warnings and cautions
5 WARNINGS AND PRECAUTIONS Neuropsychiatric 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 SYNDROS does not affect them adversely. ( 5.1 ) Hemodynamic 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 SYNDROS. ( 5.2 ) Interaction with Disulfiram and Metronidazole : May cause disulfiram-like reaction. Discontinue products containing disulfiram or metronidazole at least 14 days before and do not administer 7 days after treatment with SYNDROS. ( 4 , 5.3 , 7.1 ) Seizures and Seizure-like Activity : Weigh the potential risk versus benefits before prescribing SYNDROS 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. ( 5.4 ) Multiple Substance Abuse : Assess risk for abuse or misuse in patients with a history of substance abuse or dependence, prior to prescribing SYNDROS and monitor for the development of associated behaviors or conditions. ( 5.5 ) Paradoxical Nausea, Vomiting, or Abdominal Pain : Consider dose reduction or discontinuation, if worsening of symptoms while on treatment. ( 5.6 ) Toxicities Related to Propylene Glycol in Preterm Neonates : The safety and effectiveness of SYNDROS have not been established in pediatric patients. Avoid use in preterm neonates in the immediate postnatal period. ( 5.7 ) 5.1 Neuropsychiatric Adverse Reactions Psychiatric Adverse Reactions Dronabinol has been reported to exacerbate mania, depression, or schizophrenia. Prior to initiating treatment with SYNDROS, 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 SYNDROS has been associated with cognitive impairment and altered mental state. Reduce the dose of SYNDROS or discontinue use of SYNDROS if signs or symptoms of cognitive impairment develop. Elderly and pediatric patients may be more sensitive to the neurological and psychoactive effects of SYNDROS [see Use in Specific Populations ( 8.4 , 8.5 )] . Hazardous Activities SYNDROS 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, lithium, opioids, buspirone, scopolamine, antihistamines, tricyclic antidepressants, other anticholinergic agents, and muscle relaxants). Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that SYNDROS does not affect them adversely. 5.2 Hemodynamic Instability Patients may experience occasional hypotension, possible hypertension, syncope, or tachycardia while taking SYNDROS [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 SYNDROS. 5.3 Interaction with Disulfiram and Metronidazole SYNDROS contains 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol. Use of SYNDROS may cause a disulfiram-like reaction, characterized by abdominal cramps, nausea, vomiting, headaches, and flushing, in patients receiving disulfiram or other drugs that produce this reaction (e.g., metronidazole). Discontinue products containing disulfiram or metronidazole at least 14 days before starting treatment with SYNDROS and do not administer these products within 7 days of completing treatment with SYNDROS [see Contraindications ( 4 ), Drug Interactions ( 7.3 )] . When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations of propylene glycol. However, the contribution of propylene glycol, if any, to the interaction between disulfiram and SYNDROS is unknown. 5.4 Seizures Seizures and seizure-like activity have been reported in patients receiving dronabinol. Weigh this potential risk against the benefits before prescribing SYNDROS 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 SYNDROS therapy. If a seizure occurs, advise patients to discontinue SYNDROS and contact a healthcare provider immediately. 5.5 Multiple Substance Abuse Patients with a history of substance abuse or dependence, including marijuana or alcohol, may be more likely to abuse SYNDROS as well. SYNDROS contains 50% (w/w) dehydrated alcohol. Assess each patient’s risk for abuse or misuse prior to prescribing SYNDROS and monitor patients with a history of substance abuse during treatment with SYNDROS for the development of these behaviors or conditions. 5.6 Paradoxical Nausea, Vomiting, or Abdominal Pain New or worsening nausea, vomiting, or abdominal pain can occur during treatment with synthetic delta-9 tetrahydrocannabinol (delta-9-THC), the active ingredient in SYNDROS. 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 or worsening of nausea, vomiting, or abdominal pain while being treated with SYNDROS. Consider dose reduction or discontinuing SYNDROS if a patient develops worsening nausea, vomiting, or abdominal pain while on treatment. 5.7 Toxicity in Preterm Neonates SYNDROS contains the excipients dehydrated alcohol (50%, w/w) and propylene glycol (5.5%, w/w). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations of propylene glycol. Preterm neonates may be at increased risk of propylene glycol-associated adverse reactions due to a diminished ability to metabolize propylene glycol, thereby, leading to accumulation. The safety and effectiveness of SYNDROS have not been established in pediatric patients. Avoid SYNDROS in preterm neonates in the immediate postnatal period because of possible propylene glycol-associated toxicities including: hyperosmolarity, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias, electrocardiogram (ECG) changes, and hemolysis.