Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral:
Epidiolex: 100 mg/mL (100 mL) [contains alcohol, usp, sesame oil; strawberry flavor]
Pharmacology
Mechanism of Action
The exact antiepileptic mechanism of action of cannabidiol is unknown; however, it does not appear to involve its effects on cannabinoid receptors.
Pharmacokinetics/Pharmacodynamics
Absorption
High fat/high calorie meals increase extent of absorption
Distribution
Vd: 20,963 L to 42,849 L
Metabolism
Hepatic (primarily) and gut by CYP2C19, CYP3A4, UGT1A7, UGT1A9, and UGT2B7 to active metabolite 7-OH-CBD and then to inactive metabolite 7-COOH-CBD
Excretion
Feces; urine (minor)
Onset of Action
Within 4 weeks
Time to Peak
2.5 to 5 hours at steady state
Half-Life Elimination
56 to 61 hours
Protein Binding
>94%
Use in Specific Populations
Special Populations: Hepatic Function Impairment
Patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment had a higher AUC
Use: Labeled Indications
Seizure disorders: Treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients ≥2 years of age.
Contraindications
Hypersensitivity to cannabidiol or any component of the formulation.
Dosage and Administration
Dosing: Adult
Note: Assess ALT, AST, and total bilirubin prior to initiating treatment, with dose changes or the addition of or changes in hepatotoxic medications.
Seizure disorders: Oral: Initial: 2.5 mg/kg twice daily; may increase after 1 week to a maintenance dose of 5 mg/kg twice daily; if needed and tolerated, may increase in weekly increments of 2.5 mg/kg twice daily to a maximum dosage of 10 mg/kg twice daily. In patients needing a more rapid titration from 5 mg/kg twice daily to 10 mg/kg twice daily, may increase dose as quickly as every other day in increments of 2.5 mg/kg twice daily. Note: The 20 mg/kg/day dosage resulted in somewhat greater reductions in seizure rates, but with an increase in adverse reactions. When discontinuing, the dose should be decreased gradually; avoid abrupt discontinuation.
Dosing: Geriatric
Refer to adult dosing; use with caution.
Dosing: Pediatric
Note: Baseline serum transaminases (ALT and AST) and total bilirubin levels should be checked in all patients before starting treatment. Avoid abrupt withdrawal; decrease dose gradually.
Seizures: Children ≥2 years and Adolescents: Oral: Initial: 2.5 mg/kg/dose twice daily, may increase in 1 week to a maintenance dose of 5 mg/kg/dose twice daily. If additional seizure control is needed, may increase weekly by 2.5 mg/kg/dose twice daily; maximum daily dose: 20 mg/kg/day. For rapid titration, may increase no more frequently than every other day.
Administration
Oral: High-fat/high-calorie meals significantly increase absorption; consistent administration in the fasted or fed state will minimize variability in drug levels. Administer using the provided calibrated measuring device (1 or 5 mL oral syringe).
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Do not freeze. Use within 12 weeks of first opening the bottle; discard any unused solution.
Drug Interactions
Brivaracetam: Cannabidiol may increase the serum concentration of Brivaracetam. Monitor therapy
Cilostazol: CYP2C19 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Cilostazol. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Reduce the cilostazol dose to 50 mg twice daily in patients who are also receiving moderate inhibitors of CYP2C19. Monitor clinical response to cilostazol closely. Consider therapy modification
Citalopram: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a moderate CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (eg, serotonin syndrome, QT prolongation). Consider therapy modification
CloBAZam: Cannabidiol may increase serum concentrations of the active metabolite(s) of CloBAZam. Cannabidiol may increase the serum concentration of CloBAZam. Monitor therapy
Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification
CNS Depressants: Cannabidiol may enhance the CNS depressant effect of CNS Depressants. Monitor therapy
CYP2C19 Inducers (Strong): May decrease the serum concentration of Cannabidiol. Monitor therapy
CYP2C19 Inhibitors (Moderate): May increase the serum concentration of Cannabidiol. Monitor therapy
CYP2C19 Inhibitors (Strong): May increase the serum concentration of Cannabidiol. Monitor therapy
CYP2C19 Substrates (High risk with Inhibitors): CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors). Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Cannabidiol. Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Cannabidiol. Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Cannabidiol. Monitor therapy
Flibanserin: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Monitor therapy
Valproate Products: May enhance the hepatotoxic effect of Cannabidiol. Monitor therapy
Test Interactions
May cause a false-positive cannabis screening.
