Dronabinol

Name: Dronabinol

Warnings

Contraindications

Hypersensitivity to dronabinol

Capsule: Hypersensitivity to sesame seed oil

Oral solution

  • History of hypersensitivity reaction to alcohol
  • Patients who are receiving, or have received, disulfiram- or metronidazole-containing products within the past 14 days
  • Contains 50% (w/w) dehydrated alcohol and 5.5% (w/w) propylene glycol

Cautions

Neurologic effects

  • May cause psychiatric and cognitive effects and impair mental and/or physical abilities
  • Monitor patients with mania, depression, or schizophrenia; dronabinol may exacerbate these illnesses
  • Avoid in patients with a psychiatric history
  • Monitor for symptoms and avoid concomitant use of drugs with similar effects; reduce the dose or discontinue use if signs or symptoms of cognitive impairment develop
  • Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that dronabinol does not affect them adversely

Hemodynamic instability

  • Patients with cardiac disorders may experience hypotension, hypertension, syncope, or tachycardia
  • Avoid concomitant use of drugs with similar effects and monitor for hemodynamic changes; monitor patients for changes in blood pressure, heart rate, and syncope after initiating or increasing the dosage
  • Caution when initiating or increasing the dosage
  • Caution in elderly patients; may be more sensitive to neurological, psychoactive, and postural hypotensive effects of drug

Seizures

  • Seizures and seizurelike activity reported
  • Weigh potential risk before prescribing to patients with a history of seizures, including those with factors that can lower seizure threshold
  • If a seizure occurs, discontinue dronabinol immediately

Multiple substance abuse

  • Patients with a history of substance abuse or dependence, including marijuana or alcohol, may be more likely to abuse dronabinol
  • Assess risk for abuse or misuse before prescribing

Paradoxical nausea, vomiting, or abdominal pain

  • New or worsening nausea, vomiting, or abdominal pain can occur during treatment with synthetic delta-9 tetrahydrocannabinol (delta-9-THC), the active ingredient in dronabinol
  • In some cases, these adverse reactions were severe (eg, dehydration, electrolyte abnormalities) and required dose reduction or drug discontinuation
  • Symptoms are similar to cannabinoid hyperemesis syndrome (CHS), which is described as cyclical events of abdominal pain, nausea, and vomiting in chronic, long-term users of delta-9-THC products
  • Patients may not recognize these symptoms as abnormal; specifically monitor for development of worsening nausea, vomiting, or abdominal pain

Toxicities related to propylene glycol in preterm neonates

  • Contains the excipients dehydrated alcohol (50%, w/w) and propylene glycol (5.5%, w/w)
  • When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations of propylene glycol
  • Preterm neonates may be at increased risk of propylene glycol-associated adverse reactions due to a diminished ability to metabolize propylene glycol, thereby, leading to accumulation
  • The safety and effectiveness of dronabinol have not been established in pediatric patients

Drug interaction overview

  • Coadministration with disulfiram or metronidazole may cause a disulfiramlike reactions (eg, abdominal cramps, nausea, vomiting, headaches, and flushing); discontinue disulfiram or metronidazole at least 14 days before initiating dronabinol and do not administer these products within 7 days of completing treatment with dronabinol
  • Inhibitors and inducers of CYP2C9 and CYP3A4: May alter dronabinol systemic exposure; monitor for dronabinol-related adverse reactions or loss of efficacy
  • Highly protein-bound drugs: Potential for displacement of other drugs from plasma proteins; monitor for adverse reactions to concomitant narrow therapeutic index drugs (eg, warfarin, cyclosporine, or amphotericin B) when initiating dronabinol or increasing the dosage
  • Caution in patients receiving concomitant therapy with sedatives, hypnotics or other psychoactive drugs because of potential for additive or synergistic CNS effects

Caution in pregnant patients, nursing mothers, or pediatric patients; not studied

Administration

Oral Administration

Oral solution

  • Always use the enclosed calibrated oral dosing syringe when administering to ensure the dose is measured and administered accurately
  • The calibrated oral syringe measures a maximum dronabinol dose of 5 mg; if the prescribed dose exceeds 5 mg, the total dose will need to be divided and drawn up in 2 or more portions using the oral syringe
  • Take each dose with a full glass of water (6-8 oz)
  • Meals
    • CINV: Take first dose on an empty stomach at least 30 minutes before eating; subsequent doses can be taken without regard to meals
    • Anorexia: Take BID 1 hr before lunch and dinner

Storage

Oral capsules

  • Store in well-closed container in a cool environment at 8-15°C (46-59°F); alternatively could be stored in a refrigerator
  • Protect from freezing

Oral solution

  • Store refrigerated at 2-8°C (36-46°F); excursions permitted to 15-25°C (59-77°F)
  • The opened bottle can be stored at 25°C (77°F)
  • Discard unused portion 28 days after first opening

Marinol Side Effects

What Are the Most Common and Serious Side Effects of Marinol?

