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Data Sheet

EMEND^®

aprepitant

40 mg, 80 mg & 125 mg capsule

Presentation

40 mg: A size #4 opaque, hard gelatine capsule with white body and mustard yellow cap with "464" and "40 mg" printed radially in black ink. (Not currently available in New Zealand.) Dimensions are overall length 14.3 mm.

80 mg: A size #2 opaque, hard gelatin capsule with white body and white cap with "461" and "80 mg" printed radially in black ink. Dimensions are overall length 18.0 mm.

125 mg: A size #1 opaque, hard gelatin capsule with white body and pink cap with "462" and "125 mg" printed radially in black ink. Dimensions are overall length 19.4 mm.

Therapeutic Class

EMEND (aprepitant, MSD), is a substance P neurokinin 1 (NK₁) receptor antagonist.

Indications

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 (see Dosage and Administration)
• moderately emetogenic cancer chemotherapy (see Dosage and Administration).

EMEND is indicated for the prevention of postoperative nausea and vomiting.

Dosage and Administration

Prevention of Chemotherapy Induced Nausea and Vomiting

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 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 IV™ (fosaprepitant) for intravenous administration is also available. It is a lyophilised prodrug of aprepitant containing polysorbate 80 (PS80) and may be substituted for oral EMEND (125 mg), 30 minutes prior to chemotherapy, on Day 1 only of the CINV regimen as an infusion administered over 15 minutes.

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

	Day 1	Day 2	Day 3	Day 4
EMEND*	125 mg orally	80 mg orally	80 mg orally	none
Dexamethasone**	12 mg orally	8 mg orally	8 mg orally	8 mg orally
Ondansetron†	32 mg IV	none	none	none

* EMEND was administered orally 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.

** 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 Medicine interactions.

^† Ondansetron was administered 30 minutes prior to chemotherapy treatment on Day 1.

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

	Day 1	Day 2	Day 3
EMEND*	125 mg orally	80 mg orally	80 mg orally
Dexamethasone**	12 mg orally	none	none
Ondansetron†	2 x 8 mg orally	none	none

* EMEND was administered orally 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.

** Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone was chosen to account for medicine interactions.

^† 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.

Prevention of Postoperative Nausea and Vomiting

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

General Information

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 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 haemodialysis.

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).

Contraindications

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 medicines, potentially causing serious or life-threatening reactions (see Interactions).

Warnings and Precautions

EMEND, a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant orally administered medicinal products that are primarily metabolised through CYP3A4; some chemotherapy agents are metabolised 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). Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter the plasma concentrations of these concomitant medicinal products to a clinically significant degree. 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).

Co-administration of EMEND with warfarin may result in a clinically significant decrease in International Normalised 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 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 one month following the last dose of EMEND (see Interactions).

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 foetus.

Nursing Mothers

Aprepitant is excreted in the milk of lactating rats. It is not known whether this medicine is excreted in human milk. Because many medicines 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 medicine, taking into account the importance of the medicine to the mother.

Paediatric Use

Safety and effectiveness of EMEND in paediatric 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.

Animal Toxicology

Acute Toxicity

The approximate oral LD₅₀ of aprepitant was >2000 mg/kg in female mice and rats. The approximate intraperitoneal LD₅₀ of aprepitant was >800 mg/kg, but <2000 mg/kg in female rats and >2000 mg/kg in female mice.

Chronic Toxicity

The toxicity potential of aprepitant was evaluated in a series of repeated-dose oral toxicity studies in rats and in dogs for up to 1 year.

In rats, oral administration of aprepitant for 6 months at doses up to the maximum feasible dose of 1000 mg/kg twice daily (approximately equivalent to [females] or lower than [males] the adult human dose based on systemic exposure) produced increased hepatic weights that correlated with hepatocellular hypertrophy, increased thyroidal weights that correlated with thyroid follicular cell hypertrophy and/or hyperplasia, and pituitary cell vacuolation. These findings are a species-specific consequence of hepatic CYP enzyme induction in the rat, and are consistent with changes observed in rats with other structurally and pharmacologically dissimilar compounds that have been shown to induce hepatic CYP enzymes.

In dogs administered aprepitant orally for 9 months at doses ≥5 mg/kg twice daily (greater than or equal to 13 times the adult human dose based on systemic exposure), toxicity was characterised by slight increases in serum alkaline phosphatase activity and decreases in the albumin/globulin ratio. Significantly decreased body weight gain, testicular degeneration, and prostatic atrophy were observed at doses ≥25 mg/kg twice daily (greater than or equal to 31 times the adult human dose based on systemic exposure). A slight increase in hepatic weights with no histologic correlate was seen at 500 mg/kg twice daily (70 times the adult human dose based on systemic exposure). No toxicity was observed in dogs administered 32 mg/kg/day (6 times the adult human dose based on systemic exposure) for 1 year.

