Aprepitant

FDA Drug Information • Also known as: Aponvie, Aprepitant, Cinvanti, Emend

Brand Names: Aponvie, Aprepitant, Cinvanti, Emend
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION CINVANTI injectable emulsion contains the active ingredient, aprepitant. Aprepitant is a substance P/neurokinin 1 (NK 1 ) receptor antagonist, an antiemetic agent, chemically described as 5-[[(2 R ,3 S )-2-[(1 R )-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3 H -1,2,4-triazol-3-one. Its empirical formula is C 23 H 21 F 7 N 4 O 3 , 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. CINVANTI (aprepitant) injectable emulsion is a sterile, opaque, off-white to amber liquid in a single-dose vial for intravenous use. Each vial contains 130 mg aprepitant in 18 mL of emulsion. The emulsion also contains the following inactive ingredients: egg lecithin (2602 mg), dehydrated alcohol (513 mg), sodium oleate (87 mg), soybean oil (1734 mg), sucrose (973 mg), and water for injection (12142 mg). Chemical Structure

What Is Aprepitant Used For?

1 INDICATIONS AND USAGE 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. CINVANTI is a substance P/neurokinin-1 (NK 1 ) receptor antagonist, indicated in adults, in combination with other antiemetic agents, 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. ( 1 ) delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) as a single-dose regimen. ( 1 ) nausea and vomiting associated with initial and repeat courses of MEC as a 3-day regimen. ( 1 ) Limitations of Use : CINVANTI has not been studied for treatment of established nausea and vomiting. ( 1 ) Limitations of Use CINVANTI has not been studied for the treatment of established nausea and vomiting.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Recommended Dosage ( 2.1 ): Administer CINVANTI intravenously as an injection over 2 minutes or an infusion over 30 minutes; complete the injection or infusion approximately 30 minutes prior to chemotherapy. HEC and MEC (Single-Dose Regimen) : The recommended dosage in adults is 130 mg on Day 1. MEC (3-Day Regimen) : The recommended dosage in adults is 100 mg on Day 1. Aprepitant capsules (80 mg) are given orally on Days 2 and 3. CINVANTI is part of a regimen that includes a corticosteroid and a 5-HT 3 antagonist. Preparation : See the full prescribing information for instructions. ( 2.2 ) 2.1 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 (2) minute period or by infusion over a thirty (30) 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 1 Day 2 Day 3 Day 4 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. Also administer dexamethasone in the evenings on Days 3 and 4. A 50% dosage reduction of dexamethasone on Days 1 and 2 is recommended to account for a drug interaction with aprepitant [see Clinical Pharmacology (12.3) ] . 12 mg orally 8 mg orally 8 mg orally twice daily 8 mg orally twice daily 5-HT 3 antagonist See selected 5-HT 3 antagonist prescribing information for recommended dosage None None None Table 2. Recommended Dosage of CINVANTI for the Prevention of Nausea and Vomiting Associated with MEC (Single-Dose Regimen) Agent Day 1 CINVANTI 130 mg intravenously Dexamethasone Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with aprepitant [see Clinical Pharmacology (12.3) ] . 12 mg orally 5-HT 3 antagonist See selected 5-HT 3 antagonist prescribing information for recommended dosage Table 3. Recommended Dosage of CINVANTI for the Prevention of Nausea and Vomiting Associated with MEC (3-Day Regimen with Oral Aprepitant on Days 2 and 3) Agent Day 1 Day 2 Day 3 CINVANTI 100 mg intravenously None None Oral Aprepitant None 80 mg orally 80 mg orally Dexamethasone Administer dexamethasone 30 minutes prior to chemotherapy treatment on Day 1. A 50% dosage reduction of dexamethasone is recommended to account for a drug interaction with aprepitant [see Clinical Pharmacology (12.3) ] . 12 mg orally None None 5-HT 3 antagonist See selected 5-HT 3 antagonist prescribing information for...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions are: Single-dose fosaprepitant with MEC (≥2%): fatigue, diarrhea, neutropenia, asthenia, anemia, peripheral neuropathy, leukopenia, dyspepsia, urinary tract infection, pain in extremity. ( 6.1 ) 3-day oral aprepitant with MEC (≥1% and greater than standard therapy): fatigue and eructation. ( 6.1 ) Single-dose fosaprepitant with HEC: generally similar to 3-day oral aprepitant. In addition, infusion site reactions (3%) occurred. ( 6.1 ) Single-dose CINVANTI (≥2%): headache and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Heron Therapeutics, Inc. at 1-844-437-6611 and www.CINVANTI.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 [see Clinical Studies (14) ] . 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 [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. 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. Intravenous fosaprepitant, ondansetron, and dexamethasone Intravenous fosaprepitant regimen (N=504) Ondansetron and dexamethasone Standard therapy (N=497) Fatigue 15% 13% Diarrhea 13% 11% Neutropenia 8% 7% Asthenia 4% 3% Anemia 3% 2% Peripheral Neuropathy 3% 2% Leukopenia 2% 1% Dyspepsia 2% 1% Urinary Tract Infection 2% 1% Pain In Extremity 2% 1% Infusion-site reactions were reported in 2.2% of patients treated with the intravenous fosaprepitant...

