Granisetron

5 WARNINGS AND PRECAUTIONS Progressive Ileus and Gastric Distention : Granisetron may mask a progressive ileus and/or gastric distention; consider before use in patients with abdominal surgery. Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction. ( 5.1 ) Serotonin Syndrome : Serotonin syndrome has been reported with 5-HT 3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. If such symptoms occur, discontinue SANCUSO and initiate supportive treatment. If concomitant use of SANCUSO with other serotonergic drugs is clinically warranted, patients should be aware of a potential increased risk of serotonin syndrome. ( 5.2 , 7.1 ) Skin Reactions : Mild application site reactions have occurred; remove SANCUSO transdermal system if severe reactions or a generalized skin reaction occur. ( 5.3 ) Increased Drug Exposure with Use of External Heat Sources: Avoid exposing SANCUSO transdermal system and surrounding area to direct external heat sources, such as heating pads ( 5.4 ). Phototoxicity with Ultraviolet Light Exposure : Avoid direct exposure of application site to natural or artificial sunlight, including sunlamps, by covering with clothing throughout the period of wear and for 10 days after removal. ( 5.5 ) 5.1 Progressive Ileus and Gastric Distention SANCUSO may mask a progressive ileus and/or gastric distention. This should be particularly considered before use of SANCUSO in patients who have had recent abdominal surgery. Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction. 5.2 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 SANCUSO and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue SANCUSO and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if SANCUSO is used concomitantly with other serotonergic drugs. [see Drug Interactions ( 7 )]. 5.3 Skin Reactions In clinical trials with SANCUSO, application site reactions were reported that were generally mild in intensity and did not lead to discontinuation of use. The incidence of reactions was comparable with placebo. If severe reactions, or a generalized skin reaction occur (e.g., allergic rash, including erythematous, macular, papular rash or pruritus), remove the SANCUSO transdermal system. 5.4 Increased Drug Exposure with Use of External Heat Sources Prolonged exposure to heat results in increasing plasma concentrations of granisetron during the period of heat exposure [see Clinical Pharmacology ( 12.3 )] . Do not apply a heat pad or heat lamp over or in the vicinity of the SANCUSO transdermal system and avoid extended exposure to heat [see Dosage and Administration ( 2 )]. 5.5 Phototoxicity with Ultraviolet Light Exposure Granisetron may be affected by direct natural or artificial sunlight, including sunlamps. An in vitro study using Chinese hamster ovary cells suggests that granisetron has the potential for photogenotoxicity [see Nonclinical Toxicology ( 13.3 )] . To avoid a potential skin reaction, advise patients to cover the application site of the transdermal system with clothing if there is a risk of exposure to direct natural or artificial sunlight throughout the period of wear and for 10 days following its removal.

6 ADVERSE REACTIONS The following are serious or otherwise clinically significant adverse reactions reported in other sections of labeling: Progressive ileus and gastric distention [see Warnings and Precautions ( 5.1 )] Serotonin syndrome [see Warnings and Precautions ( 5.2 )] Skin reactions [see Warnings and Precautions ( 5.3 )] Increased drug exposure with use of external heat sources [see Warnings and Precautions ( 5.4 )] Phototoxicity with ultraviolet light exposure [se Warnings and Precautions ( 5.5 )] The most common adverse reaction (≥ 3%) is constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cumberland Pharmaceuticals Inc. at 1-877-484-2700 (X 225) 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 SANCUSO was evaluated in a total of 404 patients undergoing chemotherapy who participated in two double-blind, comparator studies with transdermal system treatment durations of up to 7 days. The control groups included a total of 406 patients who received a daily dose of 2 mg oral granisetron, for 1 to 5 days. Adverse reactions occurred in 9% (35/404) of patients receiving SANCUSO and 7% (29/406) of patients receiving oral granisetron. The most common adverse reaction was constipation that occurred in 5% of patients in the SANCUSO group and 3% of patients in the oral granisetron group. Table 1 lists the adverse reactions that occurred in at least 3% of patients treated with SANCUSO or oral granisetron. Table 1: Incidence of Adverse Reactions in Double-Blind, Active Comparator Controlled Studies in Cancer Patients Receiving Chemotherapy (³ 3% in either group) SANCUSO Transdermal System Oral granisetron Body System N=404 N=406 Preferred Term (%) (%) Gastrointestinal disorders Constipation 5 3 Nervous system disorders Headache 1 3 5-HT 3 receptor antagonists, such as granisetron, may be associated with arrhythmias or ECG abnormalities. Three ECGs were performed on 588 patients in a randomized, parallel group, double-blind, double-dummy study: at baseline before treatment, the first day of chemotherapy, and 5 to 7 days after starting chemotherapy. QTcF prolongation greater than 450 milliseconds was seen in a total of 11 (1.9%) patients after receiving granisetron, 8 (2.7%) on oral granisetron, and 3 (1.1%) on the transdermal system. No new QTcF prolongation greater than 480 milliseconds was observed in any patient in this study. No arrhythmias were detected in this study. Adverse reactions reported in clinical trials with other formulations of granisetron include the following: Gastrointestinal: abdominal pain, diarrhea, constipation, elevation of ALT and AST levels, nausea and vomiting Cardiovascular: hypertension, hypotension, angina pectoris, atrial fibrillation and syncope have been observed rarely Central Nervous System: dizziness, insomnia, headache, anxiety, somnolence and asthenia Hypersensitivity: rare cases of hypersensitivity reactions, sometimes severe (e.g. anaphylaxis, shortness of breath, hypotension, urticaria) have been reported Other: fever; events often associated with chemotherapy have also been reported: leucopenia, decreased appetite, anemia, alopecia, thrombocytopenia. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of SANCUSO. 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. General Disorders and Administration Site Conditions: Application site reactions (pain, pruritus, erythema, rash, irritation, vesicles, burn, discoloration, urticaria) [see Warnings and Precautions ( 5.3 )] ; transdermal system non-adhesion. Cardiac Disorders : bradycardia, chest pain, palpitations, sick sinus syndrome

