DailyMed Label: MARINOL

DailyMed Label: MARINOL

2023

DailyMed Prescription

MARINOL

Dronabinol

ThePharmaNetwork, LLC

NDC: 53097-571

NDC: 53097-572

NDC: 53097-573

NDC: 53097-571

NDC: 53097-572

NDC: 53097-573

NDC: 53097-571

NDC: 53097-572

NDC: 53097-573

NDC: 53097-571

NDC: 53097-572

NDC: 53097-573

NDC: 53097-571

NDC: 53097-571

NDC: 53097-572

NDC: 53097-572

NDC: 53097-573

NDC: 53097-573

Dronabinol is a cannabinoid designated chemically as (6aR,10aR)-6a,7,8,10a-Tetrahydro-6,6,9- trimethyl-3-pentyl-6H-dibenzo[b,d]-pyran-1-ol. Dronabinol has the following empirical and structural formulas: C 21 H 30 O 2 (molecular weight = 314.46) Dronabinol, the active ingredient in MARINOL (dronabinol capsules, USP), is synthetic delta-9- tetrahydrocannabinol (delta-9-THC). Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7. Each MARINOL capsule strength is formulated with the following inactive ingredients: 2.5 mg capsule contains gelatin, glycerin, sesame oil, and titanium dioxide; 5 mg capsule contains iron oxide red and iron oxide black, gelatin, glycerin, sesame oil, and titanium dioxide; 10 mg capsule contains iron oxide red and iron oxide yellow, gelatin, glycerin, sesame oil, and titanium dioxide. marinol-str.jpg

MARINOL 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. MARINOL 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 )

Anorexia Associated with Weight Loss in Adult Patients with AIDS ( 2.1 ): The recommended adult starting dosage is 2.5 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 ( 2.2 ): The recommended starting dosage is 5 mg/m 2 , administered 1 to 3 hours prior to the administration of 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. Starting Dosage The recommended adult starting dosage of MARINOL is 2.5 mg orally twice daily, one hour before lunch and dinner. In elderly patients or patients unable to tolerate 2.5 mg twice daily, consider initiating MARINOL at 2.5 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 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 2.5 mg in the evening or at bedtime. Dosage Titration If tolerated and further therapeutic effect is desired, the dosage may be increased gradually to 2.5 mg one hour before lunch and 5 mg one hour before dinner. Increase the dose of MARINOL gradually in order to reduce the frequency of dose-related adverse reactions [see Warnings and Precautions ( 5.1 )]. Most patients respond to 2.5 mg twice daily, but the dose may be further increased to 5 mg one hour before lunch and 5 mg one hour before dinner, as tolerated to achieve a therapeutic effect. Maximum Dosage: 10 mg twice daily. Starting Dosage The recommended starting dosage of MARINOL is 5 mg/m 2 , orally administered 1 to 3 hours prior to the administration of chemotherapy and then every 2 to 4 hours after chemotherapy, for a total of 4 to 6 doses per day. In elderly patients, consider initiating MARINOL at 2.5 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 )]. Administer the first dose on an empty stomach at least 30 minutes before eating. Subsequent doses can be taken without regard to meals [see Clinical Pharmacology ( 12.3) ]. 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 response, as tolerated to achieve a clinical effect, in increments of 2.5 mg/m 2 . The maximum dosage is 15 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 2.5 mg once daily 1 to 3 hours prior to chemotherapy to reduce the risk of CNS adverse reactions.

MARINOL is supplied as round, soft gelatin capsules for oral use as follows: 2.5 mg white capsules (Identified M2) 5 mg dark brown capsules (Identified M5) 10 mg orange capsules (Identified MX) Capsules: 2.5 mg, 5 mg, 10 mg ( 3 )

MARINOL ® (dronabinol capsules, USP), is contraindicated in patients with a history of a hypersensitivity reaction to dronabinol or sesame oil. Reported hypersensitivity reactions to dronabinol capsules include lip swelling, hives, disseminated rash, oral lesions, skin burning, flushing and throat tightness [see Adverse Reactions ( 6.2 )]. History of a hypersensitivity reaction to dronabinol or sesame oil ( 4 )

