage Adults and Pediatric Patients 12 Years of Age and Older The recommended oral dosage of EMEND capsules, dexamethasone, and a 5-HT 3 antagonist in adults and pediatric patients 12 years of age and older who can swallow oral capsules, for the prevention of nausea and vomiting associated with administration of HEC or MEC is shown in Table 1 or Table 2, respectively. For patients who cannot swallow oral capsules, EMEND for oral suspension can be used instead of EMEND capsules as shown in Table 3. Table 1: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with HEC If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4.
A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with EMEND. Pediatric Patients 6 Months to less than 12 Years of Age or Pediatric and Adult Patients Unable to Swallow Capsules The recommended dose of EMEND for oral suspension to be administered with a 5-HT 3 antagonist, with or without a corticosteroid, for the prevention of nausea and vomiting associated with administration of HEC or MEC is specified in Table 3. Dosing in pediatric patients less than 6 kg is not recommended.
Table 3: Recommended Dosing in Pediatric Patients 6 Months to Less than 12 Years of Age or Pediatric and Adult Patients Unable to Swallow Capsules Population Day EMEND for oral suspension After preparation, the final concentration of EMEND for oral suspension is 25 mg/mL.
Preparation Instructions for EMEND for Oral Suspension -- for Healthcare Providers EMEND for oral suspension should be prepared by a healthcare provider. Once prepared, it may be administered either by a healthcare provider, patient, or caregiver. Before preparing EMEND: Do not open the pouch of EMEND until ready to prepare the medicine.
Store the pouch at room temperature. Table 4: Instructions for Healthcare Providers on How to Prepare EMEND for Oral Suspension 10. If the dose is not administered immediately after measuring, store filled oral dosing dispenser(s) in the refrigerator for up to 72 hours prior to use.
When ready to use, the mixture can be kept at room temperature for up to 3 hours. 13. Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure
Administration Instructions
EMEND capsules and EMEND for oral suspension can be administered with or without food. EMEND capsules Swallow capsules whole. EMEND for oral suspension The dose will be prepared by the healthcare provider and dispensed to the patient or caregiver in an oral dispenser.
Keep the dispenser in the refrigerator until administered to the patient. The dose can be stored at room temperature for up to 3 hours before use. When ready to use, take the cap off the dispenser, place the dispenser in the patient's mouth along the inner cheek on either the right or left side.
Slowly dispense the medicine. The dose must be used within 72 hours of preparation. Discard any doses remaining after 72 hours.
| Population | Day 1 | Day 2 | Day 3 | Day 4 | |
|---|---|---|---|---|---|
| EMEND capsules Administer EMEND capsules 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days 2 and 3, administer EMEND capsules in the morning. | Adults and Pediatric Patients 12 Years and Older | 125 mg orally | 80 mg orally | 80 mg orally | none |
| Dexamethasone | Adults | 12 mg orally | 8 mg orally | 8 mg orally | 8 mg orally |
| Pediatric Patients 12 Years and Older | If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 [see Clinical Studies (14.3) ]. Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with EMEND [see Clinical Pharmacology (12.3) ]. | ||||
| 5-HT 3 antagonist | Adults and Pediatric Patients 12 Years and Older | See selected 5-HT 3 antagonist prescribing information for the recommended dosage | none | none | none |
| Population | Day 1 | Day 2 | Day 3 | |
|---|---|---|---|---|
| EMEND capsules Administer EMEND capsules 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days 2 and 3, administer EMEND capsules in the morning. | Adults and Pediatric Patients 12 Years and Older | 125 mg orally | 80 mg orally | 80 mg orally |
| Dexamethasone | Adults | 12 mg orally | none | none |
| Pediatric Patients 12 Years and Older | If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 [see Clinical Studies (14.3) ]. Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with EMEND [see Clinical Pharmacology (12.3) ]. | |||
| 5-HT 3 antagonist | Adults and Pediatric Patients 12 Years and Older | See the selected 5-HT 3 antagonist prescribing information for recommended dosage | none | none |
| Population | Day 1 | Day 2 | Day 3 | Day 4 | |
|---|---|---|---|---|---|
| EMEND for oral suspension After preparation, the final concentration of EMEND for oral suspension is 25 mg/mL [see Dosage and Administration (2.3) ]. Administer EMEND for oral suspension 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy is given on Days 2 and 3, administer EMEND for oral suspension in the morning. | Pediatric Patients 6 Months to Less than12 Years or Pediatric and Adult Patients Unable to Swallow Capsules | 3 mg/kg orally Maximum dose 125 mg | 2 mg/kg orally Maximum dose 80 mg | 2 mg/kg orally Maximum dose 80 mg | none |
