Emend Tri-Pack

Aprepitant.

Therapeutic Class: EMEND (aprepitant), is a substance P neurokinin 1 (NK₁) receptor antagonist.

EMEND, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of: highly emetogenic cancer chemotherapy, including high-dose cisplatin (see Dosage & Administration); moderately emetogenic cancer chemotherapy (see Dosage & Administration).

EMEND (aprepitant) is available as capsules for oral administration.
EMEND is given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT₃ antagonist. The package insert for the co-administered 5-HT₃ antagonist must be consulted prior to initiation of treatment with EMEND. 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.
Recommended dosing for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy: See Table 1.

Click on icon to see table/diagram/image

Recommended dosing for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy: See Table 2.

Click on icon to see table/diagram/image

See Interactions for additional information on the administration of EMEND with corticosteroids.
Refer to the full prescribing information for co-administered antiemetic agents.
EMEND may be taken with or without food.
No dosage adjustment is necessary based on age, gender, race or Body Mass Index (BMI).
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).

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.

EMEND is contraindicated in patients who are hypersensitive to any component of the product.
EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Dose-dependent 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 Interactions).

EMEND, a dose-dependent inhibitor of CYP3A4 should be used with caution in patients receiving concomitant orally administered medicinal products that are primarily metabolized through CYP3A4; some chemotherapy agents are metabolized by CYP3A4 (see Interactions). Moderate inhibition of CYP3A4 by aprepitant, 125 mg/80 mg regimen, could result in elevated plasma concentrations of these concomitant medicinal products administered orally (see Interactions). The effect of EMEND on the pharmacokinetics of orally administered CYP3A4 substrates is greater than the effect of EMEND on the pharmacokinetics of intravenously administered CYP3A4 substrates (see Interactions).
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 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 (see Interactions).
The efficacy of hormonal contraceptives during and for 28 days after administration 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 Interactions).
Use in Children: Safety and effectiveness of EMEND in pediatric patients have not been established.
Use in the Elderly: 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.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. EMEND should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and the fetus.
Nursing Mothers: Aprepitant is excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the possible adverse effects of EMEND on nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The overall safety of aprepitant was evaluated in approximately 6500 individuals.
Prevention of Chemotherapy Induced Nausea and Vomiting (CINV): Highly Emetogenic Chemotherapy (HEC): In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy (HEC), 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 (aprepitant regimen) and was generally well tolerated. Most adverse experiences reported in these clinical studies were described as mild to moderate in intensity.
In Cycle 1, drug-related clinical adverse experiences were reported in approximately 19% of patients treated with the aprepitant regimen compared with approximately 14% of patients treated with standard therapy. Treatment was discontinued due to drug-related clinical adverse experiences in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy.
The most common drug-related adverse experiences reported in patients treated with the aprepitant regimen and greater than standard therapy were: hiccups (4.6%), ALT increased (2.8%), dyspepsia (2.6%), constipation (2.4%), headache (2.0%), and decreased appetite (2.0%).
In an additional active-controlled clinical study in 1169 patients receiving aprepitant and HEC, the adverse experience profile was generally similar to that seen in the other HEC studies with aprepitant.
Moderately Emetogenic Chemotherapy (MEC): In 2 well-controlled clinical trials in patients receiving moderately emetogenic cancer chemotherapy (MEC), 868 patients were treated with aprepitant during Cycle 1 of chemotherapy and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In both studies, EMEND was given in combination with ondansetron and dexamethasone (aprepitant regimen) and was generally well tolerated. Most adverse experiences reported in these clinical studies were described as mild to moderate in intensity. In the combined analysis of Cycle 1 data for these 2 studies, drug-related adverse experiences were reported in approximately 14% of patients treated with the aprepitant regimen compared with approximately 15% of patients treated with standard therapy. Treatment was discontinued due to drug-related adverse experiences in 0.7% of patients treated with the aprepitant regimen compared with 0.2% of patients treated with standard therapy.
The most common drug-related adverse experience reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy was fatigue (1.4%).
Highly and Moderately Emetogenic Chemotherapy: In a pooled analysis of the HEC and MEC studies, the following drug-related adverse experiences were reported in patients treated with the aprepitant regimen and at a greater incidence than standard therapy: [Common (≥1/100, <1/10), Uncommon (≥1/1,000, <1/100), Rare (≥1/10,000, <1/1,000)].
Infection and infestations: Rare: candidiasis, staphylococcal infection.
Blood and the lymphatic system disorders: Uncommon: anemia, febrile neutropenia.
Metabolism and nutrition disorders: Common: decreased appetite.
Rare: polydipsia.
Psychiatric disorders: Uncommon: anxiety.
Rare: disorientation, euphoric mood.
Nervous system disorders: Uncommon: dizziness, somnolence.
Rare: cognitive disorder, lethargy, dysgeusia.
Eye disorders: Rare: conjunctivitis.
Ear and labyrinth disorders: Rare: tinnitus.
