Jacob Bell
New Member
500012 Rev Sep 2004
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.
NDA 18-651/S-021
Page 4
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)
NDA 18-651/S-021
Page 5
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 steadystate
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, doubleblind,
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.
NDA 18-651/S-021
Page 6
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/m2 increased the frequency of adverse experiences, with no additional antiemetic
benefit.
MARINOL® Capsules Dose: Response Frequency and Adverse Experiences*
(N = 750 treatment courses)
MARINOL® Capsules Response Frequency (%) Adverse Events Frequency (%)
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.
NDA 18-651/S-021
Page 7
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 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.
NDA 18-651/S-021
Page 8
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 caution 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 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® 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.
NDA 18-651/S-021
Page 9
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 genotoxic 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 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 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/m2, equivalent to 0.2 to 5 times maximum recommended human dose (MRHD)
NDA 18-651/S-021
Page 10
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*.
NDA 18-651/S-021
Page 11
*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.
NDA 18-651/S-021
Page 12
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/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).
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)
2.5 mg white capsules (Identified UM or RL).
NDA 18-651/S-021
Page 13
NDC 0051-0021-21 (Bottle of 60 capsules).
5 mg dark brown capsules (Identified UM or RL).
NDC 0051-0022-11 (Bottle of 25 capsules).
10 mg orange capsules (Identified UM or RL).
NDC 0051-0023-21 (Bottle of 60 capsules).
MARINOL® is a registered trademark of Unimed Pharmaceuticals, Inc. and is
Manufactured by Banner Pharmacaps, Inc.
High Point, NC 27265
500012 Rev Sep 2004
© 2004 Solvay Pharmaceuticals, Inc.
A Solvay Pharmaceuticals, Inc. Company
Marietta, GA 30062
NDA 18-651/S-021
Source: Marinol
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.
NDA 18-651/S-021
Page 4
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)
NDA 18-651/S-021
Page 5
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 steadystate
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, doubleblind,
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.
NDA 18-651/S-021
Page 6
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/m2 increased the frequency of adverse experiences, with no additional antiemetic
benefit.
MARINOL® Capsules Dose: Response Frequency and Adverse Experiences*
(N = 750 treatment courses)
MARINOL® Capsules Response Frequency (%) Adverse Events Frequency (%)
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.
NDA 18-651/S-021
Page 7
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 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.
NDA 18-651/S-021
Page 8
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 caution 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 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® 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.
NDA 18-651/S-021
Page 9
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 genotoxic 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 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 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/m2, equivalent to 0.2 to 5 times maximum recommended human dose (MRHD)
NDA 18-651/S-021
Page 10
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*.
NDA 18-651/S-021
Page 11
*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.
NDA 18-651/S-021
Page 12
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/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).
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)
2.5 mg white capsules (Identified UM or RL).
NDA 18-651/S-021
Page 13
NDC 0051-0021-21 (Bottle of 60 capsules).
5 mg dark brown capsules (Identified UM or RL).
NDC 0051-0022-11 (Bottle of 25 capsules).
10 mg orange capsules (Identified UM or RL).
NDC 0051-0023-21 (Bottle of 60 capsules).
MARINOL® is a registered trademark of Unimed Pharmaceuticals, Inc. and is
Manufactured by Banner Pharmacaps, Inc.
High Point, NC 27265
500012 Rev Sep 2004
© 2004 Solvay Pharmaceuticals, Inc.
A Solvay Pharmaceuticals, Inc. Company
Marietta, GA 30062
NDA 18-651/S-021
Source: Marinol
