Marinol

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/m², 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/m² 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/m².

The maximum dosage is 15 mg/m² 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.

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. 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.

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 (5.3)]
• Paradoxical Nausea, Vomiting, and Abdominal Pain [see Warnings and Precautions (5.5)]

Studies of AIDS-related weight loss included 157 patients receiving MARINOL at a dose of 2.5 mg twice daily and 67 receiving placebo. Studies of nausea and vomiting related to cancer chemotherapy included 317 patients receiving MARINOL and 68 receiving placebo. In the tables below is a summary of the adverse reactions in 474 patients exposed to MARINOL in studies.

Studies of different durations were combined by considering the first occurrence of events during the first 28 days.

A cannabinoid dose-related “high” (easy laughing, elation and heightened awareness) has been reported by patients receiving MARINOL 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 MARINOL. 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 at an incidence greater than 1%.

Less Common Adverse Reactions

The following adverse reactions were reported in clinical trials at an incidence less than or equal to 1%.

The following adverse reactions have been identified during post-approval use of dronabinol capsules. 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 (5.3)], disorientation, movement disorder, loss of consciousness

Psychiatric disorders: Delirium, insomnia, panic attack

Vascular disorders: Syncope [see Warnings and Precautions (5.2)]

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.

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.

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. Because of the possible adverse effects from MARINOL on the breastfeeding infant, advise women with nausea and vomiting associated with cancer chemotherapy not to breastfeed during treatment with MARINOL and for 9 days after the last dose.

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 contains dronabinol capsules, a Schedule III controlled substance.

MARINOL 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.

In an open-label study in patients with AIDS who received MARINOL for up to five months, no abuse, diversion or systematic change in personality or social functioning were observed despite the inclusion of a substantial number of patients with a past history of drug abuse.

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

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. The appearance of a withdrawal syndrome when administration of the drug is terminated is the only actual evidence of physical dependence. Physical dependence can develop during chronic therapy with MARINOL, and develops after chronic abuse of marijuana.

A withdrawal syndrome was reported after the abrupt discontinuation of dronabinol in subjects receiving dosages of 210 mg per day for 12 to 16 consecutive days. Within 12 hours after discontinuation, subjects manifested symptoms such as irritability, insomnia, and restlessness. By approximately 24 hours post-dronabinol discontinuation, withdrawal symptoms intensified to include “hot flashes,” sweating, rhinorrhea, loose stools, hiccoughs, and anorexia. These withdrawal symptoms gradually dissipated over the next 48 hours.

Electroencephalographic changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after abrupt dechallenge. Patients also complained of disturbed sleep for several weeks after discontinuing therapy with high dosages of dronabinol.

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.

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 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/m², equivalent to 2 to 10 times the MRHD of 15 mg/m²/day in AIDS patients or 0.3 to 1.5 times the MRHD of 90 mg/m²/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 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.