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Dronabinol
Dronabinol is a cannabinoid designated chemically as (6aR-trans)-6a,7,8,10a-tetrahydro- C21H30O2 (molecular weight =
314.47) Dronabinol is also chemically synthesized and 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:
Marinol is supplied as round, soft gelatin capsules containing either
2.5 mg, 5 mg, or 10 mg dronabinol.
Each Marinol capsule
is formulated with the following inactive ingredients: sesame oil,
gelatin, glycerin, methylparaben, propylparaben, FD&C Yellow
No. 6 (5 mg and 10 mg), and
titanium dioxide.
Marinol (dronabinol) is 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.
Appetite stimulation: Initially, 2.5 mg Marinol (dronabinol) should be administered orally twice daily (b.i.d.), before lunch and supper. For patients unable to tolerate this 5 mg/day dosage of Marinol, 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 Marinol, administered in divided oral doses. Caution should be exercised in escalating the dosage of Marinol because of the increased frequency of dose-related adverse experiences at higher dosages (see PRECAUTIONS). Antiemetic: Marinol is 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). HOW SUPPLIED MARINOL® CAPSULES (dronabinol solution
in sesame oil in soft gelatin
capsules) 5 mg dark brown capsules
(Identified RL). 10 mg orange capsules
(Identified RL). MARINOL® is a registered trademark of Unimed Pharmaceuticals,
Inc. and is marketed by DEA ORDER FORM REQUIRED Caution: Federal law
prohibits dispensing without prescription.
Adverse experiences information summarized in the tables below was derived from well-controlled clinical trials conducted in the US and US territories involving 474 patients exposed to Marinol (dronabinol). 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 Marinol 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 Marinol. 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%. Body as a whole: Asthenia.
Cardiovascular: Palpitations, tachycardia, vasodilation/facial flush. Digestive: Abdominal pain*, nausea*, vomiting*. Nervous system: (Amnesia), anxiety/nervousness, (ataxia), confusion, depersonalization, dizziness*, euphoria*, (hallucination), paranoid reaction*, somnolence*, thinking abnormal*. *Incidence of events 3% to 10%
PROBABLY CAUSALLY RELATED: Incidence less than 1%. Cardiovascular: Conjunctivitis*, hypotension*.
Digestive: Diarrhea*, fecal incontinence. Musculoskeletal: Myalgias. Nervous System: Depression, nightmares, speech difficulties, tinnitus. Skin and Appendages: Flushing*. Special Senses: Vision difficulties. *Incidence of events 0.3% to 1%.
CAUSAL RELATIONSHIP UNKNOWN: Incidence less than 1%. Body as a whole: Chills, headache, malaise.
Digestive: Anorexia, hepatic enzyme elevation. Respiratory: Cough, rhinitis, sinusitis. Skin and Appendages: Sweating. DRUG ABUSE AND DEPENDENCE
Marinol (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, judgement, 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 Marinol for therapeutic purposes. 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. 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.
In studies involving patients with AIDS and/or cancer, Marinol (dronabinol) has been co-administered with a variety of medications (e.g., cytotoxic agents, anti-infective agents, sedatives, or opioid analgesics) without resulting in any clinically significant drug/drug interactions. Although no drug/drug interactions were discovered during the clinical trials of Marinol, cannabinoids may interact with other medications through both metabolic and pharmacodynamic mechanisms. Dronabinol is highly protein bound to plasma proteins, and therefore, might displace other protein-bound drugs. Although this displacement has not been confirmed in vivo, practitioners should monitor patients for a change in dosage requirements when administering dronabinol to patients receiving other highly protein-bound drugs. Published reports of drug/drug interactions involving cannabinoids are summarized in the following table.
Marinol (dronabinol) is a medication with a potential for abuse. Physicians and pharmacists should use the same care in prescribing and accounting for Marinol as they would with other drugs controlled under Schedule III (CIII) of the Controlled Substances Act. Because of the risk of diversion, it is recommended that prescriptions be limited to the amount necessary for the period between clinic visits. Patients receiving treatment with Marinol 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.
General The risk/benefit ratio of Marinol (dronabinol) use should be carefully evaluated in patients with the following medical conditions because of individual variation in response and tolerance to the effects of Marinol. Marinol should be used with caution in patients with cardiac disorders because of occasional hypotension, possible hypertension, syncope, or tachycardia (see CLINICAL PHARMACOLOGY). Marinol should be used with caution in patients with a history of substance abuse, including alcohol abuse or dependence, because they may be more prone to abuse Marinol as well. Multiple substance abuse is common and marijuana, which contains the same active compound, is a frequently abused substance. Marinol should be used with caution and careful psychiatric monitoring in patients with mania, depression, or schizophrenia because Marinol may exacerbate these illnesses. Marinol should be used with caution in patients receiving concomitant therapy with sedatives, hypnotics or other psychoactive drugs because of the potential for additive or synergistic CNS effects. Marinol should be used with caution in pregnant patients, nursing mothers, or pediatric patients because it has not been studied in these patient populations. Marinol should be used with caution for treatment of anorexia and weight loss in elderly patients with AIDS because they may be more sensitive to the psychoactive effects and because its use in these patients has not been studied. Information for Patients Patients receiving treatment with Marinol (dronabinol) should be alerted to the potential for additive central nervous system depression if Marinol is used concomitantly with alcohol or other CNS depressants such as benzodiazepines and barbiturates. Patients receiving treatment with Marinol 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. Patients using Marinol should be advised of possible changes in mood and other adverse behavioral effects of the drug so as to avoid panic in the event of such manifestations. Patients should remain under the supervision of a responsible adult during initial use of Marinol and following dosage adjustments. Drug Interactions See DRUG INTERACTIONS section. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with dronabinol. Mutagenicity testing of dronabinol was negative in an Ames test. In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/m², equivalent to 0.3 to 1.5 times maximum recommended human dose (MRHD) of 90 mg/m²/day in cancer patients or 2 to 10 times MRHD of 15 mg/m²/day in AIDS patients, reduced ventral prostate, seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases is 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. Pregnancy Pregnancy Category C. Reproduction studies with dronabinol have been performed in mice at 15 to 450 mg/m², equivalent to 0.2 to 5 times maximum recommended human dose (MRHD) of 90 mg/m²/day in cancer patients or 1 to 30 times MRHD of 15 mg/m²/day in AIDS patients, and in rats at 74 to 295 mg/m² (equivalent to 0.8 to 3 times MRHD of 90 mg/m² in cancer patients or 5 to 20 times MRHD of 15 mg/m²/day in AIDS patients). These studies have revealed no evidence of teratogenicity due to dronabinol. At these dosages in mice and rats, dronabinol decreased maternal weight gain and number of viable pigs and increased fetal mortality and early resorptions. Such effects were dose dependent and less apparent at lower doses which produced less maternal toxicity. There are no adequate and well-controlled studies in pregnant women. Dronabinol should be used only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Use of Marinol is not recommended in nursing mothers since, in
addition to the secretion
of HIV virus
in breast milk, dronabinol
is concentrated in and secreted in human
breast milk
and is absorbed by the nursing
baby.
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