AHFS Class:

• Anticonvulsants, Miscellaneous 28:12.92

Generic Name(s):

• Cannabidiol

Chemical Name:

• 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol

Molecular Formula:

• C₂₁H₃₀O₂

Cannabidiol, a naturally occurring cannabinoid derived from the Cannabis sativa L . plant, is an anticonvulsant.1,5,8,11,13

Cannabidiol oral solution (Epidiolex^®) is used for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex (TSC) in patients 1 year of age or older.1,2,3,4,17 The drug is a highly purified, plant-derived formulation of cannabidiol that has been approved by the FDA for treatment of these seizure disorders.1,18 Cannabidiol oral solution is designated an orphan drug by FDA for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and TSC.6

Seizure Disorders

Seizures Associated with Lennox-Gastaut Syndrome

Cannabidiol oral solution (Epidiolex^®) is used for the treatment of seizures associated with Lennox-Gastaut syndrome in adults and pediatric patients 1 year of age or older.1,2,3

Lennox-Gastaut syndrome is a rare and severe form of epilepsy characterized by early childhood onset (usually between 3-5 years of age), multiple seizure types including drop seizures, an EEG pattern of slow spike and wave activity, and cognitive impairment.2,3 Management of Lennox-Gastaut syndrome can be difficult given the multiple seizure types that can occur and the refractory nature of the condition.2,244

Efficacy of cannabidiol for the treatment of seizures associated with Lennox-Gastaut syndrome was established in 2 randomized, multicenter, double-blind, placebo-controlled studies (GWPCARE3 and GWPCARE4).1,2,3 The studies included patients 2-55 years of age with Lennox-Gastaut syndrome whose seizures were inadequately controlled with stable dosages of at least one anticonvulsant, with or without vagal nerve stimulation and/or a ketogenic diet.1,2,3 Patients who had experienced at least 2 drop seizures (atonic, tonic, or tonic-clonic seizures that resulted or could have resulted in a fall or injury) per week during a 4-week baseline period were randomized to receive add-on therapy with cannabidiol (10 or 20 mg/kg daily) or placebo for 14 weeks in addition to their existing pharmacologic and nonpharmacologic therapy.1,2,3 In both studies, 94% of patients were taking at least 2 concomitant anticonvulsants (most frequently clobazam, valproate, lamotrigine, levetiracetam, and rufinamide).1,2,3 The primary measure of efficacy was the percent change from baseline in monthly (i.e., over 28 days) frequency of drop seizures during the 14-week treatment period.1,2,3

In both studies, drop seizure frequency was substantially reduced in patients receiving cannabidiol compared with those receiving placebo.1 The median reduction in seizure frequency was 42-44% with cannabidiol 20 mg/kg daily, 37% with cannabidiol 10 mg/kg daily, and 17-22% with placebo.1,2 The treatment effect was observed within 4 weeks of initiating cannabidiol therapy and generally remained consistent over the 14-week treatment period.1 Total seizure frequency (including drop seizures and other seizure types) also was substantially reduced with cannabidiol (median decrease of 36-41%) compared with placebo (median decrease of 14-18%) in both studies.1 In addition, cannabidiol was more effective than placebo in improving scores on a patient- or caregiver-rated global impression of change scale in both studies.1

Seizures Associated with Dravet Syndrome

Cannabidiol oral solution (Epidiolex^®) is used for the treatment of seizures associated with Dravet syndrome in adults and pediatric patients 1 year of age or older.1,4

Dravet syndrome (also known as severe myoclonic epilepsy of infancy) is a rare and severe type of epilepsy characterized by early onset of multiple refractory seizure types, frequent episodes of status epilepticus, and developmental delay with cognitive and psychomotor impairment.5,9,10 Up to 85% of patients with Dravet syndrome have mutations in the SCN1A gene encoding the voltage-gated sodium channel.5,9,10 Patients typically present within the first year of life with recurrent generalized tonic-clonic or hemiconvulsive seizures, which are often prolonged and triggered by fever (i.e., febrile seizures).5,8,9,10 Early mortality is high; the leading causes of death are sudden unexplained death in epilepsy (SUDEP) and status epilepticus.8,9,10 Seizures in patients with Dravet syndrome are generally refractory to current anticonvulsant drug options,5,8,11 and anticonvulsants that inhibit the sodium channel (e.g., carbamazepine, oxcarbazepine, lamotrigine, phenytoin) or vigabatrin may exacerbate the condition.9,10 Because complete seizure freedom is typically not achievable, treatment is generally aimed at eliminating or significantly reducing prolonged convulsive seizures and status epilepticus.10

