These highlights do not include all the information needed to use EMEND safely and effectively. See full prescribing information for EMEND. EMEND (aprepitant) CapsulesInitial U.S. Approval: 2003

EMEND, in combination with other antiemetic agents, is indicated for the:

EMEND is indicated for the prevention of postoperative nausea and vomiting [see Dosage and Administration (2.2)].

EMEND has not been studied for the treatment of established nausea and vomiting.

Chronic continuous administration is not recommended [see Warnings and Precautions (5.5)].

Capsules of EMEND (aprepitant) are given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT antagonist. The recommended dose of EMEND is 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80 mg orally once daily in the morning on Days 2 and 3.

EMEND may be taken with or without food.

EMEND (fosaprepitant dimeglumine) for Injection (115 mg) is a prodrug of aprepitant and may be substituted for oral EMEND (125 mg), 30 minutes prior to chemotherapy, on Day 1 only of the CINV regimen as an intravenous infusion administered over 15 minutes.

In clinical studies with EMEND, the following regimen was used for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy:

In a clinical study with EMEND, the following regimen was used for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy:

The recommended oral dosage of EMEND is 40 mg within 3 hours prior to induction of anesthesia.

EMEND may be taken with or without food.

No dosage adjustment is necessary for the elderly.

No dosage adjustment is necessary for patients with renal impairment or for patients with end stage renal disease (ESRD) undergoing hemodialysis.

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical data in patients with severe hepatic impairment (Child-Pugh score >9).

For additional information on dose adjustment for corticosteroids when coadministered with EMEND, see Drug Interactions (7.1) .

Refer to the full prescribing information for coadministered antiemetic agents.

EMEND is contraindicated in patients who are hypersensitive to any component of the product.

EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions (7.1)].

EMEND (aprepitant), a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 by aprepitant, 125 mg/80 mg regimen, could result in elevated plasma concentrations of these concomitant medications.

Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree.

When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity aprepitant plasma concentrations could be reduced and this may result in decreased efficacy of EMEND [see Drug Interactions (7.1)].

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 (125 mg/80 mg regimen) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions.

In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when EMEND (125 mg/80 mg regimen) was co-administered.

Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions (7.1)].

Coadministration of EMEND with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40 mg dose of EMEND for the prevention of postoperative nausea and vomiting [see Drug Interactions (7.1)].

Upon coadministration with EMEND, the efficacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND [see Drug Interactions (7.1)].

There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when EMEND is administered in these patients [see Clinical Pharmacology (12.3) and Dosage and Administration (2.5)].

Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied; and because the drug interaction profile may change during chronic continuous use.

The overall safety of aprepitant was eva luated in approximately 5300 individuals.

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.

Chemotherapy Induced Nausea and Vomiting

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. EMEND was given in combination with ondansetron and dexamethasone.

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%.

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 2 moderately emetogenic chemotherapy studies, 868 patients were treated with the aprepitant regimen and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In the combined analysis of Cycle 1 data for these 2 studies, adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 72% of patients treated with standard therapy.

In the combined analysis of Cycle 1 data for these 2 studies, the adverse experience profile in both moderately emetogenic chemotherapy studies 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%.

In a combined analysis of these two studies, isolated cases of serious adverse experiences were similar in the two treatment groups.

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 in either HEC or MEC studies:

Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, oral candidiasis, 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, hot flush, hypertension, hypotension.

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

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

Skin and subcutaneous tissue disorders: acne, diaphoresis, pruritus, 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, pain, rigors.

Investigations: weight loss.

Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study.

Laboratory Adverse Experiences

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

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 experience profiles 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.

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 IV.

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 IV. Table 4 shows the percent of patients with clinical adverse experiences reported at an incidence ≥3% of the combined studies.

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

Infections and infestations: postoperative infection

Metabolism and nutrition disorders: hypokalemia, hypovolemia.

Nervous system disorders: dizziness, hypoesthesia, syncope.

Vascular disorders: hematoma

Respiratory, thoracic and mediastinal disorders: dyspnea, hypoxia, respiratory depression.

