Drug Interactions
No pharmakinetic studies to determine the effect of EMEND on the concentration of etoposide or paclitaxel were performed.
Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of EMEND with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached cautiously. Moderate CYP3A4 inhibitors (e.g., diltiazem) resulted in a 2-fold increase in plasma concentrations of aprepitant; therefore, concomitant administration should also be approached with caution.
Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of EMEND.
In a separate pharmacokinetic study, EMEND (125 mg/80 mg regimen) did not influence the pharmacokinetics of vinorelbine.
EMEND may be administered with or without food.
Interactions with laboratory tests have not been established.
In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron administered intravenously, granisetron administered orally, or hydrodolasetron (the active metabolite of dolasetron) following oral administration of dolasetron.
As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of coadministered medicinal products that are metabolized through CYP3A4. EMEND may increase the plasma concentration of orally administered CYP3A4 substrates to a greater extent than if the substrate was administered intravenously.
Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of EMEND with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs.
Interactions with herbal products have not been established.
EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND with digoxin in a clinical drug interaction study.
Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, EMEND was administered with the following chemotherapeutic agents metabolized primarily or in part by CYP3A4: etoposide, vinorelbine, docetaxel, and paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. However, caution is advised and additional monitoring may be appropriate in patients receiving chemotherapy agents known to be metabolized by CYP3A4, especially those not studied in the clinical trials, including vinblastine, vincristine and ifosfamide (see Warnings and Precautions).
In a clinical study, EMEND did not influence the pharmacokinetics of docetaxel.
Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9.
Chronic continuous use of EMEND is not recommended because it has not been studied and because the drug interaction profile may change during chronic dosing.
Information for the Patient
Emend
Dosage and Administration
EMEND is indicated for use for a maximum of 3 consecutive days per chemotherapy cycle.
EMEND has not been demonstrated to be effective as a single anti-emetic agent and must be administered with other anti-emetic agents.
The recommended dose of EMEND is 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80 mg once daily in the morning on Days 2 and 3.
In clinical studies with EMEND, the following regimen was used for the prevention of nausea and vomiting associated with cisplatin-based highly emetogenic cancer chemotherapy:
| | Day 1 | Day 2 | Day 3 | Day 4 |
| EMENDa | 125 mg | 80 mg | 80 mg | none |
| Dexamethasoneb | 12 mg orally | 8 mg orally | 8 mg orally | 8 mg orally |
| Ondansetronc | 32 mg IV | none | none | none |
a. EMEND was administered orally 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.
b. Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4.
The dose of dexamethasone was chosen to account for drug interactions. Increasing the dose of dexamethasone is not recommended (see Drug Interactions). c. Ondansetron was administered 30 minutes prior to chemotherapy treatment on Day 1.
For highly emetic chemotherapy, there is only limited efficacy data with EMEND in combination with oral ondansetron or other 5-HT3 antagonist class of antiemetics and dexamethasone.
In a clinical study with EMEND, the following regimen was used for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy:
| | Day 1 | Day 2 | Day 3 |
| EMENDa | 125 mg | 80 mg | 80 mg |
| Dexamethasoneb | 12 mg orally | none | none |
| Ondansetronc | 2×8 mg orally | none | none |
a. EMEND was administered orally 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.
b. Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1.
The dose of dexamethasone was chosen to account for drug interactions. Increasing the dose of dexamethasone is not recommended (see Drug Interactions). c. Ondansetron 8-mg capsule was administered 30 to 60 minutes prior to chemotherapy treatment and one 8-mg capsule was administered 8 hours after the first dose on Day 1.
For moderately emetogenic chemotherapy, there is only limited efficacy data with EMEND in combination with other 5-HT3 antagonist class of antiemetics and dexamethasone.
See Drug Interactions for additional information on the administration of EMEND with corticosteroids.
Refer to each product's respective Product Monograph for additional information on coadministered antiemetic agents.
EMEND may be taken with or without food.
No dosage adjustment is necessary for the elderly.
No dosage adjustment is necessary based on gender or race.
No dosage adjustment is necessary for patients with severe renal insufficiency (creatinine clearance <30 mL/min) or for patients with end stage renal disease undergoing hemodialysis.
No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency (Child-Pugh score 5 to 9). There are no clinical data in patients with severe hepatic insufficiency (Child-Pugh score >9).
Adverse Reactions
Regardless of causality with EMEND, the following adverse events have been reported rarely or very rarely and occur with multiple confounding factors: loss of consciousness, depressed level of consciousness, convulsion, somnolence, paresthesia, syndrome of inappropriate antidiuretic hormone, hallucination, pruritus, rash, urticaria, and hypersensitivity reactions including anaphylactic reactions.
In 2 well-controlled clinical trials in patients receiving cisplatin-based chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. EMEND was given in combination with ondansetron and dexamethasone and was generally well tolerated. Most adverse experiences reported in these clinical studies were described as mild to moderate in intensity.
