Intravenous Injection over a period of 2 minutes

For intravenous injection over a period of 2 minutes, administer 130 mg of CINVANTI as part of a HEC or MEC regimen or 100 mg as part of a MEC regimen as a single dose on Day 1.

Aseptically withdraw 18 mL for the 130 mg dose or 14 mL for the 100 mg dose from the vial. Do not dilute.

The infusion line should be flushed with normal saline before and after administration of CINVANTI.

Intravenous Infusion over a period of 30 minutes

Table 4 includes preparation instructions for CINVANTI for HEC or MEC as a 130 mg single-dose regimen, and for MEC as a 100 mg single-dose followed by 2 days of oral aprepitant as a 3-day regimen. Differences in preparation for each dose are displayed as bolded text.

Caution: Do not mix CINVANTI with solutions for which physical and chemical compatibility have not been established.

In-Use Storage Conditions for CINVANTI in Acceptable Intravenous Diluents

Diluted CINVANTI solution is stable at ambient room temperature for up to 6 hours in 0.9% Sodium Chloride Injection, USP or 12 hours in 5% Dextrose Injection, USP or up to 72 hours if stored under refrigeration in 0.9% Sodium Chloride Injection, USP or in 5% Dextrose Injection, USP.

Safety of CINVANTI

A total of 200 healthy subjects received a single 130 mg dose of CINVANTI as a 30-minute infusion. Adverse reactions reported in at least 2% of subjects were headache (3%) and fatigue (2%). The safety profile of CINVANTI in 50 healthy subjects who received a single 2-minute injection was similar to that seen with a 30-minute infusion.

Single-Dose Intravenous Fosaprepitant -- HEC

In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1143 patients receiving a single intravenous dose of fosaprepitant, a prodrug of aprepitant, compared to 1169 patients receiving a 3-day regimen of oral aprepitant [see Clinical Studies (14.1)]. When administered intravenously, fosaprepitant is converted to aprepitant within 30 minutes. The safety profile was generally similar to that seen in prior HEC studies with a 3-day regimen of oral aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the intravenous fosaprepitant group (3%) compared to those in the oral aprepitant group (0.5%). The reported infusion-site reactions included: infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration and infusion-site thrombophlebitis.

Adverse reactions associated with oral aprepitant may also be expected to occur with CINVANTI. See the full prescribing information for oral aprepitant for complete safety information.

Single-Dose Intravenous Fosaprepitant -- MEC

In an active-controlled clinical trial in patients receiving MEC, safety was evaluated in 504 patients receiving a single dose of intravenous fosaprepitant in combination with ondansetron and dexamethasone (intravenous fosaprepitant regimen) compared to 497 patients receiving ondansetron and dexamethasone alone (standard therapy). The most common adverse reactions are listed in Table 5.

Infusion-site reactions were reported in 2.2% of patients treated with the intravenous fosaprepitant regimen compared to 0.6% of patients treated with standard therapy. The infusion-site reactions included: infusion-site pain (1.2%, 0.4%), injection-site irritation (0.2%, 0.0%), vessel puncture-site pain (0.2%, 0.0%), and 8 infusion-site thrombophlebitis (0.6%, 0.0%), reported in the intravenous fosaprepitant regimen compared to standard therapy, respectively.

3-Day Oral Aprepitant -- MEC

In 2 active-controlled clinical trials in patients receiving MEC, 868 patients were treated with a 3-day oral aprepitant regimen during Cycle 1 of chemotherapy and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In both studies, oral aprepitant was given in combination with ondansetron and dexamethasone (oral aprepitant regimen) and was compared to ondansetron and dexamethasone alone (standard therapy) [see Clinical Studies (14.2)].

In the combined analysis of Cycle 1 data for these 2 studies, adverse reactions 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 adverse reactions in 0.7% of patients treated with the aprepitant regimen compared with 0.2% of patients treated with standard therapy.

The most common adverse reactions reported in patients treated with the oral aprepitant regimen with an incidence of at least 1% and greater than standard therapy are listed in Table 6.

A listing of adverse reactions reported in less than 1% in patients treated with the oral aprepitant regimen that occurred at an incidence greater than in patients treated with standard therapy are presented in the Less Common Adverse Reactions subsection below.

Risk Summary

There are no available data on CINVANTI use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Avoid use of CINVANTI 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 aprepitant approximately equivalent to the exposure at the recommended human dose (RHD) of CINVANTI 130 mg (see Data).

The estimated 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. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CINVANTI and any potential adverse effects on the breastfed infant from CINVANTI or from the underlying maternal condition.