Efficacy of cannabidiol for the treatment of seizures associated with Dravet syndrome was established in a randomized, double-blind, placebo-controlled study (GWPCARE1) in 120 patients 2-18 years of age with Dravet syndrome who had inadequately controlled seizures despite receiving stable dosages of at least one anticonvulsant, with or without vagal nerve stimulation and/or a ketogenic diet.1,4 Patients who had experienced at least 4 convulsive seizures during the 4-week baseline period were randomized to receive add-on therapy with cannabidiol (20 mg/kg daily) or placebo for 14 weeks in addition to their existing pharmacologic and nonpharmacologic regimen.1,4 The majority (93%) of patients were taking at least 2 concomitant anticonvulsants (most frequently clobazam, valproate, stiripentol, levetiracetam, and topiramate).1 The primary measure of efficacy was the percent change from baseline in monthly (e.g., over 28 days) frequency of convulsive seizures (i.e., all countable atonic, tonic, and tonic-clonic seizures) during the 14-week treatment period.1,4

Patients receiving cannabidiol experienced a substantially greater reduction in convulsive seizure frequency compared with those receiving placebo (median reduction of 39 versus 13%, respectively).1,4 Seizure freedom was achieved in 4 patients in the cannabidiol group and no patients in the placebo group.1 The treatment effect was observed within 4 weeks of initiating cannabidiol therapy and generally remained consistent over the 14-week treatment period.1 In addition, patients receiving cannabidiol were more likely than those receiving placebo to be judged by their caregivers as experiencing an overall improvement in their condition as assessed by a global impression of change scale.1,4

Interim results of an ongoing open-label extension study indicate that the reductions in convulsive seizure frequency observed in the GWPCARE1 study were maintained with continued cannabidiol therapy and that long-term cannabidiol therapy had an acceptable safety profile.8

Seizures Associated with Tuberous Sclerosis Complex

Cannabidiol oral solution (Epidiolex^®) is used for the treatment of seizures associated with tuberous sclerosis complex (TSC) in adults and pediatric patients 1 year of age or older.1

TSC is a genetic disorder caused by mutations affecting the mechanistic target of rapamycin (mTOR) pathway.17 Manifestations include excessive cell growth and proliferation resulting in the development of benign hematomas in multiple organs, most frequently the brain, skin, lungs, kidneys, heart, and eyes.17 Epilepsy is the most common neurologic manifestation of TSC, which is often resistant to treatment.17

Efficacy of cannabidiol for the treatment of seizures associated with TSC has been established in a randomized, double-blind, placebo-controlled multicenter study (GWPCARE6).1,17 The study included 224 patients 1-65 years of age with TSC who had at least 8 TSC-associated seizures during a 4-week baseline period (with at least one seizure occurring in at least 3 of the 4 weeks) while receiving at least one anticonvulsant drug with or without vagal nerve stimulation and a ketogenic diet.1 The study population had a high baseline burden of treatment-resistant (primarily focal) seizures; the baseline TSC-associated seizure frequency was 57 per 28 days.1,17 Patients were randomized to receive cannabidiol 25 mg/kg daily, cannabidiol 50 mg/kg daily, or placebo for 16 weeks.1 Treatment with cannabidiol 25 mg/kg daily was associated with substantial reduction in seizure frequency from baseline compared with placebo (median reduction from baseline of 43 versus 20%).1 The reduction in seizure frequency was observed within 4 weeks of initiating therapy and generally remained consistent over the duration of treatment.1 Seizure freedom was achieved in 4 patients who received cannabidiol 25 mg/kg daily compared with no patients who received placebo.1 Although the 50-mg/kg daily dosage of cannabidiol showed similar efficacy to the 25-mg/kg daily dosage of the drug, the higher dosage was associated with a greater incidence of certain adverse effects; in addition, half of the patients who were randomized to the 50-mg/kg daily dosage were unable to reach or maintain that dosage.17 Most of the patients in the study were not receiving concomitant clobazam; however, because of the known pharmacokinetic interaction between clobazam and cannabidiol, a prespecified subgroup analysis was performed to determine whether the efficacy of cannabidiol was independent of clobazam.17 The analysis showed evidence of treatment effect regardless of whether clobazam was used concomitantly.17

General

Because cannabidiol may cause hepatocellular injury, serum aminotransferase (ALT and AST) and total bilirubin concentrations should be assessed prior to initiating therapy.1 (See Hepatic Effects under Cautions.)

As with all anticonvulsant agents, cannabidiol should be withdrawn gradually to minimize the potential for increased seizure frequency and status epilepticus.1 (See Discontinuance of Therapy under Cautions.)

Patients receiving therapy with an anticonvulsant, including cannabidiol, for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), or any unusual changes in mood or behavior.1 (See Suicidality Risk under Cautions.)

Restricted Distribution

Cannabidiol can only be obtained through designated specialty pharmacies.16 Clinicians may contact the manufacturer at 833-426-4243 or consult the Epidiolex^® website ([Web]) for additional information.16

Administration

Cannabidiol is administered orally twice daily as the commercially available oral solution (Epidiolex^®).1 If necessary, the oral solution may be administered enterally through a non-PVC feeding tube (e.g., nasogastric or gastrostomy tube).1 Because food may increase exposure to cannabidiol, consistent dosing with respect to meals is recommended to reduce variability in drug exposure.1,5 (See Description.)

