Most common adverse reactions during treatment (frequency ≥5%): vomiting, nausea, constipation, dyspnea, and somnolence. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Insys Therapeutics, Inc., at 1-855-978-2797 or FDA at 1-800-FDA-1088 or www.fda.gov/ medwatch. 6.1 Clinical Studies 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. The safety of SUBSYS has been evaluated in a total of 359 opioid-tolerant patients with breakthrough cancer pain. The duration of SUBSYS use varied during the open-label study. Safety data from a long-term extension study showed that the average duration of therapy in the open-label study was 66 days. The maximum duration of therapy was 149 days. The dose range studied in these trials ranged from 100 mcg per dose to 1600 mcg per dose. The most commonly observed adverse reactions seen with SUBSYS are typical opioid side effects such as nausea, vomiting, somnolence, and constipation. Expect opioid side effects and manage them accordingly. The most serious adverse reactions associated with all opioids including SUBSYS are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms of respiratory depression. The most common adverse reaction leading to discontinuation of SUBSYS was nausea. There were also adverse reactions of abdominal distension, anorexia, confusional state, disorientation, somnolence, and constipation. The clinical trials of SUBSYS were designed to evaluate safety and efficacy in treating breakthrough cancer pain; all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received SUBSYS for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. Table 3 lists adverse reactions with an overall frequency of 5% or greater that occurred during titration in the clinical trials. Adverse reactions are listed in descending order of frequency within each system organ class. Table 3. Percent of Patients with Specific Adverse Events During Titration in the Clinical Trials (Events in 5% or More of Patients) System Organ Class Titration n=359 (%) Gastrointestinal Disorders Nausea 47 (13.1%) Vomiting 37 (10.3%) Constipation 18 (5.0%) Nervous System Disorders Somnolence 34 (9.5%) Dizziness 26 (7.2%) A patient was counted only once within each category. The following adverse reactions occurred during titration in the clinical trials with an overall frequency of 1% or greater and are listed in descending order of frequency within each system organ class. Cardiac Disorders: Tachycardia Gastrointestinal Disorders: Diarrhea, stomatitis, dry mouth General Disorders and Administration Site Conditions: Application site irritation, pyrexia, edema peripheral, fatigue, asthenia Metabolism and Nutrition Disorders: Decreased appetite Nervous System Disorders: Lethargy, sedation, tremor, headache Psychiatric Disorders: Depression, confusional state, hallucination, insomnia Respiratory, Thoracic and Mediastinal Disorders: Dyspnea Skin and Subcutaneous Tissue Disorders: Pruritus The following reactions occurred during titration in the clinical trials with an overall frequency of less than 1% and are listed in descending order of frequency within each system organ class. Eye Disorders: Vision blurred, dry eye Gastrointestinal Disorders: Abdominal pain Infections and Infestations: Oral candidiasis, cellulitis Injury, Poisoning and Procedural Complications: Fall Metabolism and Nutrition Disorders: Dehydration, anorexia Musculoskeletal and Connective Tissue Disorders: Back pain, arthralgia, joint swelling Psychiatric Disorders: Anxiety, agitation Renal and Urinary Disorders: Urinary retention Respiratory, Thoracic and Mediastinal Disorders: Cough, increased bronchial secretion, dysphonia, pharyngolaryngeal pain Skin and Subcutaneous Tissue Disorders: Hyperhidrosis Vascular Disorders: Hot flush Table 4 lists adverse reactions with an overall frequency of 5% or greater for the total safety database subsequent to titration during the clinical trials. Table 4. Adverse Reactions Subsequent to Titration in 5% or More of Patients System Organ Class Dosing n=269 Gastrointestinal Disorders Vomiting 43 (16.0%) Nausea 28 (10.4%) Constipation 28 (10.4%) General Disorders and Administration Site Conditions Asthenia 26 (9.7%) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 28 (10.4%) Psychiatric Disorders Anxiety 16 (5.9%) A patient was counted only once within each category. The following adverse reactions occurred during the dosing period of the clinical trial with an overall frequency of 1% or greater and are listed in descending order of frequency within each system organ class. Blood and Lymphatic System Disorders: Anemia, neutropenia, lymphadenopathy, thrombocytopenia, leukopenia Cardiac Disorders: Tachycardia, sinus tachycardia Gastrointestinal Disorders: Diarrhea, stomatitis, abdominal pain, abdominal distension, gastritis, dysphagia, dyspepsia, gastroesophageal reflux disease, ascites, hematemesis General Disorders and Administration Site Conditions: Edema peripheral, fatigue, pyrexia, chest pain, drug withdrawal syndrome, chills, irritability, malaise, application site irritation Infections and Infestations: Oral candidiasis, pneumonia, urinary tract infection, oral herpes, gastroenteritis, laryngitis Injury, Poisoning and Procedural Complications: Contusion Investigations: Weight decreased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood glucose increased, blood lactate increased Metabolism and Nutrition Disorders: Anorexia, dehydration, hypokalemia, decreased appetite, hyponatremia, hypocalcemia, hypoalbuminemia, cachexia Musculoskeletal and Connective Tissue Disorders: Back pain, arthralgia, muscular weakness Nervous System Disorders: Hypoesthesia, lethargy, sedation, tremor, somnolence, headache, dizziness Psychiatric Disorders: Depression, restlessness, agitation, confusional state, insomnia, hallucination, disorientation Renal and Urinary Disorders: hypertension, hypotension Respiratory, Thoracic and Mediastinal Disorders: Cough, increased bronchial secretion, wheezing, pharyngolaryngeal pain, hypoxia, dyspnea exertional Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus In a single-dose mucositis study, a group of patients with Grade 1 or 2 oral mucositis (n=9) and without oral mucositis (n=9) were included in a clinical trial designed to support the safety of SUBSYS. Two of the nine subjects with mucositis (one with Grade 1 and one with Grade 2) reported a burning sensation in the oral mucosa after treatment. Both of these events were considered mild and probably related to treatment. There was no change in grade of mucositis after treatment for any subject.