| Dexamethasone | Adults Unable to Swallow Capsules | See Table 1 or 2 | See Table 1 or 2 | See Table 1 or 2 | See Table 1 or 2 |
| Pediatric Patients 6 Months to Less than12 Years or Pediatric Patients Unable to Swallow Capsules | If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4 [see Clinical Studies (14.3) ]. Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with EMEND [see Clinical Pharmacology (12.3) ]. | ||||
| 5-HT 3 antagonist | Pediatric Patients 6 Months to Less than12 Years or Pediatric and Adult Patients Unable to Swallow Capsules | See selected 5-HT 3 antagonist prescribing information for the recommended dosage | none | none | none |
| EMEND for oral suspension is packaged as a kit with one 1 mL oral dosing dispenser, one 5 mL oral dosing dispenser, one cap and one mixing cup. | |
| 1. Fill the mixing cup with room temperature drinking water. | |
| 2. Fill the 5 mL oral dosing dispenser with 4.6 mL of water from the mixing cup. Make sure no air is in the dispenser - if air is present, remove. | |
| 3. Discard all the unused water remaining in the mixing cup. | |
| 4. Add the 4.6 mL of water from the dispenser back into the mixing cup. | |
| 5. Each pouch of EMEND for oral suspension contains 125 mg of aprepitant which is to be suspended in 4.6 mL of water giving a final concentration of 25 mg/mL. Hold the EMEND for oral suspension pouch upright and shake the contents to the bottom before opening the pouch. 6. Pour the entire contents of the pouch into the 4.6 mL of water in the mixing cup and snap the lid shut. | |
| 7. Mix the EMEND suspension gently by swirling 20 times; then gently invert the mixing cup 5 times. To prevent foaming, do not shake the mixing cup. The mixture will be cloudy pink to light pink. | |
| 8. Check the EMEND mixture for any clumps or foaming: If any clumps are present, repeat Step 7 until there are no clumps. If there is any foam, wait for the foam to disappear before going on to Step 9. | |
| 9. Fill the dispenser with the prescribed dose shown above in Table 3. Choose the dispenser based on dose: Use 1 mL dispenser if dose is 1 mL or less. Use 5 mL dispenser if dose is more than 1 mL. Fill the dispenser with the prescribed dose from the cup. If the dose is less than 1 mL round to the nearest 0.1 mL. If the dose is more than 1 mL round to the nearest 0.2 mL. It is common to have medicine leftover in the cup. | |
| Make sure no air is in the dispenser - if air is present, remove. Make sure the dispenser contains the prescribed dose. | |
| 10. Place the cap on the dispenser until it clicks. 11. If the dose is not administered immediately after measuring, store filled oral dosing dispenser(s) in the refrigerator [between 36°F-46°F (2°C-8°C)] for up to 72 hours prior to use. When dispensing dose(s) to the patient or caregiver, instruct them to refrigerate the oral dosing dispenser(s) until they are ready to administer the dose. 12. When ready to use, the mixture can be kept at room temperature [between 68°F-77°F (20°C-25°C)] for up to 3 hours. | |
| 13. Discard the mixing cup along with any remaining suspension. |
Side Effects of Emend
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The overall safety of EMEND was evaluated in approximately 6800 individuals. Adults In 2 active-controlled, double-blind clinical trials in patients receiving highly emetogenic chemotherapy (HEC) (Studies 1 and 2), EMEND in combination with ondansetron and dexamethasone (EMEND regimen) was compared to ondansetron and dexamethasone alone (standard therapy).
In 2 active-controlled clinical trials in patients receiving moderately emetogenic chemotherapy (MEC) (Studies 3 and 4), EMEND in combination with ondansetron and dexamethasone (EMEND regimen) was compared to ondansetron and dexamethasone alone (standard therapy). The most common adverse reactions reported in patients who received HEC and MEC in pooled Studies are listed in Table 5. Table 5: Most Common Adverse Reactions in Patients Receiving HEC and MEC from a Pooled Analysis of HEC and MEC Studies Reported in ≥ 3% of patients treated with the EMEND regimen and at a greater incidence than standard therapy.
In a pooled analysis of the HEC and MEC studies, less common adverse reactions reported in patients treated with the EMEND regimen are listed in Table 6. In an additional active-controlled clinical study in 1169 patients receiving EMEND and HEC, the adverse reactions were generally similar to that seen in the other HEC studies with EMEND. In another CINV study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving the EMEND regimen with cancer chemotherapy.