A calibrated measuring device (i.e., oral dosing syringe) should be used to measure and administer the prescribed dose of cannabidiol oral solution; a household teaspoon or tablespoon is not an adequate measuring device.1 If the prescribed dose is less than 1 mL, the manufacturer states that a 1-mL oral syringe should be obtained (e.g., from the pharmacy).1 If the prescribed dose is greater than 5 mL, the total dose should be administered in portions using the 5-mL oral syringe supplied by the manufacturer.1 The dose should be administered directly into the patient's mouth against the inside of the cheek.1

Any unused portions of cannabidiol oral solution should be discarded 12 weeks after the container is first opened.1

Dosage

Lennox-Gastaut Syndrome

For the treatment of seizures associated with Lennox-Gastaut syndrome in adults and pediatric patients 1 year of age or older, the recommended initial dosage of cannabidiol is 5 mg/kg daily (given as 2.5 mg/kg twice daily).1 After 1 week, the dosage may be increased to the recommended maintenance dosage of 10 mg/kg daily (given as 5 mg/kg twice daily).1 Patients who require further reduction of seizures and are tolerating a dosage of 10 mg/kg daily may benefit from an additional increase to the maximum recommended dosage of 20 mg/kg daily (given as 10 mg/kg twice daily).1 Dosage should be titrated in weekly increments of 5 mg/kg daily (2.5 mg/kg twice daily) as tolerated.1 However, if a more rapid titration is necessary, dosage may be increased in increments of 5 mg/kg daily no more frequently than every other day.1

In clinical studies, a cannabidiol dosage of 20 mg/kg daily demonstrated slightly greater efficacy than the recommended maintenance dosage of 10 mg/kg daily, but was associated with an increased incidence of adverse effects.1

Dravet Syndrome

For the treatment of seizures associated with Dravet syndrome in adults and pediatric patients 1 year of age or older, the recommended initial dosage of cannabidiol is 5 mg/kg daily (given as 2.5 mg/kg twice daily).1 After 1 week, the dosage may be increased to the recommended maintenance dosage of 10 mg/kg daily (given as 5 mg/kg twice daily).1 Patients who require further reduction of seizures and are tolerating a dosage of 10 mg/kg daily may benefit from an additional increase to the maximum recommended dosage of 20 mg/kg daily (given as 10 mg/kg twice daily).1 Dosage should be titrated in weekly increments of 5 mg/kg daily (2.5 mg/kg twice daily) as tolerated.1 However, if a more rapid titration is necessary, dosage may be increased in increments of 5 mg/kg daily no more frequently than every other day.1

In clinical studies, a cannabidiol dosage of 20 mg/kg daily demonstrated slightly greater efficacy than the recommended maintenance dosage of 10 mg/kg daily, but was associated with an increased incidence of adverse effects.1

Tuberous Sclerosis Complex

For the treatment of seizures associated with TSC in adults and pediatric patients 1 year of age or older, the recommended initial dosage of cannabidiol is 5 mg/kg daily (given as 2.5 mg/kg twice daily).1 Dosage may be increased in weekly increments of 5 mg/kg daily (given as 2.5 mg/kg twice daily) as tolerated up to the recommended maintenance dosage of 25 mg/kg daily (given as 12.5 mg/kg twice daily).1 If more rapid titration to a dosage of 25 mg/kg daily is necessary, dosage may be increased no more frequently than every other day.1

The effectiveness of dosages lower than 12.5 mg/kg twice daily has not been studied in patients with TSC.1

Special Populations

Hepatic Impairment in Patients with Lennox-Gastaut Syndrome or Dravet Syndrome

Dosage reductions of cannabidiol are recommended in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment, and slower dosage titration may be necessary in these patients.1 Dosage adjustment is not necessary in patients with mild hepatic impairment (Child-Pugh class A).1 (See Hepatic Impairment under Cautions.)

In patients with moderate hepatic impairment, the manufacturer recommends an initial cannabidiol dosage of 2.5 mg/kg daily (given as 1.25 mg/kg twice daily) and a maintenance dosage of 5-10 mg/kg daily (given as 2.5-5 mg/kg twice daily).1

In patients with severe hepatic impairment, the manufacturer recommends an initial cannabidiol dosage of 1 mg/kg daily (given as 0.5 mg/kg twice daily) and a maintenance dosage of 2-4 mg/kg daily (given as 1-2 mg/kg twice daily).1

Hepatic Impairment in Patients with Tuberous Sclerosis Complex

Dosage reductions of cannabidiol are recommended in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment, and slower dosage titration may be necessary in these patients.1 Dosage adjustment is not necessary in patients with mild hepatic impairment (Child-Pugh class A).1 (See Hepatic Impairment under Cautions.)

In patients with moderate hepatic impairment, the manufacturer recommends an initial cannabidiol dosage of 2.5 mg/kg daily (given as 1.25 mg/kg twice daily) and a maintenance dosage of 12.5 mg/kg daily (given as 6.25 mg/kg twice daily).1

In patients with severe hepatic impairment, the manufacturer recommends an initial cannabidiol dosage of 1 mg/kg daily (given as 0.5 mg/kg twice daily) and a maintenance dosage of 5 mg/kg daily (given as 2.5 mg/kg twice daily).1

Renal Impairment

Dosage adjustment is not necessary in patients with renal impairment.5 (See Renal Impairment under Cautions.)