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 MARINOL ® (dronabinol capsules, USP), 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 MARINOL. ( 5.2 ) Seizures and Seizure-like Activity: Weigh the potential risk versus benefits before prescribing MARINOL 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 ) Multiple Substance Abuse: Assess risk for abuse or misuse in patients with a history of substance abuse or dependence, prior to prescribing MARINOL 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 ) 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 MARINOL in antiemetic studies. Prior to initiating treatment with MARINOL, 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 MARINOL has been associated with cognitive impairment and altered mental state. Reduce the dose of MARINOL or discontinue use of MARINOL if signs or symptoms of cognitive impairment develop. Elderly patients may be more sensitive to the neurological and psychoactive effects of MARINOL [see Use in Specific Populations ( 8.4 , 8.5 )]. Hazardous Activities MARINOL 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 MARINOL does not affect them adversely. Patients may experience occasional hypotension, possible hypertension, syncope, or tachycardia while taking MARINOL [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 MARINOL. Seizure and seizure-like activity have been reported in patients receiving dronabinol. Weigh this potential risk against the benefits before prescribing MARINOL 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 MARINOL therapy. If a seizure occurs, advise patients to discontinue MARINOL and contact a healthcare provider immediately. Patients with a history of substance abuse or dependence, including marijuana or alcohol, may be more likely to abuse MARINOL as well. Assess each patient’s risk for abuse or misuse prior to prescribing MARINOL and monitor patients with a history of substance abuse during treatment with MARINOL for the development of these behaviors or conditions. Nausea, vomiting, or abdominal pain can occur during treatment with synthetic delta-9- tetrahydrocannabinol (delta-9-THC), the active ingredient in MARINOL ® (dronabinol capsules, USP). 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 MARINOL. Consider dose reduction or discontinuing MARINOL if a patient develops worsening nausea, vomiting, or abdominal pain while on treatment.

Inhibitors and inducers of CYP2C9 and CYP3A4: May alter dronabinol systemic exposure; monitor for potential dronabinol-related adverse reactions or loss of efficacy. ( 7.3 ) Highly protein-bound drugs: Potential for displacement of other drugs from plasma proteins; monitor for adverse reactions to concomitant highly protein-bound drugs and narrow therapeutic index drugs (e.g., warfarin, cyclosporine, amphotericin B) when initiating or increasing the dosage of MARINOL. ( 7.4 ) Additive CNS effects (e.g., dizziness, confusion, sedation, somnolence) may occur when MARINOL is taken concomitantly with drugs that have similar effects on the central nervous system such as CNS depressants [see Warnings and Precautions ( 5.1 )]. Additive cardiac effects (e.g., hypotension, hypertension, syncope, tachycardia) may occur when MARINOL is taken concomitantly with drugs that have similar effects on the cardiovascular system [see Warnings and Precautions ( 5.2 )]. Dronabinol is primarily metabolized by CYP2C9 and CYP3A4 enzymes based on published in vitro studies. 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 MARINOL. Monitor for potentially increased dronabinol-related adverse reactions when MARINOL 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). 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 that are highly protein-bound (e.g., warfarin, cyclosporine, amphotericin B) when initiating treatment or increasing the dosage of MARINOL.

