Safety of APONVIE

A total of 51 healthy subjects received a single 32 mg dose of APONVIE as a 30 second intravenous injection. Adverse reactions reported in at least 3% of subjects were constipation (8%), fatigue (6%), and headache (4%).

Safety of Oral Aprepitant

In 2 active-controlled, double-blind clinical studies in patients receiving general anesthesia (Studies 1 and 2), 40 mg oral aprepitant was compared to 4 mg intravenous ondansetron [see Clinical Studies (14)].

There were 564 patients treated with oral aprepitant and 538 patients treated with ondansetron.

The most common adverse reactions reported in patients treated with oral aprepitant for PONV in pooled Studies 1 and 2 are listed in Table 1.

In a pooled analysis of PONV studies, less common adverse reactions reported in more than 0.5% of patients treated with oral aprepitant and at a greater incidence than ondansetron were dizziness and urticaria.

In addition, two serious adverse reactions were reported in PONV clinical studies of oral aprepitant in patients taking a higher than recommended dose: one case of constipation, and one case of sub-ileus.

Other Studies

Angioedema, urticaria, and Stevens-Johnson syndrome were reported as serious adverse reactions in patients receiving oral aprepitant in non-PONV studies.

Risk Summary

There are insufficient data on aprepitant use in pregnant women to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Avoid use of APONVIE in pregnant women due to the alcohol content (see Clinical Considerations). In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic drug concentrations (area under the plasma-concentration time curve [AUC]) of oral aprepitant approximately 4.8 times the exposure at the recommended human dose of APONVIE (see Data).

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Data

Risk Summary

There are no data on the presence of aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production. Aprepitant is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for APONVIE and any potential adverse effects on the breastfed infant from APONVIE or from the underlying maternal condition.

Contraception

Upon administration of APONVIE, the efficacy of hormonal contraceptives may be reduced. Advise females of reproductive potential using hormonal contraceptives to use an effective alternative or back-up non-hormonal contraceptive (such as condoms or spermicides) for 1 month following administration of APONVIE [see Warnings and Precautions (5.4), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

Juvenile Animal Study

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 1000 mg/kg twice daily 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.

NK1 Receptor Occupancy

In two single-blind, multiple-dose, randomized, and placebo-controlled studies, healthy young men received oral aprepitant doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3), or 300 mg (N=5) once daily (0.08, 0.24, 0.8, and 2.4 times a single 125 mg dose of oral aprepitant, respectively) for 14 days with 2 or 3 subjects on placebo. Both plasma aprepitant concentration and NK1 receptor occupancy in the corpus striatum by PET were evaluated, at predose and 24 hours after the last dose. At aprepitant plasma concentrations of approximately 10 ng/mL and 100 ng/mL, the NK1 receptor occupancies were approximately 50% and 90%, respectively. The oral aprepitant regimen produced mean trough plasma aprepitant concentrations greater than 500 ng/mL in adults, which would be expected to, based on the fitted curve with the Hill equation, result in greater than 95% brain NK1 receptor occupancy. However, the receptor occupancy for the PONV dosing regimen has not been determined. In addition, the relationship between NK1 receptor occupancy and the clinical efficacy of aprepitant has not been established.

Cardiac Electrophysiology

In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200 mg intravenous dose of fosaprepitant, a prodrug of aprepitant, had no effect on the QTc interval. QT prolongation with the recommended APONVIE dosing regimen is not expected.

Absorption

Following administration of a single intravenous 32 mg dose of APONVIE administered as a 30 second injection to healthy subjects, mean (CV%) area under the plasma concentration-time curve (AUC0-∞) was 7.8 (27.4%) mcg∙hr/mL and mean plasma concentration at 5 minutes post-dose was 2.1 (19%) mcg/mL.

In healthy subjects, a single dose of 32 mg of APONVIE administered as a 30 second intravenous injection resulted in a 13% higher AUC0-∞ of aprepitant compared to a single oral dose of 40 mg aprepitant, which was not considered clinically meaningful.

Distribution

Aprepitant was greater than 99% bound to plasma proteins. The mean volume of distribution following APONVIE administration was approximately 72 L in healthy subjects.

Aprepitant crossed the blood-brain barrier in humans [see Clinical Pharmacology (12.1)].

Elimination

Specific Populations

Drug Interactions Studies

Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter.

Aprepitant acts as a weak inhibitor of CYP3A4 when administered as a single intravenous 32 mg dose of APONVIE.

Carcinogenesis

Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced systemic exposures to aprepitant (AUC) approximately 5.1 times the human exposure from APONVIE 32 mg. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure approximately 11.5 times the human exposure at the recommended human dose of APONVIE. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice.

Mutagenesis

Aprepitant was not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test, and the mouse micronucleus test.

Impairment of Fertility

Oral aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male and female rats higher than the exposure at the recommended human dose of APONVIE).

Warfarin: Instruct patients on chronic warfarin therapy to follow instructions from their healthcare provider regarding blood draws to monitor their INR during the 2-week period, particularly at 7 to 10 days, following administration of APONVIE [see Warnings and Precautions (5.3)].

Hormonal Contraceptives: Advise patients that administration of APONVIE may reduce the efficacy of hormonal contraceptives. Instruct patients to use effective alternative or back-up methods of non-hormonal contraception (such as condoms or spermicides) for 1 month following administration of APONVIE [see Warnings and Precautions (5.4) and Use in Specific Populations (8.3)].