Common side effects of Marinol include:

  • Weakness
  • Sudden feeling of warmth
  • Stomach pain
  • Nausea or vomiting
  • Memory loss
  • Anxiety
  • Confusion
  • Dizziness
  • Lack of balance
  • Feeling like you are outside your body
  • ''High'' or elevated mood
  • Hallucinations (seeing things or hearing voices that do not exist)
  • Sleepiness
  • Strange or unusual thoughts

Serious side effects can also occur. If you have any of these side effects, stop taking dronabinol and call your doctor right away:

  • Seizures
  • Fast or pounding heartbeat

Because dronabinol may be habit-forming, stopping it abruptly may cause withdrawal symptoms, such as:

  • Irritability
  • Trouble sleeping
  • Restlessness
  • Hot flashes
  • Sweating
  • Runny nose
  • Diarrhea
  • Hiccups
  • Loss of appetite

Uses of Dronabinol

Dronabinol is a prescription medication used to treat nausea and vomiting caused by chemotherapy in people who have already taken other medications to treat this type of nausea and vomiting without good results. Dronabinol is also used to treat loss of appetite and weight loss in people who have acquired immunodeficiency syndrome (AIDS).

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

 

Dronabinol side effects

Get emergency medical help if you have signs of an allergic reaction: hives, skin rash or burning; mouth sores; warmth, redness, or tingly feeling; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • a seizure;

  • fast or pounding heartbeats;

  • a light-headed feeling, like you might pass out;

  • confusion, trouble sleeping, problems with memory or concentration;

  • unusual changes in mood or behavior;

  • restlessness, feeling nervous or irritable;

  • slurred speech, drowsiness;

  • severe or ongoing nausea, vomiting, or stomach pain; or

  • increased blood pressure--severe headache, blurred vision, pounding in your neck or ears, anxiety, nosebleed.

Common side effects may include:

  • feeling "high";

  • dizziness, drowsiness, thinking problems;

  • unusual thoughts or fears;

  • feelings of extreme happiness; or

  • nausea, vomiting, stomach pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Interactions for Dronabinol

Dronabinol is a synthetic version of a naturally occurring component of Cannabis sativa L (marijuana); interactions reported with marijuana also may occur with dronabinol.1

Protein-bound Drugs

Potential for displacement of other protein-bound drugs.1 Monitor patients and adjust dosages as necessary.1

Specific Drugs

Drug

Interaction

Comments

Alcohol

Possible additive drowsiness and CNS depression1 23

Anticholinergic agents (e.g., antihistamines, atropine, scopolamine)

Possible additive or super-additive anticholinergic effects 1

Antidepressants, tricyclic (e.g., amitriptyline, amoxapine, desipramine)

Possible additive tachycardia, hypertension, or drowsiness1

Antipyrine

Possible decreased antipyrine clearance1 23

CNS depressants (e.g., antihistamines, barbiturates, benzodiazepines, buspirone, hypnotics, lithium, muscle relaxants, opiates, sedatives)

Possible additive drowsiness and CNS depression1

Possible decreased barbiturate clearance 1 23

Administer with caution1

Disulfiram

Reversible hypomanic reaction reported in a disulfiram-treated patient who smoked marijuana 1

Fluoxetine

Hypomanic reaction reported in a fluoxetine-treated patient after smoking marijuana1

HIV protease inhibitors (e.g., nelfinavir, ritonavir)

Increased plasma dronabinol concentrations predicted with concomitant use of ritonavir25

No effect observed on plasma concentrations of HIV protease inhibitors with smoked (marijuana) or oral cannabinoids (dronabinol)2

Reduction in dronabinol dosage may be necessary if used concomitantly with ritonavir; caution advised25

Naltrexone

Enhanced effects of oral delta-9-tetrahydrocannabinol observed during opiate receptor blockade18 24

