Epidiolex (cannabidiol)

• Epidiolex is a prescription medicine that is used to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in people 1 year of age and older.
• It is not known if Epidiolex is safe and effective in children under 1 year of age.

The most common side effects of Epidiolex include:

• sleepiness
• decreased appetite
• diarrhea
• increase in liver enzymes
• feeling very tired and weak
• rash
• sleep problems
• fever
• vomiting
• infections

These are not all of the possible side effects of Epidiolex. For more information ask your healthcare provider or pharmacist.

Tell your healthcare provider about any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Drug Abuse And Dependence

Controlled Substance

Epidiolex is not a controlled substance.

Abuse

• Animal abuse-related studies show that cannabidiol does not produce cannabinoid-like behavioral responses, including generalization to delta-9-tetrahydrocannabinol (THC) in a drug discrimination study.
• Cannabidiol also does not produce animal self-administration, suggesting it does not produce rewarding effects. In a human abuse potential study, acute administration of cannabidiol to non-dependent adult recreational drug users at therapeutic and supratherapeutic doses of 750, 1500, and 4500 mg in the fasted state (equivalent respectively to 10, 20, and 60 mg/kg in a 75 kg adult) produced responses on positive subjective measures such as Drug Liking and Take Drug Again that were within the acceptable placebo range.
• In contrast, 10 and 30 mg of dronabinol (synthetic THC) and 2 mg alprazolam produced large increases on positive subjective measures compared to placebo that were statistically significantly greater than those produced by cannabidiol.
• In other Phase 1 clinical studies conducted with cannabidiol, there were no reports of abuse-related adverse events.

Dependence

• In a human physical dependence study, administration of cannabidiol 1500 mg/day (750 mg twice daily) to adults for 28 days did not produce signs or symptoms of withdrawal over a 6-week assessment period beginning three days after drug discontinuation.
• This suggests that cannabidiol likely does not produce physical dependence.

Assessments Prior To Initiating Epidiolex

• Because of the risk of hepatocellular injury, obtain serum transaminases (ALT and AST) and total bilirubin levels in all patients prior to starting treatment with Epidiolex.

Dosing For Seizures Associated With Lennox-Gastaut Syndrome Or Dravet Syndrome

• The starting dosage is 2.5 mg/kg by mouth twice daily (5 mg/kg/day).
• After one week, the dosage can be increased to a maintenance dosage of 5 mg/kg twice daily (10 mg/kg/day).
• Patients who are tolerating Epidiolex at 5 mg/kg twice daily and require further reduction of seizures may benefit from a dosage increase up to a maximum recommended maintenance dosage of 10 mg/kg twice daily (20 mg/kg/day), in weekly increments of 2.5 mg/kg twice daily (5 mg/kg/day), as tolerated. For patients in whom 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.

Dosing For Seizures Associated With Tuberous Sclerosis Complex

• The starting dosage is 2.5 mg/kg by mouth twice daily (5 mg/kg/day).
• Increase the dose in weekly increments of 2.5 mg/kg twice daily (5 mg/kg/day), as tolerated, to a recommended maintenance dosage of 12.5 mg/kg twice daily (25 mg/kg/day). For patients in whom a more rapid titration to 25 mg/kg/day is warranted, the dosage may be increased no more frequently than every other day.
• The effectiveness of doses lower than 12.5 mg/kg twice daily has not been studied in patients with TSC.

Administration Instructions

• Food may affect Epidiolex levels. Consistent dosing of Epidiolex with respect to meals is recommended to reduce variability in cannabidiol plasma exposure.
• A calibrated measuring device (either 5 mL or 1 mL oral syringe) will be provided and is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device.
• Oral administration is recommended. When necessary, can be enterally administered via feeding tubes, such as nasogastric or gastrostomy tubes. Do not use with tubes made of polyvinyl chloride (PVC).
• Discard any unused Epidiolex remaining 12 weeks after first opening the bottle.

Discontinuation Of Epidiolex

• When discontinuing Epidiolex, the dose should be decreased gradually. As with most antiepileptic drugs, abrupt discontinuation should be avoided when possible, to minimize the risk of increased seizure frequency and status epilepticus.