Adverse reactions in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1. Pediatric Patients 6 Months to 17 Years of Age In a pooled analysis of 2 active-controlled clinical trials in pediatric patients aged 6 months to 17 years who received highly or moderately emetogenic cancer chemotherapy (Study 5 and a safety study, Study 6), EMEND in combination with ondansetron with or without dexamethasone (EMEND regimen) was compared to ondansetron with or without dexamethasone (control regimen). Table 7: Most Common Adverse Reactions in EMEND-Treated Pediatric Patients in HEC and MEC Pooled Studies 5 and 6 Reported in ≥3% of patients treated with the EMEND regimen and at a greater incidence than control regimen.
Forty-nine patients were treated with ifosfamide chemotherapy in each arm. Two of the patients treated with ifosfamide in the aprepitant arm developed behavioral changes (agitation = 1; abnormal behavior = 1), whereas no patient treated with ifosfamide in the control arm developed behavioral changes. Aprepitant has the potential for increasing ifosfamide-mediated neurotoxicity through induction of CYP3A4.
Non-CINV Studies Serious adverse reactions reported in adult patients receiving a non-recommended dosage of EMEND in non-CINV studies include single cases of each of the following: angioedema and urticaria, constipation, and sub-ileus. EMEND is only approved in the CINV population.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of EMEND. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis.
Immune system disorders: hypersensitivity reactions including anaphylactic reactions. Nervous system disorders: ifosfamide-induced neurotoxicity reported after EMEND and ifosfamide coadministration.
| EMEND, ondansetron, and dexamethasone EMEND regimen (N=1412) | Ondansetron and dexamethasone Standard therapy (N=1396) | |
|---|---|---|
| fatigue | 13% | 12% |
| diarrhea | 9% | 8% |
| asthenia | 7% | 6% |
| dyspepsia | 7% | 5% |
| abdominal pain | 6% | 5% |
| hiccups | 5% | 3% |
| white blood cell count decreased | 4% | 3% |
| dehydration | 3% | 2% |
| alanine aminotransferase increased | 3% | 2% |
| Infection and Infestations | oral candidiasis, pharyngitis |
| Blood and the Lymphatic System Disorders | anemia, febrile neutropenia, neutropenia, thrombocytopenia |
| Metabolism and Nutrition Disorders | decreased appetite, hypokalemia |
| Psychiatric Disorders | anxiety |
| Nervous System Disorders | dizziness, dysgeusia, peripheral neuropathy |
| Cardiac Disorders | palpitations |
| Vascular Disorders | flushing, hot flush |
| Respiratory, Thoracic and Mediastinal Disorders | cough, dyspnea, oropharyngeal pain |
| Gastrointestinal Disorders | dry mouth, eructation, flatulence, gastritis, gastroesophageal reflux disease, nausea, vomiting |
| Skin and Subcutaneous Tissue Disorders | alopecia, hyperhidrosis, rash |
| Musculoskeletal and Connective Tissue Disorders | musculoskeletal pain |
| General Disorders and Administration Site Condition | edema peripheral, malaise |
| Investigations | aspartate aminotransferase increased, blood alkaline phosphatase increased, blood sodium decreased, blood urea increased, proteinuria, weight decreased |
| EMEND and ondansetron EMEND regimen (N=184) | Ondansetron Control regimen (N=168) | |
|---|---|---|
| neutropenia | 13% | 11% |
| headache | 9% | 5% |
| diarrhea | 6% | 5% |
| decreased appetite | 5% | 4% |
| cough | 5% | 3% |
| fatigue | 5% | 2% |
| hemoglobin decreased | 5% | 4% |
| dizziness | 5% | 1% |
| hiccups | 4% | 1% |
Warnings & Cautions for Emend
Clinically Significant CYP3A4 Drug Interactions Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Use of EMEND with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug. Use of pimozide with EMEND is contraindicated due to the risk of significantly increased plasma concentrations of pimozide, potentially resulting in prolongation of the QT interval, a known adverse reaction of pimozide.
Use of EMEND with strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, diltiazem) may increase plasma concentrations of aprepitant and result in an increased risk of adverse reactions related to EMEND. Use of EMEND with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of EMEND. See Table 8 and Table 9 for a listing of potentially significant drug interactions.
Decrease in INR with Concomitant Warfarin Coadministration of EMEND with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle.
