Continuing Education Activity

Dronabinol is synthetic tetrahydrocannabinol ('THC'), which obtained FDA approval in 1985 for the treatment of HIV/AIDs-induced anorexia and chemotherapy-induced nausea and vomiting in patients who have failed to respond to conventional antiemetics. Dronabinol has also been used off-label for the treatment of OSA. This activity will provide an overview of the pharmacology of dronabinol, its indications and usage, adverse effects, contraindications, and other pertinent information.

Objectives:

• Describe the indications for dronabinol.
• Describe the mechanism of action for dronabinol.
• Review the potential toxicity of dronabinol.
• Identify potential drug interactions with dronabinol.

Indications

Dronabinol is a synthetic form of tetrahydrocannabinol ('THC'), which obtained FDA approval in 1985 for the treatment of HIV/AIDs-induced anorexia and chemotherapy-induced nausea and vomiting ('CINV') in patients who do not successfully respond to conventional antiemetics. Dronabinol also has off-label use to treat obstructive sleep apnea with mixed and unclear efficacy (only Phase II trials). Therefore, the American Academy of Sleep Medicine does not support its use until reliable data is available (such as Phase III trials).[1] Recent studies also utilized dronabinol in chronic pain patients, which showed efficacy compared to placebo, but further research is necessary.[2] Additionally, current fields exploring the use of dronabinol include substance abuse and withdrawal.[3] 

As such, the indications for this cannabinoid in adults are HIV/AIDs-induced anorexia and chemotherapy-induced nausea and vomiting in patients who do not successfully respond to conventional antiemetics.[4][5]

Mechanism of Action

Dronabinol is an orally active cannabinoid (a synthetic form of the active delta-9-tetrahydrocannabinol). The majority of effects of cannabinoids and endocannabinoids (endogenous cannabinoids) appear to be carried out by two inhibitory G-protein coupled-receptors (GPCRs), CB1 (present in high levels in several brain regions, including the prefrontal cortex, hippocampus, amygdala, basal ganglia, and the cerebellum) and CB2 (present in a restricted distribution in the brain stem and periphery including immune cells and neurons).[6][7]

When activated, CB1 generally reduces neuronal excitation. Dronabinol, like THC, is a partial agonist at the CB1 receptor. Cannabinoid signaling carries implications in many pathways, including pain modulation, cognition, appetite stimulation, anti-nausea, among others. The anti-emetic and appetite stimulation effects of the CB1 receptor appear to mediate the therapeutic effects of dronabinol.[8][9]

Administration

Dronabinol is an orally active cannabinoid (a synthetic form of the active Delta-9-tetrahydrocannabinol) that is available in round, soft gelatin 2.5 mg (white), 5 mg (dark brown), and 10mg (orange) capsules. Dronabinol is insoluble in water. As such, it is formulated in sesame oil (providers must inquire about patient allergies). Dosing for specific therapy is outlined below:

HIV/AIDs-induced Anorexia 

The recommended starting adult dosage is 2.5 mg orally twice a day, one hour before lunch and dinner. 

Dosing Considerations: Elderly patients may not be able to tolerate 2.5 mg twice daily. One may consider 2.5 mg once a day (later in the day may reduce unwanted CNS symptoms)) and titrate up to reduce unwanted CNS symptoms. The unwanted effects of feeling high, dizziness, confusion, and somnolence usually resolve in 1 to 3 days. 

Titration and Maximum Dosage: Increase gradually to 2.5 mg 1 hour before lunch and 5 mg 1 hour before dinner. Most patients will receive the desired therapeutic effect with this dosage, but dosing can be increased slowly to a maximum of 10 mg twice daily.[10]

Chemotherapy-induced Nausea and Vomiting ('CINV') in Patients Who Have Failed to Respond to Conventional Antiemetics

The recommended starting adult dosage is 5 mg orally, which should be taken 1 hour or up to 3 hours before chemotherapy, followed by 5 mg every 2 to 4 hours (4 to 6 total doses in a day). The initial dose should be on an empty stomach and generally is taken more than 30 minutes before a meal. The patient does not need to consider the timing of meals or food intake regarding subsequent doses after the first dose.

Dosing Considerations: Similar to dosing for anorexia, elderly patients may be started on a lower dose of 2.5 mg once daily before chemotherapy to reduce CNS symptoms.

Titration and Maximum Dosage: The drug can be titrated up in amounts of 2.5 mg. The maximum dose is 15 mg for each dose (4 to 6 total doses in a day).[10]

Careful attention is necessary regarding the potential adverse effects of dronabinol during upward titration. See the 'Adverse Effects' and 'Monitoring' sections for further details.

Adverse Effects

Hypersensitivity to Dronabinol or Sesame Oil: Clinical staff should monitor patients for signs of hypersensitivity reactions. Reported signs include lip swelling, hive, rash, oral lesions, skin burning, and throat tightness.

Other Adverse Effects: The most common adverse reactions (≥3%) include abdominal pain, dizziness, euphoria, nausea, paranoid reaction, somnolence, abnormal thinking, and vomiting. Please also see the 'Toxicity' section below.

