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`500012 Rev Sep 2004
`MARINOL®
`(Dronabinol)
`Capsules
`DESCRIPTION
`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 empirical and structural
`formulas:
` Dronabinol, the active ingredient in MARINOL® 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: MARINOL® Capsules 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: FD&C Blue No. 1 (5 mg), FD&C Red No. 40 (5 mg), FD&C
`Yellow No. 6 (5 mg and 10 mg), gelatin, glycerin, methylparaben, propylparaben, sesame oil, and
`titanium dioxide.
`CLINICAL PHARMACOLOGY
`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.
`Pharmacodynamics
`Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection.
`Its effects on blood pressure are inconsistent, but occasional subjects have experienced orthostatic
`hypotension and/or syncope upon abrupt standing.
`This label may not be the latest approved by FDA.
`For current labeling information, please
`visit https://www.fda.gov/drugsatfda
`HELSINN EXHIBIT 2042
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
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` 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 interpatient 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 and other
`cannabinoids with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the
`pharmacodynamics of chronic dronabinol exposure, healthy male volunteers (N = 12) received 210
`mg/day dronabinol, 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 volunteers
`developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12
`days of treatment initiation.
`
` Tachyphylaxis and tolerance do not, however, appear to develop to the appetite stimulant effect of
`MARINOL® Capsules. In studies involving patients with Acquired Immune Deficiency Syndrome
`(AIDS), the appetite stimulant effect of MARINOL® Capsules has been sustained for up to five
`months in clinical trials, at dosages ranging from 2.5 mg/day to 20 mg/day.
`
`Pharmacokinetics
`Absorption and Distribution: MARINOL® (Dronabinol) Capsules 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. Dronabinol
`has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The
`plasma protein binding of dronabinol and its metabolites is approximately 97%.
`
` The elimination phase 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. Because of its
`large volume of distribution, dronabinol and its metabolites may be excreted at low levels for
`prolonged periods of time.
`
`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; BID) have been studied in healthy women and men.
`
`Summary of Multiple-Dose Pharmacokinetic Parameters of Dronabinol
`in Healthy Volunteers (n=34; 20-45 years) under Fasted Conditions
`
`Mean (SD) PK Parameter Values
`BID
`Dose
`Cmax
` ng/mL
`Median Tmax
`(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)
`
`This label may not be the latest approved by FDA.
`For current labeling information, please
`visit https://www.fda.gov/drugsatfda
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`A slight increase in dose proportionality on mean Cmax and AUC (0-12) of dronabinol was
`observed with increasing dose over the dose range studied.
`
`
`
`Metabolism: Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by microsomal
`hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active
`metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma.
`Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral
`dosing and decline over several days. Values for clearance average about 0.2 L/kg-hr, but are highly
`variable due to the complexity of cannabinoid distribution.
`
`Elimination: 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.
`
` 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® 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.
`
`Special Populations: The pharmacokinetic profile of MARINOL® Capsules has not been investigated
`in either pediatric or geriatric patients.
`
`Clinical Trials
`Appetite Stimulation: The appetite stimulant effect of MARINOL® (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 MARINOL® 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 MARINOL® Capsules appeared to have been
`associated with an increased frequency of adverse experiences, as compared to dosing later in the day.
`The effect of MARINOL® 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.
`
` As compared to placebo, MARINOL® Capsules treatment resulted in a statistically significant
`improvement in appetite as measured by visual analog scale (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®
`Capsules in an open-label study, in which there was a sustained improvement in appetite.
`
`This label may not be the latest approved by FDA.
`For current labeling information, please
`visit https://www.fda.gov/drugsatfda
`Page 3 of 12
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`Antiemetic: MARINOL® (Dronabinol) Capsules 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 MARINOL® Capsules was greatest in patients receiving
`cytotoxic therapy with MOPP for Hodgkin’s and non-Hodgkin’s lymphomas. MARINOL® 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 MARINOL® Capsules
`dose above 7 mg/m
`2 increased the frequency of adverse experiences, with no additional antiemetic
`benefit.
`
`MARINOL® Capsules Dose: Response Frequency and Adverse Experiences*
`(N = 750 treatment courses)
`Response Frequency (%) Adverse Events Frequency (%) MARINOL® Capsules
`Dose
`Complete Partial Poor None Nondysphoric Dysphoric
`<7 mg/m2 36 32 32 23 65 12
`>7 mg/m2 33 31 36 13 58 28
` *Nondysphoric events consisted of drowsiness, tachycardia, etc.