Risk of Reduced Efficacy of Hormonal Contraceptives
Upon coadministration with EMEND, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of EMEND. Advise patients to use effective alternative or back-up methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND.
Drug Interactions with Emend
Effect of Aprepitant on the Pharmacokinetics of Other Drugs Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Aprepitant acts as a moderate inhibitor of CYP3A4 when administered as a 3-day regimen (125-mg/80-mg/80-mg) and can increase plasma concentrations of concomitant drugs that are substrates for CYP3A4.
Some substrates of CYP3A4 are contraindicated with EMEND. Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 8. Table 8: Effects of Aprepitant on the Pharmacokinetics of Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions.
Intervention Monitor for benzodiazepine-related adverse reactions. Depending on the clinical situation (e.g., elderly patients) and degree of monitoring available, reduce the dose of intravenous midazolam Dexamethasone Clinical Impact Increased dexamethasone exposure. Intervention Reduce the dose of oral dexamethasone by approximately 50%.
Methylprednisolone Clinical Impact Increased methylprednisolone exposure. Intervention Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents Monitor for chemotherapeutic-related adverse reactions. Hormonal Contraceptives Clinical Impact Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of EMEND.
Decreased warfarin exposure and decreased prothrombin time (INR). Intervention In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day EMEND regimen with each chemotherapy cycle. Other 5-HT 3 Antagonists Clinical Impact No change in the exposure of the 5-HT 3 antagonist.
Intervention No dosage adjustment needed Examples ondansetron, granisetron, dolasetron
Co-administration of EMEND with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of aprepitant, respectively, as shown in Table 9. Table 9: Effects of Other Drugs on Pharmacokinetics of Aprepitant Moderate to Strong CYP3A4 Inhibitors Clinical Impact Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with EMEND. Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of EMEND.
Intervention Avoid concomitant use of EMEND. Examples rifampin, carbamazepine, phenytoin
| CYP3A4 Substrates | |
| Pimozide | |
| Clinical Impact | Increased pimozide exposure. |
| Intervention | EMEND is contraindicated [see Contraindications (4) ]. |
| Benzodiazepines | |
| Clinical Impact | Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions [see Clinical Pharmacology (12.3) ]. |
| Intervention | Monitor for benzodiazepine-related adverse reactions. Depending on the clinical situation (e.g., elderly patients) and degree of monitoring available, reduce the dose of intravenous midazolam |
| Dexamethasone | |
| Clinical Impact | Increased dexamethasone exposure [see Clinical Pharmacology (12.3) ]. |
| Intervention | Reduce the dose of oral dexamethasone by approximately 50% [see Dosage and Administration (2.1) ]. |
| Methylprednisolone | |
| Clinical Impact | Increased methylprednisolone exposure [see Clinical Pharmacology (12.3) ]. |
| Intervention | Reduce the dose of intravenous methylprednisolone by approximately 25% Reduce the dose of oral methylprednisolone by approximately 50% |
| Chemotherapeutic agents that are metabolized by CYP3A4 | |
| Clinical Impact | Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions [see Clinical Pharmacology (12.3) ]. |
| Intervention | Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents Monitor for chemotherapeutic-related adverse reactions. Etoposide, vinorelbine, paclitaxel, and docetaxel No dosage adjustment needed. |
| Hormonal Contraceptives | |
| Clinical Impact | Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of EMEND [see Warnings and Precautions (5.3), Use in Specific Populations (8.3), Clinical Pharmacology (12.3) ]. |
| Intervention | Effective alternative or back-up methods of contraception (such as condoms and spermicides) should be used during treatment with EMEND and for 1 month following the last dose of EMEND. |
| Examples | birth control pills, skin patches, implants, and certain IUDs |
| CYP2C9 Substrates | |
| Warfarin | |
| Clinical Impact | Decreased warfarin exposure and decreased prothrombin time (INR) [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3) ]. |
| Intervention | In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day EMEND regimen with each chemotherapy cycle. |
| Other | |
| 5-HT 3 Antagonists | |
| Clinical Impact | No change in the exposure of the 5-HT 3 antagonist [see Clinical Pharmacology (12.3) ]. |
| Intervention | No dosage adjustment needed |
| Examples | ondansetron, granisetron, dolasetron |
| Moderate to Strong CYP3A4 Inhibitors | |
| Clinical Impact | Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with EMEND [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ]. |
| Intervention | Avoid concomitant use of EMEND. |
| Examples | Moderate inhibitor: diltiazem Strong inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir |
| Strong CYP3A4 Inducers | |
| Clinical Impact | Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of EMEND [see Clinical Pharmacology (12.3) ]. |
| Intervention | Avoid concomitant use of EMEND. |
| Examples | rifampin, carbamazepine, phenytoin |
Pregnancy Safety for Emend
Pregnancy Risk Summary There are insufficient data on use of EMEND in pregnant women 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 1.5 times the adult human exposure at the 125-mg/80-mg/80-mg EMEND regimen. 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 respectively. Data Animal Data In embryofetal development studies in rats and rabbits, 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 125 mg/kg/day were approximately 1.5 times the adult exposure at the 125-mg/80-mg/80-mg EMEND regimen. Aprepitant crosses the placenta in rats and rabbits.
