CINVANTI

5 WARNINGS AND PRECAUTIONS CYP3A4 Interactions : Aprepitant is a substrate, weak-to-moderate (dose-dependent) inhibitor and an inducer of CYP3A4; see Full Prescribing Information for recommendations regarding contraindications, risk of adverse reactions, and dosage adjustment of CINVANTI and concomitant drugs. ( 4 , 5.1 , 7.1 , 7.2 ) Hypersensitivity Reactions (including anaphylaxis ): May occur during or soon after administration. If symptoms occur, discontinue CINVANTI and do not reinitiate it. ( 4 , 5.2 ) Warfarin (a CYP2C9 substrate) : Risk of decreased INR of prothrombin time; monitor INR in 2–week period, particularly at 7 to 10 days, following initiation of CINVANTI. ( 5.3 , 7.1 ) Hormonal Contraceptives : Efficacy of contraceptives may be reduced during and 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 Clinically Significant CYP3A4 Drug Interactions Aprepitant is a substrate, weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Use of CINVANTI with other drugs that are CYP3A4 substrates may result in increased plasma concentration of the concomitant drug. Use of pimozide with CINVANTI is contraindicated due to the risk of significantly increased plasma concentrations of pimozide, potentially resulting in prolongation of the QT interval, a known adverse reaction of pimozide [see Contraindications (4) ] . Use of CINVANTI with strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, diltiazem) may increase plasma concentrations of aprepitant and result in an increased risk of adverse reactions related to CINVANTI. Use of CINVANTI with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of CINVANTI. See Table 8 and Table 9 for a listing of potentially significant drug interactions [see Drug Interactions (7.1 , 7.2) ]. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis during or soon after administration of CINVANTI 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, discontinue CINVANTI and administer appropriate medical therapy. Do not reinitiate CINVANTI in patients who experience these symptoms with previous use. 5.3 Decrease in INR with Concomitant Warfarin Coadministration of CINVANTI 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 initiation of CINVANTI with each chemotherapy cycle [see Drug Interactions (7.1) ] . 5.4 Risk of Reduced Efficacy of Hormonal Contraceptives Upon coadministration with CINVANTI, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of CINVANTI [see Clinical Pharmacology (12.3) ] . Advise patients to use effective alternative or back-up methods of non-hormonal contraception during treatment with CINVANTI and for 1 month following administration of CINVANTI or oral aprepitant, whichever is administered last [see Drug Interactions (7.1) , 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 (5.2) ] 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 regimen compared to 0.6% of patients treated with standard therapy. The infusion-site reactions included: infusion-site pain (1.2%, 0.4%), injection-site irritation (0.2%, 0.0%), vessel puncture-site pain (0.2%, 0.0%), and 8 infusion-site thrombophlebitis (0.6%, 0.0%), reported in the intravenous fosaprepitant regimen compared to standard therapy, respectively. 3-Day Oral Aprepitant -- MEC In 2 active-controlled clinical trials in patients receiving MEC, 868 patients were treated with a 3-day oral aprepitant regimen during Cycle 1 of chemotherapy and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. 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) [see Clinical Studies (14.2) ] . 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. The most common adverse reactions reported in patients treated with the oral aprepitant regimen with an incidence of at least 1% and greater than standard therapy are listed in Table 6. 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 Infection and infestations candidiasis, staphylococcal infection Blood and the lymphatic system disorders anemia, febrile neutropenia Metabolism and nutrition disorders weight gain, polydipsia Psychiatric disorders disorientation, euphoria, anxiety Nervous system disorders dizziness, dream abnormality, cognitive disorder, lethargy, somnolence Eye disorders conjunctivitis Ear and labyrinth disorders tinnitus Cardiac disorders bradycardia, cardiovascular disorder, palpitations Vascular disorders hot flush, flushing Respiratory, thoracic and mediastinal disorders pharyngitis, sneezing, cough, postnasal drip, throat irritation Gastrointestinal disorders nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, feces hard, neutropenic colitis, flatulence, stomatitis Skin and subcutaneous tissue disorders rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion Musculoskeletal and connective tissue disorders muscle cramp, myalgia, muscular weakness Renal and urinary disorders polyuria, dysuria, pollakiuria General disorders and administration site condition edema, chest discomfort, malaise, thirst, chills, gait disturbance Investigations alkaline phosphatase increased, hyperglycemia, microscopic hematuria, hyponatremia, weight decreased, neutrophil count decreased 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. 6.2 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 [see Warnings and Precautions (5.2) ] . Immune system disorders : hypersensitivity reactions including anaphylaxis and anaphylactic shock [see Contraindications (4) , Warnings and Precautions (5.2) ] . Nervous system disorders : ifosfamide-induced neurotoxicity reported after aprepitant and ifosfamide coadministration.

