The overall safety of aprepitant was evaluated in approximately 4900 individuals. Since EMEND for Injection is converted to aprepitant, those adverse experiences associated with aprepitant might also be expected to occur with EMEND for Injection.

Fosaprepitant (intravenous formulation)

In a randomized, open-label, incomplete crossover, bioequivalence study, 66 subjects were dosed with 115 mg of EMEND for Injection intravenously and 72 subjects received 125 mg of aprepitant orally. Systemic exposure of 115 mg of intravenous EMEND for Injection is equivalent to 125 mg oral aprepitant. The following clinical adverse experiences, regardless of causality, were reported in subjects dosed with EMEND for Injection: infusion site pain, 5 (7.6%); infusion site induration, 1(1.5%); headache, 2(3%).

Oral Aprepitant

Highly Emetogenic Chemotherapy

In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer 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. Oral aprepitant 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 4 shows the percent of patients with clinical adverse experiences reported at an incidence ≥3%.

Table 4: Percent of Patients Receiving Highly Emetogenic Chemotherapy With Clinical Adverse Experiences (Incidence ≥3%) - Cycle 1

In addition, isolated cases of serious adverse experiences, regardless of causality, of bradycardia, disorientation, and perforating duodenal ulcer were reported in highly emetogenic CINV clinical studies.

Moderately Emetogenic Chemotherapy

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 5 shows the percent of patients with clinical adverse experiences reported at an incidence ≥3%.

Table 5: Percent of Patients Receiving Moderately Emetogenic Chemotherapy With Clinical Adverse Experiences (Incidence ≥3%) — Cycle 1

Isolated cases of serious adverse experiences, regardless of causality, of dehydration, enterocolitis, febrile neutropenia, hypertension, hypoesthesia, neutropenic sepsis, pneumonia, and sinus tachycardia were reported in the moderately emetogenic CINV clinical study.

Highly and Moderately Emetogenic Chemotherapy

The following additional clinical adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen:

Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, pharyngitis, septic shock, upper respiratory infection, urinary tract infection.

Neoplasms benign, malignant and unspecified (including cysts and polyps): malignant neoplasm, non- small cell lung carcinoma.

Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia.

Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia.

Psychiatric disorders: anxiety disorder, confusion, depression.

Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor.

Eye disorders: conjunctivitis.

Cardiac disorders: myocardial infarction, palpitations, tachycardia.

Vascular disorders: deep venous thrombosis, flushing, hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, nasal secretion, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance.

Gastrointestinal disorders: acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased.

Skin and subcutaneous tissue disorders: acne, diaphoresis, rash.

Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia.

Renal and urinary disorders: dysuria, renal insufficiency.

Reproductive system and breast disorders: pelvic pain.

General disorders and administrative site conditions: edema, malaise, rigors.

Investigations: weight loss.

Laboratory Adverse Experiences

Table 6 shows the percent of patients with laboratory adverse experiences reported at an incidence ≥3% in patients receiving highly emetogenic chemotherapy.

Table 6: Percent of Patients Receiving Highly Emetogenic Chemotherapy With Laboratory Adverse Experiences (Incidence ≥3%) - Cycle 1

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 that 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.

Other Studies with Postoperative Nausea and Vomiting

In well-controlled clinical studies in patients receiving general anesthesia, 564 patients were administered 40 mg aprepitant orally and 538 patients were administered 4 mg ondansetron I.V. EMEND was generally well tolerated. Most adverse experiences reported in these clinical studies were described as mild to moderate in intensity. Clinical adverse experiences were reported in approximately 60% of patients treated with 40 mg aprepitant compared with approximately 64% of patients treated with 4 mg ondansetron I.V.

Additional adverse experiences were observed in patients receiving general anesthesia. In the patients treated with aprepitant (40 mg) for postoperative nausea and vomiting, the following additional adverse experiences were reported, regardless of causality, at an incidence ≥3%: anemia, bradycardia, flatulence, hypotension, pruritus, pyrexia.

The following adverse experiences were reported, regardless of causality, in patients treated with aprepitant for postoperative nausea and vomiting at an incidence of >0.5% and greater than with ondansetron: abdominal pain, abdominal pain upper, blood pressure decreased, dizziness, dyspepsia, hematoma, hypoesthesia, hypothermia, hypovolemia, hypoxia, operative hemorrhage, pain, postoperative infection, respiratory depression, syncope, urticaria, wound dehiscence.

