Emend Drug Information
Generic name: APREPITANT
Substance P/Neurokinin-1 Receptor Antagonist [EPC]
Uses of 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 ® capsules, in combination with other antiemetic agents, is indicated in patients 12 years 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. EMEND for oral suspension is indicated in combination with other antiemetic agents, in patients 6 months of age and older for 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 capsules is indicated in combination with other antiemetic agents, in patients 12 years of age and older for 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) Limitations of Use EMEND has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND is not recommended.
Limitations of Use EMEND has not been studied for the treatment of established nausea and vomiting. Chronic continuous administration of EMEND is not recommended because it has not been studied, and because the drug interaction profile may change during chronic continuous use.
Dosage & Administration of Emend
| EMEND capsules | Adults and Pediatric Patients 12 Years and Older |
|---|---|
| Dexamethasone | Adults |
| 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 |
| 5-HT3 antagonist | Adults and Pediatric Patients 12 Years and Older |
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 reaction reported in patients who received MEC in pooled Studies 3 and 4 was dyspepsia (6% versus 4%). Across these 4 studies there were 1412 patients treated with the EMEND regimen during Cycle 1 of chemotherapy and 1099 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy.
The most common adverse reactions reported in patients who received HEC and MEC in pooled Studies 1, 2, 3 and 4 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. 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% 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. Table 6: Less Common Adverse Reactions in EMEND-Treated Patients from a Pooled Analysis of HEC and MEC Studies Reported in > 0.5% of patients treated with the EMEND regimen, at a greater incidence than standard therapy and not previously described in Table 5. 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 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). There were 184 patients treated with the EMEND regimen during Cycle 1 and 215 patients received open-label EMEND for up to 9 additional cycles of chemotherapy.
In Cycle 1, the most common adverse reactions reported in pediatric patients treated with the EMEND regimen in pooled Studies 5 and 6 are listed in Table 7. 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. 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% 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.
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 Other Drugs CYP3A4 Substrates Pimozide Clinical Impact Increased pimozide exposure. Intervention EMEND is contraindicated . Benzodiazepines Clinical Impact 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 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 . 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 . 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) . 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
Effect of Other Drugs on the Pharmacokinetics of Aprepitant Aprepitant is a
CYP3A4 substrate . 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 . 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 . 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 2 to 4% and 15 to 20%, 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. Use of EMEND in these age groups is supported by evidence from 302 pediatric patients in a randomized, double-blind, active comparator controlled clinical study (n = 207 patients aged 6 months to less than 12 years, n = 95 patients aged 12 through 17 years). 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
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. Of the 550 patients who were randomized to receive the EMEND regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial.
The EMEND-treated patients in these clinical studies ranged from 14 to 84 years of age, with a mean age of 56 years. A total of 170 patients were 65 years or older, with 29 patients being 75 years or older. Table 11: HEC Treatment Regimens – Studies 1 and 2 EMEND placebo and dexamethasone placebo were used to maintain blinding.
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 . 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 The antiemetic activity of EMEND was evaluated during the acute phase (0 to 24 hours post-cisplatin treatment), the delayed phase (25 to 120 hours post-cisplatin treatment) and overall (0 to 120 hours post-cisplatin treatment) in Cycle 1. 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 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 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: Percent of Patients Receiving HEC Who Remain Emesis Free Over Time — Cycle 1 p-Value <0.001 based on a log rank test for Study 1 and Study 2; nominal p-values not adjusted for multiplicity. 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. In each of the 2 studies, a higher proportion of patients receiving the EMEND regimen reported minimal or no impact of nausea and vomiting on daily life (Study 1: 74% versus 64%; Study 2: 75% versus 64%). 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. In Study 3, in breast cancer patients, EMEND in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone) in patients receiving a MEC regimen that included cyclophosphamide 750-1500 mg/m 2 ; or cyclophosphamide 500-1500 mg/m 2 and doxorubicin (less than or equal to 60 mg/m 2 ) or epirubicin (less than or equal to 100 mg/m 2 ). 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. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and less than 1% Other. The EMEND-treated patients in this clinical study ranged from 25 to 78 years of age, with a mean age of 53 years; 70 patients were 65 years or older, with 12 patients being over 74 years.
Table 13: MEC Treatment Regimens – Studies 3 and 4 EMEND placebo and dexamethasone placebo were used to maintain blinding. 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 . 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 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. In Study 3, a statistically significantly (p=0.015) higher proportion of patients receiving the EMEND regimen (51%) in Cycle 1 had a complete response (primary endpoint) during the overall phase compared with patients receiving standard therapy (42%). 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 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 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. The distribution by race was 67% White, 6% Black or African American, 11% Asian, and 12% multiracial. Classified by ethnicity, 36% were Hispanic and 64% were non-Hispanic.
The EMEND-treated patients in this clinical study ranged from 22 to 85 years of age, with a mean age of 57 years; approximately 59% of the patients were 55 years or older with 32 patients being over 74 years. The antiemetic activity of EMEND was evaluated based on no vomiting (with or without rescue therapy) in the overall period (0 to 120 hours post-chemotherapy) and complete response (defined as no vomiting and no use of rescue therapy) in the overall period. A summary of the key results from Study 4 is shown in Table 15. In Study 4, a statistically significantly higher proportion of patients receiving the EMEND regimen (76%) in Cycle 1 had no vomiting during the overall phase compared with patients receiving standard therapy (62%). In addition, a higher proportion of patients receiving the EMEND regimen (69%) in Cycle 1 had a complete response in the overall phase (0-120 hours) compared with patients receiving standard therapy (56%). In the acute phase (0 to 24 hours following initiation of chemotherapy), a higher proportion of patients receiving EMEND compared to patients receiving standard therapy were observed to have no vomiting (92% and 84%, respectively) and complete response (89% and 80%, respectively). In the delayed phase (25 to 120 hours following initiation of chemotherapy), a higher proportion of patients receiving EMEND compared to patients receiving standard therapy were observed to have no vomiting (78% and 67%, respectively) and complete response (71% and 61%, respectively). 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.
For sex, the difference in complete response rates between the EMEND and standard regimen groups was 14% in females (64.5% and 50.3%, respectively) and 4% in males (82.2% and 78.2%, respectively) during the overall phase. 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 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
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. Of the 152 pediatric patients randomized to receive the EMEND regimen, 55% were male, 45% female, 78% White, 7% Asian, 0% Black, 24% Hispanic, and 13% Multi-Racial. The most common primary malignancies in subjects receiving the EMEND regimen were osteosarcoma (11%), Ewing's sarcoma (11%), neuroblastoma (9%) and rhabdomyosarcoma (8%). 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. 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 in the control regimen. for Pediatric Patients 6 Months to 17 Years of Age— Study 5 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 The antiemetic activity of EMEND was evaluated over a 5-day (120 hour) period following the initiation of chemotherapy on Day 1. The primary endpoint in Study 5 was complete response in the delayed phase (25 to 120 hours following chemotherapy) in Cycle 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. Table 17: Percent of Patients Who Responded to Treatment by Treatment Group and Phase – Cycle 1 of Study 5 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 p<0.01 when compared to Control Regimen 39/150 OTHER PRESPECIFIED ENDPOINTS Complete Response – Acute phase 101/152 p<0.05 when compared to Control Regimen 78/150 Complete Response – Overall phase 61/152 30/150
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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