Pregnancy: May cause fetal harm. ( 8.1 ) Lactation : Advise HIV-infected women not to breastfeed due to the potential for HIV transmission. Weight should be monitored in breastfed infants of mothers with nausea and vomiting associated with cancer chemotherapy in whom breastfeeding is appropriate. ( 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. ( 2.1 , 2.2 , 5.1 , 5.2 , 8.5) Risk Summary MARINOL, a synthetic cannabinoid, may cause fetal harm. Avoid use of MARINOL in pregnant women. Although there is little published data on the use of synthetic cannabinoids during pregnancy, use of cannabis (e.g., marijuana) during pregnancy has 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 dose) 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 adverse clinical signs, increased stillbirths and mortality of offspring, and reduced pup bodyweight at 2 and 6 times the MRHD for patients with AIDS, and less than or equal to the MRHD for patients with cancer. No evidence of neurodevelopmental adverse effects was observed in the offspring at doses up to 6 times the MRHD for patients with AlDS, and up to 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.  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 Reproduction studies with dronabinol have been performed in mice at 15 to 450 mg/m2, equivalent to 1 to 30 times the MRHD of 15 mg/m2/day in patients with AIDS or 0.2 to 5 times the MRHD of 90 mg/m2/day in patients with cancer, and in rats at 74 to 295 mg/m2 (equivalent to 5 to 20 times the MRHD of 15 mg/m2/day in patients with AIDS or 0.8 to 3 times the MRHD of 90 mg/m2/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 postnatal development study, female rats were administered dronabinol by oral gavage at doses of 0.5, 5, or 15 mg/kg /day (equivalent to 0.2, 2, and 6 times the MRHD for patients with AIDS and 0.03, 0.33, and 1.0 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 including adverse clinical signs (i.e., decreased motor activity, low carriage, abnormal gait, hunched posture, vocalization to touch, ungroomed coat, mild dehydration, piloerection, and splayed hindlimbs), reduced body weight and body weight gain, and decreased food consumption were observed during the gestation period at 2 and 6 times the MRHD for patients with AIDS and 0.33 and 1.0 times the MRHD for patients with cancer, respectively. At the same doses, reduced pup bodyweight, increased stillbirths, and mortality of offspring were observed. No neurodevelopmental adverse effects (i.e., neurobehavioral function, sensory function, motor activity, learning and memory) were observed in pups at maternal doses up 15 mg/kg/day (6 times the MRHD in patients with AIDS or 1.0 times the MRI-ID in patients with cancer). Risk Summary For mothers infected with the Human Immunodeficiency Virus (HIV), the Centers for Disease Control and Prevention recommends 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 MARINOL ® (dronabinol capsules, USP). 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. In rat offspring exposed to dronabinol in utero and during lactation, reduced bodyweight was observed during the preweaning (lactation) stage with maternal administration of dronabinol at 2 times and less than the MRHD for patients with AIDS and cancer, respectively.  Breastfeeding infants should have their weight monitored. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for MARlNOL and any potential adverse effects on the breastfed infant from MARINOL or from the underlying maternal condition. The safety and effectiveness of MARINOL have not been established in pediatric patients. Pediatric patients may be more sensitive to neurological and psychoactive effects of MARINOL [see Warnings and Precautions ( 5.1 )]. Clinical studies of MARINOL in AIDS and cancer patients did not include the 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 MARINOL [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 MARINOL [see Warnings and Precautions ( 5.1 )]. These patients should be monitored closely and placed on fall precautions prior to initiating MARINOL 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 ( 2.1 , 2.2 )]. Published data suggest that systemic clearance of dronabinol may be reduced and concentrations may be increased in the presence of CYP2C9 genetic polymorphism. Monitoring for potentially increased adverse reactions is recommended in patients known to carry genetic variants associated with diminished CYP2C9 function [see Clinical Pharmacology ( 12.5 )].

MARINOL ® (dronabinol capsules, USP) 2.5 mg white capsules (Identified M2). NDC 53097-571-60 (Bottle of 60 capsules). 5 mg dark brown capsules (Identified M5). NDC 53097-572-60 (Bottle of 60 capsules). 10 mg orange capsules (Identified MX). NDC 53097-573-60 (Bottle of 60 capsules). Storage Conditions MARINOL capsules should be packaged in a well-closed container and stored in a cool environment between 8° and 15°C (46° and 59°F) and alternatively could be stored in a refrigerator. Protect from freezing.

Dronabinol is an orally active cannabinoid which 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. 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 has 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 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 210 mg per day of MARINOL, administered orally 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 MARINOL. In clinical studies involving AIDS patients, the appetite stimulant effect of MARINOL was sustained for up to five months at dosages ranging from 2.5 mg to 20 mg per day. Absorption Dronabinol (delta-9-THC) is almost completely absorbed (90 to 95%) after single oral doses. 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. Concentrations of both parent drug and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing and decline over several days. The pharmacokinetics of dronabinol after single doses (2.5, 5, and 10 mg) and multiple doses (2.5, 5, and 10 mg given twice a day) have been studied in healthy subjects.  Summary of Multiple-Dose Pharmacokinetic Parameters of Dronabinol in Healthy Subjects (n=34; 20-45 years) under Fasted Conditions Mean (SD) PK Parameter Values     Twice Daily Dose   C max ng/mL Median T max (range), hr AUC (0-12) ng•hr/mL 2.5 mg 1.32 (0.62) 1.00 (0.50-4.00) 2.88 (1.57) 5 mg 2.96 (1.81) 2.50 (0.50-4.00) 6.16 (1.85) 10 mg 7.88 (4.54) 1.50 (0.50-3.50) 15.2 (5.52) C max : maximum observed plasma concentration; T max : time to maximum observed plasma concentration; AUC (0-12) : area under the plasma concentration-time curve from 0 to 12 hours. A slight increase in dose proportionality on mean C max and AUC (0-12) of dronabinol was observed with increasing dose over the dose range studied. Effect of Food: In a published study, the effect of food on the pharmacokinetics of dronabinol was studied by concomitant dosing of MARINOL ® (dronabinol capsules, USP) 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, resulting in a 4-hour delay in mean T max and 2.9-fold increase in total exposure (AUC inf ), but C max was not significantly changed [see Dosage and Administration ( 2.2 )]. 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 ( 7.4) ]. Elimination The pharmacokinetics of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 4 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. Dronabinol and its principal active metabolite, 11-hydroxy-delta-9-THC, are present in approximately equal concentrations in plasma. Published in vitro data indicates 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 elimination 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 at low levels for prolonged periods of time. Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5 weeks in the urine and feces. In a study of MARINOL 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 )]. Published data indicate a potentially 2-to 3-fold higher dronabinol exposure in individuals carrying genetic variants associated with diminished CYP2C9 function.

