Cannabidiol

Indications

Cannabidiol is used for: Indicated for seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) or tuberous sclerosis complex (TSC)

Adult Dose

Seizures Indicated for seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) LGS or DS 2.5 mg/kg PO BID initially; after 1 week, may increase to maintenance dose of 5 mg/kg BID If 5 mg/kg BID tolerated and further seizure reduction required, patient may benefit from a dosage increase up to a maximum recommended maintenance dosage of 10 mg/kg BID (ie, 20 mg/kg/day) Increasing to 10 mg/kg BID may be achieved by increased weekly increments of 2.5 mg/kg BID, as tolerated If a more rapid titration from 10 mg/kg/day to 20 mg/kg/day is warranted, the dosage may be increased no more frequently than every other day Administration of the 20-mg/kg/day dosage resulted in somewhat greater reductions in seizure rates than the recommended maintenance dosage of 10 mg/kg/day, but with an increase in adverse reactions TSC Starting dose: 2.5 mg/kg PO BID Increase dose in weekly increments of 2.5 mg/kg BID as tolerated, to recommended maintenance dose of 12.5 mg/kg BID If a more rapid titration is warranted, the dosage may be increased no more frequently than every other day Effectiveness of doses <12.5 mg/kg BID has not been studied in patients with TSC

Child Dose

Seizures Indicated for seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in patients aged >1 yr Age >1 year LGS or DS 2.5 mg/kg PO BID initially; after 1 week, may increase to maintenance dose of 5 mg/kg BID If 5 mg/kg BID tolerated and further seizure reduction required, patient may benefit from a dosage increase up to a maximum recommended maintenance dosage of 10 mg/kg BID (ie, 20 mg/kg/day) Increasing to 10 mg/kg BID may be achieved by increased weekly increments of 2.5 mg/kg BID, as tolerated If a more rapid titration from 10 mg/kg/day to 20 mg/kg/day is warranted, the dosage may be increased no more frequently than every other day Administration of the 20-mg/kg/day dosage resulted in somewhat greater reductions in seizure rates than the recommended maintenance dosage of 10 mg/kg/day, but with an increase in adverse reactions TSC Starting dose: 2.5 mg/kg PO BID Increase dose in weekly increments of 2.5 mg/kg BID as tolerated, to recommended maintenance dose of 12.5 mg/kg BID If a more rapid titration is warranted, the dosage may be increased no more frequently than every other day Effectiveness of doses <12.5 mg/kg BID has not been studied in patients with TSC

Renal Dose

Administration

Oral Administration Food may affect cannabidiol plasma concentration levels; consistent dosing with respect to meals is recommended to reduce variability in cannabidiol plasma exposure Measuring dose Administer orally by calibrated oral dosing syringes in order to accurately measure and deliver the prescribed dose Packaged in carton with two 5-mL calibrated oral dosing syringes and a bottle adapter Pharmacy provides 1-mL calibrated oral dosing syringe when doses <1 mL are required Do not use household teaspoon or tablespoon; it is not an adequate measuring device

Contra Indications

Hypersensitivity to cannabidiol or any of the ingredients in the product

Precautions

Can cause somnolence and sedation that is dose-related; clobazam and other CNS depressants, including alcohol, may potentiate this adverse effect; monitor for somnolence and sedation and advise patients not to drive or operate machinery until they have gained sufficient experience on drug to gauge whether it adversely affects their ability to safely drive or operate machinery Antiepileptic drugs (AEDs), including cannabidiol, increase risk of suicidal thoughts or behavior in patients taking these drugs for any indication; patients should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior MONITORING PARAMETERS Monitor liver function at baseline, at 1 month, 3 months, and 6 months of treatment, then periodically thereafter; more frequent monitoring is recommended in patients with raised baseline ALT or AST or taking valproate. Restart the monitoring schedule if the dose increases above 10 mg/kg/day. If transaminase or bilirubin levels increase significantly or symptoms of hepatic dysfunction occur, treatment should be withheld or permanently discontinued based on the severity

Pregnancy-Lactation

Pregnancy There are no available data regarding use in pregnant women Animal data Administration of cannabidiol to pregnant animals produced evidence of developmental toxicity (increased embryofetal mortality in rats and decreased fetal body weights in rabbits decreased growth, delayed sexual maturation, long-term neurobehavioral changes, and adverse effects on the reproductive system in rat offspring) at maternal plasma exposures similar to (rabbit) or greater than (rat) that in humans at therapeutic doses Lactation There are no data on the presence of cannabidiol or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production

Interactions

Coadministration with other CNS depressants, including alcohol, may increase risk of sedation and somnolence Effect of other drugs on cannabidiol Moderate or strong CYP3A4 or CYP2C19 inhibitors: Consider cannabidiol dose reduction Strong CYP3A4 or CYP2C19 inducers: Consider cannabidiol dose increase Coadministration of cannabidiol and valproate increases the incidence of liver enzyme elevations; discontinuation or reduction of cannabidiol and/or concomitant valproate should be considered CYP1A2 and CYP2B6 substrates may also require dose adjustment

Adverse Effects

Side effects of Cannabidiol : >10% Infections, all (40-41%) Somnolence (23-25%) Infection, other (21-25%) Decreased appetite (16-22%) Diarrhea (9-20%) Transaminases elevated (8-16%) Rash (7-13%) Fatigue, malaise, asthenia (11-12%) Infection, viral (7-11%) Insomnia (5-11%) 1-10% Irritability, agitation (5-9%) Pneumonia (5-8%) Sedation (3-6%) Anger, aggression (3-5%) Decreased weight (3-5%) Gastroenteritis (4%) Hypoxia, respiratory failure (3%) Infection, fungal (1-3%)

Mechanism of Action

Purified cannabidiol (CBD); the exact mechanism by which CBD produces its anticonvulsant effects is unknown Cannabidiol is a structurally novel anticonvulsant; it does not appear to exert its anticonvulsant effects through CB1 receptors, nor through voltage-gated sodium channels CBD may exert a cumulative anticonvulsant effect, modulating a number of endogenous systems including, but not limited to, neuronal inhibition (synaptic and extrasynaptic GABA channels), modulation of intracellular calcium (TRPV, VDAC, GPR55), and possible anti-inflammatory effects (adenosine)