Carcinogenesis

Carcinogenicity studies were conducted in mice and rats for 2 years. Mice developed hepatocellular adenomas and/or carcinomas at doses of 500 to 2000 mg/kg/day (females) and hepatocellular carcinomas at doses of 1000 and 2000 mg/kg/day (males). Systemic exposures at these doses in mice were approximately 2.5 to 3.6 times the exposure in humans at the recommended dose. Rats developed hepatocellular adenomas at doses of 5 to 1000 mg/kg twice daily (females) and 125 mg/kg twice daily (males), hepatocellular carcinomas at doses of 125 to 1000 mg/kg twice daily (females), thyroid follicular cell adenomas at doses of 125 to 1000 mg/kg twice daily (females and males), and thyroid follicular cell carcinomas at doses of 125 to 1000 mg/kg twice daily (males). Systemic exposures at these doses in rats were lower than or up to approximately 2 times the exposure in humans at the recommended dose. Liver and thyroid tumours of these types are a species-specific consequence of hepatic CYP enzyme induction in rodents, and are consistent with changes observed in rodents with other structurally and pharmacologically dissimilar compounds that have been shown to induce hepatic CYP enzymes.

Mutagenesis

Aprepitant was neither mutagenic nor genotoxic in assays conducted to detect mutagenicity, DNA strand breaks, and chromosomal aberrations. Aprepitant was negative in the in vitro microbial and TK6 human lymphoblastoid cell mutagenesis assays, the in vitro alkaline elution/rat hepatocyte DNA strand break test, the in vitro chromosomal aberration assay in Chinese hamster ovary cells, and the in vivo mouse micronucleus assay in bone marrow.

Reproduction

Aprepitant administered to female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (approximately equivalent to the adult human dose based on systemic exposure) had no effects on mating performance, fertility, or embryonic/foetal survival.

Administration of aprepitant to male rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (lower than the adult human dose based on systemic exposure) produced no effects on mating performance, fertility, embryonic/foetal survival, sperm count and motility, testicular weights, or the microscopic appearance of the testes and epididymides.

Development

In rats and rabbits administered oral doses of aprepitant up to 1000 mg/kg twice daily and 25 mg/kg/day, respectively (up to 1.5 times the systemic exposure at the adult human dose), there was no evidence of developmental toxicity as assessed by embryonic/foetal survival, foetal body weight, and foetal external, visceral, and skeletal morphology. Placental transfer of aprepitant occurred in rats and rabbits at these doses. Concentrations of aprepitant in foetal plasma were approximately 27% and 56% of maternal plasma concentrations in rats and rabbits, respectively.

Significant concentrations of aprepitant were observed in the milk of lactating rats administered 1000 mg/kg twice daily. At this dose, the mean milk Medicine concentration was 90% of the mean maternal plasma concentration.

Effects on the Ability to Drive and Use Machinery

No studies of the effects of EMEND on the ability to drive and use of machines have been performed. However, certain side effects that have been reported with EMEND may affect some patients' ability to drive or operate machinery. Individual responses to EMEND may vary. (See Adverse Effects.)

Adverse Effects

The overall safety of aprepitant was evaluated in approximately 5300 individuals.

PREVENTION OF 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 (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, medicine-related clinical adverse experiences were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to medicine-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 medicine-related adverse experiences reported in patients treated with the aprepitant regimen and greater than standard therapy were: hiccups (4.6%), asthenia/fatigue (2.9%), ALT increased (2.8%), constipation (2.2%), headache (2.2%), and anorexia (2.0%).

Moderately Emetogenic Chemotherapy

In 2 well-controlled clinical trials in patients receiving moderately emetogenic cancer chemotherapy, 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 date for these 2 studies, medicine-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 medicine-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 medicine-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

The following medicine-related adverse experiences were observed in either HEC or MEC studies in patients treated with the aprepitant regimen and at a greater incidence than standard therapy:
[Common (>1/100, <1/10) Uncommon (>1/1000, <1/100)]

Infection and infestations:

Uncommon: candidiasis, staphylococcal infection.

Blood and the lymphatic system disorders:

Uncommon: anaemia, febrile neutropenia.

Metabolism and nutrition disorders:

Common: anorexia
Uncommon: weight gain, polydipsia.

Psychiatric disorders:

Uncommon: disorientation, euphoria, anxiety.

