Controlled Substance Schedule: V
Seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex.
Cannabidiol is a cannabinoid that naturally occurs in the Cannabis sativa plant. Mechanism of anticonvulsant effect unknown; does not work by interacting with cannabinoid receptors.
Reduction in frequency of atonic, tonic, clonic, and tonic-clonic seizures.
Absorption: Extent of absorption unknown. High fat/high calorie meals increase extent of absorption.
Distribution: Extensively distributed to tissues.
Protein Binding: >94%.
Metabolism and Excretion: Primarily metabolized in the liver by the CYP2C9 and CYP3A4 isoenzymes to an active metabolite (7-OH-CBD). Primarily excreted in feces.
Half-life: 56–61 hr.
TIME/ACTION PROFILE (plasma concentrations)
- Hypersensitivity to cannabidiol or sesame oil.
Use Cautiously in:
- Concurrent use of valproic acid or clobazam;
- Concurrent use of sedatives, hypnotics, or other psychoactive drugs (↑ risk of adverse effects);
- Elevated liver enzymes (at baseline);
- Moderate to severe hepatic impairment;
- OB: Use during pregnancy only if the potential maternal benefit justifies the potential fetal risk;
- Lactation: Use while breast feeding only if the potential maternal benefit justifies the potential risk to the infant;
- Pedi: Children <2 yr (safety and effectiveness not established)
- Geri: Choose dose carefully in older adults, considering concurrent disease states, drug therapy, and age-related ↓ in hepatic and renal function.
Adverse Reactions/Side Effects
EENT: dry mouth
GI: ↓ appetite, diarrhea, hepatotoxicity, ↑ liver enzymes, abdominal pain, ↓ weight
GU: ↑ serum creatinine
Neuro: SUICIDAL THOUGHTS/BEHAVIORS, fatigue, insomnia, sedation, aggressive behavior, agitation, ataxia
Misc: HYPERSENSITIVITY REACTIONS (including angioedema), infection, physical dependence, psychological dependence (high doses or prolonged therapy)
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- Concurrent use of valproic acid may ↑ risk of hepatotoxicity.
- Moderate or strong CYP2C9 inhibitors and moderate or strong CYP3A4 inhibitors may ↑ levels and risk of toxicity; consider ↓ cannabidiol dose.
- Strong CYP2C9 inducers or strong CYP3A4 inducers may ↓ levels and effectiveness; consider ↑ cannabidiol dose.
- May ↑ levels of CYP1A2 substrates, including theophylline and tizanidine ; consider ↓ dose of CYP1A2 substrate.
- May ↑ levels of CYP2B6 substrates, including bupropion and efavirenz ; consider ↓ dose of CYP2B6 substrate.
- May ↑ levels and risk of toxicity of CYP2C8 substrates and CYP2C9 substrates ; consider ↓ dose of CYP2C8 or CYP2C9 substrate.
- May ↑ levels of CYP2C19 substrates, including diazepam ; consider ↓ dose of CYP2C19 substrate.
- May ↑ levels of active metabolite of clobazam which may ↑ risk of toxicity associated with clobazam.
- May ↑ levels and risk of toxicity of stiripentol and everolimus.
- Additive CNS depression with alcohol, antihistamines, barbiturates, benzodiazepines, muscle relaxants, opioid analgesics, tricyclic antidepressants, and sedative/hypnotics.
Seizures Associated with Lennox-Gastaut Syndrome or Dravet Syndrome
PO (Adults and Children ≥1 yr): 2.5 mg/kg twice daily; can ↑ dose to 5 mg/kg twice daily in 1 wk. If further reduction in seizure frequency needed, may continue to ↑ dose on weekly basis (every other day if more rapid titration warranted) in increments of 2.5 mg/kg twice daily (max dose = 10 mg/kg twice daily).