Geriatric Patients

In geriatric patients, dosage should be selected cautiously, usually starting at the lower end of the dosage range.1

Contraindications

Known hypersensitivity to cannabidiol or any excipient in the formulation, including sesame seed oil.1 (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

Hepatic Effects

Dose-related elevations in serum aminotransferase concentrations (ALT and/or AST) have been reported in patients receiving cannabidiol, in some cases requiring hospitalization.1,17,18

In controlled studies in patients with Lennox-Gastaut syndrome or Dravet syndrome receiving cannabidiol dosages of 10 or 20 mg/kg daily, ALT concentrations exceeding 3 times the upper limit of normal (ULN) occurred in 13% of cannabidiol-treated patients compared with 1% of those who received placebo.1 In the controlled study in patients with TSC receiving cannabidiol 25 mg/kg daily, ALT concentrations exceeding 3 times the ULN occurred in 12% of patients receiving the drug.1 Elevations of ALT or AST concentrations to more than 20 times the ULN occurred in less than 1% of cannabidiol-treated patients.1 Such liver enzyme elevations typically occurred in the first 2 months of therapy; however, some cases were reported up to 18 months after initiation of treatment, particularly in patients receiving valproate concomitantly.1 Increases in liver enzymes were not associated with any clinical manifestations of liver injury and were generally reversible following discontinuance or dosage reduction of cannabidiol and/or concomitant valproate.1,2,5 Although small increases in bilirubin concentrations were observed in these studies, these levels generally remained within normal limits.5

Risk factors for the development of treatment-emergent hepatic enzyme elevations include use of higher dosages of cannabidiol, concomitant use of valproate or clobazam, and baseline aminotransferase concentrations above the ULN.1,18 In clinical studies, ALT elevations exceeding 3 times the ULN were reported in 17 or 12% of patients receiving cannabidiol 20 or 25 mg/kg daily, respectively, compared with 1% of patients receiving cannabidiol 10 mg/kg daily.1 The majority of ALT elevations occurred in patients who were also receiving valproate; concomitant use of clobazam also increased the incidence of hepatic enzyme elevations, but to a lesser extent.1 In clinical studies in patients with Lennox-Gastaut syndrome or Dravet syndrome, ALT elevations greater than 3 times the ULN occurred in 30% of cannabidiol-treated patients receiving both valproate and clobazam concomitantly, 21% of patients receiving concomitant valproate (without clobazam), 4% of patients receiving concomitant clobazam (without valproate), and 3% of patients not receiving either of these anticonvulsants concomitantly.1 (See Drug Interactions.)

Serum aminotransferase (ALT and AST) and total bilirubin concentrations should be assessed prior to initiating cannabidiol therapy; such monitoring should be repeated at 1, 3, and 6 months after initiation of therapy, and then periodically thereafter or as clinically indicated.1 Serum aminotransferase and bilirubin concentrations also should be assessed within 1 month following any change in cannabidiol dosage or any addition or change to concomitant therapy with other potentially hepatotoxic drugs.1 More frequent monitoring should be considered in patients receiving concomitant therapy with valproate or who have elevated liver enzymes at baseline.1

Patients with baseline ALT or AST concentrations exceeding 3 times the ULN with concurrent bilirubin concentrations exceeding 2 times the ULN should be evaluated prior to initiating cannabidiol.1 Cannabidiol therapy should be discontinued in patients with ALT or AST concentrations exceeding 3 times the ULN and bilirubin concentrations exceeding 2 times the ULN, and also in patients with sustained aminotransferase elevations exceeding 5 times the ULN.1 If signs or symptoms suggestive of liver injury occur (e.g., unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, and/or dark urine), serum aminotransferase and total bilirubin concentrations should be assessed promptly and cannabidiol therapy should be interrupted or discontinued as appropriate.1 Patients with prolonged elevations of ALT or AST should be evaluated for other possible causes.1

If cannabidiol is used concomitantly with other potentially hepatotoxic drugs (e.g., valproate, clobazam), dosage adjustment of the coadministered drug should be considered.1 (See Drug Interactions.)

Somnolence and Sedation

Cannabidiol can cause dose-related somnolence and sedation.1 These effects generally occur early in treatment and may diminish with continued therapy.1 In controlled studies of patients with Lennox-Gastaut syndrome or Dravet syndrome, somnolence or sedation (including lethargy) was reported in 27 or 34% of patients receiving cannabidiol 10 or 20 mg/kg daily, respectively, compared with 11% of those receiving placebo and was generally dose related.1 In a controlled study in patients with TSC, somnolence or sedation was reported in 19% of patients receiving cannabidiol 25 mg/kg daily compared with 17% of those receiving placebo.1 In all of these studies, the incidence of somnolence and sedation was higher in patients who were also receiving clobazam.1,17 (See Clobazam under Drug Interactions.)

Patients should be monitored for somnolence and sedation during cannabidiol therapy, particularly if they are receiving other CNS depressants (including alcohol) concomitantly.1 (See Advice to Patients.)

