SANCUSO

SANCUSO contains granisetron, which is a serotonin-3 (5-HT 3 ) receptor antagonist. Chemically it 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, while its chemical structure is: Granisetron is a white to off-white solid that is insoluble in water. The inactive ingredients are acrylate-vinylacetate copolymer, polyester, titanium dioxide, polyamide resin and polyethylene wax. SANCUSO is a 52 cm 2 thin, translucent, matrix-type transdermal system that is rectangular- shaped with rounded corners, consisting of a backing (polyester), the drug matrix (acrylate- vinylacetate copolymer) and a release liner (siliconized polyester). Chemical Structure

SANCUSO ® is indicated for the prevention of nausea and vomiting in adults receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration. SANCUSO is a serotonin-3 (5-HT 3 ) receptor antagonist indicated for the prevention of nausea and vomiting in adults receiving moderately and/or highly emetogenic chemotherapy for up to 5 consecutive days. ( 1 )

The recommended dosage is a single transdermal system applied to the upper outer arm a minimum of 24 hours, up to a maximum of 48 hours, before chemotherapy. The transdermal system should be worn at minimum, 24 hours after chemotherapy is finished. The transdermal system can be worn for up to 7 days. Application and Removal Instructions Each transdermal system releases 3.1 mg of granisetron per 24 hours for up to 7 days. Each transdermal system is packed in a pouch and should be applied directly after the pouch has been opened. Only wear one transdermal system at any time. Do not cut the transdermal system. Open the pouch and apply the transdermal system to clean, dry, nearly hairless, intact healthy skin on the upper outer arm. Do not place SANCUSO transdermal system on skin that is red, irritated, or damaged. Do not apply a heat pad or heat lamp over or in vicinity of the transdermal system and avoid extended exposure to heat [see Warnings and Precautions ( 5.4 )] . 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 [see Warnings and Precautions ( 5.5 )] . After the transdermal system is applied, wash hands thoroughly. Remove the transdermal system by peeling off gently from the skin. Upon removal, fold the transdermal system in half with the sticky side together, and discard in the household trash in a manner that prevents accidental contact or ingestion by children, pets or others. SANCUSO contains granisetron. Do not use other granisetron-containing products with SANCUSO. The recommended dosage is a single transdermal system applied to the upper outer arm a minimum of 24 hours, up to a maximum of 48 hours, before chemotherapy. The transdermal system should be worn at minimum, 24 hours after chemotherapy is finished. The transdermal system can be worn for up to 7 days. ( 2 )

SANCUSO is contraindicated in patients with known hypersensitivity to granisetron or to any of the components of the transdermal system [see Description ( 11 )] . Known hypersensitivity to granisetron or to any of the components of the transdermal system ( 4 )

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

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 SANCUSO and initiate supportive treatment [see Warnings and Precautions ( 5.4 )] . 7.2 Concomitant Use Medications There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs. However, in humans, granisetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection also does not appear to interact with emetogenic cancer therapies. In agreement with these data, no clinically relevant drug interactions have been reported in clinical studies with SANCUSO.