Pediatric Use of Emend
Pediatric Use The safety and effectiveness of EMEND for oral suspension have been established in pediatric patients 6 months of age and older and EMEND capsules in pediatric patients 12 years of age and older for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of HEC, including high-dose cisplatin, and MEC. EMEND was studied in combination with ondansetron with or without dexamethasone (at the discretion of the physician). Adverse reactions were similar to those reported in adult patients.
The safety and effectiveness of EMEND for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients less than 6 months. Juvenile Animal Study A study was conducted in young rats to evaluate the effects of aprepitant on growth and on neurobehavioral and sexual development. Rats were treated at oral doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended pediatric human dose and exposure in female rats equivalent to the pediatric human exposure) from the early postnatal period (Postnatal Day 10) through Postnatal Day 58.
Slight changes in the onset of sexual maturation were observed in female and male rats; however, there were no effects on mating, fertility, embryonic-fetal survival, or histomorphology of the reproductive organs. There were no effects in neurobehavioral tests of sensory function, motor function, and learning and memory.
Contraindications for Emend
EMEND is contraindicated in patients: who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions have been reported. taking pimozide. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of this drug which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide.
Known hypersensitivity to any component of this drug. Concurrent use with pimozide.
Overdosage Information for Emend
No specific information is available on the treatment of overdosage. Drowsiness and headache were reported in one patient who ingested 1440 mg of EMEND (approximately 11 times the maximum recommended single dose). In the event of overdose, EMEND should be discontinued and general supportive treatment and monitoring should be provided.
Because of the antiemetic activity of EMEND, drug-induced emesis may not be effective in cases of EMEND overdosage. Aprepitant is not removed by hemodialysis.
Clinical Studies of Emend
Prevention of Nausea and Vomiting Associated with HEC in Adults Oral administration of EMEND in combination with ondansetron and dexamethasone (EMEND regimen) has been shown to prevent acute and delayed nausea and vomiting associated with HEC including high-dose cisplatin, and nausea and vomiting associated with MEC. In Studies 1 and 2, both multicenter, randomized, parallel, double-blind, controlled clinical studies in adults, EMEND in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone alone) in patients receiving a chemotherapy regimen that included cisplatin greater than 50 mg/m 2 (mean cisplatin dose = 80.2 mg/m 2 ). See Table 11.
In these studies, 95% of the patients in the EMEND group received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common chemotherapeutic agents and the number of EMEND patients exposed follows: etoposide, fluorouracil, gemcitabine, vinorelbine, paclitaxel, cyclophosphamide, doxorubicin, docetaxel. The EMEND-treated patients in these clinical studies ranged from 14 to 84 years of age, with a mean age of 56 years.
Table 11: HEC Treatment Regimens – Studies 1 and 2 EMEND placebo and dexamethasone placebo were used to maintain blinding. The 12 mg dose of dexamethasone on Day 1 reflects a dosage adjustment to account for a drug interaction with the EMEND regimen. Efficacy was based on evaluation of the following endpoints in which emetic episodes included vomiting, retching, or dry heaves: Primary endpoint: complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries) Other prespecified endpoints: complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale score less than 25 mm on a 0 to 100 mm scale) no emesis (defined as no emetic episodes regardless of use of rescue therapy) no nausea (maximum VAS less than 5 mm on a 0 to 100 mm scale) no significant nausea (maximum VAS less than 25 mm on a 0 to 100 mm scale) A summary of the key study results from each individual study analysis is shown in Table 12.
In both studies, a statistically significantly higher proportion of patients receiving the EMEND regimen in Cycle 1 had a complete response in the overall phase (primary endpoint), compared with patients receiving standard therapy. A statistically significant difference in complete response in favor of the EMEND regimen was also observed when the acute phase and the delayed phase were analyzed separately. Table 12: Percent of Patients Receiving HEC Responding by Treatment Group and Phase — Cycle 1 In both studies, the estimated time to first emesis after initiation of cisplatin treatment was longer with the EMEND regimen, and the incidence of first emesis was reduced in the EMEND regimen group compared with standard therapy group as depicted in the Kaplan-Meier curves in Figure 1.
