APONVIE

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 The recommended dose is 32 mg administered as a 30 second intravenous injection prior to induction of anesthesia. ( 2.1 ) 2.1 Recommended Dosage The recommended dose in adults of APONVIE is 32 mg administered as a 30 second intravenous injection prior to induction of anesthesia. 2.2 Preparation and Administration Inspect the vial for particulate matter and discoloration prior to administration; discard if present. APONVIE is opaque and off-white to amber in color. Aseptically withdraw 4.4 mL from the vial. Flush the infusion line with normal saline before and after administration of APONVIE. 2.3 Compatibilities APONVIE is compatible with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, and solutions containing divalent cations (e.g., calcium, magnesium), including Lactated Ringer's Solution.

4 CONTRAINDICATIONS APONVIE is contraindicated in patients: with a history of hypersensitivity to aprepitant or any component of the product [see Description (11) ] . Hypersensitivity reactions have included anaphylaxis [see Warnings and Precautions (5.1) ] . 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 Drug Interactions (7.1) ] . Known hypersensitivity to any component of this product. ( 4 , 5.1 ) Concurrent use with pimozide. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions (including anaphylaxis) : May occur during or soon after administration. If symptoms occur, administer appropriate medical therapy. ( 4 , 5.1 ) CYP3A4 Interactions : Aprepitant is a substrate, weak-to-moderate inhibitor, and inducer of CYP3A4; see full prescribing information. ( 5.2 , 7.2 ) Warfarin (a CYP2C9 substrate) : Risk of decreased INR of prothrombin time; monitor INR in 2-week period, particularly at 7 to 10 days, following administration of APONVIE. ( 5.3 , 7.1 ) Hormonal Contraceptives : Efficacy of contraceptives may be reduced for 28 days following administration of aprepitant. Use effective alternative or back-up methods of non-hormonal contraception. ( 5.4 , 7.1 , 8.3 ) 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, during or soon after administration of aprepitant have occurred. Symptoms including dyspnea, eye swelling, flushing, pruritus, and wheezing have been reported [see Adverse Reactions (6.2) ] . Monitor patients during and after administration. If hypersensitivity reactions occur, administer appropriate medical therapy. Do not administer APONVIE in patients who experience these symptoms with previous use of aprepitant. 5.2 Clinically Significant CYP3A4 Drug Interactions Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Use of pimozide, a CYP3A4 substrate, with APONVIE is contraindicated [see Contraindications (4) ] . Use of APONVIE with strong CYP3A4 inhibitors (e.g., ketoconazole) may increase plasma concentrations of aprepitant and result in an increased risk of adverse reactions related to APONVIE [see Drug Interactions (7.2) ] . Use of APONVIE with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of APONVIE [see Drug Interactions (7.2) ]. 5.3 Decrease in INR with Concomitant Warfarin Use of aprepitant with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in the International Normalized Ratio (INR) of prothrombin time [see Clinical Pharmacology (12.3) ] . Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following administration of APONVIE [see Drug Interactions (7.1) ] . 5.4 Risk of Reduced Efficacy of Hormonal Contraceptives The efficacy of hormonal contraceptives may be reduced for 28 days following administration of APONVIE [see Clinical Pharmacology (12.3) ] . Advise patients to use effective alternative or back-up methods of non-hormonal contraception for 1 month following administration of APONVIE [see Drug Interactions (7.1) and Use in Specific Populations (8.3) ] .

7 DRUG INTERACTIONS See full prescribing information for a list of clinically significant drug interactions. ( 4 , 5.2 , 5.3 , 5.4 , 7.1 , 7.2 ) 7.1 Effect of Aprepitant on the Pharmacokinetics of Other Drugs Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9 [see Clinical Pharmacology (12.3) ] . Table 2 includes drug interactions affecting drugs co-administered with APONVIE and instructions for preventing or managing them. Table 2: Drug Interactions Affecting Drugs When Co-Administered with APONVIE Pimozide Clinical Impact Increased pimozide exposure. Intervention APONVIE is contraindicated [see Contraindications (4) ] . Hormonal Contraceptives Clinical Impact Decreased hormonal exposure for 28 days after administration of APONVIE [see Warnings and Precautions (5.3) , Use in Specific Populations (8.3) , and Clinical Pharmacology (12.3) ] . Intervention Effective alternative or back-up methods of contraception (such as condoms and spermicides) should be used for 1 month following administration of APONVIE. Examples birth control pills, transdermal systems, implants, and certain intrauterine systems CYP2C9 Substrates Warfarin Clinical Impact Decreased warfarin exposure and decreased prothrombin time (INR) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . Intervention In patients on chronic warfarin therapy, monitor prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following administration of APONVIE. 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 Corticosteroids Clinical Impact No clinically significant change in the exposure of dexamethasone or methylprednisolone [see Clinical Pharmacology (12.3) ]. Intervention No dosage adjustment needed. 7.2 Effect of Other Drugs on the Pharmacokinetics of Aprepitant Aprepitant is a CYP3A4 substrate [see Clinical Pharmacology (12.3) ] . Table 3 includes drug interactions affecting APONVIE when co-administered with other drugs and instructions for preventing them. Table 3: Drug Interactions Affecting APONVIE When Co-Administered with Other Drugs Strong CYP3A4 Inhibitors Clinical Impact Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with APONVIE [see Clinical Pharmacology (12.3) ]. Intervention Avoid concomitant use of APONVIE. Examples 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 APONVIE [see Clinical Pharmacology (12.3) ]. Intervention Avoid concomitant use of APONVIE. Examples rifampin, carbamazepine, phenytoin

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.

8.1 Pregnancy 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 Fetal/Neonatal Adverse Reactions APONVIE 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 APONVIE 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 125 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 4.8 times the exposure at the recommended human dose of APONVIE. Aprepitant crosses the placenta in rats and rabbits.