cannabidiol (Rx)

>10% (LGS or DS)

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%)

>10% (TSC)

Diarrhea (31%)

Elevated transaminases (25%)

Decreased appetite (20%)

Pyrexia (19%)

Vomiting (17%)

Somnolence (13%)

1-10% (LGS or DS)

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%)

1-10% (TSC)

Gait disturbance (9%)

Nausea (9%)

Gastroenteritis (8%)

Ear infection (8%)

Rash (8%)

Decreased weight (7%)

Anemia (7%)

Decreased platelet count (5%)

Increased eosinophil count (5%)

Fatigue, malaise, asthenia (5%)

Urinary tract infection (5%)

Pneumonia (4%)

Rhinorrhea (4%)

Contraindications

Hypersensitivity to cannabidiol or any of the product ingredients

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 (eg, pruritus, erythema, angioedema)

As with other AEDs, cannabidiol should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus; if withdrawal is needed because of a serious adverse event, rapid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

Therapy can cause weight loss, which may be dose-related

A decrease in hemoglobin and hematocrit reported with no effect on red blood indices

Elevation of serum creatinine reported within 2 weeks of initiating therapy that was reversible in healthy adults; mechanism not determined

Hepatocellular injury

• Dose-related liver transaminases (ALT and/or AST) elevations reported, typically within the first 2 months of treatment
• Majority of ALT elevations occurred when coadministered with valproate and, to a lesser extent, with clobazam
• In 25 mg/kg/day treated patients with TSC, the incidence of ALT elevations greater than 3 times the ULN was 20% in patients taking both concomitant valproate and clobazam, 25% in patients taking concomitant valproate (without clobazam), 0% in patients taking concomitant clobazam (without valproate), and 6% 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 afterward; 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

  • Evaluate prolonged serum transaminases elevations 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
  • No dedicated drug-drug interaction studies have been conducted with mTOR inhibitors (eg, everolimus) or calcineurin inhibitors (eg, tacrolimus); reports in literature suggest cannabidiol administration resulted in increased serum levels of everolimus, sirolimus, or tacrolimus; consider a reduction in dosage of everolimus, sirolimus, or tacrolimus, if adverse reactions known to occur with those medications are experienced when co-administered with cannabidiol

Pregnancy

There are no available data regarding use in pregnant women

Based on animal data, may cause fetal harm

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.

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

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

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