SUSTOL

SUSTOL (granisetron) extended-release injection, contains granisetron, a serotonin-3 (5-HT 3 ) receptor antagonist. Granisetron is 1-methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide with a molecular weight of 312.4. Its empirical formula is C 18 H 24 N 4 O, with the following chemical structure: Granisetron is a white to off-white crystalline solid that is insoluble in water. SUSTOL is a sterile, clear, colorless to slightly yellow, viscous liquid supplied in a single-dose, pre-filled syringe. Each syringe contains 10 mg granisetron incorporated in an extended-release polymer formulation; the inactive ingredients are triethylene glycol poly(orthoester) polymer, 392 mg and polyethylene glycol monomethyl ether, NF, 98 mg. image of the chemical structure

SUSTOL is indicated in combination with other antiemetics in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens. SUSTOL is a serotonin-3 (5-HT 3 ) receptor antagonist indicated in combination with other antiemetics in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens. ( 1 )

Administration ( 2.1 ): For subcutaneous injection only. Intended for administration by a healthcare provider. Administer in skin of the back of the upper arm or in the skin of the abdomen at least 1 inch away from the umbilicus. Do not administer anywhere the skin is burned, hardened, inflamed, swollen, or otherwise compromised. Due to the viscosity, administration requires a slow, sustained injection over 20 to 30 seconds. Recommended Dosage ( 2.2 ): The recommended dosage in adults is 10 mg administered as a single subcutaneous injection at least 30 minutes before the start of emetogenic chemotherapy on Day 1. Do not administer SUSTOL more frequently than once every 7 days. See full prescribing information for recommended dosage of concomitant dexamethasone. Renal Impairment ( 2.3 ): In patients with moderate renal impairment (Clcr 30-59 mL/min), administer SUSTOL not more frequently than once every 14 days. Avoid SUSTOL in patients with severe renal impairment (CLcr < 30 mL/min). 2.1 Important Administration Instructions For subcutaneous injection only. SUSTOL is intended for administration by a health care provider. SUSTOL is supplied as a refrigerated kit consisting of a single-dose, pre-filled, sterile syringe, a special thin walled 18 Ga 5/8" administration needle, two syringe warming pouches, and a Point Lok ® needle protection device. See the SUSTOL Instructions for Use included in the kit for complete administration instructions with illustrations. Do not substitute non-kit components for any of the components from the kit for administration. Preparation At least 60 minutes prior to administration, remove the SUSTOL kit from refrigeration. Unpack the kit to allow the SUSTOL syringe and all other contents to warm to room temperature. Activate one of the syringe warming pouches, and wrap the SUSTOL syringe in the warming pouch for 5 to 6 minutes to warm SUSTOL to body temperature. Prior to administration, inspect the SUSTOL syringe visually for particulate matter and discoloration. Note that the syringe is amber colored glass. SUSTOL should not be administered if particulate matter or discoloration is observed, the tip cap is missing or has been tampered with, or if the Luer fitting is missing or dislodged. Administration Use standard aseptic technique when performing the injection. Administer SUSTOL as a single subcutaneous injection in the skin of the back of the upper arm or in the skin of the abdomen at least one inch away from the umbilicus. Avoid injecting SUSTOL anywhere the skin is burned, hardened, inflamed, swollen, or otherwise compromised [see Warnings and Precautions ( 5.1 )] . Topical anesthetic may be used at the injection site prior to administration of SUSTOL. Due to the viscosity of SUSTOL, the time required for injection is greater than most medications administered subcutaneously. SUSTOL requires a slow, sustained injection which may take up to 20 to 30 seconds . Pressing the plunger harder will NOT expel SUSTOL faster. 2.2 Recommended Dosage The recommended dosage of SUSTOL is 10 mg administered subcutaneously. Administer SUSTOL in combination with dexamethasone at least 30 minutes before the initiation of MEC or AC combination chemotherapy. Administer SUSTOL on Day 1 of chemotherapy and not more frequently than once every 7 days because of the extended-release properties of the formulation. For patients receiving MEC, the recommended dexamethasone dosage is 8 mg intravenously on Day 1. For patients receiving AC combination chemotherapy regimens, the recommended dexamethasone dosage is 20 mg intravenously on Day 1, followed by 8 mg orally, twice a day, on Days 2, 3 and 4. If SUSTOL is administered with an NK 1 receptor antagonist, see the prescribing information of the NK 1 receptor antagonist for the recommended dexamethasone dosage. 2.3 Dosage Adjustment in Renal Impairment In patients with moderate renal impairment (creatinine clearance of 30 to 59 mL/min), administer SUSTOL on Day 1 of chemotherapy and not more frequently than once every 14 days. Avoid SUSTOL in patients with severe renal impairment (creatinine clearance of less than 30 mL/min) [see Use in Specific Populations ( 8.6 )] .

