APREPITANT

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 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 [see Clinical Pharmacology (12.3) ]. Intervention No dosage adjustment needed. Examples ondansetron, granisetron, dolasetron 7.2 Effect of Other Drugs on the Pharmacokinetics of Aprepitant Aprepitant is a CYP3A4 substrate [see Clinical Pharmacology (12.3) ] . 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 [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ]. Intervention Avoid concomitant use of CINVANTI. Examples Moderate inhibitor : diltiazem Strong inhibitors : ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir Strong CYP3A4 Inducers Clinical Impact Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of CINVANTI [see Clinical Pharmacology (12.3) ]. Intervention Avoid concomitant use of CINVANTI. Examples rifampin, carbamazepine, phenytoin

1 INDICATIONS AND USAGE APONVIE is indicated for the prevention of postoperative nausea and vomiting (PONV) in adults. APONVIE is a substance P/neurokinin-1 (NK 1 ) receptor antagonist, indicated for the prevention of postoperative nausea and vomiting (PONV) in adults. Limitations of Use : APONVIE has not been studied for treatment of established nausea and vomiting. ( 1 ) Limitations of Use APONVIE has not been studied for the treatment of established nausea and vomiting.

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 recommended dosage None None 2.2 Preparation of CINVANTI 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. 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. Table 4. Preparation Instructions for CINVANTI Intravenous Infusion Note: The differences in preparation for each recommended dosage of CINVANTI are displayed in bolded text (see Table 1 for HEC Regimen and Table 2 for MEC Regimen). Step 1 Aseptically withdraw 18 mL for the 130 mg dose or 14 mL for the 100 mg dose from the vial and transfer it into an infusion bag Use only Non-DEHP tubing, non-PVC infusion bags filled with 100 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose for Injection, USP. Step 2 Gently invert the bag 4 to 5 times. Avoid shaking. Step 3 Before administration, inspect the bag for particulate matter and discoloration. Discard the bag if particulate and/or discoloration are observed. 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. 2.3 Compatibilities CINVANTI is compatible with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. 2.4 Incompatibilities CINVANTI is incompatible with any solutions containing divalent cations (e.g. calcium, magnesium), including Lactated Ringer's Solution and Hartmann's Solution.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Most common adverse reactions (incidence ≥3%) are ( 6.1 ): Single-dose APONVIE: constipation, fatigue, and headache. Single-dose oral aprepitant: constipation and hypotension. To report SUSPECTED ADVERSE REACTIONS, contact Heron Therapeutics, Inc. at 1-844-437-6611 and www.APONVIE.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 APONVIE for prevention of PONV was evaluated as a single dose in healthy subjects and established from adequate and well-controlled studies of oral aprepitant [see Clinical Studies (14) ] . Adverse reactions observed in these studies are described below. 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. Table 1: Most Common Adverse Reactions in Oral Aprepitant-Treated Patients in a Pooled Analysis of PONV Studies Reported in ≥3% of patients treated with oral aprepitant 40 mg and at a greater incidence than with ondansetron. Oral Aprepitant 40 mg (N = 564) Ondansetron (N = 538) Constipation 9% 8% hypotension 6% 5% 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of 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 [see Warnings and Precautions (5.1) ] . Immune system disorders : hypersensitivity reactions including anaphylaxis and anaphylactic shock [see Contraindications (4) and Warnings and Precautions (5.1) ] . Nervous system disorders : ifosfamide-induced neurotoxicity reported after aprepitant and ifosfamide coadministration.