Nervous system disorders:

Common: headache, dizziness
Uncommon: dream abnormality, cognitive disorder, lethargy, somnolence.

Eye disorders:

Uncommon: conjunctivitis.

Ear and labyrinth disorders:

Uncommon: tinnitus.

Cardiac disorders:

Uncommon: bradycardia, palpitations.

Vascular disorders:

Uncommon: hot flush.

Respiratory, thoracic and mediastinal disorders:

Common: hiccups
Uncommon: pharyngitis, sneezing, cough, post nasal drip, throat irritation.

Gastrointestinal disorders:

Common: constipation, diarrhoea, dyspepsia, eructation
Uncommon: nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, enterocolitis, flatulence, stomatitis.

Skin and subcutaneous tissue disorders:

Uncommon: rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion.

Musculoskeletal and connective tissue disorders:

Uncommon: muscle cramp, myalgia.

Renal and urinary disorders:

Uncommon: polyuria, dysuria, pollakiuria.

General disorders and administration site conditions:

Common: asthenia/fatigue
Uncommon: oedema, flushing, sneezing, chest discomfort, malaise, thirst.

Investigations:

Common: ALT increased, AST increased
Uncommon: alkaline phosphatase increased, hyperglycaemia, microscopic haematuria, hyponatraemia, weight 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 chemotherapy induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy.

PREVENTION OF POSTOPERATIVE NAUSEA AND VOMITING

In well-controlled clinical studies in patients receiving general balanced anaesthesia, 564 patients were administered 40 mg aprepitant orally and 538 patients were administered 4 mg ondansetron IV. EMEND was generally well tolerated. Most adverse experiences reported in these clinical studies were described as mild to moderate in intensity.

The most common medicine-related adverse experience reported in patients treated with aprepitant and at a greater incidence than ondansetron was ALT increased (1.1%).

The following medicine-related adverse experiences were observed in patients treated with aprepitant and at a greater incidence than ondansetron:
[Common (>1/100, <1/10) Uncommon (>1/1000, <1/100)]

Psychiatric disorders:

Uncommon: insomnia.

Nervous system disorders:

Uncommon: dysarthria, hypoaesthesia, sensory disturbance.

Eye disorders:

Uncommon: miosis, visual acuity reduced.

Cardiac disorders:

Uncommon: bradycardia.

Respiratory, thoracic and mediastinal disorders:

Uncommon: dyspnoea, wheezing.

Gastrointestinal disorders:

Uncommon: abdominal pain upper, bowel sounds abnormal, dry mouth, nausea, stomach discomfort.

Investigations:

Common: ALT increased.

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

Other Studies

Angioedema and urticaria were reported as serious adverse experiences 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 medicine.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria

Immune system disorders: hypersensitivity reactions including anaphylactic reactions

Interactions

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 weak (40 mg) to moderate (125 mg/80 mg) inhibitor of CYP3A4, aprepitant can increase plasma concentrations of orally co-administered medicinal products that are metabolised through CYP3A4. Aprepitant (40 mg and 125 mg/80 mg) can increase plasma concentrations of intravenously co-administered medicinal products metabolised through CYP3A4 to a lesser extent.

EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Dose-dependent inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these medicines, potentially causing serious or life-threatening reactions (see Contraindications).

Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolised through CYP2C9. Co-administration of EMEND with these medicines that are known to be metabolised by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these medicines.

EMEND is unlikely to interact with medicines that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND with digoxin in a clinical medicine interaction study.

5-HT3 antagonists

In clinical medicine 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 co-administered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone co-administered 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 co-administered 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). A single dose of EMEND (40 mg), when co-administered 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 1.3-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was co-administered 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 co-administered 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

In clinical studies, EMEND (125 mg/80 mg regimen) was administered with the following chemotherapeutic agents metabolised primarily or in part by CYP3A4: etoposide, vinorelbine, docetaxel, and paclitaxel. The doses of these agents were not adjusted to account for potential medicine interactions.

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 stabilised on chronic warfarin therapy. Although there was no effect of EMEND on the plasma AUC of R(+) or S(-) warfarin (a CYP2C9 substrate) determined on Day 3, there was a 34% decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalised 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 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.

In another study, a single 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 co-administration of the oral contraceptive with EMEND 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone.

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 one 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 co-administered 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 metabolised via CYP3A4 (alprazolam, triazolam) should be considered when co-administering 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 co-administered on Day 1 with EMEND 40 mg; this effect was not considered clinically important.

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, co-administration of EMEND with medicines 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, co-administration of EMEND with medicines 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. Co-administration of EMEND with medicines 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

Co-administration 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.

