Usage
Cannabidiol (CBD) is an anticonvulsant prescribed for seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in patients one year of age and older. It is also indicated for seizures associated with CDKL5 deficiency disorder (CDD) or Aicardi syndrome.
Alternate Names
CBD is also known as Epidiolex (brand name).
How It Works
Pharmacodynamics: CBD’s precise mechanism of action is not fully understood but it is thought to exert its anticonvulsant effects through multiple mechanisms. These may include modulation of neuronal excitability, interaction with several receptor pathways, and indirect effects on receptors. It does not appear to bind directly to the cannabinoid receptors CB1 or CB2 with high affinity.
Pharmacokinetics:
- Absorption: CBD is readily absorbed orally, with peak plasma concentrations reached approximately 3 hours post-administration. Food can affect CBD levels.
- Metabolism: CBD is extensively metabolized in the liver, primarily by CYP3A4 and CYP2C19 enzymes. Multiple metabolites have been identified, including 7-carboxy-CBD (7-COOH-CBD) and 7-hydroxy-CBD (7-OH-CBD).
- Elimination: CBD is primarily eliminated through hepatic metabolism, with a small fraction excreted unchanged in urine and feces. The elimination half-life is variable, ranging from 18 to 56 hours.
- Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: CBD appears to influence certain ion channels and acts on a variety of receptor targets, including G-protein-coupled receptors, nuclear receptors (PPARγ), and serotonin receptors (5-HT1A receptor). It may also be an allosteric modulator of CB1 receptors and potentially inhibits adenosine reuptake, enhancing adenosine signaling.
Dosage
Standard Dosage
Adults and Children ≥1 year:
- Initial dose: 2.5 mg/kg orally twice daily (5 mg/kg/day).
- Maintenance dose: After one week, increase to 5 mg/kg orally twice daily (10 mg/kg/day). Based on individual clinical response and tolerability, the dose can be further increased in weekly increments of 2.5 mg/kg twice daily (5 mg/kg/day) up to a maximum of:
- LGS and DS: 10 mg/kg twice daily (20 mg/kg/day).
- TSC: 12.5 mg/kg twice daily (25 mg/kg/day).
- CDD: 10mg/kg twice daily (20 mg/kg/day).
- Aicardi Syndrome: 20mg/kg twice daily (40mg/kg/day).
- Rapid Titration: If necessary, the dose can be increased every other day.
- Administration: Administer orally at consistent times, with or without food.
Children <1 year:
Safety and efficacy have not been established in children under one year old.
Special Cases:
- Elderly Patients (≥65 years): Start at the low end of the dosing range and titrate cautiously due to potential age-related decreases in hepatic, renal, or cardiac function.
- Patients with Renal Impairment: No dose adjustment is required.
- Patients with Hepatic Impairment (Child-Pugh Class):
- Mild (Child-Pugh A): No dose adjustment is necessary.
- Moderate (Child-Pugh B):
- Starting dose: 1.25 mg/kg twice daily.
- Maintenance dose: Titrate slowly up to 2.5-5 mg/kg twice daily.
- Severe (Child-Pugh C):
- Starting dose: 0.5 mg/kg twice daily.
- Maintenance dose: Titrate slowly up to a maximum recommended dose of 2 mg/kg twice daily (4 mg/kg/day) for LGS and DS or 2.5mg/kg twice daily (5 mg/kg/day) for TSC. Higher doses in TSC and severe hepatic impairment can be considered if the potential benefits are likely to outweigh the risks.
Clinical Use Cases
CBD is not indicated for use in situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations such as status epilepticus or cardiac arrest outside of the approved indications listed above. Its use is specifically limited to treating seizures associated with LGS, DS, TSC, CDD, or Aicardi syndrome as described above.
Dosage Adjustments
Dose adjustments are recommended for patients with moderate to severe hepatic impairment as outlined above. Dosage modifications may also be necessary based on individual patient response and tolerability, drug interactions, or other patient-specific factors.
Side Effects
Common Side Effects:
- Decreased appetite, diarrhoea, somnolence, pyrexia, vomiting, upper respiratory tract infection, fatigue, rash, sleep disorder, bronchitis, and increased transaminase levels.
Rare but Serious Side Effects:
- Suicidal behavior and ideation, drug-induced liver injury (monitor liver enzymes).
Long-Term Effects:
Long-term effects beyond those observed in clinical trials are not well-established.
Adverse Drug Reactions (ADR):
Severe allergic reactions or hypersensitivity.
Contraindications
- Hypersensitivity to cannabidiol or any component of the formulation.
Drug Interactions
CBD is primarily metabolized by CYP3A4 and CYP2C19. Therefore, co-administration with strong inhibitors or inducers of these enzymes can alter CBD levels.
- CYP3A4 and CYP2C19 inhibitors: May increase CBD plasma concentrations.
- CYP3A4 and CYP2C19 inducers: May decrease CBD plasma concentrations.
Pregnancy and Breastfeeding
- Pregnancy: CBD can cause fetal harm. Advise patients to avoid pregnancy during treatment.
- Breastfeeding: It is unknown if CBD is present in human milk. Due to the potential for serious adverse reactions in the breastfed child, advise patients to avoid breastfeeding.
Drug Profile Summary
- Mechanism of Action: Exact mechanism unknown, potentially through modulation of neuronal excitability and interaction with various receptor pathways.
- Side Effects: Decreased appetite, somnolence, diarrhoea, pyrexia, increased transaminase levels; rare but serious side effects include suicidal behavior and drug-induced liver injury.
- Contraindications: Hypersensitivity to cannabidiol.
- Drug Interactions: CYP3A4 and CYP2C19 inducers and inhibitors.
- Pregnancy & Breastfeeding: Avoid use in pregnancy and breastfeeding.
- Dosage: See detailed dosing guidelines above.
- Monitoring Parameters: Liver enzymes, especially during dose titration or concomitant use of hepatotoxic drugs.
Popular Combinations
CBD is typically used as an add-on therapy to existing antiepileptic drugs.
Precautions
- General Precautions: Monitor liver function.
- Specific Populations: See dosing recommendations for elderly and patients with hepatic impairment.
- Lifestyle Considerations: May cause somnolence; caution patients about driving or operating machinery.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Cannabidiol?
A: See detailed dosing guidelines above.
Q2: What are the common side effects of CBD?
A: Decreased appetite, diarrhoea, somnolence, pyrexia, vomiting.
A: Primarily by CYP3A4 and CYP2C19 hepatic enzymes.
Q4: What are the contraindications for CBD use?
A: Hypersensitivity to CBD.
Q5: Can CBD be used during pregnancy or breastfeeding?
A: No, CBD is contraindicated in pregnancy and breastfeeding due to potential fetal harm and unknown safety in infants.
Q6: How should CBD dosage be adjusted in patients with hepatic impairment?
A: See specific dosage adjustments for mild, moderate, and severe hepatic impairment in the dosage section.
Q7: What are the potential drug interactions with CBD?
A: Primarily with strong inhibitors or inducers of CYP3A4 and CYP2C19.
Q8: What monitoring parameters should be considered when prescribing CBD?
A: Monitor liver function tests, especially transaminases and bilirubin.
Q9: What are the approved indications for CBD (Epidiolex)?
A: Seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, Tuberous Sclerosis Complex, CDKL5 Deficiency Disorder, and Aicardi syndrome.
Q10: Should the CBD dose be adjusted for renal impairment?
A: No, dose adjustment is not necessary for renal impairment.