Other concerns include:

• Neuropsychiatric Reactions: Dronabinol can precipitate psychiatric and cognitive changes (may need to be avoided in those with psychiatric history). It may also result in mental or physical impairment. Patients should not operate heavy machinery or motor vehicles until one is certain that the drug does not impair their ability to operate. 
• Hemodynamics: Dronabinol can cause hemodynamic instability in patients with existing cardiac disorders. As such, they may experience decreased or increased blood pressure, syncope, or rapid heart rate. Monitor for these changes after beginning treatment and changing doses. Avoid drugs that also affect hemodynamics.
• Seizures: Dronabinol can cause seizures or similar events in patients with a prior medical history of seizures. These patients also require close monitoring, and therapy should stop if a seizure occurs.
• Substance abuse: As with any controlled substance or drug with abuse potential, patients should be monitored and assessed for drug misuse risk (especially in those with substance abuse history). 
• Paradoxical Nausea and Vomiting: Consider stopping or reducing the treatment dose with dronabinol if the patient experiences a paradoxical increase in nausea and vomiting.[5]

Contraindications

Dronabinol formulations contain sesame oil. As such, this drug is contraindicated in patients who have a history of hypersensitivity reaction to sesame oil or THC derivatives. Careful attention is necessary for signs of hypersensitivity reactions (see Monitoring below).[4]

Monitoring

Metabolism: Liver via extensive first-pass, cytochrome P450 2C9, and cytochrome P450 3A4.

The onset of Action: Generally 0.5 to 1 hour

Half-life: 4 hours.

Bioavailability:10 to 20%

Therapeutic Index (TI): TI is wide, and dosing is limited by adverse effects as a lethal dose of IV dronabinol is estimated at 30 mg/kg or greater. As such, max doses reflect increased rates of adverse effects. See the 'Administration' section for max doses.

Hypersensitivity to Dronabinol or Sesame Oil: Patients should be monitored for signs of hypersensitivity reactions. Reported signs include lip swelling, hive, rash, oral lesions, skin burning, and throat tightness.

Other Adverse Effects: The most common adverse reactions (which generally occur in greater than 3% but less than 10% of patients) include pain in the abdomen, nausea or vomiting, feelings of joy, feelings of paranoia, and abnormal thinking. Please also see the 'Toxicity' section below.

Important Drug Interaction: Drugs that inhibit or induce cytochrome P450 2C9 and cytochrome P450 3A4 can affect the plasma concentration of dronabinol. Drugs that are typically highly bound by proteins in plasma can be displaced by dronabinol as it is a highly protein-bound drug (with a higher affinity for carrier proteins than most others), increasing patient exposure. Drugs with narrow therapeutic windows, such as warfarin, require close monitoring when co-administered with dronabinol.[4]

Toxicity

Toxicity

The estimated lethal dose of IV dronabinol is 30 mg/kg (note this is for illustrative purposes as dronabinol dosing is oral). As such, the CNS toxicity (adverse CNS effects) of dronabinol is more applicable as a measure for monitoring dose-limiting toxicity. Signs and symptoms of toxicity include:

Mild Intoxication: sleepiness, feelings of joy, heightened sensory vigilance, time perception difficulties, conjunctival injection, dry oral cavity, and elevated heart rate.

Moderate Intoxication: Memory difficulty, feelings of detachment, mood changes, retention of urine, and decreased bowel motility.

Severe: Decreased coordination of motor function, lethargy, slurring of speech, and orthostatic hypotension.

Panic attacks in those with apprehension and seizures in those with a history of seizures can also occur.[11]

Management of Serious Ingestion

There is no specific antidote for the treatment of dronabinol toxicity. If there is a history of recent excessive ingestion, the patient should have gut decontamination with activated charcoal (at a dosage of 30 to 100g for adults, 1 to 2 g/kg in infants). Delivery through a nasogastric tube may be necessary for an unconscious patient with a secure airway. Patients with intense psychiatric complications (such as depressive episodes, hallucinations, or psychosis) may need to be isolated in a quiet and peaceful area and frequently reassured by the provider or staff. Benzodiazepines, such as diazepam (5 to 10 mg PO), can be utilized for extreme agitation. Hypotension is manageable with Trendelenburg positioning and isotonic IV hydration.[11]

Enhancing Healthcare Team Outcomes

Managing anorexia associated with weight loss in patients with AIDs/HIV and nausea and vomiting that can accompany chemotherapy in patients who have not responded to traditional conventional antiemetics requires an interprofessional team of healthcare professionals that may include clinicians of various types (MDs, DOs, NPs, and PAs), palliative care specialists, oncology specialists, pharmacists, nursing staff, and other clinicians from other specialties. The interprofessional model will involve open communication and information sharing, with each interprofessional team member empowered to contribute to the patient case from their own expertise to drive optimal patient outcomes. [Level 5]

Anorexia Associated with Weight Loss in Patients with AIDs/HIV

Level 1: Treatment of AIDs-related anorexia and weight loss was proven effective in a randomized, double-blind, placebo-controlled study with 139 patients. A statistically significant difference between dronabinol and placebo was observable in appetite. Additional measured trends included improved body weight and mood and decreases in nausea. Recent metanalyses have also shown dronabinol to be efficacious.[12]

Nausea and Vomiting Associated with Chemotherapy in Patients Who Have Not Responded to Traditional Conventional Antiemetic

Level 1: Treatment of chemotherapy-induced nausea and vomiting ('CINV') with dronabinol has been extensively studied as monotherapy and combined with other more traditional antiemetics such as ondansetron. Recent metanalyses have also shown dronabinol to be efficacious.[13][14]