In 2-year carcinogenicity studies, there was no evidence of carcinogenicity in rats at doses up to 50 mg/kg/day dronabinol (approximately 20 times the MRHD in AIDS patients on a body surface area basis) or in mice at doses up to 500 mg/kg/day (approximately 100 times the MRHD in AIDS patients on a body surface area basis). Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in Chinese hamster ovary cells, and the in vivo mouse micronucleus test. However, dronabinol produced a weak positive response in a sister chromatid exchange test in Chinese hamster ovary cells. In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/m 2 , equivalent to 2 to 10 times the MRHD of 15 mg/m 2 /day in AIDS patients or 0.3 to 1.5 times the MRHD of 90 mg/m 2 /day in cancer patients, reduced ventral prostate, seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also observed. However, sperm count, mating success, and testosterone levels were not affected. The significance of these animal findings in humans is not known.

The effectiveness of MARINOL has been established based on studies for the treatment of anorexia associated with weight loss in patients with AIDS and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. The appetite stimulant effect of MARINOL in the treatment of AIDS-related anorexia associated with weight loss was studied in a randomized, double-blind, placebo-controlled study involving 139 patients. The initial dosage of MARINOL in all patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before dinner. In pilot studies, early morning administration of MARINOL appeared to have been associated with an increased frequency of adverse experiences, as compared to dosing later in the day. The effect of MARINOL on appetite, weight, mood, and nausea was measured at scheduled intervals during the six-week treatment period. Side effects (feeling high, dizziness, confusion, somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was reduced to 2.5 mg/day, administered as a single dose at supper or bedtime. Of the 112 patients that completed at least 2 visits in the randomized, double-blind, placebo-controlled study, 99 patients had appetite data at 4-weeks (50 received MARINOL and 49 received placebo) and 91 patients had appetite data at 6-weeks (46 received MARINOL and 45 received placebo). A statistically significant difference between MARINOL and placebo was seen in appetite as measured by the visual analog scale at weeks 4 and 6 (see figure). Trends toward improved body weight and mood, and decreases in nausea were also seen. After completing the 6-week study, patients were allowed to continue treatment with MARINOL in an open-label study, in which there was a sustained improvement in appetite. marinol-fig1.jpg

PRINCIPAL DISPLAY PANEL- BOTTLE OF 60 CAPSULES NDC 53097-571-60 MARINOL ® (dronabinol Capsules, USP) 2.5 mg Rx Only  60 Capsules ThePharmaNetwork, LLC PRINCIPAL DISPLAY PANEL- CARTON  OF 60 CAPSULES  NDC 53097-571-60 MARINOL(dronabinol Capsules, USP) 2.5 mg PRESCRIPTION REPACK UNIT-OF-USE Rx Only  60 Capsules ThePharmaNetwork, LLC PRINCIPAL DISPLAY PANEL- BOTTLE OF 60 CAPSULES NDC 53097-572-60 MARINOL®(dronabinol Capsules, USP) 5 mg Rx Only  60 Capsules ThePharmaNetwork, LLC PRINCIPAL DISPLAY PANEL- CARTON  OF 60 CAPSULES  NDC 53097-572-60 MARINOL(dronabinol Capsules, USP) 5 mg PRESCRIPTION REPACK UNIT-OF-USE Rx Only  60 Capsules ThePharmaNetwork, LLC PRINCIPAL DISPLAY PANEL- BOTTLE OF 60 CAPSULES NDC 53097-573-60 MARINOL®(dronabinol Capsules, USP) 10 mg Rx Only  60 Capsules ThePharmaNetwork, LLC PRINCIPAL DISPLAY PANEL- CARTON  OF 60 CAPSULES  NDC 53097-573-60 MARINOL(dronabinol Capsules, USP) 10 mg PRESCRIPTION REPACK UNIT-OF-USE Rx Only  60 Capsules ThePharmaNetwork, LLC marinol-cont-25.jpg marinol-car-25.jpg marinol-cont-5.jpg marinol-car-5.jpg marinol-cont-10.jpg marinol-car-10.jpg