Granisetron

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 )

SUSTOL is supplied as a clear, colorless to slightly yellow, viscous liquid and is available as an: Extended-Release Injection: 10 mg/0.4 mL in a single-dose pre-filled syringe. Extended-Release Injection: 10 mg/0.4 mL in a single-dose, pre-filled syringe. ( 3 )

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 )

Serious or severe injection site reactions (ISRs): Infection, prolonged bleeding, bruising, hematomas, nodules, pain, and tenderness have been reported. Patients who are neutropenic or receiving antiplatelet agents or anticoagulants may be at greater risk. Monitor for ISRs during treatment with SUSTOL. Inform patients that some ISRs may occur 2 weeks or more after SUSTOL administration. For ongoing ISRs, administer SUSTOL at a site away from the affected area and consider discontinuing SUSTOL for severe or persistent ISRs. ( 5.1 ) Gastrointestinal disorders: Monitor for constipation and consider optimizing patients' current bowel regimens used for managing preexisting constipation. Also monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction. Instruct patients to seek immediate medical care if signs and symptoms of ileus occur. ( 5.2 ) Hypersensitivity reactions: Serious reactions have been reported and may occur up to 7 days or longer following SUSTOL administration and may have an extended course. If a reaction occurs, administer appropriate treatment and monitor until signs and symptoms resolve. ( 5.3 ) Serotonin syndrome: Reported with 5-HT receptor antagonists alone but particularly with concomitant use of serotonergic drugs. If such symptoms occur, discontinue SUSTOL and initiate supportive treatment. If concomitant use of SUSTOL with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome. ( 5.4 , 7.1 )

5.1 Serious Injection Site Reactions Serious or severe injection site reactions (ISRs), including infections (e.g., abscess, cellulitis with gangrene), prolonged bleeding, bruising, hematomas, nodules, pain, and tenderness have been reported in clinical trials [ see Adverse Reactions ( 6.1 ) ] and/or postmarketing. Some postmarketing cases required emergent medical attention, hospitalization, surgical debridement, intravenous antibiotics, and/or incision and drainage. Patients who are neutropenic or receiving concomitant anticoagulant and antiplatelet medications may be at greater risk. Monitor patients for development of ISRs during treatment with SUSTOL. Inform patients that some ISRs may occur up to 2 weeks or more after SUSTOL administration. For ongoing ISRs, administer SUSTOL at a site away from the affected area [see Dosage and Administration ( 2.1 )]. Consider discontinuing SUSTOL for severe or persistent ISRs.

5.2 Gastrointestinal Disorders Constipation In clinical trials, 224 of 1131 (20%) of patients treated with SUSTOL 10 mg reported constipation compared to 13% to 15% in the 5-HT 3 receptor antagonist control arms. Hospitalization due to constipation or fecal impaction was reported in 5 SUSTOL-treated patients (0.3%). Monitor patients for the development of constipation while receiving treatment with SUSTOL taking into consideration the extended-release properties of the SUSTOL polymer formulation over at least 5 to 7 days, particularly in patients receiving opioid medications. Consider optimizing bowel regimens in patients using SUSTOL. Progressive Ileus and Gastric Distention SUSTOL may mask a progressive ileus and/or gastric distention. This should be particularly considered before use of SUSTOL in patients who have had recent abdominal surgery. Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction.

5.3 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, have been reported in granisetron-treated patients who have exhibited hypersensitivity to other 5-HT 3 receptor antagonists [see Contraindications ( 4 )] . Avoid SUSTOL in patients who have had hypersensitivity reactions to other 5-HT 3 receptor antagonists [see Contraindications ( 4 )] . Due to the extended-release properties of the SUSTOL polymer formulation, exposure to granisetron may continue for 5 to 7 days following administration. Hypersensitivity reactions may occur up to 7 days or longer following SUSTOL administration and may have an extended course. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur. If hypersensitivity reactions occur, administer appropriate treatment and monitor patients until signs and symptoms resolve.

5.4 Serotonin Syndrome The development of serotonin syndrome has been reported with 5-HT 3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT 3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT 3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of SUSTOL and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue SUSTOL and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if SUSTOL is used concomitantly with other serotonergic drugs [see Drug Interactions ( 7.1 )] .