Suicidality Risk

The risk of suicidality (suicidal behavior or ideation) is increased in patients receiving anticonvulsants, including cannabidiol, for any indication.1 An analysis of suicidality reports from 199 placebo-controlled studies involving 11 different anticonvulsants in patients with epilepsy, psychiatric disorders, and other conditions found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1 This increased suicidality risk was consistent among anticonvulsants with varying mechanisms of actions and across a range of indications, and was observed as early as 1 week after beginning therapy.1 Because most of these studies did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior with anticonvulsant treatment beyond 24 weeks is not known.1 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1

Clinicians who prescribe cannabidiol or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness.1 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1 All patients treated with an anticonvulsant for any indication should be closely monitored for the emergence or worsening of suicidal thoughts and behavior.1 If any such symptoms emerge during anticonvulsant therapy, the clinician should consider whether they may be related to the illness being treated.1 (See Advice to Patients.)

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions may occur with cannabidiol.1 Some patients in clinical studies developed hypersensitivity reactions with symptoms of pruritus, erythema, and angioedema that required treatment with antihistamines and corticosteroids.1 If a hypersensitivity reaction occurs, cannabidiol oral solution should be discontinued and appropriate therapy initiated; the drug should not resumed in patients who have previously experienced a hypersensitivity reaction.1 (See Contraindications under Cautions.)

Discontinuance of Therapy

As with all anticonvulsant agents, cannabidiol therapy should be withdrawn gradually to reduce the risk of increased seizure frequency and status epilepticus.1 Abrupt discontinuance of the drug should be avoided when possible unless safety concerns require rapid withdrawal.1 In clinical studies, dosage of cannabidiol was tapered over a period of 10 days at the end of the treatment period.2,4

Abuse Potential and Dependence

Cannabidiol is not a controlled drug.1

Abuse-related adverse events were not observed in phase 1 clinical studies of cannabidiol.1 However, since cannabidiol is derived from the Cannabis sativa plant, a thorough evaluation of the drug's abuse potential has been conducted.5 Receptor binding studies have not identified any affinity of cannabidiol for cannabinoid (CB₁ or CB₂) receptors or other receptors associated with abuse potential.5 In a drug discrimination study in animals, cannabidiol did not produce cannabinoid-like behavioral responses, including generalization to tetrahydrocannabinol (THC; the psychoactive component of Cannabis sativa 11,13,14 ); self-administration of cannabidiol also was not observed in animals, suggesting that the drug does not possess rewarding properties.1 In an abuse potential study that compared cannabidiol to dronabinol (synthetic THC), alprazolam, and placebo in non-dependent adult recreational drug users, administration of therapeutic and supratherapeutic doses of cannabidiol (equivalent to 10-60 mg/kg in an adult weighing 75 kg) produced positive subjective responses (e.g., “drug liking,” “take drug again”) that were comparable to placebo.1 In contrast, dronabinol (10 and 30 mg) and alprazolam (2 mg) produced substantially greater positive subjective responses than cannabidiol.1

Cannabidiol is not likely to produce physical dependence.1 In a physical dependence study in humans, no withdrawal symptoms were observed following discontinuance of cannabidiol after 28 days of administration.1

Laboratory Test Interferences.

Treatment with cannabidiol may result in positive drug tests for cannabis.1

Specific Populations

Pregnancy

There are no adequate data on the developmental risks associated with the use of cannabidiol in pregnant women.1 Cannabidiol produced developmental toxicity (e.g., embryofetal mortality, decreased fetal body weight, decreased growth, delayed sexual maturation, long-term neurobehavioral changes) when administered orally to pregnant animals at exposure levels similar to or higher than those associated with the recommended human dosage.1

Women who are pregnant while receiving cannabidiol should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or [Web].1

Lactation

It is not known whether cannabidiol or its metabolites are distributed into milk, affects milk production, or affects the breast-fed infant.1 The benefits of breast-feeding should be considered along with the importance of cannabidiol to the woman and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of cannabidiol have not been established in pediatric patients younger than 1 year of age.1

Geriatric Use

There is no experience with cannabidiol in patients 55 years of age and older to determine whether these patients respond differently than younger adults.1

Hepatic Impairment

Systemic exposure to cannabidiol is increased by approximately 2.5- to 5.2-fold in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment compared with individuals with normal hepatic function; dosage adjustments are recommended in such patients.1,5 (See Special Populations under Dosage and Administration.)

