dronabinol 10 MG Oral Capsule [Marinol]

INDICATIONS AND USAGE Dronabinol oral solution is indicated in adults for the treatment of: anorexia associated with weight loss in patients with Acquired Immune Deficiency Syndrome (AIDS). nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. Dronabinol oral solution is a cannabinoid indicated in adults for the treatment of: anorexia associated with weight loss in patients with AIDS. ( 1 ) nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. ( 1 )

DOSAGE AND ADMINISTRATION Administration ( 2.1 ): Always use the enclosed calibrated oral dosing syringe. The calibrated oral syringe measures a maximum dronabinol oral solution dose of 5 mg. If the prescribed dose is greater than 5 mg, the total dose will need to be divided and drawn up in two or more portions using the oral syringe. Take dronabinol oral solution with a full glass of water (6 to 8 ounces). Dronabinol oral solution can be administered via silicone enteral feeding tubes. Anorexia Associated with Weight Loss in Adult Patients with AIDS ( 2.2 ): The recommended starting dosage is 2.1 mg orally twice daily, one hour before lunch and dinner. See the full prescribing information for dosage titration to manage adverse reactions and to achieve desired therapeutic effect. Nausea and Vomiting Associated with Chemotherapy in Adult Patients Who Failed Conventional Antiemetics ( 2.3 ): The recommended starting dosage is 4.2 mg/m 2 , administered 1 to 3 hours prior to chemotherapy, then every 2 to 4 hours after chemotherapy for a total of 4 to 6 doses per day. Administer the first dose on an empty stomach at least 30 minutes prior to eating; subsequent doses can be taken without regard to meals. See the full prescribing information for dosage titration to manage adverse reactions and to achieve desired therapeutic effect. 2.1 Important Administration Instructions Oral Administration Always use the enclosed calibrated oral dosing syringe when administering dronabinol oral solution to ensure the dose is measured and administered accurately. The calibrated oral syringe measures a maximum dronabinol oral solution dose of 5 mg. If the prescribed dose is greater than 5 mg, the total dose will need to be divided and drawn up in two or more portions using the oral syringe. Take each dose of dronabinol oral solution with a full glass of water (6 to 8 ounces). For information on dosing dronabinol oral solution with regard to meals, see Dosage and Administration 2.2 and 2.3 . Administration via Feeding Tube (silicone only, greater than or equal to 14 French) Dronabinol oral solution can be administered via enteral feeding tubes that are manufactured using silicone, size greater than or equal to 14 French, such as Naso-Gastric (NG), Gastrostomy Tube (G-tube), Percutaneous Endoscopic Gastrostomy tube (PEG-tube) and Gastro-Jejunostomy tube (GJ-tube). Do not use tubes manufactured of polyurethane. Draw up the prescribed dose with the calibrated dosing syringe packaged with dronabinol oral solution. If the prescribed dose is greater than 5 mg, the total dose will need to be divided and drawn up in two or more portions using the oral syringe. Using the calibrated dosing syringe, administer the dose via the feeding tube. Using a catheter-tip syringe, flush the feeding tube with 30 mL of water. 2.2 Anorexia Associated with Weight Loss in Adult Patients with AIDS Starting Dosage The recommended adult starting dosage of dronabinol oral solution is 2.1 mg orally twice daily, one hour before lunch and one hour before dinner. In elderly patients, or patients unable to tolerate 2.1 mg twice daily, consider initiating dronabinol oral solution at 2.1 mg once daily one hour before dinner or at bedtime to reduce the risk of central nervous system (CNS) symptoms [see Use in Specific Populations (8.5) ]. Dosing later in the day may reduce the frequency of Central Nervous System (CNS) adverse reactions. CNS adverse reactions are dose-related [see Warnings and Precautions (5.1) ] ; therefore, monitor patients and reduce the dosage as needed. If CNS adverse reactions of feeling high, dizziness, confusion, and somnolence occur, they usually resolve in 1 to 3 days and usually do not require dosage reduction. If CNS adverse reactions are severe or persistent, reduce the dosage to 2.1 mg once daily one hour before dinner or in the evening at bedtime. Dosage Titration If tolerated and further therapeutic effect is desired, the dosage may be increased gradually to 2.1 mg one hour before lunch and 4.2 mg one hour before dinner. Increase the dose of dronabinol oral solution gradually in order to reduce the frequency of dose-related adverse reactions [see Warnings and Precautions (5.1) ]. Most patients respond to 2.1 mg twice daily, but the dose may be further increased to 4.2 mg one hour before lunch and 4.2 mg one hour before dinner, as tolerated to achieve a therapeutic effect. Maximum Dosage: 8.4 mg twice daily. 