Gastrointestinal disorders: abdominal pain, abdominal pain upper, dry mouth, dyspepsia.

Skin and subcutaneous tissue disorders: urticaria

General disorders and administrative site conditions: hypothermia, pain.

Investigations: blood pressure decreased

Injury, poisoning and procedural complications: operative hemorrhage, wound dehiscence.

Other adverse experiences (incidence ≤0.5%) reported in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included:

Nervous system disorders: dysarthria, sensory disturbance.

Eye disorders: miosis, visual acuity reduced.

Respiratory, thoracic and mediastinal disorders: wheezing

Gastrointestinal disorders: bowel sounds abnormal, stomach discomfort.

There were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical studies in patients taking 40 mg aprepitant.

Laboratory Adverse Experiences

One laboratory adverse experience, hemoglobin decreased (40 mg aprepitant 3.8%, ondansetron 4.2%), was reported 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 40 mg (1.1%) as in patients treated with ondansetron 4 mg (1.0%).

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.

The following adverse reactions have been identified during postmarketing use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the drug.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria.

Immune system disorders: hypersensitivity reactions including anaphylactic reactions.

Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9.

CYP3A4 Substrates:

Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. However, higher aprepitant doses or repeated dosing at any aprepitant dose may have a clinically significant effect.

As a moderate inhibitor of CYP3A4 at a dose of 125 mg/80 mg, aprepitant can increase plasma concentrations of concomitantly administered oral medications that are metabolized through CYP3A4 [see Contraindications (4)]. The use of fosaprepitant may increase CYP3A4 substrate plasma concentrations to a lesser degree than the use of oral aprepitant (125 mg).

5-HT 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: EMEND, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and EMEND 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 EMEND (125 mg/80 mg regimen), to achieve exposures of dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered in clinical chemotherapy induced nausea and vomiting studies with EMEND reflects an approximate 50% reduction of the dose of dexamethasone [see Dosage and Administration (2.1)]. A single dose of EMEND (40 mg) when coadministered with a single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. Therefore, no dose adjustment is recommended.

Methylprednisolone: EMEND, 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 IV methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with EMEND (125 mg/80 mg regimen) to achieve exposures of methylprednisolone similar to those obtained when it is given without EMEND. Although the concomitant administration of methylprednisolone with the single 40 mg dose of aprepitant has not been studied, a single 40 mg dose of EMEND produces a weak inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically significant degree. Therefore, no dose adjustment is recommended.

Chemotherapeutic agents: [see Warnings and Precautions (5.1)]

Docetaxel: In a pharmacokinetic study, EMEND (125 mg/80 mg regimen) did not influence the pharmacokinetics of docetaxel.

Vinorelbine: In a pharmacokinetic study, EMEND (125 mg/80 mg regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree.

CYP2C9 Substrates (Warfarin, Tolbutamide):

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.

Warfarin: A single 125-mg dose of EMEND 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 EMEND 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 EMEND. 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 EMEND with each chemotherapy cycle, or following administration of a single 40 mg dose of EMEND for the prevention of postoperative nausea and vomiting.

Tolbutamide: EMEND, 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 EMEND and on Days 4, 8, and 15.

EMEND, when given as a 40-mg single oral dose on Day 1, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of EMEND 40 mg and on Days 2, 4, 8, and 15. This effect was not considered clinically important.

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 EMEND 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 IV 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 EMEND 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.

In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norgestimate (which is converted to norelgestromin) was administered on Days 1 through 21, and EMEND 40 mg was given on Day 8. In the study, the AUC of ethinyl estradiol decreased by 4% and 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with EMEND 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone.

The coadministration of EMEND may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of EMEND. Alternative or back-up methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND.

Midazolam: EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, 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 EMEND 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 EMEND (125 mg/80 mg). A single dose of EMEND (40 mg) increased the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with EMEND 40 mg; this effect was not considered clinically important.

I

Manufacturer

Merck Sharp & Dohme Corp.

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
•  Last Updated: 2nd of March 2011