Mild hepatic impairment (Child-Pugh class A) does not have a clinically important effect on systemic exposure to cannabidiol or its metabolites; therefore, dosage adjustment is not necessary in such patients.1,5

Renal Impairment

Renal impairment (mild, moderate, or severe) does not have a clinically important effect on systemic exposure to cannabidiol; therefore, dosage adjustment is not necessary in patients with renal impairment.5

Common Adverse Effects

Adverse effects reported in at least 10% of patients with Lennox-Gastaut syndrome or Dravet syndrome receiving cannabidiol and more frequently than placebo include somnolence, decreased appetite, transaminase elevations, fatigue, malaise, asthenia, rash, insomnia, sleep disorder, poor sleep quality, and infections.1

Adverse effects reported in at least 10% of patients with TSC receiving cannabidiol and more frequently than placebo include diarrhea, transaminase elevations, decreased appetite, somnolence, pyrexia, and vomiting.1

Cannabidiol is metabolized by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C19, and also by uridine 5'-diphospho-glucuronosyltransferase (UGT) isoenzymes 1A7, 1A9, and 2B7.1

Cannabidiol has the potential to inhibit CYP isoenzymes 2C8, 2C9, and 2C19, and may induce or inhibit CYP1A2 and CYP2B6 at clinically relevant concentrations.1

Cannabidiol also inhibits UGT1A9 and UGT2B7, but does not inhibit UGT1A1, 1A3, 1A4, 1A6, or 2B17.1

Cannabidiol and its active metabolite (7-OH-CBD) are not expected to affect breast cancer resistance protein (BCRP) and bile salt export pump (BSEP), P-glycoprotein (P-pg), organic anion transporters (OAT) 1 and OAT3, organic cation transporters (OCT) 1 and OCT2, multidrug and toxin extrusion transporters (MATE) 1 and MATE2K, or organic anion transport proteins (OATP) 1B1 or OATP1B3.1 The inactive metabolite, 7-COOH-CBD, inhibits BCRP and BSEP transport at clinically relevant concentrations.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent Inducers of CYP3A4 or CYP2C19

Concomitant use of cannabidiol with potent inducers of CYP3A4 or CYP2C19 may decrease plasma cannabidiol concentrations and reduce efficacy of the drug.1 A dosage increase of cannabidiol (by up to twofold) should be considered (based on clinical response and tolerability) if the drug is used concomitantly with a potent CYP3A4 and/or CYP2C19 inducer.1

Potent Inhibitors of CYP3A4 or CYP2C19

In drug interaction studies evaluating the effects of potent CYP3A4 and CYP2C19 inhibitors on the pharmacokinetics of cannabidiol, no clinically meaningful changes in exposure to cannabidiol were observed.1

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP1A2, CYP2C8, CYP2C9, and CYP2C19 Substrates

When cannabidiol is administered concomitantly with drugs that are metabolized by CYP1A2 (e.g., caffeine, theophylline, tizanidine), CYP2C8, CYP2C9 (e.g., phenytoin), or CYP2C19, there is a potential for inhibition of enzyme activity, thereby increasing exposure to the substrate drug; dosage reduction of the substrate drug should be considered as clinically appropriate if adverse effects occur.1

CYP2B6 Substrates

There is a potential for both induction and inhibition of enzyme activity when cannabidiol is administered concomitantly with CYP2B6 substrates (e.g., bupropion, efavirenz); dosage adjustment of the substrate drug should be considered as clinically appropriate.1

CYP3A4 Substrates

Coadministration of cannabidiol with midazolam (a sensitive CYP3A4 substrate) did not alter plasma midazolam concentrations.1

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase Enzymes

Drug interactions are expected when cannabidiol is administered concomitantly with UGT1A9 substrates (e.g., diflunisal, propofol, fenofibrate) or UGT2B7 substrates (e.g., gemfibrozil, lamotrigine, morphine, lorazepam) because cannabidiol can inhibit these UGT enzymes.1 Potential increased concentrations of the UGT substrate may occur; therefore, a reduction in dosage of the substrate drug should be considered as clinically appropriate if adverse effects occur during concomitant use.1

Alcohol

Peak plasma concentrations and AUC of cannabidiol increased by 93 and 63%, respectively, when coadministered with alcohol.1 Patients receiving these drugs concomitantly should be monitored for sedation and somnolence.1

Anticonvulsants

Clobazam

Concomitant use of cannabidiol and clobazam can increase the risk of hepatic enzyme elevations.1

In addition, a clinically important pharmacokinetic interaction has been observed between cannabidiol and clobazam.1 Cannabidiol has been shown to increase peak plasma concentrations and AUC of the active metabolite of clobazam, N -desmethylclobazam, by approximately threefold; such increased concentrations of N -desmethylclobazam can increase the risk of clobazam-related adverse effects.1,5 In clinical studies, the incidence of somnolence was higher in cannabidiol-treated patients who were also receiving clobazam compared with those patients who were not receiving clobazam.1 (See Somnolence and Sedation under Cautions.) Clobazam also had an effect on the pharmacokinetics of cannabidiol, increasing peak plasma concentrations and AUC of the active cannabidiol metabolite by 73 and 47%, respectively.1

The manufacturer states that dosage reduction of clobazam should be considered if clobazam-related adverse effects occur during concomitant use with cannabidiol.1 If hepatic enzyme elevations occur in a patient receiving cannabidiol and clobazam concomitantly, dosage reduction or discontinuance of clobazam therapy should be considered.1 (See Hepatic Effects under Cautions.)