In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Table 1 shows the percent of patients with clinical adverse experiences reported at an incidence ≥3%.
appetite decreased, diabetes mellitus, hypokalemia.
myocardial infarction, palpitations, tachycardia.
The following additional laboratory adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia. The adverse experiences of increased AST and ALT were generally mild and transient.
The following laboratory adverse experiences were reported at an incidence ≥3% during Cycle 1 of the moderately emetogenic chemotherapy study in patients treated with the aprepitant regimen or standard therapy, respectively: decreased hemoglobin (2.3%, 4.7%) and decreased white blood cell count (9.3%, 9.0%).
The adverse experience profiles in the Multiple-Cycle extensions for up to 6 cycles of chemotherapy were generally similar to those observed in Cycle 1.
Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study.
All Laboratory Abnormalities, Regardless of Causality, (incidence ≥3%) Occurring in Patients Receiving Highly Emetogenic Chemotherapy Who Were Treated with the aprepitant Regimen for CINV in Clinical Studies (Cycle 1)
| | Aprepitant
Regimen
N=544
% | Standard
Therapy
N=550
% |
| ALT increased | (6.0) | (4.3) |
| AST increased | (3.0) | (1.3) |
| Blood urea nitrogen increased | (4.7) | (3.5) |
| Serum creatinine increased | (3.7) | (4.3) |
| Proteinuria | (6.8) | (5.3) |
cough, dyspnea, nasal secretion, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance.
dysuria, renal insufficiency.
arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia.
candidiasis, herpes simplex, lower respiratory infection, pharyngitis, septic shock, upper respiratory infection, urinary tract infection.
peripheral neuropathy, sensory neuropathy, taste disturbance, tremor.
deep venous thrombosis, flushing, hypertension, hypotension.
anemia, febrile neutropenia, thrombocytopenia.
acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased.
anxiety disorder, confusion, depression.
During Cycle 1 of a moderately emetogenic chemotherapy study, 438 patients were treated with the aprepitant regimen and 385 of these patients continued into the Multiple-Cycle extension for up to 4 cycles of chemotherapy.
In Cycle 1, clinical adverse experiences were reported in approximately 73% of patients treated with the aprepitant regimen compared with approximately 75% of patients treated with standard therapy.
The adverse experience profile in the moderately emetogenic chemotherapy study was generally comparable to the highly emetogenic chemotherapy studies. Table 2 shows the percent of patients with clinical adverse experiences reported at an incidence ≥3%.
malignant neoplasm, non-small cell lung carcinoma.
Indications and Clinical Use
In clinical studies, the efficacy and safety of EMEND in the elderly (≥65 years) were comparable to those seen in younger patients (<65 years). No dosage adjustment is necessary in elderly patients.
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
No specific information is available on the treatment of overdosage with EMEND. Single doses up to 600 mg of aprepitant were generally well tolerated in healthy subjects. Aprepitant was generally well tolerated when administered as 375 mg once daily for up to 42 days to patients in non-CINV studies. In 33 cancer patients, administration of a single 375-mg dose of aprepitant on Day 1 and 250 mg once daily on Days 2 to 5 was generally well tolerated.
Drowsiness and headache were reported in one patient who ingested 1440 mg of aprepitant.
In the event of overdose, EMEND should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective.
Aprepitant cannot be removed by hemodialysis.
Dosage Forms, Composition and Packaging
Each white, opaque hard gelatin capsule with 461 and 80 mg printed radially in black ink, contains: aprepitant 80 mg. Nonmedicinal ingredients: hydroxypropyl cellulose, microcrystalline cellulose, sodium lauryl sulfate and sucrose; capsule shell: gelatin and titanium dioxide. Blister packages of 2. Tri-Pack contains 2 capsules of 80 mg and 1 capsule of 125 mg.
Each opaque, hard gelatin capsule with white body and pink cap with 462 and 125 mg printed radially in black ink, contains: aprepitant 125 mg. Nonmedicinal ingredients: hydroxypropyl cellulose, microcrystalline cellulose, sodium lauryl sulfate and sucrose; capsule shell: gelatin, red ferric oxide, titanium dioxide and yellow ferric oxide. Blister packages of 6. Tri-Pack contains 2 capsules of 80 mg and 1 capsule of 125 mg.
Warnings and Precautions
Safety and effectiveness of EMEND in pediatric patients have not been established.
In 2 well-controlled clinical studies, of the total number of patients (N=544) treated with EMEND, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary.
Reproductive studies have been performed in rats and rabbits at doses up to 1.5 times the systemic exposure at the adult human dose and have revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. However, there are no adequate and well-controlled studies in pregnant women; therefore, EMEND is not recommended for use during pregnancy unless clearly necessary.
Aprepitant is excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk; therefore, breastfeeding is not recommended during treatment with EMEND.
Storage and Stability
Blisters: Store at room temperature (15-30°C) in the original package.