Contraception

Upon administration of CINVANTI, 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) during treatment with CINVANTI and for 1 month following the last dose of CINVANTI or oral aprepitant, whichever is administered last [see Warnings and Precautions (5.4), Drug Interactions (7.1), Clinical Pharmacology (12.3)].

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. In a cross-study comparison, maximum aprepitant concentrations (Cmax) after a single 200 mg dose of fosaprepitant were 1.04- and 1.5-fold higher than that achieved with CINVANTI 130 mg dose and 100 mg dose given as a 30-minute infusion, respectively.

Distribution

Aprepitant is greater than 99% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) was approximately 70 L in humans.

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

Elimination

Specific Populations

Drug Interactions Studies

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

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 approximately equivalent to (female rats) or less than (male rats) the human exposure at the CINVANTI RHD of 130 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 to1000 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 2 times the human exposure at the RHD of CINVANTI 130 mg. 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 rats lower than the exposure at the RHD of CINVANTI 130 mg and exposure in female rats approximately equivalent to the human exposure).

Single-Dose Intravenous Fosaprepitant – MEC

In a randomized, parallel, double-blind, active comparator-controlled study, 150 mg fosaprepitant as a single intravenous infusion (N=502) in combination with ondansetron and dexamethasone (intravenous fosaprepitant regimen) was compared with ondansetron and dexamethasone alone (standard therapy) (N=498) (see Table 13) in patients receiving a MEC regimen. Patient demographics were similar between the two treatment groups. Of the total 1,000 patients included in the efficacy analysis, 41% were men, 84% White, 4% Asian, 1% American Indian/Alaska Native, 2% Black, 10% Multi-Racial, and 19% Hispanic/Latino ethnicity. Patient ages ranged from 23 to 88 years of age, with a mean age of 60 years. The most commonly administered MEC chemotherapeutic agents were carboplatin (51%), oxaliplatin (24%), and cyclophosphamide (12%).

The primary endpoint was complete response (defined as no vomiting and no rescue therapy) in the delayed phase (25 to 120 hours) of chemotherapy-induced nausea and vomiting. The results by treatment group are shown in Table 14.

3-Day Oral Aprepitant -- MEC

In a multicenter, randomized, double-blind, parallel-group, clinical study in breast cancer patients, a 3-day oral aprepitant regimen was compared with a standard of care therapy in patients receiving a MEC regimen that included cyclophosphamide 750 to1500 mg/m2; or cyclophosphamide 500 to1500 mg/m2 and doxorubicin (≤ 60 mg/m2) or epirubicin (≤ 100 mg/m2). Patients (N = 866) were randomized to either the aprepitant regimen (N = 438) or standard therapy (N = 428). The treatment regimens are defined in Table 15.

In this study, the most common chemotherapy combinations were cyclophosphamide plus doxorubicin (61%); and cyclophosphamide plus epirubicin and fluorouracil (22%).

Of the 438 patients who were randomized to receive the oral aprepitant regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and < 1% Other. The aprepitant-treated patients in this clinical study ranged from 25 to 78 years of age, with a mean age of 53 years; 70 patients were 65 years or older, with 12 patients being over 74 years.

The antiemetic activity of oral aprepitant was evaluated based on the following endpoints in which emetic episodes included vomiting, retching, or dry heaves:

Primary endpoint:

• complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries) in the overall phase (0 to 120 hours post-chemotherapy)

Other prespecified endpoints:

• no emesis (defined as no emetic episodes regardless of use of rescue therapy)
• no nausea (maximum nausea visual analogue scale [VAS] score < 5 mm on a 0 to 100 mm scale)
• no significant nausea (maximum VAS score < 25 mm on a 0 to 100 mm scale)
• complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum VAS score < 25 mm on a 0 to 100 mm scale)
• complete response during the acute and delayed phases.

A summary of the key results from this study is shown in Table 16.

In this study, a statistically significantly (p = 0.015) higher proportion of patients receiving the oral aprepitant regimen in Cycle 1 had a complete response (primary endpoint) during the overall phase compared with patients receiving standard therapy. The difference between treatment groups was primarily driven by the "No Emesis Endpoint", a principal component of this composite primary endpoint. In addition, a higher proportion of patients receiving the oral aprepitant regimen in Cycle 1 had a complete response during the acute (0 to 24 hours) and delayed (25 to 120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments.

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 initiation of CINVANTI with each chemotherapy cycle [see Warnings and Precautions (5.3)].

Hormonal Contraceptives: Advise patients that administration of CINVANTI 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) during treatment with CINVANTI and for 1 month following administration of CINVANTI or oral aprepitant, whichever is administered last [see Warnings and Precautions (5.4), Use in Specific Populations (8.3)].