2.3 Nausea and Vomiting Associated with Cancer Chemotherapy in Adult Patients Who Failed Conventional Antiemetics Starting Dosage The recommended starting dosage of dronabinol oral solution is 4.2 mg/m 2 orally administered 1 to 3 hours prior to chemotherapy and then every 2 to 4 hours after chemotherapy for a total of 4 to 6 doses per day. Calculate the starting dose by following the steps below: Starting dose (mg) = Patient body surface area (BSA) in m 2 multiplied by 4.2 mg/m 2 Round dose to the nearest 0.1 mg increment Convert from milligrams (mg) to milliliters (mL): Starting dose (mg) rounded to the nearest 0.1 mg increment divided by 5 = Starting dose in milliliters (mL) To correspond with the calibrated oral dosing syringe, the dose may need to be rounded to the nearest 0.1 mL increment. In elderly patients, consider initiating dronabinol oral solution at 2.1 mg/m 2 once daily 1 to 3 hours prior to chemotherapy to reduce the risk of CNS symptoms [see Use in Specific Populations (8.5) ] . Because food delays the absorption of dronabinol oral solution, administer the first dose on an empty stomach at least 30 minutes before eating. Subsequent doses can be taken without regard to meals. Because food can substantially change the systemic exposure to dronabinol and its active metabolite, the timing of dosing in relation to meal times should be kept consistent for each chemotherapy cycle, once the dosage has been determined from the titration process. Dosage Titration The dosage can be titrated to clinical response during a chemotherapy cycle or subsequent cycles, based upon initial effect, as tolerated to achieve a clinical effect, in increments of 2.1 mg/m 2 . Maximum Dosage: 12.6 mg/m 2 per dose for 4 to 6 doses per day. Adverse reactions are dose-related and psychiatric symptoms increase significantly at the maximum dosage [see Warnings and Precautions (5.1) ] . Monitor patients for adverse reactions and consider decreasing the dose to 2.1 mg once daily 1 to 3 hours prior to chemotherapy to reduce the risk of CNS adverse reactions.

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 dronabinol oral solution 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 dronabinol oral solution. ( 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 dronabinol oral solution. ( 4 , 5.3 , 7.1 ) Seizures and Seizure-like Activity : Weigh the potential risk versus benefits before prescribing dronabinol oral solution 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 dronabinol oral solution 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 dronabinol oral solution 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 dronabinol oral solution, 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 oral solution has been associated with cognitive impairment and altered mental state. Reduce the dose of dronabinol oral solution or discontinue use dronabinol oral solution if signs or symptoms of cognitive impairment develop. Elderly and pediatric patients may be more sensitive to the neurological and psychoactive effects of dronabinol oral solution [see Use in Specific Populations ( 8.4 , 8.5 )] . Hazardous Activities Dronabinol oral solution 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 dronabinol oral solution does not affect them adversely. 5.2 Hemodynamic Instability Patients may experience occasional hypotension, possible hypertension, syncope, or tachycardia while taking dronabinol oral solution [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 oral solution. 5.3 Interaction with Disulfiram and Metronidazole Dronabinol oral solution contains 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol. Use of dronabinol oral solution 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 dronabinol oral solution and do not administer these products within 7 days of completing treatment with dronabinol oral solution [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 dronabinol oral solution 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 dronabinol oral solution 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 oral solution therapy. If a seizure occurs, advise patients to discontinue dronabinol oral solution 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 dronabinol oral solution as well. Dronabinol oral solution contains 50% (w/w) dehydrated alcohol. Assess each patient’s risk for abuse or misuse prior to prescribing dronabinol oral solution and monitor patients with a history of substance abuse during treatment with dronabinol oral solution 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 dronabinol oral solution . 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 dronabinol oral solution. Consider dose reduction or discontinuing dronabinol oral solution if a patient develops worsening nausea, vomiting, or abdominal pain while on treatment. 5.7 Toxicity in Preterm Neonates Dronabinol oral solution 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 dronabinol oral solution have not been estab