Action and Clinical Pharmacology
EMEND was well tolerated in patients with mild to moderate hepatic insufficiency. Following administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 and 3 to patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), the AUC0-24hr of aprepitant was 11% lower on Day 1 and 36% lower on Day 3, as compared with healthy subjects given the same regimen. In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), the AUC0-24hr of aprepitant was 10% higher on Day 1 and 18% higher on Day 3, as compared with healthy subjects given the same regimen. These differences in AUC0-24hr are not considered clinically meaningful; therefore, no dosage adjustment for EMEND is necessary in patients with mild to moderate hepatic insufficiency.
There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9).
Following oral administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 through 5, the AUC0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (≥65 years) relative to younger adults. The Cmax was 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful. No dosage adjustment for EMEND is necessary in elderly patients.
Aprepitant is greater than 95% bound to plasma proteins. The geometric mean apparent volume of distribution at steady state (Vdss) is approximately 66 L in humans.
Aprepitant crosses the placenta in rats, and crosses the blood brain barrier in rats and ferrets. PET studies in humans indicate that aprepitant crosses the blood brain barrier (see Action and Clinical Pharmacology).
The mean absolute oral bioavailability of aprepitant is approximately 60 to 65% and the mean peak plasma concentration (Cmax) of aprepitant occurred at approximately 4 hours (Tmax). Oral administration of the capsule with a standard breakfast had no clinically meaningful effect on the bioavailability of aprepitant.
The pharmacokinetics of aprepitant are non-linear across the clinical dose range. In healthy young adults, the increase in AUC0-∞ was 26% greater than dose proportional between 80-mg and 125-mg single doses administered in the fed state.
Following oral administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 and 3, the AUC0-24hr was approximately 19.5 μg·hr/mL and 20.1 μg·hr/mL on Day 1 and Day 3, respectively. The Cmax of 1.5 μg/mL and 1.4 μg/mL were reached in approximately 4 hours (Tmax) on Day 1 and Day 3, respectively.
| | Cmax
(μg/mL) | AUC0-24hr
(μg·hr/mL) |
| Day 1 oral dose aprepitant 125 mg | 1.5 | 19.5 |
| Day 3 oral dose aprepitant 80 mg | 1.4 | 20.1 |
Aprepitant has a unique mode of action; it is a selective high affinity antagonist at human substance P neurokinin 1 (NK1) receptors. Counter-screening assays showed that aprepitant was at least 3000-fold selective for the NK1 receptor over other enzyme, transporter, ion channel and receptor sites including the dopamine and serotonin receptors that are targets for existing chemotherapy induced nausea and vomiting (CINV) therapies.
NK1-receptor antagonists have been shown pre-clinically to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Preclinical and human Positron Emission Tomography (PET) studies with aprepitant have shown that it is brain penetrant and occupies brain NK1 receptors. Preclinical studies show that aprepitant has a long duration of central activity, inhibits both the acute and delayed phases of cisplatin-induced emesis, and augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone against cisplatin-induced emesis.
Following oral administration of a single 125-mg dose of EMEND, the AUC0-24hr is approximately 25% and 29% higher in Hispanics as compared with Caucasians and Blacks, respectively. The Cmax is 22% and 31% higher in Hispanics as compared with Caucasians and Blacks, respectively. These differences are not considered clinically meaningful. No dosage adjustment for EMEND is necessary based on race.
Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. Following administration of a single oral 300-mg dose of [14C]-aprepitant to healthy subjects, 5% of the radioactivity was recovered in urine and 86% in feces.
The apparent plasma clearance of aprepitant ranged from approximately 60 to 84 mL/min. The apparent terminal half-life ranged from approximately 9 to 13 hours.
A single 240-mg dose of EMEND was administered to patients with severe renal insufficiency (CrCl <30 mL/min) and to patients with end stage renal disease (ESRD) requiring hemodialysis.
In patients with severe renal insufficiency, the AUC0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and Cmax decreased by 32%, relative to healthy subjects. In patients with ESRD undergoing hemodialysis, the AUC0-∞ of total aprepitant decreased by 42% and Cmax decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal insufficiency compared with healthy subjects. Hemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.
No dosage adjustment for EMEND is necessary for patients with severe renal insufficiency or for patients with ESRD undergoing hemodialysis.
Following oral administration of a single 125-mg dose of EMEND, the Cmax for aprepitant is 16% higher in females as compared with males. The half-life of aprepitant is 25% lower in females as compared with males and its Tmax occurs at approximately the same time. No dosage adjustment for EMEND is necessary based on gender.
Aprepitant undergoes extensive metabolism. In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [14C]-aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring and its side chains. In vitro studies using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19, and no metabolism by CYP2D6, CYP2C9, or CYP2E1.
The pharmacokinetics of EMEND have not been evaluated in patients below 18 years of age.
Contraindications
Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see Dosage Forms, Composition and Packaging.
EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions (see Drug Interactions).