`
` Combination antiemetic therapy with MARINOL® 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 MARINOL® (Dronabinol) Capsules are dose-related and subject to
`considerable interpatient variability. Therefore, dosage individualization is critical in achieving the
`maximum benefit of MARINOL® Capsules treatment.
`
`Appetite Stimulation: In the clinical trials, the majority of patients were treated with 5 mg/day
`MARINOL® 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.
`
`This label may not be the latest approved by FDA.
`For current labeling information, please
`visit https://www.fda.gov/drugsatfda
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`2. If CNS symptoms are severe or persistent, reduc e 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 fu rther 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 MARINOL® 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 MARINOL®
`Capsules with phenothiazines, such as prochlorperazine, has resulted in improved efficacy as
`compared to either drug alone, without additional toxicity.
`
`Pediatrics: MARINOL® Capsules is 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
`MARINOL® Capsules for children because of the psychoactive effects.
`
`Geriatrics: Caution is advised in prescribing MARINOL® Capsules in elderly patients because they
`are generally more sensitive to the psychoactive effects of drugs. In antiemetic studies, no difference
`in tolerance or efficacy was apparent in patients >55 years old.
`
`INDICATIONS AND USAGE
`MARINOL® (Dronabinol) Capsules 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.
`
`CONTRAINDICATIONS
`MARINOL® (Dronabinol) Capsules is contraindicated in any patient who has a history of
`hypersensitivity to any cannabinoid or sesame oil.
`
`WARNINGS
`Patients receiving treatment with MARINOL® 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.
`
`PRECAUTIONS
`General: The risk/benefit ratio of MARINOL® (Dronabinol) Capsules 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® Capsules.
`
`This label may not be the latest approved by FDA.
`For current labeling information, please
`visit https://www.fda.gov/drugsatfda
`Page 5 of 12
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` MARINOL® Capsules should be used with caution in patients with cardiac disorders because of
`occasional hypotension, possible hypertension, syncope, or tachycardia (see CLINICAL
`PHARMACOLOGY).
`
` MARINOL® Capsules 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®
`Capsules as well. Multiple substance abuse is common and marijuana, which contains the same active
`compound, is a frequently abused substance.
`
` MARINOL® Capsules should be used with caution and careful psychiatric monitoring in patients
`with mania, depression, or schizophrenia because MARINOL® Capsules may exacerbate these
`illnesses.
`
` MARINOL® Capsules 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® Capsules should be used with cauti on in pregnant patients, nursing mothers, or
`pediatric patients because it has not been studied in these patient populations.
`
`Information for Patients: Patients receiving treatment with MARINOL® (Dronabinol) Capsules
`should be alerted to the potential for additive central nervous system depression if MARINOL®
`Capsules is used concomitantly with alcohol or other CNS depressants such as benzodiazepines and
`barbiturates.
`
` Patients receiving treatment with MARINOL® 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.
`
` Patients using MARINOL® Capsules should be advised of possibl e 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® Capsules
`and following dosage adjustments.
`
`Drug Interactions: In studies involving patients with AIDS and/or cancer, MARINOL®
`(Dronabinol) Capsules 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® Capsules, 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.
`
`
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please
`visit https://www.fda.gov/drugsatfda
`Page 6 of 12
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`CONCOMITANT DRUG CLINICAL EFFECT(S)
`Amphetamines, cocaine, other
`sympathomimetic agents
`Additive hypertension, tachycardia,
`possibly cardiotoxicity
`Atropine, scopolamine, antihistamines,
`other anticholinergic agents
`Additive or super-additive tachycardia,
`drowsiness
`Amitriptyline, amoxapine, desipramine,
`other tricyclic antidepressants
`Additive tachycardia, hypertension,
`drowsiness
`Barbiturates, benzodiazepines, ethanol,
`lithium, opioids, buspirone, antihistamines,
`muscle relaxants, other CNS depressants
`Additive drowsiness and CNS depression
`Disulfiram A reversible hypomanic reaction was
`reported in a 28 y/o man who smoked
`marijuana; confirmed by dechallenge and
`rechallenge
`Fluoxetine A 21 y/o female with depression and
`bulimia receiving 20 mg/day fluoxetine X
`4 wks became hypomanic after smoking
`marijuana; symptoms resolved after 4 days
`Antipyrine, barbiturates Decreased clearance of these agents,
`presumably via competitive inhibition of
`metabolism
`Theophylline Increased theophylline metabolism
`reported with smoking of marijuana; effect
`similar to that following smoking tobacco
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies in mice and rats
`have been conducted under the US National Toxicology Program (NTP). In the 2-year carcinogenicity
`study in rats, there was no evidence of carcinogenicity at doses up to 50 mg/kg/day, about 20 times the
`maximum recommended human dose on a body surface area basis. In the 2-year carcinogenicity study
`in mice, treatment with dronabinol at 125 mg/kg/day, about 25 times the maximum recommended
`human dose on a body surface area basis, produced thyroid follicular cell adenoma in both male and
`female mice but not at 250 or 500 mg/kg/day.