Adverse Reactions
>10%:
Central nervous system: Drowsiness (≤32%), lethargy (≤32%), sedation (≤32%), fatigue (≤12%), malaise (≤12%), insomnia (≤11%), sleep disorder (≤11%), sleep disturbance (≤11%)
Dermatologic: Skin rash (7% to 13%)
Endocrine & metabolic: Weight loss (3% to 18%)
Gastrointestinal: Decreased appetite (16% to 22%), diarrhea (9% to 20%)
Hematologic & oncologic: Anemia (30%)
Hepatic: Increased serum alanine aminotransferase (>3x ULN: 13% to 17%), increased serum transaminases (8% to 16%)
Infection: Infection (25% to 41%), viral infection (7% to 11%)
Neuromuscular & skeletal: Asthenia (≤12%)
1% to 10%:
Central nervous system: Agitation (≤9%), irritability (≤9%), aggressive behavior (≤5%), outbursts of anger (≤5%), drooling (≤4%), abnormal gait (2% to 3%)
Gastrointestinal: Gastroenteritis (4%), sialorrhea (≤4%), abdominal distress (≤3%), abdominal pain (≤3%)
Infection: Fungal infection (1% to 3%)
Respiratory: Pneumonia (5% to 8%), hypoxia (≤3%), respiratory failure (≤3%)
Frequency not defined:
Hematologic & oncologic: Decreased hematocrit, decreased hemoglobin
Hepatic: Increased serum aspartate aminotransferase, increased serum transaminases (>20x ULN)
Hypersensitivity: Hypersensitivity reaction
Renal: Increased serum creatinine
<1%, postmarketing, and/or case reports: Angioedema, erythema, pruritus
Warnings/Precautions
Concerns related to adverse effects:
- CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving). Sedation and somnolence are dose-related, most common early in treatment, have a higher incidence in combination with clobazam, and may resolve with continued use.
- Hepatic effects: Dose-related elevations of liver transaminases (ALT and/or AST) have been reported, some resulting in hospitalization. Elevations typically occur within the first 2 months of treatment, but have occurred as late as 18 months after treatment initiation. Risk factors include high cannabidiol dose, concomitant hepatotoxic drugs (especially clobazam and valproate), and elevated baseline transaminases. Identifying elevated transaminases early may decrease the risk of serious hepatocellular injury. Although in clinical trials, transaminase levels normalized after continuing cannabidiol in some patients, others required discontinuation or lowering the dose of cannabidiol and/or concomitant hepatotoxic drugs. Interrupt and/or discontinue treatment (as appropriate) and check liver transaminases and bilirubin if clinical signs or symptoms of hepatic dysfunction develop (eg, unexplained anorexia, dark urine, fatigue, jaundice, nausea, right upper quadrant pain, vomiting). Discontinue treatment if transaminase levels >3 x ULN, bilirubin levels >2 x ULN, or sustained transaminase elevations >5 x ULN. In patients with elevated transaminases and bilirubin at baseline or prolonged elevations during cannabidiol treatment, assess for other possible causes of hepatotoxicity.
- Hypersensitivity: Hypersensitivity reactions, including angioedema, erythema and pruritus requiring antihistamines, have been reported. Discontinue cannabidiol if hypersensitivity reactions occur.
- Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify health care provider immediately if symptoms occur.
Disease-related concerns:
- Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment required in moderate or severe hepatic impairment.
Other warnings/precautions:
- Withdrawal: Antiepileptics should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency and status epilepticus, unless safety concerns require a more rapid withdrawal.
Monitoring Parameters
ALT, AST, and total bilirubin (baseline and 1, 3, and 6 months after initiation, followed by periodic monitoring as clinically indicated [eg, within 1 month of dose change or initiation of concomitant hepatotoxic drug or clinical signs or symptoms of hepatic dysfunction]).
Pregnancy
Pregnancy Considerations
Adverse events were observed in animal reproduction studies.
Cannabidiol can be detected in the umbilical cord serum and meconium following maternal use of inhaled, non-medicinal cannabis during pregnancy (Kim 2018).
Patients exposed to cannabidiol during pregnancy are encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.
Patient Education
What is this drug used for?
- It is used to help control certain kinds of seizures.
Frequently reported side effects of this drug
- Fatigue
- Lack of appetite
- Weight loss
- Diarrhea
- Loss of strength and energy
- Trouble sleeping
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
- Infection
- Depression like thoughts of suicide, anxiety, emotional instability, or confusion
- Irritability
- Panic attacks
- Mood changes
- Behavior changes
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