Patients With Hepatic Impairment

• Dose adjustment is recommended in patients with moderate (Child-Pugh B) hepatic impairment or severe (Child-Pugh C) hepatic impairment. It may be necessary to have slower dose titration in patients with moderate or severe hepatic impairment than in patients without hepatic impairment (see Table 1).
• Epidiolex does not require dose adjustment in patients with mild (Child-Pugh A) hepatic impairment.

Table 1: Dose Adjustments in Patients with Hepatic Impairment

Effect Of Other Drugs On Epidiolex

Strong CYP3A4 Or CYP2C19 Inducers

• Coadministration with a strong CYP3A4 and CYP2C19 inducer (rifampin 600 mg once daily) decreased cannabidiol and 7-OH-CBD plasma concentrations by approximately 32% and 63%.
• The impact of such changes on efficacy of Epidiolex are not known.
• Consider an increase in Epidiolex dosage (based on clinical response and tolerability) up to 2-fold, when coadministered with a strong CYP3A4 and/or CYP2C19 inducer.

Effect Of Epidiolex On Other Drugs

UGT1A9, UGT2B7, CYP1A2, CYP2B6, CYP2C8, CYP2C9 And CYP2C19 Substrates

• In vitro data predict drug-drug interactions with CYP1A2 substrates (e.g., theophylline, caffeine), CYP2B6 substrates (e.g., bupropion, efavirenz), uridine 5'-diphospho-glucuronosyltransferase 1A9 (UGT1A9) substrates (e.g., diflunisal, propofol, fenofibrate), and UGT2B7 substrates (e.g., gemfibrozil, lamotrigine, morphine, lorazepam) when coadministered with Epidiolex.
• Coadministration of Epidiolex is also predicted to cause clinically significant interactions with CYP2C8 and CYP2C9 (e.g., phenytoin) substrates.
• Because of potential inhibition of enzyme activity, consider a reduction in dosage of substrates of UGT1A9, UGT2B7, CYP2C8, and CYP2C9, as clinically appropriate, if adverse reactions are experienced when administered concomitantly with Epidiolex.
• Because of potential for both induction and inhibition of enzyme activity, consider adjusting dosage of substrates of CYP1A2 and CYP2B6 as clinically appropriate.

Sensitive CYP2C19 Substrates

• In vivo data show that coadministration of Epidiolex increases plasma concentrations of drugs that are metabolized by (i.e., are substrates of) CYP2C19 (e.g., diazepam) and may increase the risk of adverse reactions with these substrates.
• Consider a reduction in dosage of sensitive CYP2C19 substrates, as clinically appropriate, when coadministered with Epidiolex.

Clobazam

• Coadministration of Epidiolex produces a 3-fold increase in plasma concentrations of N-desmethylclobazam, the active metabolite of clobazam (a substrate of CYP2C19), with no effect on clobazam levels.
• The increase in N-desmethylclobazam may increase the risk of clobazam-related adverse reactions.
• Consider a reduction in dosage of clobazam if adverse reactions known to occur with clobazam are experienced when co-administered with Epidiolex.

Concomitant Use Of Epidiolex And Valproate

• Concomitant use of Epidiolex and valproate increases the incidence of liver enzyme elevations.
• If such elevations occur, discontinuation or reduction of Epidiolex and/or concomitant valproate should be considered.
• Insufficient data are available to assess the risk of concomitant administration of other hepatotoxic drugs and Epidiolex.

Concomitant Use Of Epidiolex And Mammalian Target Of Rapamycin (mTOR) Or Calcineurin Inhibitors

• No dedicated drug-drug interaction studies have been conducted with mTOR inhibitors (e.g., everolimus) or calcineurin inhibitors (e.g., tacrolimus).
• Reports in the literature suggest that cannabidiol administration resulted in increased serum levels of everolimus, sirolimus, or tacrolimus.
• The mechanism of increase in mTOR or calcineurin inhibitors concentrations is not clearly understood.
• 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 Epidiolex.

CNS Depressants And Alcohol

• Concomitant use of Epidiolex with other CNS depressants (including alcohol) may increase the risk of sedation and somnolence.

• There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as Epidiolex, during pregnancy.
• Encourage women who are taking Epidiolex 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/.
• 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.
• The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Epidiolex and any potential adverse effects on the breastfed infant from Epidiolex or from the underlying maternal condition.