FDA label 206ddf5f-e160-4091-8ec0-ae92a1ef4898

5 WARNINGS AND PRECAUTIONS N e u r o p s y chiatric Adverse Reactions : May cause psychiatric and cognitive effects and impair mental and/or physical abilities. Avoid use in patients with a psychiatric history. Monitor for symptoms and avoid concomitant use of drugs with similar effects. Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that dronabinol capsules, does not affect them adversely. ( 5.1 ) H e m o d y n amic Instability : Patients with cardiac disorders may experience hypotension, hypertension, syncope or tachycardia. Avoid concomitant use of drugs with similar effects and monitor for hemodynamic changes after initiating or increasing the dosage of dronabinol capsules. ( 5.2 ) S e izures and Seizure-like Activity : Weigh the potential risk versus benefits before prescribing dronabinol capsules to patients with a history of seizures, including those requiring anti-epileptic medication or with other factors that lower the seizure threshold. Monitor patients and discontinue if seizures occur. ( 5.3 ) Mu lt iple Substance Abuse : Assess risk for abuse or misuse in patients with a history of substance abuse or dependence, prior to prescribing dronabinol capsules and monitor for the development of associated behaviors or conditions. ( 5.4 ) Paradoxical Nausea, Vomiting, or Abdominal Pain: Consider dose reduction or discontinuation, if worsening of symptoms while on treatment. ( 5.5 ) 5.1 Neuropsychiatric Adverse Reactions Psychiatric Adverse Reactions Dronabinol has been reported to exacerbate mania, depression, or schizophrenia. Significant CNS symptoms followed oral doses of 0.4 mg/kg (28 mg per 70 kg patient) of dronabinol in antiemetic studies. Prior to initiating treatment with dronabinol capsules, screen patients for a history of these illnesses. Avoid use in patients with a psychiatric history or, if the drug cannot be avoided, monitor patients for new or worsening psychiatric symptoms during treatment. Also, avoid concomitant use with other drugs that are associated with similar psychiatric effects. Cognitive Adverse Reactions Use of dronabinol capsules has been associated with cognitive impairment and altered mental state. Reduce the dose of dronabinol capsules or discontinue use of dronabinol capsules if signs or symptoms of cognitive impairment develop. Elderly patients may be more sensitive to the neurological and psychoactive effects of dronabinol capsules [see Use in Specific Populations (8.4, 8.5)] . Hazardous Activities Dronabinol capsules can cause and may impair the mental and/or physical abilities required for the performance of hazardous tasks such as driving a motor vehicle or operating machinery. Concomitant use of other drugs that cause dizziness, confusion, sedation, or somnolence such as CNS depressants may increase this effect (e.g., barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, scopolamine, antihistamines, tricyclic antidepressants, other anticholinergic agents, muscle relaxants). Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that dronabinol capsules does not affect them adversely. 5.2 Hemodynamic Instability Patients may experience occasional hypotension, possible hypertension, syncope, or tachycardia while taking dronabinol capsules [see Clinical Pharmacology (12.2)] . Patients with cardiac disorders may be at higher risk. Avoid concomitant use of other drugs that are also associated with similar cardiac effects (e.g., amphetamines, other sympathomimetic agents, atropine, amoxapine, scopolamine, antihistamines, other anticholinergic agents, amitriptyline, desipramine, other tricyclic antidepressants). Monitor patients for changes in blood pressure, heart rate, and syncope after initiating or increasing the dosage of dronabinol capsules. 5.3 Seizures Seizure and seizure-like activity have been reported in patients receiving dronabinol. Weigh this potential risk against the benefits before prescribing dronabinol capsules to patients with a history of seizures, including those receiving anti-epileptic medication or with other factors that can lower the seizure threshold. Monitor patients with a history of seizure disorders for worsened seizure control during dronabinol capsules therapy. If a seizure occurs, advise patients to discontinue dronabinol capsules and contact a healthcare provider immediately. 5.4 Multiple Substance Abuse Patients with a history of substance abuse or dependence, including marijuana or alcohol, may be more likely to abuse dronabinol capsules as well. Assess each patient’s risk for abuse or misuse prior to prescribing dronabinol capsules and monitor patients with a history of substance abuse during treatment with dronabinol capsules for the development of these behaviors or conditions. 5.5 Paradoxical Nausea, Vomiting, or Abdominal Pain Nausea, vomiting, or abdominal pain can occur during treatment with synthetic delta-9­ tetrahydrocannabinol (delta-9-THC), the active ingredient in dronabinol capsules. In some cases, these adverse reactions were severe (e.g., dehydration, electrolyte abnormalities) and required dose reduction or drug discontinuation. Symptoms are similar to cannabinoid hyperemesis syndrome (CHS), which is described as cyclical events of abdominal pain, nausea, and vomiting in chronic, long-term users of delta-9-THC products. Because patients may not recognize these symptoms as abnormal, it is important to specifically ask patients or their caregivers about the development of worsening of nausea, vomiting, or abdominal pain while being treated with dronabinol capsules. Consider dose reduction or discontinuing dronabinol capsules if a patient develops worsening nausea, vomiting, or abdominal pain while on treatment.

6 ADVERSE REACTIONS • Most common adverse reactions (≥3%) are: abdominal pain, dizziness, euphoria, nausea, paranoid reaction, somnolence, thinking abnormal and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascent Pharmaceuticals Inc. at 1-855-221-1622 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. The following serious adverse reactions are described below and elsewhere in the labeling. Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.1)] Hemodynamic Instability [see Warnings and Precautions (5.2)] Seizures [see Warnings and Precautions (5.3)] Paradoxical Nausea, Vomiting, and Abdominal Pain [see Warnings and Precautions (5.5)] Studies of AIDS-related weight loss included 157 patients receiving dronabinol capsules at a dose of 2.5 mg twice daily and 67 receiving placebo. Studies of nausea and vomiting related to cancer chemotherapy included 317 patients receiving dronabinol capsules and 68 receiving placebo. In the tables below is a summary of the adverse reactions in 474 patients exposed to dronabinol capsules in studies. Studies of different durations were combined by considering the first occurrence of events during the first 28 days. A cannabinoid dose-related “high” (easy laughing, elation and heightened awareness) has been reported by patients receiving dronabinol capsules in both the antiemetic (24%) and the lower dose appetite stimulant clinical trials (8%). The most frequently reported adverse experiences in patients with AIDS during placebo-controlled clinical trials involved the CNS and were reported by 33% of patients receiving dronabinol capsules. About 25% of patients reported a CNS adverse reaction during the first 2 weeks and about 4% reported such a reaction each week for the next 6 weeks thereafter. adr 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of dronabinol capsules. 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: Fatigue Hypersensitivity reactions: Lip swelling, hives, disseminated rash, oral lesions, skin burning, flushing, throat tightness [see Contraindications (4)] Injury, poisoning and procedural complications: Fall [see Use in Specific Populations (8.5)] Nervous system disorders: Seizures [see Warnings and Precautions (5.3)] , disorientation, movement disorder, loss of consciousness Psychiatric disorders: Delirium, insomnia, panic attack Vascular disorders: Syncope [see Warnings and Precautions (5.2)]