Other adverse experiences (incidence ≤0.5%) reported, regardless of causality, in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included: bowel sounds abnormal, dysarthria, miosis, sensory disturbance, stomach discomfort, visual acuity reduced, wheezing.

Laboratory Adverse Experiences with Postoperative Nausea and Vomiting

One laboratory adverse experience, hemoglobin decreased (40 mg aprepitant), was reported, regardless of causality, at an incidence ≥3% in a patient receiving general anesthesia.

The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present.

The adverse experience of ALT increased occurred with similar incidence in patients treated with aprepitant as in patients treated with ondansetron.

Other Studies

In addition, two serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of sub-ileus.

Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study.

Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. The following information was derived from data with oral aprepitant and one study conducted with fosaprepitant and oral midazolam.

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3- day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9.

Effect of aprepitant on the pharmacokinetics of other agents

As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of orally coadministered medicinal products that are metabolized through CYP3A4 (see CONTRAINDICATIONS).

Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of fosaprepitant or oral aprepitant 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.

Fosaprepitant or aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin in a clinical drug interaction study.

5-HT₃ antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Corticosteroids

Dexamethasone: Oral aprepitant, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and oral aprepitant when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant followed by aprepitant, to achieve exposures of dexamethasone similar to those obtained when dexamethasone is given without aprepitant. The daily dose of dexamethasone administered in clinical CINV studies with oral aprepitant reflects an approximate 50% reduction of the dose of dexamethasone (see DOSAGE AND ADMINISTRATION).

Methylprednisolone: Oral aprepitant, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The I.V. methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant followed by aprepitant to achieve exposures of methylprednisolone similar to those obtained when it is given without aprepitant.

Chemotherapeutic agents: See PRECAUTIONS, General.

Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel.

Vinorelbine: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree.

Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with oral aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of fosaprepitant followed by aprepitant with each chemotherapy cycle.

Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15.

Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%.

In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and oral aprepitant was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg I.V. on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of oral aprepitant on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21. The coadministration of fosaprepitant or aprepitant may reduce the efficacy of hormonal contraceptives during and for 28 days after administration of the last dose of either. Alternative or back-up methods of contraception should be used during treatment with fosaprepitant or aprepitant and for 1 month following the last dose.

Midazolam: A study was completed with fosaprepitant and oral midazolam. Fosaprepitant was given at a dose of 100 mg over 15 minutes along with a single dose of midazolam 2 mg. The plasma AUC of midazolam was increased by 1.6-fold. This effect was not considered clinically important.

Oral aprepitant increased the AUC of midazolam by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of oral aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with a 3-day regimen of fosaprepitant followed by aprepitant. In another study with intravenous administration of midazolam, oral aprepitant was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg I.V. was given prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. Oral aprepitant increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of oral aprepitant on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline.

An additional study was completed with intravenous administration of midazolam and oral aprepitant. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of oral aprepitant 125 mg. The plasma AUC of midazolam was increased by 1.5-fold.

Effect of other agents on the pharmacokinetics of aprepitant

Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy.

Ketoconazole: When a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously.

Rifampin: When a single 375-mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold.

Coadministration of fosaprepitant or aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy.

Additional interactions

Diltiazem: In a study in 10 patients with mild to moderate hypertension, intravenous infusion of 100 mg fosaprepitant over 15 minutes with diltiazem 120 mg 3 times daily, resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful further maximum decrease in diastolic blood pressure [mean (SD) of 24.3 (± 10.2) mm Hg with fosaprepitant versus 15.6 (± 4.1) mm Hg without fosaprepitant] and resulted in a small further maximum decrease in systolic blood pressure [mean (SD) of 29.5 (± 7.9) mm Hg with fosaprepitant versus 23.8 (± 4.8) mm Hg without fosaprepitant], which may be clinically meaningful, but did not result in a clinically meaningful further change in heart rate or PR interval, beyond those changes induced by diltiazem alone.

In the same study, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate or blood pressure beyond those changes induced by diltiazem alone.

Paroxetine: Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine.

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