Cardiac disorders: Uncommon: palpitations.
Rare: bradycardia, cardiovascular disorder.
Vascular disorders: Uncommon: hot flush.
Respiratory, thoracic and mediastinal disorders: Common: hiccups.
Rare: oropharyngeal pain, sneezing, cough, postnasal drip, throat irritation.
Gastrointestinal disorders: Common: dyspepsia.
Uncommon: eructation, nausea, gastroesophageal reflux disease, vomiting, abdominal pain, dry mouth, flatulence.
Rare: feces hard, duodenal ulcer perforation, neutropenic colitis, stomatitis, abdominal distension.
Skin and subcutaneous tissue disorders: Uncommon: rash, acne.
Rare: photosensitivity reaction, hyperhidrosis, seborrhoea, skin lesion, rash pruritic.
Musculoskeletal and connective tissue disorders: Rare: muscle spasms, muscular weakness.
Renal and urinary disorders: Uncommon: dysuria.
Rare: pollakiuria.
General disorders and administration site conditions: Common: fatigue.
Uncommon: asthenia, malaise.
Rare: edema, chest discomfort, gait disturbance.
Investigations: Common: ALT increased.
Uncommon: AST increased, blood alkaline phosphatase increased.
Rare: urine output increased, red blood cells urine positive, blood sodium decreased, weight decreased, glucose urine present, neutrophil count decreased.
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 those observed in Cycle 1.
In another CINV study, Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy.
Other Studies: Single 40-mg doses of EMEND have also been studied for the prevention of post-operative nausea and vomiting (PONV) in non-chemotherapy patients receiving general balanced anesthesia. In these studies, additional adverse reactions that were observed at a greater incidence than with the active comparator (ondansetron) included: ALT increased, abdominal pain upper, bowel sounds abnormal, dysarthria, dyspnoea, hypoaesthesia, insomnia, miosis, nausea, sensory disturbance, stomach discomfort, visual acuity reduced, wheezing.
In addition, two serious adverse experiences were reported in PONV clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of sub-ileus.
One case of angioedema and urticaria was reported as a serious adverse event in a patient receiving aprepitant in a non-CINV/non-PONV study.
Post-Marketing Experience: The following adverse reactions have been identified during post-marketing 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, Stevens-Johnson syndrome/toxic epidermal necrolysis.
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.
Effect of aprepitant on the pharmacokinetics of other agents: As a moderate (125 mg/80 mg) inhibitor of CYP3A4, aprepitant can increase plasma concentrations of orally coadministered medicinal products that are metabolized through CYP3A4. Aprepitant (125 mg/80 mg) can increase plasma concentrations of intravenously coadministered medicinal products metabolized through CYP3A4 to a lesser extent.
EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Dose-independent inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions (see Contraindications).
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.
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.
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: 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 usual 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 & Administration).
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 1.3-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 usual IV methylprednisolone dose should be reduced by approximately 25%, and the usual 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.
Chemotherapeutic agents: In clinical studies, EMEND (125 mg/80 mg regimen) was administered with the following chemotherapeutic agents metabolized primarily or in part by CYP3A4: etoposide, vinorelbine, docetaxel, ifosfamide, cyclophosphamide, irinotecan, and paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. Caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4. Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitant and ifosfamide coadministration (see Precautions).
Docetaxel: In a separate pharmacokinetic study, EMEND (125 mg/80 mg regimen) did not influence the pharmacokinetics of docetaxel.
Vinorelbine: In a separate pharmacokinetic study, EMEND (125 mg/80 mg regimen) did not influence the pharmacokinetics of vinorelbine.
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.
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.
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 single dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21 with EMEND, given as a 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.
The efficacy of hormonal contraceptives during and for 28 days after administration 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.
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).
In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND 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 EMEND 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 EMEND. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. This effect was not considered clinically important.
Effect of other agents on the pharmacokinetics of aprepitant: 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) should be approached cautiously; but concomitant administration of EMEND with moderate CYP3A4 inhibitors (e.g., diltiazem) does not result in clinically meaningful changes in plasma concentrations of aprepitant.
Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that strongly induce CYP3A4 activity (e.g., rifampin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of EMEND.
Ketoconazole: When a single 125-mg dose of EMEND 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 EMEND with strong CYP3A4 inhibitors should be approached cautiously.
Rifampin: When a single 375-mg dose of EMEND 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 EMEND with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of EMEND.
Additional interactions: Diltiazem: In patients with mild to moderate hypertension, 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 C_max by approximately 20% of both aprepitant and paroxetine.

Antiemetics / Supportive Care Therapy

A04AD12 - aprepitant ; Belongs to the class of other antiemetics.

P₁S₁S₃