Dronabinol

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.

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 Wellhouse Pharma, LLC at 1-844-558-8289 or FDA at MedWatch phone number 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 ( 5.4 )] Paradoxical Nausea, Vomiting, and Abdominal Pain [see Warnings and Precautions ( 5.6 )] Toxicity in Preterm Neonates [see Warnings and Precautions ( 5.7 )] The safety of SYNDROS has been established based on studies of dronabinol capsules. Studies of AIDS-related weight loss included 157 patients receiving dronabinol capsules 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 adverse reactions 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. Common Adverse Reactions The following adverse reactions were reported in clinical trials of dronabinol capsules at an incidence greater than 1%. *Actual Incidence 3% to 10% System Organ Class Adverse Reactions General Asthenia Cardiovascular Palpitations, tachycardia, vasodilation/facial flush Gastrointestinal Abdominal pain*, nausea*, vomiting* Central Nervous System Dizziness*, euphoria*, paranoid reaction*, somnolence*, thinking abnormal*, amnesia, anxiety/nervousness, ataxia, confusion, depersonalization, hallucination Less Common Adverse Reactions The following adverse reactions were reported in clinical trials of dronabinol capsules at an incidence less than or equal to 1%. System Organ Class Adverse Reactions General Chills, headache, malaise Cardiovascular Hypotension, conjunctival injection [see Clinical Pharmacology ( 12.2 )] Gastrointestinal Diarrhea, fecal incontinence, anorexia, hepatic enzyme elevation Musculoskeletal Myalgias Central Nervous System Depression, nightmares, speech difficulties, tinnitus Respiratory Cough, rhinitis, sinusitis Skin Flushing, sweating Sensory Vision difficulties 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of another oral formulation of dronabinol. 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 ( 5.4 )] , disorientation, movement disorder, loss of consciousness. Psychiatric disorders: delirium, insomnia, panic attack. Vascular disorders: syncope [see Warnings and Precautions ( 5.2 )] .

7 DRUG INTERACTIONS Inhibitors and Inducers of CYP2C9 and CYP3A4 : May alter dronabinol systemic exposure; monitor for dronabinol-related adverse reactions or loss of efficacy. ( 7.2 ) Highly Protein-Bound Drugs : Potential for displacement of other drugs from plasma proteins; monitor for adverse reactions to concomitant narrow therapeutic index drugs (e.g., warfarin, cyclosporine, or amphotericin B) when initiating or increasing the dosage of SYNDROS. ( 7.3 ) 7.1 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 [see Contraindications ( 4 ), Warnings and Precautions ( 5.3 )] . 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. 7.2 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). 7.3 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.

8 USE IN SPECIFIC POPULATIONS Pregnancy : May cause fetal harm. ( 8.1 ) Lactation : Advise HIV infected women not to breastfeed due to the potential for HIV transmission. ( 8.2 ) Geriatric Use: Elderly patients may be more sensitive to the neuropsychiatric and postural hypotensive effects. Consider a lower starting dose in elderly patients. ( 2.2 , 2.3 , 5.1 , 5.2 , 8.5 ) 8.1 Pregnancy Risk Summary SYNDROS, a synthetic cannabinoid containing alcohol, may cause fetal harm. Avoid use of SYNDROS in pregnant women. Although there is little published data on the use of synthetic cannabinoids during pregnancy, use of cannabis (e.g., marijuana) and use of alcohol during pregnancy have been associated with adverse fetal/neonatal outcomes (see Clinical Considerations ) . Cannabinoids have been found in the umbilical cord blood from pregnant women who smoke cannabis. In animal reproduction studies, no teratogenicity was reported in mice administered dronabinol (delta-9-THC) at up to 30 times the MRHD (maximum recommended human doses) and up to 5 times the MRHD for patients with AIDS and cancer, respectively. Similar findings were reported in pregnant rats administered dronabinol at up to 5 to 20 times the MRHD and 3 times the MRHD for patients with AIDS and cancer, respectively. Decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions were observed in both species at doses which induced maternal toxicity. In rats, maternal administration of dronabinol from pregnancy (implantation) through weaning was associated with maternal toxicity, including mortality of pups, and adverse developmental and neurodevelopmental effects on the pups at 2 to 20 times the MRHD for patients with AIDS and less than and up to 3.3 times the MRHD for patients with cancer. (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Published studies suggest that during pregnancy, the use of cannabis, which includes THC, whether for recreational or medicinal purposes, may increase the risk of adverse fetal/neonatal outcomes including fetal growth restriction, low birth weight, preterm birth, small-for-gestational age, admission to the neonatal intensive care unit, and stillbirth. Therefore, use of cannabis during pregnancy should be avoided. SYNDROS contains alcohol. Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. Avoid use of SYNDROS in pregnant women. Data Human Data Delta-9-THC has been measured in the cord blood of some infants whose mothers reported prenatal use of cannabis, suggesting that dronabinol may cross the placenta to the fetus during pregnancy. The effects of delta-9-THC on the fetus are not known. Animal Data The recommended dose ranges for SYNDROS in patients with AIDS and patients with cancer are designed to achieve the same systemic exposure ranges to delta-9-THC as with the recommended dose ranges for dronabinol capsules. Therefore, animal to human dose multiples, as shown below, are based on the MRHDs (maximum recommended human doses) for dronabinol capsules, instead of the MRHDs for SYNDROS, which are 15% lower. This approach for dose comparison between animals and humans is supported by the demonstrated difference in dronabinol bioavailability between SYNDROS and dronabinol capsules. Reproduction studies with dronabinol have been performed in mice at 15 to 450 mg/m 2 , equivalent to 1 to 30 times the MRHD of 15 mg/m 2 /day (dronabinol capsules) in patients with AIDS or 0.2 to 5 times the MRHD of 90 mg/m 2 /day (dronabinol capsules) in patients with cancer, and in rats at 74 to 295 mg/m 2 (equivalent to 5 to 20 times the MRHD of 15 mg/m 2 /day in patients with AIDS or 0.8 to 3 times the MRHD of 90 mg/m 2 /day in patients with cancer). These studies have revealed no evidence of teratogenicity due to delta-9-THC. At these dronabinol dosages in mice and rats, delta-9-THC decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions. Such effects were dose dependent and less apparent at lower doses that produced less maternal toxicity. Review of published literature indicates that the endocannabinoid system plays a role in neurodevelopmental processes such as neurogenesis, migration, and synaptogenesis. Exposure of pregnant rats to delta-9-THC (during and after organogenesis) may modulate these processes to result in abnormal patterns of neuronal connectivity and subsequent cognitive impairments in the offspring. Nonclinical toxicity studies in pregnant rats and newborn pups have shown prenatal exposure to delta-9-THC that resulted in impairment of motor function, alteration in synaptic activity, and interference in cortical projection of neuron development in the offspring. Prenatal exposure has shown effects on cognitive function such as learning, short- and long-term memory, attention, decreased ability to remember task, and ability to discriminate between novel and same objects. Overall, prenatal exposure to delta-9-THC has resulted in significant and long-term changes in brain development, cognition, and behavior in rat offspring. In a pre- and post-natal developmental study, female rats administered dronabinol by oral gavage in a vehicle of medium chain triglycerides at doses of 5, 25 and 50 mg/kg/day (equivalent to 1.7, 10, and 20 times the MRHD for patients with AIDS and 0.33, 1.7, and 3.3 times the MRHD for patients with cancer, respectively, based on body surface area) from gestation day 6 (implantation) through lactation day 20 (weaning). Maternal toxicity caused mortality of pups at and above 10 times the MRHD for patients with AIDS and 1.7 times the MRHD for patients with cancer. At 20 times the MRHD for patients with AIDS and 3.3 times the MRHD for patients with cancer, treatment with dronabinol was associated with an increase in the number of dams with 100% pup mortality on lactation days 1 to 4. At 2 and 10 times the MRHD for patients with AIDS and 0.33 and 1.7 times the MRHD for patients with cancer, dronabinol produced adverse effects on the offspring including delays in developmental landmark parameters (e.g., surface righting reflex, negative geotaxis, and air righting reflex), decreased fertility and pregnancy index, reduced ovary and uterus weights, decreased implantations and viable embryos, and increased post-implantation loss. Neurological adverse effects such as piloerection, landing foot splay and an increase in the number of rears in open field were observed in offspring at 10 and 20 times the MRHD for patients with AIDS and 0.33 and 1.7 times the MRHD for patients with cancer. Administration of dronabinol in 50% ethanol (used in the vehicle for SYNDOS), was poorly tolerated in maternal animals. Serious adverse signs of toxicity were observed in the control group (vehicle only) and in dronabinol-containing dose groups at 10 and 20 times the MRHD for patients with AIDS and 1.7 and 3.3 times the MRHD for patients with cancer, resulting in termination of all animals at the 50 mg/kg dose level prior to delivery of litters. These animal findings are difficult to interpret due to effects of alcohol in the vehicle. 