Cannabidiol Purified

Purified cannabidiol is a plant-derived, highly purified oral solution licensed as adjunct treatment for seizures in Lennox-Gastaut syndrome, Dravet syndrome and tuberous sclerosis complex. It is expensive and specialist-initiated, with hepatotoxicity and large interactions with clobazam and valproate as its main hazards.

Mechanism. Not fully defined. It does not act through cannabinoid receptors, and may act through GPR55, TRPV1 and adenosine signalling.

Pharmacokinetics. Bioavailability is low when fasting and rises four to five times with a high-fat meal. Protein binding is over 94%. Half-life is 56 to 61 hours. It is cleared by cytochrome P450 2C19 and 3A4 and by glucuronidation, to an active 7-hydroxy metabolite.

Specialist use. Adjunct for Lennox-Gastaut syndrome and Dravet syndrome (with clobazam in some labels) from age 2 years, and for tuberous sclerosis complex.

• Oral cannabidiol: 2.5 mg/kg twice daily for 1 week, then 5 mg/kg twice daily (10 mg/kg daily). If needed, increase weekly in steps of 2.5 mg/kg twice daily to a maximum of 10 mg/kg twice daily (20 mg/kg daily).

• Tuberous sclerosis complex: usual target 12.5 mg/kg twice daily, maximum 25 mg/kg daily.

• Treatment is long term, with benefit reviewed regularly.

Kidney, liver, weight and age.

• Kidney: no adjustment; not studied in dialysis.

• Liver: moderate impairment, start 1.25 mg/kg twice daily, maintenance 2.5 mg/kg twice daily, maximum 5 mg/kg twice daily. Severe impairment, start 0.5 mg/kg twice daily, maintenance 1 mg/kg twice daily, maximum 2 mg/kg twice daily.

• Dosing is by weight in children.

Contraindications. Hypersensitivity to cannabidiol or excipients, including sesame seed oil. Transaminases over three times the upper limit with bilirubin over twice the upper limit.

Serious adverse effects. Hepatocellular injury, suicidal ideation, hypersensitivity, pneumonia and other infections, and severe somnolence.

Common adverse effects. Somnolence, reduced appetite, diarrhoea, vomiting, fever, fatigue and rash.

Interactions.

• Clobazam: active N-desmethylclobazam rises about threefold, causing sedation.

• Valproate: raises the risk of liver enzyme elevation.

• Strong cytochrome P450 2C19 inhibitors raise levels. Strong inducers such as rifampicin lower levels. Cannabidiol may raise levels of drugs cleared by cytochrome P450 2C8, 2C9 and 2C19 and by UGT enzymes.

Common prescribing errors. Missing baseline liver tests. Not reducing clobazam when sedated. Inconsistent timing with food. Equating illicit or unregulated cannabis products with purified cannabidiol.

Special groups.

• Pregnancy: limited data; avoid unless benefit outweighs risk.

• Breastfeeding: excreted into milk; avoid or monitor closely.

• Regional: very limited availability and high cost; unregulated products vary in content and are not equivalent.

Formulations. Oral solution 100 mg/mL. Use the supplied oral syringe. Take consistently in relation to food and meals, ideally with food. Discard the bottle after the labelled period once opened, often 12 weeks.

Monitoring.

• Baseline: alanine and aspartate aminotransferases and total bilirubin.

• Ongoing: repeat at 1, 3 and 6 months, then periodically, and within 2 to 4 weeks of dose changes or changes in valproate or clobazam. Stop if transaminases exceed three times the upper limit with bilirubin over twice the upper limit.

• Review sedation, appetite, weight, mood and seizure diary.

Stopping. Taper over about 10 days, reducing by 10% each day, unless safety requires faster withdrawal.

Referral and escalation. Start only under paediatric neurology or epilepsy specialist care. Refer urgently for jaundice, persistent vomiting or severe sedation.