CONTRAINDICATIONS Dronabinol oral solution 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 [see Adverse Reactions ( 6.2 )] . with a history of a hypersensitivity reaction to alcohol. who are receiving, or have recently received, disulfiram- or metronidazole-containing products within 14 days [see Warning and Precautions ( 5.3 )] . Dronabinol oral solution contains 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol. Sensitivity to dronabinol or alcohol. ( 4 ) History of hypersensitivity reaction to alcohol. ( 4 ) Patients receiving, or have received, disulfiram- or metronidazole-containing products within the past 14 days. ( 4 , 5.3 , 7.1 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Dronabinol is an orally active cannabinoid that has complex effects on the CNS, including central sympathomimetic activity. Cannabinoid receptors have been discovered in neural tissues. These receptors may play a role in mediating the effects of dronabinol. 12.2 Pharmacodynamics Effects on the Cardiovascular System Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing [see Warnings and Precautions (5.2) ] . Effects on the Central Nervous System Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great inter-patient variability. After oral administration, dronabinol capsules have an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration. Tachyphylaxis and tolerance develop to some of the cardiovascular and CNS pharmacologic effects of dronabinol with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male subjects (N = 12) received 12 times the maximum dose for anorexia associated with weight loss in patients with AIDS of dronabinol capsules in divided doses for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These subjects developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation. Tachyphylaxis and tolerance do not appear to develop to the appetite stimulant effect of dronabinol. In clinical studies of dronabinol capsules in AIDS patients, at the recommended dosage, the appetite stimulant effect was sustained for up to five months. 12.3 Pharmacokinetics Absorption Dronabinol (delta-9-THC) is almost completely absorbed (90 to 95%) after a single oral dose. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Relative bioavailability data from healthy male and female subjects suggest that a dose of 4.2 mg of dronabinol oral solution provides comparable systemic exposure (C max and AUC) to a 5 mg dronabinol capsule, under fasted conditions [see Dosage and Administration (2.1) ] . The concentrations of both dronabinol and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing with dronabinol oral solution and decline over several days. The mean inter- and intra-subject variability in dronabinol pharmacokinetics (C max and AUC inf ) was approximately 66% and 47% and 67% and 14%, respectively, following administration of dronabinol oral solution to healthy subjects. Table 1: Summary of Single-Dose Pharmacokinetic Parameters of Dronabinol After Replicated Oral Administration of Dronabinol Oral Solution (4.2 mg to Healthy Subjects under Fasted Conditions) Parameter* Dronabinol C max (ng/mL) 1.9 ± 1.3 T max (h) 1.0 [0.5 to 4.0] AUC( inf ) (ng.h/mL) 3.8 ± 1.8 t ½ (h) 5.6 ± 2.7 * Arithmetic mean ± standard deviation except T max for which the median [range] is reported Food Effect The effect of food on the pharmacokinetics of dronabinol oral solution was studied by concomitant dosing of dronabinol oral solution with a high-fat (59 grams of fat, approximately 50% of total caloric content of the meal), high calorie meal (approximately 950 calories). An appreciable food effect was observed: food resulted in approximately a 2.5-fold increase in total exposure (AUC inf ) and approximately a 5 hour delay in median T max . Food also decreased C max by approximately 20% [see Dosage and Administration ( 2.2 , 2.3 )] . Distribution Dronabinol has an apparent volume of distribution of approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97% [see Drug Interactions (7.3) ] . Elimination The pharmacokinetics of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 5 hours and a terminal (beta) half-life of 25 to 36 hours. Values for clearance average about 0.2 L/kg-hr; but are highly variable due to the complexity of cannabinoid distribution. Metabolism Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by hydroxylation, yielding both active and inactive metabolites. The major metabolite (11-hydroxy-delta-9-THC) is pharmacologically active. Published in vitro data indicate that CYP2C9 and CYP3A4 are the primary enzymes in the metabolism of dronabinol. CYP2C9 appears to be the enzyme responsible for the formation of the primary active metabolite [see Clinical Pharmacology (12.5) ] . Excretion Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of excretion with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces. Due to its re-distribution, dronabinol and its metabolites may be excreted for prolonged periods of time. Following single dose administration, dronabinol metabolites have been detected for more than 5 weeks in the urine and feces. In a study of dronabinol capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine ratio was closely correlated with dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol. Drug Interaction Studies Formal drug-drug interaction studies have not been conducted with dronabinol. The enzyme inhibition and induction potential of dronabinol and its active metabolite are not completely understood. Published data showed an increase in the elimination half-life of pentobarbital by 4 hours when concomitantly dosed with dronabinol [see Warnings and Precautions (5.1) ] . 12.5 Pharmacogenomics Published data indicate a 2- to 3-fold higher dronabinol exposure in individuals carrying genetic variants associated with diminished CYP2C9 function.