dronabinol (Rx)

1-10%

Dizziness

Euphoria

Paranoid reaction

Somnolence

Abnormal thinking

Abdominal pain

Nausea

Vomiting

<1%

Depression

Nightmares

Speech difficulties

Emotional lability

Hypotension

Tremors

Flushing

Sweating

Anorexia

Hepatic enzyme elevation

Tinnitus

Frequency Not Defined

Amnesia

Anxiety/nervousness

Hallucination

Ataxia

Confusion

Depersonalization

Asthenia

Palpitations

Tachycardia

Fatigue

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

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 (eg, barbiturates, benzodiazepines, lithium, opioids, buspirone, scopolamine, antihistamines, tricyclic antidepressants, other anticholinergic agents, and muscle relaxants), 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
• Abrupt discontinuation may cause withdrawal symptoms

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 (eg, amphetamines, other sympathomimetic agents, atropine, amoxapine, scopolamine, antihistamines, other anticholinergic agents, amitriptyline, desipramine, other tricyclic antidepressants)
• 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 seizure-like 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)
• Large amounts of propylene glycol are potentially toxic and have been associated with seizures, lactic acidosis, respiratory depression, and respiratory depression
• 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

Pregnancy

May cause fetal harm; avoid use during pregnancy

Published studies suggest that during pregnancy, the use of cannabis, which includes THC, whether for recreational or medicinal purposes, may increase the risk of adverse fetal/neonatal outcomes including fetal growth restriction, low birth weight, preterm birth, small-for-gestational age, admission to the NICU, and stillbirth

Contains alcohol; alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development

Delta-9-THC has been measured in the cord blood of some infants whose mothers reported prenatal use of cannabis, suggesting that dronabinol may cross the placenta to the fetus during pregnancy

Effects of delta-9-THC on the fetus are not known

Animal data

• No teratogenicity reported in mice administered dronabinol (delta-9-THC) at up to 30 times the MRHD (maximum recommended human doses) and up to 5 times the MRHD for patients with AIDS and cancer, respectively
• Decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions were observed in both species at doses that induced maternal toxicity
• In rats, maternal administration of dronabinol from pregnancy (implantation) through weaning was associated with maternal toxicity, including mortality of pups, and adverse developmental and neurodevelopmental effects on the pups at 2 to 20 times the MRHD for patients with AIDS and less than and up to 3.3 times the MRHD for patients with cancer

Lactation

Women with HIV: Centers for disease control and prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV

Because of potential for HIV transmission (in HIV-negative infants) and serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving the drug

Women with CINV: There are limited data on presence of drugs in human milk, the effects on breastfed infants, or on milk production; the reported effects of inhaled cannabis transferred to the breastfeeding infant have been inconsistent and insufficient to establish causality

In rat offspring exposed to therapy in utero and during lactation, reduced body weight was observed during the preweaning (lactation) stage with maternal administration of this medication at 2 times and less than the MRHD for patients with AIDS and cancer, respectively; breastfeeding infants should have their weight monitored

The developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for the drug and any potential adverse effects on breastfed infant from the drug or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Dronabinol is an orally active cannabinoid which has complex effects on the 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

Has appetite stimulant effect

Antiemetic mechanism unknown but probably involves inhibition of vomiting center in medulla oblongata

Absorption

Bioavailability: 90-95%, but due to combined effects of first-pass metabolism and high lipid solubility, only 10-20% of the administered dose reaches systemic circulation

Peak plasma time: 0.5-4 hr (dronabinol and major active metabolite: 11-hydroxy-delta-9-THC)

Peak plasma concentration: 1.9 ng/mL

AUC: 3.8 ng·hr/mL

Distribution

Protein bound: ~97%

Vd: 10 L/kg

Metabolism

Extensive first-pass hepatic metabolism

Metabolites: 11-hydroxy-delta-9-tetrahydrocannabinol (active)

Elimination

Half-life: 5.6 hr (parent drug); 44-59 hr (metabolites)

Renal clearance: 18-20 mL/min

Total body clearance: 0.2 L/kg/hr

Excretion: 50% feces; 15% urine

Pharmacogenomics

Systemic clearance may be reduced and concentrations may be increased in presence of CYP2C9 genetic polymorphism 2- to 3-fold higher dronabinol exposure in individuals carrying genetic variants associated with diminished CYP2C9 function

Monitoring for increased adverse reactions is recommended in patients known to carry genetic variants associated with diminished CYP2C9 function

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