`
` Dronabinol was not genotoxi c in the Ames tests, the in vitro chromosomal aberration test in
`Chinese hamster ovary cells, and the in vivo mouse micronucleus test. It, however, 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 dronabino l at doses of 30 to 150
`mg/m
`2, 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 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.
`
`Pregnancy: Pregnancy Category C. Reproduction studies with dronabinol have been performed in
`mice at 15 to 450 mg/m
`2, equivalent to 0.2 to 5 times maximum recommended human dose (MRHD)
`This label may not be the latest approved by FDA.
`For current labeling information, please
`visit https://www.fda.gov/drugsatfda
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`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 pups 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® Capsules 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.
`
`Geriatric Use: Clinical studies of MARINOL® (Dronabinol) Capsules 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. Other reported clinical experience has not identified differences in
`responses between the elderly and 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 decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects and of
`concomitant disease or other drug therapy.
`
`ADVERSE REACTIONS
`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) 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 MARINOL® 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 MARINOL®
`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).
`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*.
`This label may not be the latest approved by FDA.
`For current labeling information, please
`visit https://www.fda.gov/drugsatfda
`Page 8 of 12
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` *Incidence of events 3% to 10%
`
`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).
`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%.
`The clinical significance of the association of these events with MARINOL® Capsules treatment is
`unknown, but they are reported as alerting information for the clinician.
`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) Capsules 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® Capsules for therapeutic purposes.
`
` In an open-label study in patients with AIDS who received MARINOL® 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.
`This label may not be the latest approved by FDA.
`For current labeling information, please
`visit https://www.fda.gov/drugsatfda
`Page 9 of 12
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`OVERDOSAGE
`Signs and symptoms following MILD MARINOL® (Dronabinol) Capsules 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
`MARINOL® 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.
`
`DOSAGE AND ADMINISTRATION
`Appetite Stimulation: Initially, 2.5 mg MARINOL® (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 MARINOL® 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 MARINOL® Capsules,
`administered in divided oral doses. Caution should be exercised in escalating the dosage of
`MARINOL® Capsules because of the increased frequency of dose-related adverse experiences at
`higher dosages (see PRECAUTIONS).
`
`Antiemetic: MARINOL® Capsules is best administered at an initial dose of 5 mg/m
`2, 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).
`
`STORAGE CONDITIONS
`MARINOL® (Dronabinol) 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.
`
`HOW SUPPLIED
`MARINOL® Capsules (dronabinol solution in sesame oil in soft gelatin capsules)
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`2.5 mg white capsules (Identified UM or RL).
`This label may not be the latest approved by FDA.
`For current labeling information, please
`visit https://www.fda.gov/drugsatfda
`Page 10 of 12
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`NDA 18-651/S-021
`Page 13
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`NDC 0051-0021-21 (Bottle of 60 capsules).
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`5 mg dark brown capsules (Identified UM or RL).
`NDC 0051-0022-11 (Bottle of 25 capsules).
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`10 mg orange capsules (Identified UM or RL).
`NDC 0051-0023-21 (Bottle of 60 capsules).
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`MARINOL® is a registered trademark of Unimed Pharmaceuticals, Inc. and is
`Manufactured by Banner Pharmacaps, Inc.
`High Point, NC 27265
`
`500012 Rev Sep 2004
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`© 2004 Solvay Pharmaceuticals, Inc.
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`A Solvay Pharmaceuticals, Inc. Company
`Marietta, GA 30062
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`This label may not be the latest approved by FDA.
`For current labeling information, please
`visit https://www.fda.gov/drugsatfda
`Page 11 of 12
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`NDA 18-651/S-021
`Page 14
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`This label may not be the latest approved by FDA.
`For current labeling information, please
`visit https://www.fda.gov/drugsatfda
`Page 12 of 12
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