Stiripentol

Concomitant use of cannabidiol and stiripentol in healthy individuals increased peak plasma concentrations and AUC of stiripentol by 28 and 55%, respectively.1 In patients with epilepsy, peak plasma concentrations and AUC of stiripentol increased by 17 and 30%, respectively.1 The clinical importance of this interaction is not known.1 Patients should be monitored for adverse effects of stiripentol if the drugs are used concomitantly.1

Valproate

Concomitant use of cannabidiol and valproate may increase the risk of hepatic enzyme elevations.1,2,12 Dosage reduction or discontinuance of cannabidiol and/or valproate should be considered if hepatic enzyme elevations occur.1 (See Hepatic Effects under Cautions.)

In healthy individuals, cannabidiol did not have any effect on systemic exposure of valproate.1,5

Other Anticonvulsants

In an open-label study evaluating potential pharmacokinetic interactions between cannabidiol and some commonly used anticonvulsant agents in patients with treatment-resistant epilepsy, cannabidiol did not appear to have a clinically important effect on serum concentrations of carbamazepine, clonazepam, ethosuximide, ezogabine, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, or vigabatrin.12 However, a substantial increase in serum concentrations of topiramate, rufinamide, N -desmethylclobazam (active metabolite of clobazam), zonisamide, and eslicarbazepine was observed when these drugs were administered concomitantly with cannabidiol.12

CNS Depressants

Concomitant use of cannabidiol with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence.1 Patients receiving cannabidiol and other CNS depressants concomitantly should be monitored for sedation and somnolence.1

Hepatotoxic Drugs

Concomitant use of cannabidiol and valproate may increase the risk of hepatic enzyme elevations.1,2,12 (See Hepatic Effects under Cautions.) Dosage reduction or discontinuance of cannabidiol and/or valproate should be considered if hepatic enzyme elevations occur.1 There are insufficient data to determine the risk of concomitant administration of other hepatotoxic drugs and cannabidiol.1

Mechanistic Target of Rapamycin (mTOR) Inhibitors

Cannabidiol can increase concentrations of mTOR inhibitors (e.g., sirolimus, everolimus), possibly via inhibition of CYP3A4.18 Some clinicians recommend that serum concentrations of the mTOR inhibitor be closely monitored.1,18 Patients also should be monitored for adverse effects of the mTOR inhibitor; dosage reduction may be necessary.1,18

Rifampin

When cannabidiol was coadministered with rifampin, the AUC of cannabidiol and the active metabolite 7-OH-CBD decreased by approximately 32 and 63%, respectively; the impact of these changes on efficacy of cannabidiol is not known.1 The manufacturer states that an increase in cannabidiol dosage by up to twofold should be considered based on clinical response and tolerability when these drugs are used concomitantly.1

Warfarin

Limited data from case reports suggest possible interaction between warfarin and cannabidiol, possibly due to inhibitory activity of CYP2C9.19 In warfarin-treated patients initiating cannabidiol, close monitoring of the INR is recommended during initiation and titration of cannabidiol therapy.19

Description

Cannabidiol is a highly purified cannabinoid extracted from the naturally occurring Cannabis sativa L. plant.1,5,8,11,13 Cannabidiol is structurally distinct from other currently available anticonvulsant drugs.5,8 The exact mechanism of action by which cannabidiol exerts its anticonvulsant activity in humans has not been fully elucidated, but does not appear to be related to a direct effect on cannabinoid receptors.1,8,11,13,14 Cannabidiol and tetrahydrocannabinol (THC) are the 2 major pharmacologically active cannabinoids.11 Unlike THC, cannabidiol has little to no affinity for cannabinoid receptors CB₁ or CB₂ and does not possess psychoactive properties resulting in a lower potential for abuse.8,13,14 (See Abuse Potential and Dependence under Cautions.) Cannabidiol has exhibited anticonvulsant activity in several animal seizure models, including maximal electroshock, audiogenic seizures, and chemically induced seizures (e.g., pentylenetetrazole, 3-mercaptopropionic acid).13 Cannabidiol also has been shown to modulate various receptors and ion channels; however, further study is needed to determine whether these effects are responsible for the anticonvulsant properties of the drug.13,14

Systemic exposure to cannabidiol increases in a less than proportional manner over a dosage range of 5-20 mg/kg daily.1 At steady state, peak plasma cannabidiol concentrations occur 2.5-5 hours following administration of the oral solution.1 Oral bioavailability of cannabidiol is low due to first-pass metabolism.11,13,14,15 Administration of cannabidiol with a high-fat, high-calorie meal increased AUC and peak plasma concentrations of the drug by fourfold and fivefold, respectively, and decreased total variability, compared with administration in the fasted state.1 Administration with a low-fat, low-calorie meal increased AUC and peak plasma concentrations by threefold and fourfold, respectively.1 (See Administration under Dosage and Administration.) Plasma protein binding of cannabidiol and its metabolites exceeds 94%.1,5 The drug is highly lipophilic and rapidly distributes into the CNS and adipose tissue.11,14 Cannabidiol is extensively metabolized in the liver and gut, principally by the CYP enzyme system (CYP2C19 and CYP3A4) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes (1A7, 1A9, and 2B7).1,5 The active metabolite, 7-hydroxy-cannabidiol (7-OH-CBD), is equipotent to cannabidiol in seizure models and has a systemic exposure that is approximately 38% lower than the parent drug.1,5 Systemic exposure to the inactive metabolite 7-carboxy-cannabidiol (7-COOH-CBD) is approximately 40-fold higher than that of the parent drug.1,5 Cannabidiol is excreted primarily in feces, with minor renal clearance.1 Following administration of a radiolabeled dose of cannabidiol, approximately 84% of the radioactivity was recovered in feces and 8% in urine.5 The mean elimination half-life of cannabidiol following repeated dosing is 56-61 hours.1,5