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available published data and postmarketing reports with granisetron use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In a published ex vivo human placental perfusion model, no transplacental passage of granisetron was detected at a concentration (5 ng/mL) that mimics the plasma concentration achieved following transdermal application of SANCUSO. 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 24 times and 16 times, respectively, the maximum recommended human dose delivered by the SANCUSO transdermal system, based on body surface area (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 risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits administered granisetron hydrochloride at intravenous doses up to 24 times and 16 times, respectively, the maximum recommended human dose delivered by the SANCUSO transdermal system, based on body surface area ( see Data ). Data Animal Data Reproduction studies with granisetron hydrochloride have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m 2 /day, about 24 times the recommended human dose delivered by the SANCUSO transdermal system, based on body surface area) and oral doses up to 125 mg/kg/day (750 mg/m 2 /day, about 326 times the recommended human dose with SANCUSO based on body surface area). Reproduction studies have been performed in pregnant rabbits at intravenous doses up to 3 mg/kg/day (36 mg/m 2 /day, about 16 times the human dose with SANCUSO based on body surface area) and at oral doses up to 32 mg/kg/day (384 mg/m 2 /day, about 167 times the human dose with SANCUSO based on body surface area). These studies did not reveal any harm to the fetus due to granisetron. 8.2 Lactation Risk Summary There are no data on the presence of granisetron in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SANCUSO and any potential adverse effects on the breastfed child from SANCUSO or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of SANCUSO have not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of SANCUSO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, cautious treatment selection for an elderly patient is prudent because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment or Hepatic Impairment Although no studies have been performed to investigate the pharmacokinetics of SANCUSO in patients with renal or hepatic impairment, pharmacokinetic information is available for intravenous granisetron [see Clinical Pharmacology ( 12.3 )] . No dosage adjustment is recommended for renal or hepatic impairment.

8.1 Pregnancy Risk Summary Available published data and postmarketing reports with granisetron use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In a published ex vivo human placental perfusion model, no transplacental passage of granisetron was detected at a concentration (5 ng/mL) that mimics the plasma concentration achieved following transdermal application of SANCUSO. 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 24 times and 16 times, respectively, the maximum recommended human dose delivered by the SANCUSO transdermal system, based on body surface area (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 risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits administered granisetron hydrochloride at intravenous doses up to 24 times and 16 times, respectively, the maximum recommended human dose delivered by the SANCUSO transdermal system, based on body surface area ( see Data ). Data Animal Data Reproduction studies with granisetron hydrochloride have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m 2 /day, about 24 times the recommended human dose delivered by the SANCUSO transdermal system, based on body surface area) and oral doses up to 125 mg/kg/day (750 mg/m 2 /day, about 326 times the recommended human dose with SANCUSO based on body surface area). Reproduction studies have been performed in pregnant rabbits at intravenous doses up to 3 mg/kg/day (36 mg/m 2 /day, about 16 times the human dose with SANCUSO based on body surface area) and at oral doses up to 32 mg/kg/day (384 mg/m 2 /day, about 167 times the human dose with SANCUSO based on body surface area). These studies did not reveal any harm to the fetus due to granisetron.