Figure 1 Additional Patient-Reported Outcomes: The impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 of both studies using the Functional Living Index–Emesis (FLIE), a validated nausea- and vomiting-specific patient-reported outcome measure. Minimal or no impact of nausea and vomiting on patients' daily lives is defined as a FLIE total score greater than 108. Multiple-Cycle Extension: In the same 2 clinical studies, patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy.
The proportion of patients with no emesis and no significant nausea by treatment group at each cycle is depicted in Figure 2. Antiemetic effectiveness for the patients receiving the EMEND regimen was maintained throughout repeat cycles for those patients continuing in each of the multiple cycles. Figure 2: Proportion of Patients Receiving HEC with No Emesis and No Significant Nausea by Treatment Group and Cycle Figure 2
Prevention of Nausea and Vomiting Associated with MEC in Adults EMEND was studied in two randomized, double-blind, parallel-group studies (Studies 3 and 4) in adult patients receiving MEC. See Table 13. In this study, the most common combinations were cyclophosphamide + doxorubicin (61%); and cyclophosphamide + epirubicin + fluorouracil (22%).
Of the 438 patients who were randomized to receive the EMEND regimen, 99.5% were women. Table 13: MEC Treatment Regimens – Studies 3 and 4 EMEND placebo and dexamethasone placebo were used to maintain blinding. The antiemetic activity of EMEND was evaluated based on the following endpoints in which emetic episodes included vomiting, retching, or dry heaves: Primary endpoint: complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries) in the overall phase (0 to 120 hours post-chemotherapy) Other prespecified endpoints: no emesis (defined as no emetic episodes regardless of use of rescue therapy) no nausea (maximum VAS less than 5 mm on a 0 to 100 mm scale) no significant nausea (maximum VAS less than 25 mm on a 0 to 100 mm scale) complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale score less than 25 mm on a 0 to 100 mm scale) complete response during the acute and delayed phases.
A summary of the key results from Study 3 is shown in Table 14. The difference between treatment groups was primarily driven by the "No Emesis Endpoint", a principal component of this composite primary endpoint. In addition, a higher proportion of patients receiving the EMEND regimen in Cycle 1 had a complete response during the acute (0-24 hours) and delayed (25-120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments.
Table 14: Percent of Patients Receiving MEC Responding by Treatment Group and Phase — Cycle 1 of Study 3 Additional Patient-Reported Outcomes: In Study 3, in patients receiving MEC, the impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 using the FLIE. A higher proportion of patients receiving the EMEND regimen reported minimal or no impact on daily life (64% versus 56%). This difference between treatment groups was primarily driven by the "No Vomiting Domain" of this composite endpoint.
Multiple-Cycle Extension: In Study 3, patients receiving MEC were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. The antiemetic effect for patients receiving the EMEND regimen was maintained during all cycles. In Study 4, EMEND in combination with ondansetron and dexamethasone was compared with a standard therapy (ondansetron and dexamethasone alone) in patients receiving a MEC regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide intravenous (less than 1500 mg/m 2 ); or cytarabine intravenous (greater than 1 g/m 2 ).
See Table 13. Patients receiving the EMEND regimen were receiving chemotherapy for a variety of tumor types including 50% with breast cancer, 21% with gastrointestinal cancers including colorectal cancer, 13% with lung cancer and 6% with gynecological cancers. Of the 430 patients who were randomized to receive the EMEND regimen, 76% were women and 24% were men.
Classified by ethnicity, 36% were Hispanic and 64% were non-Hispanic. A summary of the key results from Study 4 is shown in Table 15. In a subgroup analysis by tumor type, a numerically higher proportion of patients receiving EMEND were observed to have no vomiting and complete response compared to patients receiving standard therapy.
A similar difference for sex was observed for the no vomiting endpoint. Table 15: Percent of Patients Receiving MEC Responding by Treatment Group — Cycle 1 of Study 4
Prevention of Nausea and Vomiting Associated with HEC or MEC in Pediatric Patients In a randomized, double-blind, active comparator-controlled clinical study that included 302 pediatric patients aged 6 months to 17 years receiving HEC or MEC, EMEND in combination with ondansetron was compared to ondansetron alone (control regimen) for the prevention of CINV (Study 5). Intravenous dexamethasone was permitted as part of the antiemetic regimen in both treatment groups, at the discretion of the physician. A 50% dose reduction of dexamethasone was required for patients in the EMEND group, reflecting a dosage adjustment to account for a drug interaction.
