Dronabinol is a cannabinoid designated chemically as (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol. Dronabinol has the following molecular and structural formulas:

Dronabinol, the active ingredient in dronabinol capsules, is synthetic delta-9-tetrahydrocannabinol (delta-9-THC). Delta-9-tetrahydrocannabinol is also a naturally occurring component of Cannabis sativa L. (Marijuana).

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.

Capsules for oral administration: Dronabinol capsules are supplied as oblong, soft gelatin capsules containing 2.5 mg, 5 mg or 10 mg dronabinol. Each dronabinol capsule strength is formulated with the following inactive ingredients: FD&C Yellow No. 6, gelatin, glycerin, purified water, sesame oil, titanium dioxide, iron oxide black, shellac glaze, isopropyl alcohol, n-butyl alcohol, propylene glycol, and ammonium hydroxide.  The 2.5 mg and 5 mg also contain FD&C Blue No. 1 and FD&C Red No. 40.

Dronabinol is an orally active cannabinoid which, like other cannabinoids, has complex effects on the central nervous system (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 and other cannabinoids.

Appetite Stimulation: The appetite stimulant effect of dronabinol capsules 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 dronabinol capsules in all patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before supper. In pilot studies, early morning administration of dronabinol capsules appeared to have been associated with an increased frequency of adverse experiences, as compared to dosing later in the day. The effect of dronabinol capsules 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 dronabinol and 49 received placebo) and 91 patients had appetite data at 6-weeks (46 received dronabinol and 45 received placebo). A statistically significant difference between dronabinol capsules 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 dronabinol capsules in an open-label study, in which there was a sustained improvement in appetite.

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Antiemetic: Dronabinol treatment of chemotherapy-induced emesis was evaluated in 454 patients with cancer, who received a total of 750 courses of treatment of various malignancies. The antiemetic efficacy of dronabinol was greatest in patients receiving cytotoxic therapy with MOPP for Hodgkin’s and non-Hodgkin’s lymphomas. Dronabinol capsules dosages ranged from 2.5 mg/day to 40 mg/day, administered in equally divided doses every four to six hours (four times daily). As indicated in the following table, escalating the dronabinol dose above 7 mg/m2 increased the frequency of adverse experiences, with no additional antiemetic benefit.

    Dronabinol Dose: Response Frequency and Adverse Experiences*
                                     (N = 750 treatment courses)

Combination antiemetic therapy with dronabinol capsules and a phenothiazine (prochlorperazine) may result in synergistic or additive antiemetic effects and attenuate the toxicities associated with each of the agents.

INDIVIDUALIZATION OF DOSAGES

The pharmacologic effects of dronabinol are dose-related and subject to considerable interpatient variability. Therefore, dosage individualization is critical in achieving the maximum benefit of dronabinol treatment.

Appetite Stimulation: In the clinical trials, the majority of patients were treated with 5 mg/day dronabinol capsules, although the dosages ranged from 2.5 to 20 mg/day. For an adult:

1. Begin with 2.5 mg before lunch and 2.5 mg before supper. If CNS symptoms (feeling high, dizziness, confusion, somnolence) do occur, they usually resolve in 1 to 3 days with continued dosage.
   
   
2. If CNS symptoms are severe or persistent, reduce the dose to 2.5 mg before supper. If symptoms continue to be a problem, taking the single dose in the evening or at bedtime may reduce their severity.
   
   
3. When adverse effects are absent or minimal and further therapeutic effect is desired, increase the dose to 2.5 mg before lunch and 5 mg before supper or 5 and 5 mg. Although most patients respond to 2.5 mg twice daily, 10 mg twice daily has been tolerated in about half of the patients in appetite stimulation studies.
   
   

The pharmacologic effects of dronabinol capsules are reversible upon treatment cessation.

Antiemetic: Most patients respond to 5 mg three or four times daily. Dosage may be escalated during a chemotherapy cycle or at subsequent cycles, based upon initial results. Therapy should be initiated at the lowest recommended dosage and titrated to clinical response. Administration of dronabinol capsules with phenothiazines, such as prochlorperazine, has resulted in improved efficacy as compared to either drug alone, without additional toxicity.

Pediatrics: Dronabinol capsules are not recommended for AIDS-related anorexia in pediatric patients because it has not been studied in this population. The pediatric dosage for the treatment of chemotherapy-induced emesis is the same as in adults. Caution is recommended in prescribing dronabinol capsules for children because of the psychoactive effects.

Geriatrics: Caution is advised in prescribing dronabinol capsules in elderly patients because they may be more sensitive to the neurological, psychoactive and postural hypotensive effects of the drug. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range (See PRECAUTIONS.)

Dronabinol capsules should be used with caution when administered to elderly patients with dementia, who are at increased risk for falls as a result of their underlying disease state which may be exacerbated by the central nervous system effects of somnolence and dizziness associated with dronabinol capsules. These patients should be monitored closely and placed on fall precautions prior to initiating dronabinol therapy. In antiemetic studies, no difference in efficacy was apparent in patients >55 years old.

Dronabinol capsules are indicated for the treatment of:

1. anorexia associated with weight loss in patients with AIDS; and
   
   
2. nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.
   
   

Dronabinol capsules are contraindicated in any patient who has a known sensitivity to dronabinol or any of its ingredients. It contains cannabinoid and sesame oil and should never be used by patients allergic to these substances.