<table ID="table5" width="75%"><caption>Table 5. Most Common Adverse Reactions in Patients Receiving MEC<footnote>Reported in &#x2265;2% of patients treated with the intravenous fosaprepitant regimen and at a greater incidence than standard therapy.</footnote></caption><col width="34%" align="left" valign="top"/><col width="33%" align="center" valign="middle"/><col width="33%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Intravenous fosaprepitant, ondansetron, and dexamethasone<footnote>Intravenous fosaprepitant regimen</footnote> (N=504)</th><th styleCode="Rrule">Ondansetron and dexamethasone<footnote>Standard therapy</footnote> (N=497)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">15%</td><td styleCode="Rrule">13%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">13%</td><td styleCode="Rrule">11%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutropenia</td><td styleCode="Rrule">8%</td><td styleCode="Rrule">7%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Asthenia</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anemia</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Peripheral Neuropathy</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Leukopenia</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspepsia</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary Tract Infection</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Lrule Rrule">Pain In Extremity</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr></tbody></table>

<table ID="table6" width="75%"><caption>Table 6. Adverse Reactions (&#x2265; 1%) in Patients Receiving MEC with a Greater Incidence in the Oral 3-Day Aprepitant Regimen Relative to Standard Therapy</caption><col align="left" valign="middle" width="33%"/><col align="center" valign="middle" width="33%"/><col align="center" valign="middle" width="34%"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Oral Aprepitant Regimen (N = 868)</th><th styleCode="Rrule">Standard Therapy (N = 846)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">1.4</td><td styleCode="Rrule">0.9</td></tr><tr><td styleCode="Lrule Rrule">Eructation</td><td styleCode="Rrule">1.0</td><td styleCode="Rrule">0.1</td></tr></tbody></table>

<table ID="table7" width="75%"><caption>Table 7. Adverse Reactions (incidence &lt; 1%) in Patients Observed in Studies with a Greater Incidence in the Oral Aprepitant Regimen Relative to Standard Therapy</caption><col width="35%" align="left" valign="top"/><col width="65%" align="left" valign="top"/><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Infection and infestations</content></td><td styleCode="Rrule">candidiasis, staphylococcal infection</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Blood and the lymphatic system disorders</content></td><td styleCode="Rrule">anemia, febrile neutropenia</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Metabolism and nutrition disorders</content></td><td styleCode="Rrule">weight gain, polydipsia</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Psychiatric disorders</content></td><td styleCode="Rrule">disorientation, euphoria, anxiety</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Nervous system disorders</content></td><td styleCode="Rrule">dizziness, dream abnormality, cognitive disorder, lethargy, somnolence</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Eye disorders</content></td><td styleCode="Rrule">conjunctivitis</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Ear and labyrinth disorders</content></td><td styleCode="Rrule">tinnitus</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Cardiac disorders</content></td><td styleCode="Rrule">bradycardia, cardiovascular disorder, palpitations</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Vascular disorders</content></td><td styleCode="Rrule">hot flush, flushing</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Respiratory, thoracic and mediastinal disorders</content></td><td styleCode="Rrule">pharyngitis, sneezing, cough, postnasal drip, throat irritation</td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule"><content styleCode="italics">Gastrointestinal disorders</content></td><td styleCode="Rrule">nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, feces hard, neutropenic colitis, flatulence, stomatitis</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Skin and subcutaneous tissue disorders</content></td><td styleCode="Rrule">rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Musculoskeletal and connective tissue disorders</content></td><td styleCode="Rrule">muscle cramp, myalgia, muscular weakness</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Renal and urinary disorders</content></td><td styleCode="Rrule">polyuria, dysuria, pollakiuria</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">General disorders and administration site condition</content></td><td styleCode="Rrule">edema, chest discomfort, malaise, thirst, chills, gait disturbance</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="italics">Investigations</content></td><td styleCode="Rrule">alkaline phosphatase increased, hyperglycemia, microscopic hematuria, hyponatremia, weight decreased, neutrophil count decreased</td></tr></tbody></table>