Drug Interactions

7 DRUG INTERACTIONS See full prescribing information for a list of clinically significant drug interactions. ( 4 , 5.1 , 5.3 , 5.4 , 7.1 , 7.2 ) 7.1 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 [see Clinical Pharmacology (12.3) ] . Some substrates of CYP3A4 are contraindicated with CINVANTI [see Contraindications (4) ] . 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 CYP3A4 Substrates Pimozide Clinical Impact Increased pimozide exposure. Intervention CINVANTI is contraindicated [see Contraindications (4) ] . Benzodiazepines Clinical Impact Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions [see Clinical Pharmacology (12.3) ] . Intervention Monitor for benzodiazepine-related adverse reactions. Dexamethasone Clinical Impact Increased dexamethasone exposure [see Clinical Pharmacology (12.3) ] . Intervention Reduce the dose of oral dexamethasone by approximately 50% [see Dosage and Administration (2.1) ] . Methylprednisolone Clinical Impact Increased methylprednisolone exposure [see Clinical Pharmacology (12.3) ] . Intervention Reduce the dose of oral methylprednisolone by approximately 50% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC. Reduce the dose of intravenous methylprednisolone by 25% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC. Chemotherapeutic Agents that are Metabolized by CYP3A4 Clinical Impact Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions [see Clinical Pharmacology (12.3) ] . Intervention Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents Monitor for chemotherapeutic-related adverse reactions. Etoposide, vinorelbine, paclitaxel, and docetaxel No dosage adjustment needed. Hormonal Contraceptives Clinical Impact Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of aprepitant [see Warnings and Precautions (5.4) , Use in Specific Populations (8.3) , and Clinical Pharmacology (12.3) ] . Intervention Effective alternative or back-up methods of contraception (such as condoms or spermicides) should be used during treatment with CINVANTI and for 1 month following administration of CINVANTI or oral aprepitant, whichever is administered last. Examples birth control pills, skin patches, implants, and certain IUDs CYP2C9 Substrates Warfarin Clinical Impact Decreased warfarin exposure and decreased prothrombin time (INR) [see Warnings and Precautions (5.3) , Clinical Pharmacology (12.3) ] . Intervention In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week...

Contraindications

4 CONTRAINDICATIONS CINVANTI is contraindicated in patients: who are hypersensitive to any component of the product [see Description (11) ] . Hypersensitivity reactions including anaphylaxis have been reported [see Warnings and Precautions (5.2) , Adverse Reactions (6.2) ] . 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 [see Warnings and Precautions (5.1) ] . Known hypersensitivity to any component of this drug. ( 4 , 5.2 ) Concurrent use with pimozide. ( 4 )

Pregnancy and Breastfeeding

8.1 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 [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 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.

Overdosage

10 OVERDOSAGE 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING CINVANTI injectable emulsion is supplied as an opaque, off-white to amber emulsion in a single-dose glass vial containing 130 mg/18 mL (7.2 mg/mL) aprepitant: NDC 47426-201-01 1 single-dose vial per carton Storage CINVANTI injectable emulsion vials must be refrigerated, store at 2°C-8°C (36°F-46°F). CINVANTI injectable emulsion vials can remain at room temperature up to 60 days. Do not freeze.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.