Sympathomimetic agents (e.g., amphetamines, cocaine)

Possible additive hypertension, tachycardia, and cardiotoxicity1

Theophylline

Increased theophylline metabolism reported with marijuana smoking, similar to that reported following tobacco smoking1

Stability

Storage

Oral

Capsules

8–15ºC in tight container; may refrigerate, but protect from freezing.1

Actions

  • Exerts complex effects on CNS, including central sympathomimetic activity.1 8 17 18 20

  • Sympathomimetic activity may result in tachycardia and/or conjunctival injection.1 2 Effects on BP are inconsistent; orthostatic hypotension and/or syncope upon abrupt standing occasionally occurs.1

  • Exerts reversible effects on appetite, mood, cognition, memory, and perception; these effects appear to be dose related and exhibit considerable interpatient variability.1 Antiemetic and appetite stimulant effects may be caused in part by interaction with the cannabinoid receptor system including the cannabinoid 1 (CB1) receptors in the central and peripheral nervous system.1 8 17

  • Like other cannabinoids, may possess analgesic, antispasmodic, and muscle relaxant activity; however, further evaluation is necessary.3 20 21

Uses For dronabinol

Dronabinol is used to prevent or treat nausea and vomiting that may occur after treatment with cancer medicines. It is used only when other kinds of medicine for nausea and vomiting did not work. dronabinol is also used to increase appetite in patients with acquired immunodeficiency syndrome (AIDS).

dronabinol is available only with your doctor's prescription.

Dronabinol - 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.

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 Dronabinol capsules. In studies involving patients with Acquired Immune Deficiency Syndrome (AIDS), the appetite stimulant effect of Dronabinol 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: Dronabinol capsules are 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)

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 Dronabinol 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 Dronabinol capsules has not been investigated in either pediatric or geriatric patients.

Clinical Trials

Appetite Stimulation: The appetite stimulant effect of Dronabinol capsules in the treatment of AIDS-related anorexia associated with weight loss was studied in a randomized, double-blind, placebo-controlled study involving 139 patients. The initial dosage of Dronabinol capsules in all patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before supper. In pilot studies, early morning administration of Dronabinol capsules appeared to have been associated with an increased frequency of adverse experiences, as compared to dosing later in the day. The effect of Dronabinol capsules on appetite, weight, mood, and nausea was measured at scheduled intervals during the six-week treatment period. Side effects (feeling high, dizziness, confusion, somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was reduced to 2.5 mg/day, administered as a single dose at supper or bedtime.

Of the 112 patients that completed at least 2 visits in the randomized, double-blind, placebo-controlled study, 99 patients had appetite data at 4-weeks (50 received Dronabinol capsules and 49 received placebo) and 91 patients had appetite data at 6-weeks (46 received Dronabinol capsules and 45 received placebo). A statistically significant difference between Dronabinol capsules and placebo was seen in appetite as measured by the visual analog scale at weeks 4 and 6 (see figure). Trends toward improved body weight and mood, and decreases in nausea were also seen.

After completing the 6-week study, patients were allowed to continue treatment with Dronabinol capsules in an open-label study, in which there was a sustained improvement in appetite.

Antiemetic: 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 Dronabinol capsules was greatest in patients receiving cytotoxic therapy with MOPP for Hodgkin's and non-Hodgkin's lymphomas. Dronabinol capsules dosages ranged from 2.5 mg/day to 40 mg/day, administered in equally divided doses every four to six hours (four times daily). As indicated in the following table, escalating the Dronabinol capsules dose above 7 mg/m2 increased the frequency of adverse experiences, with no additional antiemetic benefit.

Dronabinol Capsules Dose: Response Frequency and Adverse Experiences* (N = 750 treatment courses)
*Nondysphoric events consisted of drowsiness, tachycardia, etc. 
Dronabinol
Capsules Dose
Response Frequency (%)  Adverse Events Frequency (%)
 Complete  Partial  Poor  None  Nondysphoric  Dysphoric
 <7 mg/m2  36  32  32  23  65  12
 >7 mg/m2  33  31  36  13  58  28

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

Warnings

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

Overdosage

Signs and symptoms following MILD 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 Dronabinol capsules.