PO (Adults and Children ≥1 yr): Moderate hepatic impairment (Child–Pugh B)– 1.25 mg/kg twice daily; can ↑ dose to 2.5 mg/kg twice daily in 1 wk. If further reduction in seizure frequency needed, may continue to ↑ dose on weekly basis (every other day if more rapid titration warranted) in increments of 1.25 mg/kg twice daily (max dose = 5 mg/kg twice daily); Severe hepatic impairment (Child–Pugh C)– 0.5 mg/kg twice daily; can ↑ dose to 1 mg/kg twice daily in 1 wk. If further reduction in seizure frequency needed, may continue to ↑ dose on weekly basis (every other day if more rapid titration warranted) in increments of 0.5 mg/kg twice daily (max dose = 2 mg/kg twice daily).
Seizures Associated with Tuberous Sclerosis Complex
PO (Adults and Children ≥1 yr): 2.5 mg/kg twice daily; can ↑ dose on weekly basis (every other day if more rapid titration warranted) in increments of 2.5 mg/kg twice daily to recommended maintenance dosage of 12.5 mg/kg twice daily.
PO (Adults and Children ≥1 yr): Moderate hepatic impairment (Child–Pugh B)– 1.25 mg/kg twice daily; can ↑ dose on weekly basis (every other day if more rapid titration warranted) in increments of 1.25 mg/kg twice daily to recommended maintenance dosage of 6.25 mg/kg twice daily; Severe hepatic impairment (Child–Pugh C)– 0.5 mg/kg twice daily; can ↑ dose on weekly basis (every other day if more rapid titration warranted) in increments of 0.5 mg/kg twice daily to recommended maintenance dosage of 2.5 mg/kg twice daily.
Oral solution (strawberry flavor): 100 mg/mL
- Assess location, duration, and characteristics of seizure activity. Institute seizure precautions.
- Monitor closely for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts, behavior, or depression.
- Monitor for signs and symptoms of hepatotoxicity (unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, jaundice and/or dark urine). If signs and symptoms occur, promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with cannabidiol.
- Monitor for signs and symptoms of hypersensitivity reactions (pruritus, erythema, and angioedema) during therapy. Discontinue cannabidiol if symptoms occur.
Lab Test Considerations:
Obtain serum transaminases (ALT, AST) and total bilirubin levels before starting therapy. Elevations usually respond to decreased dose or discontinuation of therapy. Monitor levels at 1, 3, and 6 mo after starting therapy, within 1 mo following dose changes, and as needed thereafter. Discontinue cannabidiol if transaminase levels >3 times upper limit of normal (ULN) and bilirubin levels >2 times ULN. Also discontinue therapy if transaminase persistently >5 times ULN.
- PO Administer orally twice daily with consistency in regard to food; food may effect cannabidiol levels. Use calibrated measuring device included with cannabidiol to ensure accurate dosing. Solution is strawberry flavored clear, colorless to yellow. Store at room temperature; do not refrigerate or freeze. Discard 12 wk after bottle is first opened.
- Instruct patient to take cannabidiol as directed. Advise patient not to stop cannabidiol without consulting health care professional; must be gradually discontinued to prevent seizures. Advise patient to read the Medication Guide before starting therapy and with each Rx refill in case of changes.
- May cause drowsiness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known. Tell patient not to resume driving until health care professional gives clearance based on control of seizure disorder and response to medication is known.
- Advise patient to notify health care professional promptly if signs and symptoms of hepatotoxicity occur.
- Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications and to avoid alcohol during therapy.
- Inform patients and families of risk of suicidal thoughts and behavior and advise that behavioral changes, emergency or worsening signs and symptoms of depression, unusual changes in mood, or emergence of suicidal thoughts, behavior, or thoughts of self-harm should be reported to health care professional immediately.
- Inform patients of potential for positive cannabis drug screens.
- Rep: Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breast feeding. Encourage patients who become pregnant to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or on the web at www.aedpregnancyregistry.org to collect information about the safety of antiepileptic medicines during pregnancy. Enrollment must be done by patients themselves.
Decreased frequency and intensity of seizure activity.
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