SYNDROS® Important Safety Information

INDICATION AND IMPORTANT SAFETY INFORMATION

INDICATIONS AND USAGE

SYNDROS® is indicated in adults for the treatment of anorexia associated with weight loss in patients with Acquired Immune Deficiency Syndrome (AIDS) and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

CONTRAINDICATIONS

SYNDROS® is contraindicated in patients:

  • With a history of a hypersensitivity reaction to dronabinol. Reported hypersensitivity reactions to dronabinol include lip swelling, hives, disseminated rash, oral lesions, skin burning, flushing, throat tightness.
  • With a history of a hypersensitivity reaction to alcohol.
  • Who are receiving, or have recently received, disulfiram- or metronidazole-containing products within 14 days. SYNDROS® contains 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol.

WARNINGS AND PRECAUTIONS

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®.

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.

HEMODYNAMIC INSTABILITY

Patients may experience occasional hypotension, possible hypertension, syncope, or tachycardia while taking SYNDROS®. 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®.

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®.

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.

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.

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.

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.

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.

ADVERSE REACTIONS

The safety of SYNDROS has been established based on studies of dronabinol capsules.  Most common adverse reactions (≥3%) are: abdominal pain, dizziness, euphoria, nausea, paranoid reaction, somnolence, thinking abnormal, and vomiting.

DRUG INTERACTIONS

Disulfiram and Metronidazole

SYNDROS® contains 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol, which can produce disulfiram-like reactions when co-administered with 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®.

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.

Effect of Other Drugs on Dronabinol

Dronabinol is primarily metabolized by CYP2C9 and CYP3A4 enzymes.  Inhibitors of these enzymes may increase, while inducers may decrease, the systemic exposure of dronabinol and/or its active metabolite resulting in an increase in dronabinol-related adverse reactions or loss of efficacy of SYNDROS®. Monitor for increased dronabinol-related adverse reactions when SYNDROS is co-administered with inhibitors of CYP2C9 (e.g., amiodarone, fluconazole) and inhibitors of CYP3A4 enzymes (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, erythromycin, grapefruit juice).

Highly Protein-Bound Drugs

Dronabinol is highly bound to plasma proteins, and therefore, might displace and increase the free fraction of other concomitantly administered protein-bound drugs.  Although this displacement has not been confirmed in vivo, monitor patients for increased adverse reactions to narrow therapeutic index drugs (e.g., warfarin, cyclosporine, amphotericin B) when initiating treatment or increasing the dosage of SYNDROS®.

USE IN SPECIFIC POPULATIONS

PREGNANCY

SYNDROS, a synthetic cannabinoid containing alcohol, may cause fetal harm. Avoid use of SYNDROS® in pregnant women. Cannabinoids have been found in the umbilical cord blood from pregnant women who smoke cannabis.

Fetal/Neonatal Adverse Reactions

Use of cannabis during pregnancy should be avoided. SYNDROS® contains alcohol.  Alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development.  Avoid use of SYNDROS® in pregnant women.

Prenatal use of cannabis suggests that dronabinol may cross the placenta to the fetus during pregnancy.  The effects of delta-9-THC on the fetus are not known.

LACTATION

Because of the potential for HIV transmission in breastfed infants, advise women infected with HIV not to breastfeed while taking SYNDROS®. Advise women with nausea and vomiting associated with cancer chemotherapy not to breastfeed during treatment with SYNDROS® and for 9 days after the final dose.

PEDIATRIC USE

The safety and effectiveness of SYNDROS® have not been established in pediatric patients.

GERIATRIC USE

Elderly patients with dementia are at increased risk for falls as a result of their underlying disease state, which may be exacerbated by the CNS effects of somnolence and dizziness associated with SYNDROS®.

DRUG ABUSE AND DEPENDENCE ABUSE

SYNDROS® contains dronabinol, the main psychoactive component in marijuana. Ingestion of high doses of dronabinol increases the risk of psychiatric adverse reactions if abused or misused, while continued administration can lead to addiction. Psychiatric adverse reactions may include psychosis, hallucinations, depersonalization, mood alteration, and paranoia.

Physical dependence can develop during chronic therapy with SYNDROS® without manipulation.

Patients should be instructed to keep SYNDROS® in a secure place out of reach of others for whom the medication has not been prescribed.

OVERDOSAGE

SYNDROS® contains 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol. Ingestion of the product over the recommended dose could result in significant toxicity.

Dronabinol

  • Signs and symptoms of dronabinol overdose include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth, tachycardia, memory impairment, depersonalization, mood alteration, urinary retention, reduced bowel motility, decreased motor coordination, lethargy, slurred speech, and postural hypotension. Patients may also experience panic reactions if they have a prior history of nervousness or anxiety and seizures may occur in patients with existing seizure disorders.
  • It is not known if dronabinol can be removed by dialysis in cases of overdose.

Alcohol

  • Signs and symptoms of alcohol overdose include changes in mood or behavior, impaired judgment or social functioning and one or more physical signs such as slurred speech, unsteadiness, lack of coordination, increased or irregular heart rate, respiratory depression, impaired attention or loss of consciousness.

Propylene Glycol

  • Signs and symptoms of acute poisoning occur only in rare circumstances where patients ingest large amounts of propylene glycol over several days. These include hypoglycemia, severe metabolic acidosis (caused by the metabolism into lactic acid), and CNS depression including coma and seizures.

Management of Overdosage

  • If over-exposure of SYNDROS® occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.