8.2 Lactation Risk Summary For mothers infected with the Human Immunodeficiency Virus (HIV), the Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of the potential for HIV transmission (in HIV-negative infants) and serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving SYNDROS. For mothers with nausea and vomiting associated with cancer chemotherapy, there are limited data on the presence of dronabinol in human milk, the effects on the breastfed infant, or the effects on milk production. The reported effects of inhaled cannabis transferred to the breastfeeding infant have been inconsistent and insufficient to establish causality. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYNDROS and any potential adverse effects on the breastfed infant from SYNDROS or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of SYNDROS have not been established in pediatric patients. Pediatric patients may be more sensitive to neurological and psychoactive effects of SYNDROS [see Warnings and Precautions ( 5.1 )] . SYNDROS contains the excipients 50% (w/w) dehydrated alcohol and 5.5% (w/w) 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 events due to diminished ability to metabolize propylene glycol, thereby, leading to accumulation [see Warnings and Precautions ( 5.7 )] . 8.5 Geriatric Use Clinical studies of dronabinol capsules in AIDS and cancer patients did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients may be more sensitive to the neuropsychiatric and postural hypotensive effects of SYNDROS [see Warnings and Precautions ( 5.1 , 5.2 )] . 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 [see Warnings and Precautions ( 5.1 )] . These patients should be monitored closely and placed on fall precautions prior to initiating SYNDROS therapy. In antiemetic studies, no difference in efficacy was apparent in patients greater than 55 years of age compared to younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of falls, decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects, and of concomitant disease or other drug therapy [see Dosage and Administration ( 2.2 , 2.3 )] . 8.6 Effect of CYP2C9 Polymorphism Published data suggest that systemic clearance of dronabinol may be reduced and concentrations may be increased in presence of CYP2C9 genetic polymorphism. Monitoring for increased adverse reactions is recommended in patients known to carry genetic variants associated with diminished CYP2C9 function [see Clinical Pharmacology ( 12.5 )] .

8.1 Pregnancy Risk Summary SYNDROS, a synthetic cannabinoid containing alcohol, may cause fetal harm. Avoid use of SYNDROS in pregnant women. Although there is little published data on the use of synthetic cannabinoids during pregnancy, use of cannabis (e.g., marijuana) and use of alcohol during pregnancy have been associated with adverse fetal/neonatal outcomes (see Clinical Considerations ) . Cannabinoids have been found in the umbilical cord blood from pregnant women who smoke cannabis. In animal reproduction studies, no teratogenicity was reported in mice administered dronabinol (delta-9-THC) at up to 30 times the MRHD (maximum recommended human doses) and up to 5 times the MRHD for patients with AIDS and cancer, respectively. Similar findings were reported in pregnant rats administered dronabinol at up to 5 to 20 times the MRHD and 3 times the MRHD for patients with AIDS and cancer, respectively. Decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions were observed in both species at doses which induced maternal toxicity. In rats, maternal administration of dronabinol from pregnancy (implantation) through weaning was associated with maternal toxicity, including mortality of pups, and adverse developmental and neurodevelopmental effects on the pups at 2 to 20 times the MRHD for patients with AIDS and less than and up to 3.3 times the MRHD for patients with cancer. (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Published studies suggest that during pregnancy, the use of cannabis, which includes THC, whether for recreational or medicinal purposes, may increase the risk of adverse fetal/neonatal outcomes including fetal growth restriction, low birth weight, preterm birth, small-for-gestational age, admission to the neonatal intensive care unit, and stillbirth. Therefore, use of cannabis during pregnancy should be avoided. SYNDROS contains alcohol. Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. Avoid use of SYNDROS in pregnant women. Data Human Data Delta-9-THC has been measured in the cord blood of some infants whose mothers reported prenatal use of cannabis, suggesting that dronabinol may cross the placenta to the fetus during pregnancy. The effects of delta-9-THC on the fetus are not known. Animal Data The recommended dose ranges for SYNDROS in patients with AIDS and patients with cancer are designed to achieve the same systemic exposure ranges to delta-9-THC as with the recommended dose ranges for dronabinol capsules. Therefore, animal to human dose multiples, as shown below, are based on the MRHDs (maximum recommended human doses) for dronabinol capsules, instead of the MRHDs for SYNDROS, which are 15% lower. This approach for dose comparison between animals and humans is supported by the demonstrated difference in dronabinol bioavailability between SYNDROS and dronabinol capsules. Reproduction studies with dronabinol have been performed in mice at 15 to 450 mg/m 2 , equivalent to 1 to 30 times the MRHD of 15 mg/m 2 /day (dronabinol capsules) in patients with AIDS or 0.2 to 5 times the MRHD of 90 mg/m 2 /day (dronabinol capsules) in patients with cancer, and in rats at 74 to 295 mg/m 2 (equivalent to 5 to 20 times the MRHD of 15 mg/m 2 /day in patients with AIDS or 0.8 to 3 times the MRHD of 90 mg/m 2 /day in patients with cancer). These studies have revealed no evidence of teratogenicity due to delta-9-THC. At these dronabinol dosages in mice and rats, delta-9-THC decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions. Such effects were dose dependent and less apparent at lower doses that produced less maternal toxicity. Review of published literature indicates that the endocannabinoid system plays a role in neurodevelopmental processes such as neurogenesis, migration, and synaptogenesis. Exposure of pregnant rats to delta-9-THC (during and after organogenesis) may modulate these processes to result in abnormal patterns of neuronal connectivity and subsequent cognitive impairments in the offspring. Nonclinical toxicity studies in pregnant rats and newborn pups have shown prenatal exposure to delta-9-THC that resulted in impairment of motor function, alteration in synaptic activity, and interference in cortical projection of neuron development in the offspring. Prenatal exposure has shown effects on cognitive function such as learning, short- and long-term memory, attention, decreased ability to remember task, and ability to discriminate between novel and same objects. Overall, prenatal exposure to delta-9-THC has resulted in significant and long-term changes in brain development, cognition, and behavior in rat offspring. In a pre- and post-natal developmental study, female rats administered dronabinol by oral gavage in a vehicle of medium chain triglycerides at doses of 5, 25 and 50 mg/kg/day (equivalent to 1.7, 10, and 20 times the MRHD for patients with AIDS and 0.33, 1.7, and 3.3 times the MRHD for patients with cancer, respectively, based on body surface area) from gestation day 6 (implantation) through lactation day 20 (weaning). Maternal toxicity caused mortality of pups at and above 10 times the MRHD for patients with AIDS and 1.7 times the MRHD for patients with cancer. At 20 times the MRHD for patients with AIDS and 3.3 times the MRHD for patients with cancer, treatment with dronabinol was associated with an increase in the number of dams with 100% pup mortality on lactation days 1 to 4. At 2 and 10 times the MRHD for patients with AIDS and 0.33 and 1.7 times the MRHD for patients with cancer, dronabinol produced adverse effects on the offspring including delays in developmental landmark parameters (e.g., surface righting reflex, negative geotaxis, and air righting reflex), decreased fertility and pregnancy index, reduced ovary and uterus weights, decreased implantations and viable embryos, and increased post-implantation loss. Neurological adverse effects such as piloerection, landing foot splay and an increase in the number of rears in open field were observed in offspring at 10 and 20 times the MRHD for patients with AIDS and 0.33 and 1.7 times the MRHD for patients with cancer. Administration of dronabinol in 50% ethanol (used in the vehicle for SYNDOS), was poorly tolerated in maternal animals. Serious adverse signs of toxicity were observed in the control group (vehicle only) and in dronabinol-containing dose groups at 10 and 20 times the MRHD for patients with AIDS and 1.7 and 3.3 times the MRHD for patients with cancer, resulting in termination of all animals at the 50 mg/kg dose level prior to delivery of litters. These animal findings are difficult to interpret due to effects of alcohol in the vehicle.