Patients receiving treatment with dronabinol capsules should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely.

Adverse experiences information summarized in the tables below was derived from well-controlled clinical trials conducted in the U.S. and U.S. territories involving 474 patients exposed to dronabinol capsules.  Studies of AIDS-related weight loss included 157 patients receiving dronabinol at a dose of 2.5 mg twice daily and 67 receiving placebo. Studies of different durations were combined by considering the first occurrence of events during the first 28 days.  Studies of nausea and vomiting related to cancer chemotherapy included 317 patients receiving dronabinol and 68 receiving placebo.

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%). (see CLINICAL TRIALS).

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 minor CNS adverse event during the first 2 weeks and about 4% reported such an event each week for the next 6 weeks thereafter.

PROBABLY CAUSALLY RELATED: Incidence greater than 1%.

Rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea (N=317). Rates were generally higher in the anti-emetic use (given in parentheses).

PROBABLY CAUSALLY RELATED: Incidence less than 1%.

Event rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea (N=317).

CAUSAL RELATIONSHIP UNKNOWN: Incidence less than 1%.

The clinical significance of the association of these events with dronabinol capsules treatment is unknown, but they are reported as alerting information for the clinician.

Postmarketing Experience

Seizure and seizure-like activity have been reported in patients receiving dronabinol capsules during marketed use of the drug and in clinical trials. (see PRECAUTIONS and OVERDOSAGE.) Reports of fatigue have also been received. A causal relationship between dronabinol capsules and these events has not been established.

Dronabinol is one of the psychoactive compounds present in cannabis, and is abusable and controlled [Schedule III (CIII)] under the Controlled Substances Act. Both psychological and physiological dependence have been noted in healthy individuals receiving dronabinol, but addiction is uncommon and has only been seen after prolonged high dose administration.

Chronic abuse of cannabis has been associated with decrements in motivation, cognition, judgment, and perception. The etiology of these impairments is unknown, but may be associated with the complex process of addiction rather than an isolated effect of the drug. No such decrements in psychological, social or neurological status have been associated with the administration of dronabinol capsules for therapeutic purposes.

In an open-label study in patients with AIDS who received dronabinol capsules 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.

An abstinence syndrome has been reported after the abrupt discontinuation of dronabinol in volunteers receiving dosages of 210 mg/day for 12 to 16 consecutive days. Within 12 hours after discontinuation, these volunteers 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.

Signs and symptoms following MILD dronabinol intoxication include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth and tachycardia; following MODERATE intoxication include memory impairment, depersonalization, mood alteration, urinary retention, and reduced bowel motility; and following SEVERE intoxication include decreased motor coordination, lethargy, slurred speech, and postural hypotension. Apprehensive patients may experience panic reactions and seizures may occur in patients with existing seizure disorders.

The estimated lethal human dose of intravenous dronabinol is 30 mg/kg (2100 mg/70 kg). Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol capsules.

Management: A potentially serious oral ingestion, if recent, should be managed with gut decontamination. In unconscious patients with a secure airway, instill activated charcoal (30 to 100 g in adults, 1 to 2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal. Patients experiencing depressive, hallucinatory or psychotic reactions should be placed in a quiet area and offered reassurance. Benzodiazepines (5 to 10 mg diazepam po) may be used for treatment of extreme agitation. Hypotension usually responds to Trendelenburg position and IV fluids. Pressors are rarely required.

Appetite Stimulation: Initially, 2.5 mg dronabinol capsules should be administered orally twice daily (b.i.d.), before lunch and supper. For patients unable to tolerate this 5 mg/day dosage of dronabinol capsules, the dosage can be reduced to 2.5 mg/day, administered as a single dose in the evening or at bedtime. If clinically indicated and in the absence of significant adverse effects, the dosage may be gradually increased to a maximum of 20 mg/day dronabinol capsules, administered in divided oral doses. Caution should be exercised in escalating the dosage of dronabinol capsules because of the increased frequency of dose-related adverse experiences at higher dosages. (see PRECAUTIONS.)

Antiemetic: Dronabinol Capsules are best administered at an initial dose of 5 mg/m2, given 1 to 3 hours prior to the administration of chemotherapy, then every 2 to 4 hours after chemotherapy is given, for a total of 4 to 6 doses/day. Should the 5 mg/m2 dose prove to be ineffective, and in the absence of significant side effects, the dose may be escalated by 2.5 mg/m2 increments to a maximum of 15 mg/m2 per dose. Caution should be exercised in dose escalation, however, as the incidence of disturbing psychiatric symptoms increases significantly at maximum dose (see PRECAUTIONS).

Dronabinol Capsules (dronabinol solution in sesame oil in soft gelatin capsules)

5 mg - opaque brown, oblong softgel capsules printed “PAR 868” in black ink.

NDC 54868-5929-0   Bottle of 60 capsules




Manufactured by:
Pharmaceutics International, Inc.
Hunt Valley, MD 21031

Manufactured for:
Par Pharmaceutical Companies, Inc.
Spring Valley, NY  10977

Revised: 11/2011

OS867-15-17-02

302850-0B

Additional barcode labeling by:
Physicians Total Care, Inc.
Tulsa, Oklahoma       74146

Bottle of 60 Capsules                                   NDC 54868-5929-0

CIII                                                                  Rx Only