Dosing & Uses
Dosage Forms & Strengths
solution, oral: Schedule V
- 100mg/mL
Seizures
Indicated for seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS)
2.5 mg/kg PO BID initially; after 1 week, dose may be increased 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
Also see Administration
Dosage Modifications
Hepatic impairment
- Mild (Child-Pugh A): No dose adjustment required
- Moderate-to-severe (Child-Pugh B or C): Dosage adjustment recommended, including slower titration
Moderate
- Starting dose: 1.25 mg/kg BID
- Maintenance dose: 2.5 mg/kg BID
- Maximum dose: 5 mg/kg BID
Severe
- Starting dose: 0.5 mg/kg BID
- Maintenance dose: 1 mg/kg BID
- Maximum dose: 2 mg/kg BID
Dosing Considerations
Because of the risk of hepatocellular injury, obtain serum transaminases (ALT and AST) and total bilirubin levels in all patients before initiating and at 1 month, 3 months, and 6 months, and periodically thereafter or as clinically indicated
Existing transaminase elevations >3 x ULN in presence of elevated bilirubin without alternative explanation are important predictors of severe liver injury and should be evaluated before initiating cannabidiol
Hepatitis (Orphan)
Orphan designation for treatment of autoimmune hepatitis
Orphan sponsor
- Revive Therapeutics Ltd; 5 Director Court, Suite 105; Vaughan, Ontario; Canada
Huntington Disease (Orphan)
Orphan designation for delta-9-THC and cannabidiol for treatment of Huntington disease
Sponsor
- MMJ International Holdings; 1895 Preston White Drive, Suite 101; Reston, Virginia 20191
Dosage Forms & Strengths
solution, oral: Schedule V
- 100mg/mL
Seizures
Indicated for seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients aged ≥2 yr
<2 years: Safety and efficacy not established
≥2 years
- 2.5 mg/kg PO BID initially; after 1 week, dose may be increased 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
- Also see Administration
Dosage Modifications
Hepatic impairment
- Mild (Child-Pugh A): No dose adjustment required
- Moderate-to-severe (Child-Pugh B or C): Dosage adjustment recommended including, slower titration
Moderate
- Starting dose: 1.25 mg/kg BID
- Maintenance dose: 2.5 mg/kg BID
- Maximum dose: 5 mg/kg BID
Severe
- Starting dose: 0.5 mg/kg BID
- Maintenance dose: 1 mg/kg BID
- Maximum dose: 2 mg/kg BID
Dosing Considerations
Because of the risk of hepatocellular injury, obtain serum transaminases (ALT and AST) and total bilirubin levels in all patients before initiating and at 1 month, 3 months, and 6 months, and periodically thereafter or as clinically indicated
Existing transaminase elevations >3 x ULN in presence of elevated bilirubin without alternative explanation are important predictors of severe liver injury and should be evaluated before initiating cannabidiol
Clinical trials did not include any patients aged >55 yr to determine whether or not they respond differently from younger patients
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>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%)
Warnings
Contraindications
Hypersensitivity to cannabidiol or any of the ingredients in the product
Cautions
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
May cause hypersensitivity reactions (see Contraindications)
As with other AEDs, cannabidiol should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus; if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered (see Administration)
Elevated liver transaminases
- Dose-related elevations of liver transaminases (ALT and/or AST) reported, typically within the first 2 months of treatment
- The majority of ALT elevations occurred when coadministered with valproate and, to a lesser extent, with clobazam (see Drug interaction overview)
- The incidence of ALT elevations >3 x ULN was 30% in patients taking both concomitant valproate and clobazam, 21% if taking concomitant valproate (without clobazam), 4% if taking concomitant clobazam (without valproate), and 3% in patients taking neither drug; consider discontinuation or dose adjustment of valproate or clobazam if liver enzyme elevations occur
- Obtain serum transaminases before initiating and regularly afterwards; consider more frequent monitoring of serum transaminases and bilirubin if also taking valproate or in patients who have elevated liver enzymes at baseline (see Dosing Considerations)
- Discontinue with transaminase levels >3 x ULN and bilirubin levels >2 x ULN
Without bilirubin elevation
- Prolonged serum transaminases elevations should be evaluated for other possible causes; consider dosage adjustment of any coadministered medication that is known to affect liver (eg, valproate and clobazam)
- Discontinue treatment with sustained transaminase elevations of >5 x ULN
Drug interaction overview
- 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
Effect of cannabidiol on other drugs
- UGT1A9, UGT2B7, CYP2C8, CYP2C9, and CYP2C19 substrates: Consider dose reduction of substrates
- Sensitive CYP2C19 substrates include diazepam and clobazam; coadministration of cannabidiol with clobazam produces a 3-fold increase in plasma concentrations of N-desmethylclobazam, the active metabolite of clobazam
- 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
Pregnancy
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
AED pregnancy registry
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs during pregnancy
- Encourage women who are taking cannabidiol during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll-free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/
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
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
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)
Absorption
Demonstrated an increase in exposure that was less than dose-proportional over the range of 5-20 mg/kg/day
Peak plasma time, steady-state: 2.5-5 hr
Food: High-fat/high-calorie meal increased peak plasma concentration by 5-fold, AUC by 4-fold, and reduced the total variability compared with healthy volunteers
Distribution
Protein bound, including metabolites: >94%
Vd: 20,963-42,849 L
Metabolism
Metabolized in the liver and the gut (primarily in the liver) by CYP2C19 and CYP3A4 enzymes, and UGT1A7, UGT1A9, and UGT2B7 isoforms
After repeat dosing, 7-OH-CBD (active metabolite), has a 38% lower AUC than the parent drug
The 7-OH-CBD metabolite is converted to 7-COO-CBD, which has ~40-fold higher AUC than the parent drug
Based on preclinical models of seizure, the 7-OH-CBD metabolite is active; however, the 7-COOH-CBD metabolite is not active
Elimination
Half-life: 56-61 hr
Clearance: 1111 L/hr (single 1500-mg dose)
Excretion: Mainly feces; minor renal clearance
Administration
Oral Administration
Food may affect cannabidiol plasma concentration levels (see Pharmacology)
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
Discontinuing
- Dose should be decreased gradually
- As with all antiepileptic drugs, avoid abrupt discontinuation when possible, to minimize the risk of increased seizure frequency and status epilepticus
Storage
Store solution in its original bottle in an upright position at room temperature 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)
Do not refrigerate or freeze
Keep the cap tightly closed
Use within 12 weeks of first opening the bottle, then discard any remainder
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Patient Handout
Formulary
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To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.
Adding plans allows you to:
- View the formulary and any restrictions for each plan.
- Manage and view all your plans together – even plans in different states.
- Compare formulary status to other drugs in the same class.
- Access your plan list on any device – mobile or desktop.