No dexamethasone dose reduction was required for patients who received the control regimen. Eligible patients had documented malignancy at either an original diagnosis or relapse and were scheduled to receive emetogenic chemotherapy or a chemotherapy regimen not previously tolerated due to vomiting along with ondansetron as part of their antiemetic regimen. Other concomitant chemotherapy agents commonly administered and the number of EMEND patients exposed were: vincristine sulfate, etoposide, doxorubicin, ifosfamide, carboplatin, and cisplatin.
The treatment regimens in Study 5 for pediatric patients are defined in Table 16. Of the pediatric patients, 29% in the EMEND regimen and 28% in the control regimen used dexamethasone as part of the antiemetic regimen in Cycle 1. Table 16: HEC and MEC Treatment Regimens Intravenous dexamethasone was permitted at the discretion of the physician.
No dexamethasone dose reduction was required for patients in the control regimen. for Pediatric Patients 6 Months to 17 Years of Age— Study 5 The antiemetic activity of EMEND was evaluated over a 5-day (120 hour) period following the initiation of chemotherapy on Day 1. Patients had the opportunity to receive open-label EMEND in subsequent cycles (Optional Cycles 2-6); however, efficacy was not assessed in these optional cycles. Overall efficacy was based on the evaluation of the following endpoints: Primary endpoint: complete response (no vomiting, retching and no use of rescue medication) in the delayed phase (25 to 120 hours following initiation of chemotherapy) Other prespecified endpoints: complete response in the acute phase (0 to 24 hours following initiation of chemotherapy) complete response in the overall phase (up to 120 hours following initiation of chemotherapy) no vomiting (defined as no emesis, retching or dry heaves, regardless of use of rescue medication) in the overall phase safety and tolerability A summary of the key study results is shown in Table 17.
| Day 1 | Day 2 | Day 3 | Day 4 | |
|---|---|---|---|---|
| CINV EMEND Regimen | ||||
| Oral EMEND EMEND was administered 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3. | 125 mg | 80 mg | 80 mg | none |
| Oral Dexamethasone Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. The 12 mg dose of dexamethasone on Day 1 reflects a dosage adjustment to account for a drug interaction with the EMEND regimen [see Clinical Pharmacology (12.3) ]. | 12 mg | 8 mg | 8 mg | 8 mg |
| Ondansetron | 5-HT 3 antagonist Ondansetron 32 mg intravenous was used in the clinical trials of EMEND. Although this dose was used in clinical trials, this is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose. | none | none | none |
| CINV Standard Therapy | ||||
| Oral Dexamethasone | 20 mg | 8 mg twice daily | 8 mg twice daily | 8 mg twice daily |
| Ondansetron | 5-HT 3 antagonist | none | none | none |
| Study 1 | Study 2 | |||||
|---|---|---|---|---|---|---|
| ENDPOINTS | EMEND Regimen (N=260) N: Number of patients (older than 18 years of age) who received cisplatin, study drug, and had at least one post-treatment efficacy evaluation. % | Standard Therapy (N=261) % | p-Value | EMEND Regimen (N=261) % | Standard Therapy (N=263) % | p-Value |
| Visual analogue scale (VAS) score range: 0 mm=no nausea; 100 mm=nausea as bad as it could be. | ||||||
| PRIMARY ENDPOINT | ||||||
| Complete Response | ||||||
| Overall Overall: 0 to 120 hours post-cisplatin treatment. | 73 | 52 | <0.001 | 63 | 43 | <0.001 |
| OTHER PRESPECIFIED ENDPOINTS | ||||||
| Complete Response | ||||||
| Acute phase Acute phase: 0 to 24 hours post-cisplatin treatment. | 89 | 78 | <0.001 | 83 | 68 | <0.001 |
| Delayed phase Delayed phase: 25 to 120 hours post-cisplatin treatment. | 75 | 56 | <0.001 | 68 | 47 | <0.001 |
| Complete Protection | ||||||
| Overall | 63 | 49 | 0.001 | 56 | 41 | <0.001 |
| Acute phase | 85 | 75 | NS Not statistically significant when adjusted for multiple comparisons. | 80 | 65 | <0.001 |
