EMADIS

Aprepitant, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, 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.

Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors.

Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV).

For the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including high-dose cisplatin (in combination with other antiemetic agents).

Aprepitant, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, 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.

Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors.

Aprepitant has little or no affinity for serotonin (5-HT 3 ), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV).

The mean absolute oral bioavailability of aprepitant is approximately 60-65%.

Aprepitant primarily undergoes

CYP3A4-mediated metabolism, as well as minor metabolism mediated by CYP1A2 and CYP2C19.

About seven metabolites of aprepitant have been identified in human plasma, which all retain weak pharmacological activity.

Hover over products below to view reaction partners Aprepitant (2S,3R)-2-ethoxy]-3-(4-fluorophenyl)morpholine 5-({amino}methyl)-2,3-dihydro-1H-1,2,4-triazol-3-one (2R)-2-(4-fluorophenyl)-2-{amino}acetic acid (2R,3S)-2-ethoxy]-3-(4-fluorophenyl)morpholine + 5-oxo-1,4-dihydro-1,2,4-triazole-3-carbaldehyde 1-ethanone + 5-{methyl}-2,4-dihydro-1,2,4-triazol-3-one.

Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted.

Aprepitant is excreted in the milk of rats.

It is not known whether this drug is excreted in human milk.

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No specific information is available on the treatment of overdosage.

Drowsiness and headache were reported in one patient who ingested 1,440 mg of aprepitant (approximately 11 times the maximum recommended single dose).

In the event of overdose, aprepitant 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 in cases of aprepitant overdosage.

Aprepitant is not removed by hemodialysis.

• 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.

Recommended Dosage for Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) •Aprepitant capsules in adults and pediatric patients 12 years of age and older: is 125 mg on Day and 80 mg on Days and 3.

• Administer aprepitant 1 hour prior to chemotherapy on Days 1, 2, and 3.

If no chemotherapy is given on

Days and 3, administer aprepitant in morning.

Information for recommended dosages of concomitant dexamethasone and 5-HT 3 antagonist for HEC and MEC.

Recommended Dosage for

• Adults: 40 mg Aprepitant capsules within 3 hours prior to induction of anesthesia.

Preparation and

• Aprepitant capsules can be administered with or without food.

• Swallow aprepitant capsules whole.

• For details on preparation see Full Prescribing Information. 2.1 Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) Adults and Pediatric Patients 12 Years of Age and Older The recommended oral dosage of aprepitant capsules, dexamethasone, and a 5-HT 3 antagonist in adults and pediatric patients 12 years of age and older who can swallow oral capsules, for the prevention of nausea and vomiting associated with administration of HEC or MEC is shown in Table 1 or Table 2, respectively.

Table 1: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with HEC Population Day 1 Day 2 Day 3 Day 4 Aprepitant capsules Adults and Pediatric Patients 12 Years and Older 125 mg orally 80 mg orally 80 mg orally none Dexamethasone Adults 12 mg orally 8 mg orally 8 mg orally 8 mg orally 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 See selected 5-HT3 antagonist prescribing information for the recommended dosage none none none Table 2: Recommended Dosing for the Prevention of Nausea and Vomiting Associated with MEC Population Day 1 Day 2 Day 3 Aprepitant capsules Adults and Pediatric Patients 12 Years and Older 125 mg orally 80 mg orally 80 mg orally Dexamethasone Adults 12 mg orally none none 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 See selected 5-HT 3 antagonist prescribing information for the recommended dosage none none 2.2 Prevention of Postoperative Nausea and Vomiting (PONV) The recommended oral dosage of aprepitant capsules is 40 mg within 30 hours prior to induction of anesthesia. 2.3 Administration Instructions Aprepitant capsules can be administered with or without food Aprepitant capsules Swallow capsules whole.

Aprepitant capsules, USP, 40 mg, are hard gelatin capsules with white body and yellow cap with "40 mg" printed in black ink on the body.

NDC 51407-701-01 Carton of 1 capsule (containing 1 x 1 unit-dose blister) NDC 51407-701-05 Carton of 5 capsules (containing 5 x 1 unit-dose blisters) Aprepitant capsules, USP, 80 mg, are hard gelatin capsules with white body and white cap with "80 mg" printed in black ink on the body.

NDC 51407-702-02 Carton of 2 capsules (containing 2 x 1 unit-dose blisters) NDC 51407-702-06 Carton of 6 capsules (containing 3 x 2 dose blisters each) Aprepitant capsules, USP, 125 mg, are hard gelatin capsules with white body and pink cap with "125 mg" printed in black ink on the body.

NDC 51407-703-06 Carton of 6 capsules (containing 6 x 1 unit-dose blister) Aprepitant capsules, USP, Tri-pack-wallet type, 3-day pack (125-mg/80-mg/80-mg) 80 mg, are hard gelatin capsules with white body and white cap with "80 mg" printed in black ink on the body. 125 mg, are hard gelatin capsules with white body and pink cap with "125 mg" printed in black ink on the body.

Blister pack of 2, 80 mg Capsules and 1, 125 mg Capsule NDC 51407-704-03 Carton of 3 capsules (3-day pack blister tri-pack containing one 125 mg capsule and two 80 mg capsules) Storage and Handling Capsules Store at to 25°C (68 to 77°F) .

There are insufficient data on use of aprepitant 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 aprepitant 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 to 4% and to 20%, respectively.

In embryofetal development studies in rats and rabbits, aprepitant was administered during the period of organogenesis at oral doses up to 1,000 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 1,000 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/80mg/80-mg aprepitant regimen.

Aprepitant crosses the placenta in rats and rabbits.

Prevention of Nausea and Vomiting Associated with HEC or MEC The safety and effectiveness of aprepitant 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 aprepitant 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).

Aprepitant 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 aprepitant for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients less than 6 months.

Prevention of Postoperative Nausea and

Vomiting (PONV) The safety and effectiveness of aprepitant have not been established for the prevention of postoperative nausea and vomiting in pediatric patients.

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 1,000 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.

Of the 544 adult cancer patients treated with aprepitant in CINV clinical studies, 31% were aged and over, while 5% were aged and over.

Of the 1,120 adult cancer patients treated with aprepitant in PONV clinical studies, 7% were aged and over, while 2% were aged and over.

Other reported clinical experience with aprepitant has not identified differences in responses between elderly and younger patients.

In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy.