Cinvanti Drug Information

CINVANTI, in combination with other antiemetic agents, is indicated in adults for the prevention of: acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin as a single-dose regimen. delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) as a single-dose regimen. nausea and vomiting associated with initial and repeat courses of MEC as a 3-day regimen. Limitations of Use: CINVANTI has not been studied for treatment of established nausea and vomiting.

Prevention of Nausea and Vomiting Associated with HEC and MEC The recommended dosages in adults of CINVANTI, dexamethasone, and a 5-HT 3 antagonist for the prevention of nausea and vomiting associated with administration of HEC or MEC are shown in Table 1, Table 2 and Table 3 respectively. Administer CINVANTI intravenously either by injection over a two minute period or by infusion over a thirty minute period on Day 1, completing the injection or infusion approximately 30 minutes prior to chemotherapy. Table 1.

Recommended Dosage of CINVANTI for the Prevention of Nausea and Vomiting Associated with HEC (Single-Dose Regimen) Agent Day CINVANTI 130 mg intravenously None None None Dexamethasone Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with aprepitant. for Administration 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. 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.

Table 4. Preparation Instructions for 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.

Compatibilities CINVANTI is compatible with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.

Incompatibilities CINVANTI is incompatible with any solutions containing divalent cations (e.g. calcium, magnesium), including Lactated Ringer's Solution and Hartmann's Solution.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of CINVANTI was evaluated as a single-dose in healthy subjects and established from adequate and well-controlled studies of intravenous fosaprepitant and/or oral aprepitant. Adverse reactions observed in these adequate and well-controlled studies are described below.

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. 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.

Table 5. Most Common Adverse Reactions in Patients Receiving MEC Reported in ≥2% of patients treated with the intravenous fosaprepitant regimen and at a greater incidence than standard therapy. 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.

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). 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.

Table 6. Adverse Reactions (≥ 1%) in Patients Receiving MEC with a Greater Incidence in the Oral 3-Day Aprepitant Regimen Relative to Standard Therapy Oral Aprepitant Regimen (N = 868) Standard Therapy (N = 846) Fatigue 1.4 0.9 Eructation 1.0 0.1 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. Less Common Adverse Reactions Adverse reactions reported in studies in patients treated with the 3-day oral aprepitant regimen with an incidence < 1% and greater than standard therapy are listed in Table 7.

Table 7. Adverse Reactions (incidence < 1%) in Patients Observed in Studies with a Greater Incidence in the Oral Aprepitant Regimen Relative to Standard Therapy In another chemotherapy-induced nausea and vomiting study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy. The adverse experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of intravenous fosaprepitant and/or intravenous or oral aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis.

Immune system disorders: hypersensitivity reactions including anaphylaxis and anaphylactic shock. Nervous system disorders: ifosfamide-induced neurotoxicity reported after aprepitant and ifosfamide coadministration.

Effect of Aprepitant on the Pharmacokinetics of Other Drugs Aprepitant is a substrate, weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Some substrates of CYP3A4 are contraindicated with CINVANTI.

Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 8. Table 8. Effects of Aprepitant on the Pharmacokinetics of Other Drugs Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions.

Intervention Monitor for benzodiazepine-related adverse reactions. Dexamethasone Clinical Impact Increased dexamethasone exposure. Intervention Reduce the dose of oral dexamethasone by approximately 50%.

Methylprednisolone Clinical Impact Increased methylprednisolone exposure. Chemotherapeutic Agents that are Metabolized by CYP3A4 Clinical Impact Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions. Intervention Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents Monitor for chemotherapeutic-related adverse reactions.

Hormonal Contraceptives Clinical Impact Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of aprepitant. Decreased warfarin exposure and decreased prothrombin time (INR). Intervention In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following administration of CINVANTI with each chemotherapy cycle.

Other Antiemetic Agents 5-HT 3 Antagonists Clinical Impact No change in the exposure of the 5-HT 3 antagonist. Intervention No dosage adjustment needed. Examples ondansetron, granisetron, dolasetron

Co-administration of CINVANTI with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of aprepitant, respectively, as shown in Table 9. Table 9. Effects of Other Drugs on Pharmacokinetics of Aprepitant Moderate to Strong CYP3A4 Inhibitors Clinical Impact Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with CINVANTI.

Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of CINVANTI. Intervention Avoid concomitant use of CINVANTI. Examples rifampin, carbamazepine, phenytoin

Pregnancy 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 ) 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 respectively.

Clinical Considerations Fetal/Neonatal adverse reactions CINVANTI contains alcohol. Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. There is no safe level of alcohol exposure in pregnancy; therefore, avoid use of CINVANTI in pregnant women.

Data Animal Data In embryofetal development studies in rats and rabbits, aprepitant was administered during the period of organogenesis at oral doses up to 1000 mg/kg twice daily (rats) and up to the maximum tolerated dose of 25 mg/kg/day (rabbits). No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats at 1000 mg/kg twice daily and in pregnant rabbits at 125 mg/kg/day were approximately equivalent to the exposure at the RHD of CINVANTI 130 mg.

Aprepitant crosses the placenta in rats and rabbits.

Pediatric Use The safety and effectiveness of CINVANTI have not been established in pediatric patients.

CINVANTI is contraindicated in patients: who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylaxis have been reported. taking pimozide. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of pimozide, 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.

There is no specific information on the treatment of overdosage with aprepitant. In the event of overdose, CINVANTI should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of CINVANTI, drug-induced emesis may not be effective in cases of CINVANTI overdosage.

Aprepitant is not removed by hemodialysis.