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

Pronunciation

(droe NAB i nol)

Index Terms

  • Delta-9 THC
  • Delta-9-tetrahydro-cannabinol
  • Syndros
  • Tetrahydrocannabinol
  • THC

Pharmacology

Dronabinol (synthetic delta-9-tetrahydrocannabinol [delta-9-THC]), an active cannabinoid and natural occurring component of Cannabis sativa L. (marijuana), activates cannabinoid receptors CB1 and CB2. Activation of the CB1 receptor produces marijuana-like effects on psyche and circulation, whereas activation of the CB2 receptor does not. Dronabinol has approximately equal affinity for the CB1 and CB2 receptors; however, efficacy is less at CB2 receptors. Activation of the cannabinoid system with dronabinol causes psychological effects that can be divided into 4 groups: affective (euphoria and easy laughter); sensory (increased perception of external stimuli and of the person's own body); somatic (feeling of the body floating or sinking in the bed); and cognitive (distortion of time perception, memory lapses, difficulty in concentration). Most effects (eg, analgesia, appetite enhancement, muscle relaxation, hormonal actions) are mediated by central cannabinoid receptors (CB1), their distribution reflecting many of the medicinal benefits and adverse effects (Grotenhermen 2003).

Absorption

Oral: 90% to 95%; 10% to 20% of dose reaches systemic circulation

Distribution

Vd: ~10 L/kg; dronabinol is highly lipophilic

Metabolism

Extensive first-pass hepatic primarily via microsomal hydroxylation to metabolites, some of which are active; 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) is the major active metabolite

Excretion

Feces (50%, <5% as unchanged drug); urine (10% to 15%)

Administration

Capsules: For appetite stimulation, administer twice-daily doses before lunch and dinner; administer single doses in the evening or at bedtime.

Oral solution: Always use the provided calibrated oral dosing syringe when administering to ensure dose is measured and administered accurately. If the prescribed dose is >5 mg, the total dose will need to be divided and drawn up in 2 or more portions using the oral syringe. Administer orally directly from oral dosing syringe; immediately follow with a full glass of water (180 to 240 mL).

Appetite stimulation in AIDS patients: Administer 1 hour before lunch and 1 hour before dinner initially; if persistent or severe CNS adverse effects occur, administering later in the day (1 hour before dinner and at bedtime) may reduce the frequency of CNS adverse effects.

Chemotherapy-induced nausea and vomiting: The first dose should be administered on an empty stomach at least 30 minutes prior to eating; subsequent doses within a chemotherapy cycle may be administered without regard to meals. Once a dose has been titrated, the timing of doses with regard to food in subsequent cycles should maintain consistency with prior cycles.

Usual Adult Dose for Nausea/Vomiting - Chemotherapy Induced

Oral solution:
-Initial dose: 4.2 mg/m2 orally 1 to 3 hours prior to chemotherapy administration, then every 2 to 4 hours after chemotherapy for a total of 4 to 6 doses a day.
-Maintenance dose: May escalate dose by 2.1 mg/m2 increments during a chemotherapy cycle or at subsequent cycles if the initial dose is ineffective and there are no significant side effects.
-Maximum dose: 12.6 mg/m2 per dose

Oral solution comments:
-The initial dose should be rounded to the nearest 0. 1 mg increment, and may need to be rounded to the nearest 0.1 mL increment (for dosing with an oral syringe).
-Patients should be given the initial dose on an empty stomach at least 30 minutes before eating; subsequent doses may be given without regard to meals.
-Healthcare providers should consider decreasing the dose to 2.1 mg orally once a day 1 to 3 hours prior to chemotherapy to decrease the risk of adverse reactions.

Oral tablets:
-Initial dose: 5 mg/m2 orally 1 to 3 hours prior to chemotherapy administration, then every 2 to 4 hours after chemotherapy for a total of 4 to 6 doses a day.
-Maintenance dose: May escalate dose by 2.5 mg/m2 increments during a chemotherapy cycle or at subsequent cycles if the initial dose is ineffective and there are no significant side effects.
-Maximum dose: 15 mg/m2 per dose

Oral tablet comments:
-Most patients respond to 5 mg given 3 or 4 times daily.
-Clinical trial data indicate escalating the dose above 7 mg/m2 increased the frequency of adverse effects with no additional antiemetic benefit.

Use: Treatment for nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments

Liver Dose Adjustments

Data not available

Dronabinol Identification

Substance Name

Dronabinol

CAS Registry Number

1972-08-3

Drug Class

Antiemetics

Cannabinoids

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