SUSTOL is contraindicated in patients with hypersensitivity to granisetron, any of the components of SUSTOL, or to any of the other 5-HT 3 receptor antagonists [see Warnings and Precautions ( 5.3 ), Description ( 11 )] . Hypersensitivity to granisetron, any of the components of SUSTOL, or to any of the other 5-HT 3 receptor antagonists. ( 4 , 5.3 )

The following clinically significant adverse reactions are described elsewhere in the labeling: Injection Site Reactions [see Warnings and Precautions ( 5.1 )] Gastrointestinal Disorders [see Warnings and Precautions ( 5.2 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )] Serotonin Syndrome [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (≥ 3%) are injection site reactions, constipation, fatigue, headache, diarrhea, abdominal pain, insomnia, dyspepsia, dizziness, asthenia, and gastroesophageal reflux. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Heron Therapeutics, Inc. at 844-HERON11 (1-844-437-6611) and www.SUSTOL.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 practice. SUSTOL The safety of a 10 mg subcutaneous dose of SUSTOL was evaluated in two double-blind, randomized, active-controlled studies, in which 210 patients (23%) received MEC and 467 patients (51%) received AC combination chemotherapy. The data described below reflect exposure to a single 10 mg dose of SUSTOL in 924 patients whose mean age was 56 years (range 19 to 91 years); 76% of patients were female; 70% of patients were Caucasian, 16% Asian, 10% Black, and 4% other races. Dexamethasone was co-administered with SUSTOL in Study 1 and Study 2 and an NK 1 receptor antagonist was co-administered with SUSTOL in Study 2. Table 1 lists the most common adverse reactions reported in at least 3% of patients following a single-dose of SUSTOL 10 mg in Study 1 and/or Study 2. Overall, injection site reactions (ISRs) were the most common group of adverse reactions in SUSTOL-treated patients. Specific types of ISRs reported by SUSTOL-treated patients are shown in Table 2 . Table 1. Adverse Reactions Occurring in at Least 3% of Patients Treated with SUSTOL 10 mg in Study 1 and/or Study 2 Study 1 Study 2 Adverse Reaction SUSTOL 10 mg subcutaneous (N=468) % Palonosetron hydrochloride 0.25 mg intravenous (N=463) % SUSTOL 10 mg subcutaneous (N=456) % Ondansetron 0.15 mg/kg intravenous (N=459) % Injection Site Reactions, any Rates of individual injection site reactions (ISRs) are shown in Table 2 37 15 The placebo subcutaneous injection for Study 1 was normal saline and for Study 2 was a SUSTOL-matched control consisting of the SUSTOL polymer vehicle without active drug. 62 See footnote Constipation 14 11 22 15 Fatigue 11 10 21 24 Headache 9 9 13 19 Diarrhea 8 7 9 8 Abdominal Pain 7 7 7 4 Insomnia 4 2 5 6 Dyspepsia 3 3 6 7 Dizziness 3 2 5 5 Asthenia 4 6 2 2 Gastroesophageal Reflux 1 1 5 4 Injection Site Reactions (ISRs) Injection site reactions occurred in 37% (175/468) in Study 1, Cycle 1 only, and 62% (281/456) in Study 2 of SUSTOL-treated patients. The ISR manifestations included pain, erythema, mass/nodule, swelling/induration, and bleeding. The incidence of individual ISRs is shown in Table 2 . Patients may have experienced one or more types of injection site reactions; a total of 213 of 924 patients had three or more. ISR reporting procedures included both investigator- and patient-reported outcomes in Study 2, while Study 1 used only investigator reporting. Table 2. Injection Site Adverse Reactions Following a Single 10 mg SUSTOL Dose Injection Site Reaction Study 1 Treatment Arm (Subcutaneous Injection) Study 2 Patient diary was used in Study 2 to collect ISR information daily. , The placebo subcutaneous injection for Study 2 was a SUSTOL-matched control consisting of the SUSTOL polymer vehicle without active drug. ISR data for this group are not shown. SUSTOL (N=456) % SUSTOL (N=468) % Saline Control (N=463) % Total Subjects with at least 1 ISR 37 15 62 Pain 3 1 20 Tenderness 4 1 27 Bruising/Hematoma 22 10 45 Bleeding 2 1 4 Erythema/Redness 11 3 17 Swelling/Induration 1 0 10 Mass/Nodule 11 1 18 Infection at injection site <1 0 1 Other Other includes injection site discoloration, vesicles, irritation, lipoma, paresthesia, pruritus, rash, reaction, scab, scar, and warmth. 2 1 1 Less common adverse reactions reported in less than 3% of SUSTOL-treated patients in clinical trials are syncope, elevation of serum transaminase levels, pancreatitis, atrial fibrillation, somnolence, flushing, and hypersensitivity reactions (e.g., anaphylaxis, urticaria). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of other formulations of granisetron. 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. System Organ Class Adverse Reactions Cardiovascular bradycardia, chest pain, palpitations, sick sinus syndrome

7.1 Serotonergic Drugs Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue SUSTOL and initiate supportive treatment [see Warnings and Precautions ( 5.4 )] .