Sustol Drug Information

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.

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 . 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.

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.

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) .

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) . 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.

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

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 .

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 . 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).

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.

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 . Hypersensitivity to granisetron, any of the components of SUSTOL, or to any of the other 5-HT 3 receptor antagonists.

There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride, as a single intravenous injection, has been reported without symptoms or with only the occurrence of headache.