The following clinically significant adverse reactions are described elsewhere in the labeling: Serious 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. Studies 1 and 2 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 (Studies 1 and 2) [see Clinical Studies ( 14 )] . 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) in Studies 1 and 2 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). Injection Site Reactions in the Safety Database Reactions at the injection site were assessed in 1814 patients with cancer treated with SUSTOL for one or multiple cycles across four studies (dosing-ranging, open-label, and/or active-controlled), including Study 1 and Study 2. Of the 1814 patients with cancer, 1131 patients were treated with the SUSTOL 10 mg dose. Additionally, infections at the injection site were assessed in 412 healthy subjects treated with any dose of SUSTOL across single- or multiple-dose studies. Infections : occurred in 7 of 1814 (0.4%) patients with cancer and 1 of 412 (0.2%) healthy subjects in clinical trials. Injection site infections had a median onset of 9 days (range 7 to 16 days) following SUSTOL administration. One patient who was neutropenic at the time of the infection was hospitalized. All patients with infection were treated with antibiotics and had complete resolution. Bruising and/or hematomas : occurred in 426 of 1131 (38%) patients treated with SUSTOL 10 mg with a median time to onset of 2 days. Injection site bruising and/or hematomas with a delayed onset (onset 5 or more days following SUSTOL administration) were reported in 175 (15%) patients. Severe bruising or hematoma (e.g., greater than 4 cm bruise or hematoma) occurred in 3% of patients. Patients receiving concomitant anticoagulant and antiplatelet medications were at greater risk for severe injection site bruising and hematomas. Bleeding : occurred in 70 of 1814 (4%) patients treated with SUSTOL. One patient required emergency management. Injection site bleeding for longer than 5 days was reported in 23 (1%) patients. Pain and tenderness : In a clinical trial that collected information about injection site pain and tenderness from patient diaries, pain with or without tenderness at the injection site was reported by 91 of 456 (20%) patients treated with SUSTOL 10 mg, and an additional 50 of 456 (11%) patients reported tenderness without pain. Pain and/or tenderness severe enough to require taking pain medication, interfere with patient activity level, or cause significant discomfort at rest was reported in 2% of patients. Among all patients who reported pain and/or tenderness with SUSTOL 10 mg, the median duration was 5 days, and pain lasting longer than 7 days occurred in 6% of patients. Nodules : occurred in 203 of 1131 (18%) patients treated with SUSTOL 10 mg and persisted for a median of 15 days; 73 patients (6%) had nodules with durations longer than 21 days.

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 )] .

8.1 Pregnancy Risk Summary There are no available data on the use of SUSTOL in pregnant women. Limited published data on granisetron use during pregnancy are not sufficient to inform a drug-associated risk. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits administered granisetron hydrochloride during organogenesis at intravenous doses up to 61 times and 41 times respectively the maximum recommended human dose (MRHD) of SUSTOL 10 mg/week [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated population 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. Data Animal Data Reproduction studies with granisetron hydrochloride have been performed in pregnant rats following administration during the period of organogenesis at intravenous doses up to 9 mg/kg/day (approximately 61 times the maximum recommended human dose (MRHD) of SUSTOL 10 mg/week, based on body surface area) and oral doses up to 125 mg/kg/day (approximately 851 times the MRHD of SUSTOL 10 mg/week, based on body surface area). Reproduction studies have been performed in pregnant rabbits in which granisetron hydrochloride was administered during the period of organogenesis at intravenous doses up to 3 mg/kg/day (approximately 41 times the MRHD of SUSTOL 10 mg/week, based on body surface area) and at oral doses up to 32 mg/kg/day (approximately 436 times the MRHD of SUSTOL 10 mg/week, based on body surface area). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to granisetron hydrochloride. Reproduction studies with the polymer vehicle for SUSTOL have been performed in pregnant rats and rabbits following administration of the polymer vehicle during the period of organogenesis at subcutaneous doses up to 0.295 and 1.18 g per day, respectively, (approximately 45 and 36 times, respectively the amount of polymer vehicle present in the maximum recommended /weekly single human dose of SUSTOL, based on body surface area). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to the polymer vehicle. A pre and postnatal development study with the polymer vehicle for SUSTOL in rats showed no evidence of any adverse effects on pre and postnatal development at subcutaneous doses (administered on gestation days 7 through lactation day 20) up to 0.295 g per day (approximately 45 times the amount of polymer vehicle present in the maximum recommended /weekly single human dose of SUSTOL, based on body surface area).

8.2 Lactation Risk Summary There are no data on the presence of SUSTOL in human milk, the effects of SUSTOL on the breastfed infant, or the effects of SUSTOL on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of SUSTOL to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SUSTOL and any potential adverse effects on the breastfed infant from SUSTOL or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of SUSTOL in pediatric patients under 18 years of age have not been established. SUSTOL is not recommended for use in pediatric patients less than 12 years of age because the product administration requires a large gauge needle and an extended administration time.

8.5 Geriatric Use Of the 738 patients administered 10 mg of SUSTOL in the comparator controlled studies, 177 (24%) were 65 and over while 39 (5%) were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients; and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment Breakdown products of the polymer vehicle in SUSTOL can be detected in urine of healthy subjects [see Clinical Pharmacology ( 12.3 )] . There are no pharmacokinetic data regarding elimination of the polymer vehicle of SUSTOL in patients with renal impairment and the clinical significance of potential prolonged elimination is not known. Avoid SUSTOL in patients with severe renal impairment. In patients with moderate renal impairment, administer SUSTOL not more frequently than once every 14 days [see Dosage and Administration ( 2.3 )] .

Granisetron is a selective 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT 1 , 5-HT 1A , 5-HT 1B/C , 5-HT 2 ; for alpha 1- , alpha 2- , or beta-adrenoreceptors; for dopamine-D 2 ; or for histamine-H 1 ; benzodiazepine; picrotoxin or opioid receptors. Serotonin receptors of the 5-HT 3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy that induces vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT 3 receptors. This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT 3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.