| Delayed phase | 66 | 52 | <0.001 | 61 | 44 | <0.001 |
| No Emesis | ||||||
| Overall | 78 | 55 | <0.001 | 66 | 44 | <0.001 |
| Acute phase | 90 | 79 | 0.001 | 84 | 69 | <0.001 |
| Delayed phase | 81 | 59 | <0.001 | 72 | 48 | <0.001 |
| No Nausea | ||||||
| Overall | 48 | 44 | NS Not statistically significant. | 49 | 39 | NS |
| Delayed phase | 51 | 48 | NS | 53 | 40 | NS |
| No Significant Nausea | ||||||
| Overall | 73 | 66 | NS | 71 | 64 | NS |
| Delayed phase | 75 | 69 | NS | 73 | 65 | NS |
| Day 1 | Day 2 | Day 3 | |
|---|---|---|---|
| CINV EMEND Regimen | |||
| Oral EMEND EMEND was administered 1 hour prior to chemotherapy treatment on Day 1 and in the mornings on Days 2 and 3. | 125 mg | 80 mg | 80 mg |
| Oral Dexamethasone | 12 mg Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The 12 mg dose of dexamethasone on Day 1 reflects a dosage adjustment to account for a drug interaction with the EMEND regimen [see Clinical Pharmacology (12.3) ]. | none | none |
| Oral Ondansetron | 8 mg × 2 doses The first ondansetron dose was administered 30 to 60 minutes prior to chemotherapy treatment on Day 1 and the second dose was administered 8 hours after first ondansetron dose. | none | none |
| CINV Standard Therapy | |||
| Oral Dexamethasone | 20 mg | none | none |
| Oral Ondansetron | 8 mg × 2 doses | 8 mg twice daily | 8 mg twice daily |
| ENDPOINTS | EMEND Regimen (N=433) N: Number of patients included in the primary analysis of complete response. % | Standard Therapy (N=424) % | p-Value |
|---|---|---|---|
| PRIMARY ENDPOINT Overall: 0 to 120 hours post-chemotherapy treatment. | |||
| Complete Response | 51 | 42 | 0.015 |
| OTHER PRESPECIFIED ENDPOINTS | |||
| No Emesis | 76 | 59 | NS NS when adjusted for prespecified multiple comparisons rule; unadjusted p-value <0.001. |
| No Nausea | 33 | 33 | NS |
| No Significant Nausea | 61 | 56 | NS |
| No Rescue Therapy | 59 | 56 | NS |
| Complete Protection | 43 | 37 | NS |
| ENDPOINTS | EMEND Regimen (N=430) N = Number of patients who received chemotherapy treatment, study drug, and had at least one post-treatment efficacy evaluation. % | Standard Therapy (N=418) % | p-Value |
|---|---|---|---|
| No Vomiting Overall | 76 | 62 | <0.0001 |
| Complete Response Overall | 69 | 56 | 0.0003 |
| Day 1 | Day 2 | Day 3 | |
|---|---|---|---|
| CINV EMEND Regimen | |||
| Pediatric Patients 6 Months to less than 12 Years of Age EMEND was administered 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy was given on Days 2 and 3, EMEND was administered in the morning. | 3 mg/kg body weight oral suspension | 2 mg/kg body weight oral suspension | 2 mg/kg body weight oral suspension |
| Pediatric Patients 12 to 17 Years of Age | 125 mg capsule | 80 mg capsule | 80 mg capsule |
| Ondansetron | Per standard of care Ondansetron was administered 30 minutes prior to chemotherapy on Day 1 | none | none |
| CINV Control Regimen EMEND placebo was used to maintain blinding. | |||
| Ondansetron | Per standard of care | none | none |
| EMEND Regimen n/m (%) | Control Regimen n/m (%) | |
|---|---|---|
| n/m = Number of patients with desired response/number of patients included in time point. | ||
| Acute Phase: 0 to 24 hours following initiation of chemotherapy. | ||
| Delayed Phase: 25 to 120 hours following initiation of chemotherapy. | ||
| Overall Phase: 0 to 120 hours following initiation of chemotherapy. | ||
| PRIMARY ENDPOINT | ||
| Complete Response Complete Response = No vomiting or retching and no use of rescue medication. - Delayed phase | 77/152 (50.7) p<0.01 when compared to Control Regimen | 39/150 (26.0) |
| OTHER PRESPECIFIED ENDPOINTS | ||
| Complete Response – Acute phase | 101/152 (66.4) p<0.05 when compared to Control Regimen | 78/150 (52.0) |
| Complete Response – Overall phase | 61/152 (40.1) | 30/150 (20.0) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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