APONVIE

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) ] .

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.

<table width="90%"><caption>Table 1: Most Common Adverse Reactions in Oral Aprepitant-Treated Patients in a Pooled Analysis of PONV Studies<footnote>Reported in &#x2265;3% of patients treated with oral aprepitant 40 mg and at a greater incidence than with ondansetron.</footnote></caption><col width="33%" align="left" valign="top"/><col width="34%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Oral Aprepitant 40 mg (N = 564)</th><th styleCode="Rrule">Ondansetron (N = 538)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">8%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">hypotension</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">5%</td></tr></tbody></table>