Advice to Patients

Importance of advising patients and/or caregivers to read the patient information (medication guide) and the instructions for use.1

Importance of instructing patients and/or caregivers regarding administration of cannabidiol oral solution.1 Importance of advising patients to discard any unused oral solution 12 weeks after the container is first opened.1

Risk of hepatic injury; importance of informing patients and/or caregivers of the need for specific monitoring during therapy.1 Importance of advising patients to inform their clinician promptly if any signs or symptoms of liver injury (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine) occur.1

Risk of somnolence and sedation, and impairment of judgment, thinking, or motor skills.1 Importance of advising patients not to drive or operate machinery until the effects of the drug are known.1

Anticonvulsants, including cannabidiol, may increase the risk of suicidal thoughts or behavior.1 Importance of patients, caregivers, and family members being alert to and immediately reporting emergence or worsening of depression, any unusual changes in mood or behavior, or emergence of suicidal thoughts, behavior, or thoughts of self harm.1

Importance of advising patients not to discontinue cannabidiol therapy without consulting with their clinician.1 The drug should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus.1

Importance of informing patients that cannabidiol may cause positive cannabis drug screens.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., clobazam, valproate) and OTC drugs, vitamins, herbal supplements, or any other cannabis-based products, as well as any concomitant illnesses (e.g., liver disease).1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of clinicians informing women about the existence of and encouraging enrollment in the North American Antiepileptic Drug Pregnancy Registry.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Greenwich Biosciences, Inc. Epidiolex^® (cannabidiol) oral solution prescribing information. Carlsbad, CA; 2020 Oct.

2. Thiele EA, Marsh ED, French JA et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet . 2018; 391:1085-1096. [PubMed 29395273]

3. Devinsky O, Patel AD, Cross JH et al. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N Engl J Med . 2018; 378:1888-1897. [PubMed 29768152]

4. Devinsky O, Cross JH, Wright S. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med . 2017; 377:699-700. [PubMed 28813226]

5. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 210365Orig1s000: Summary review. 2018 Jun 22. From FDA website. [Web]

6. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2019 Apr 24. [Web]

7. Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: placement in Schedule V of certain FDA-approved drugs containing cannabidiol; corresponding change to permit requirements. 21 CFR Parts 1308, 1312. Final Rule. [Docket No. DEA-486] Fed Regist. 2018; 83:48950-3.

8. Devinsky O, Nabbout R, Miller I et al. Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial. Epilepsia . 2019; 60:294-302. [PubMed 30582156]

9. Gataullina S, Dulac O. From genotype to phenotype in Dravet disease. Seizure . 2017; 44:58-64. [PubMed 27817982]

10. Wirrell EC, Laux L, Donner E et al. Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations From a North American Consensus Panel. Pediatr Neurol . 2017; 68:18-34.e3. [PubMed 28284397]

11. Chen JW, Borgelt LM, Blackmer AB. Cannabidiol: A New Hope for Patients With Dravet or Lennox-Gastaut Syndromes. Ann Pharmacother . 2019; 53:603-611. [PubMed 30616356]

12. Gaston TE, Bebin EM, Cutter GR et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia . 2017; 58:1586-1592. [PubMed 28782097]

13. Perucca E. Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last?. J Epilepsy Res . 2017; 7:61-76. [PubMed 29344464]

14. Gaston TE, Friedman D. Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy Behav . 2017; 70:313-318. [PubMed 28087250]

15. Friedman D, French JA, Maccarrone M. Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders. Lancet Neurol . 2019; 18:504-512. [PubMed 30910443]

16. Greenwich Biosciences. EPIDIOLEX® (cannabidiol) Cannabidiol CV is available through specialty pharmacies From Epidiolex website. Accessed 2019 Aug 13. [Web]

17. Thiele EA, Bebin EM, Bhathal H et al. Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial. JAMA Neurol . 2021; 78:285-292. [PubMedCentral][PubMed 33346789]

18. Lattanzi S, Trinka E, Striano P et al. Highly Purified Cannabidiol for Epilepsy Treatment: A Systematic Review of Epileptic Conditions Beyond Dravet Syndrome and Lennox-Gastaut Syndrome. CNS Drugs . 2021; 35:265-281. [PubMedCentral][PubMed 33754312]

19. Cortopassi J. Warfarin dose adjustment required after cannabidiol initiation and titration. Am J Health Syst Pharm . 2020; 77:1846-1851. [PubMed 33016308]

244. French JA, Kanner AM, Bautista J et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology . 2004; 62:1261-73. [PubMed 15111660]