Overdosage

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, medicine-induced emesis may not be effective.

Aprepitant cannot be removed by haemodialysis.

Actions

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 3,000-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) and postoperative nausea and vomiting (PONV) 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.

Pharmacokinetics

Absorption

The mean absolute oral bioavailability of aprepitant is approximately 60 to 65% and the mean peak plasma concentration (C_max) of aprepitant occurred at approximately 4 hours (T_max). 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. A separate clinical study in healthy young adults demonstrated that there is no clinically important effect of food on the pharmacokinetics of a single 40 mg dose of EMEND.

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 AUC_0-24hr was approximately 19.5 mcg·hr/mL and 20.1 mcg·hr/mL on Day 1 and Day 3, respectively. The C_max of 1.5 mcg/mL and 1.4 mcg/mL were reached in approximately 4 hours (T_max) on Day 1 and Day 3, respectively. Following oral administration of a single 40 mg dose of EMEND in the fasted state, the AUC_0-∞ was 7.8 mcg hr/mL, the C_max, 0.7 mcg/mL, the T_max, 3 hours, and the half-life 9 hours.

Distribution

Aprepitant is greater than 95% bound to plasma proteins. The geometric mean apparent volume of distribution at steady state (Vd_ss) 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 Actions).

Metabolism

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 metabolised primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19, and no metabolism by CYP2D6, CYP2C9, or CYP2E1.

Elimination

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 faeces.

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.

Characteristics In Patients

Gender

Following oral administration of a single 125 mg dose of EMEND, the C_max 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 T_max occurs at approximately the same time. These differences are not considered clinically meaningful. No dosage adjustment for EMEND is necessary based on gender.

Elderly

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 AUC_0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (≥65 years) relative to younger adults. The C_max 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.

Paediatric

The pharmacokinetics of EMEND have not been evaluated in patients below 18 years of age.

Race

Following oral administration of a single 125 mg dose of EMEND, the AUC_0-24hr is approximately 25% and 29% higher in Hispanics as compared with Caucasians and Blacks, respectively. The C_max 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.

Hepatic Insufficiency

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 AUC_0-24hr 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 AUC_0-24hr 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 AUC_0-24hr 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).

Renal Insufficiency

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 haemodialysis.

In patients with severe renal insufficiency, the AUC_0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and C_max decreased by 32%, relative to healthy subjects. In patients with ESRD undergoing haemodialysis, the AUC_0-∞ of total aprepitant decreased by 42% and C_max decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound medicine was not significantly affected in patients with renal insufficiency compared with healthy subjects. Haemodialysis 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 haemodialysis.

Pharmaceutical Precautions

Store at or below 30°C, usual climatic excursions permitted.

Medicine Classification

Prescription Medicine

Package Quantities

The 80 mg capsule and the 125 mg capsule are available in a single pack containing one 125 mg capsule and two 80 mg capsules.

The 40 mg capsule is available in a pack containing one 40 mg capsule (not currently available in New Zealand).

Further Information

Chemistry

Aprepitant is a structurally novel substance P neurokinin 1 (NK₁) receptor antagonist, chemically described as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.

Its empirical formula is C₂₃H₂₁F₇N₄O₃, and its structural formula is:

Aprepitant is a white to off-white crystalline solid, with a molecular weight of 534.43. It is practically insoluble in water. Aprepitant is sparingly soluble in ethanol and isopropyl acetate and slightly soluble in acetonitrile.

Active Ingredients

Each capsule of EMEND for oral administration contains either 40 mg, 80 mg or 125 mg of aprepitant.

Inactive Ingredients

Each capsule of EMEND contains the following inactive ingredients: sucrose, microcrystalline cellulose, hydroxypropyl cellulose and sodium lauryl sulphate. The capsule shell excipients are gelatin and titanium dioxide, and may contain sodium lauryl sulfate and silicon dioxide. The 40 mg capsule shell also contains yellow ferric oxide, and the 125 mg capsule shell also contains red ferric oxide and yellow ferric oxide.

Name and Address

Merck Sharp & Dohme (NZ) Ltd
P O Box 99 851
Newmarket
Auckland
NEW ZEALAND
Tel: 0800 500 673

Date of Preparation

20 May 2009

DP-EME-0509(200509)

^®Registered trademark of Merck & Co Inc., Whitehouse Station, NJ, 08889 USA
Copyright© 2007 Merck & Co., Inc.

™Trademark of Merck & Co Inc., Whitehouse Station, NJ, 08889 USA
Copyright© 2007 Merck & Co., Inc.