Cannabidiol
FDA Drug Information • Also known as: Epidiolex
- Brand Names
- Epidiolex
- Dosage Form
- POWDER
- Product Type
- BULK INGREDIENT
Description
11 DESCRIPTION Cannabidiol is a cannabinoid designated chemically as 2-[(1R,6R)-3-Methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol (IUPAC/CAS). Its empirical formula is C 21 H 30 O 2 and its molecular weight is 314.46. The chemical structure is: Cannabidiol, the active ingredient in EPIDIOLEX, is a cannabinoid that naturally occurs in the Cannabis sativa L . plant. Cannabidiol is a white to pale yellow crystalline solid. It is insoluble in water and is soluble in organic solvents. EPIDIOLEX (cannabidiol) oral solution is a clear, colorless to yellow liquid containing cannabidiol at a concentration of 100 mg/mL. Inactive ingredients include dehydrated alcohol (7.9% w/v), sesame seed oil, strawberry flavor, and sucralose. EPIDIOLEX contains no ingredient made from a gluten-containing grain (wheat, barley, or rye). chemical structure
What Is Cannabidiol Used For?
1 INDICATIONS AND USAGE EPIDIOLEX is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in patients 1 year of age and older. EPIDIOLEX is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in patients 1 year of age and older ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION
Obtain serum transaminases (ALT and AST) and total bilirubin levels in all patients prior to starting treatment. ( 2.1 , 5.1 ) See Full Prescribing Information for titration. ( 2.2 , 2.3 ) Seizures Associated with Lennox-Gastaut Syndrome or Dravet Syndrome The recommended 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). ( 2.2 ) Based on individual clinical response and tolerability, EPIDIOLEX can be increased up to a maximum recommended maintenance dosage of 10 mg/kg twice daily (20 mg/kg/day). Seizures Associated with Tuberous Sclerosis Complex The recommended starting dosage is 2.5 mg/kg by mouth twice daily (5 mg/kg/day). Increase the dose weekly by 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). ( 2.3 ) Patients with Impaired Hepatic Function Dosage adjustment is recommended for patients with moderate or severe hepatic impairment. ( 2.6 , 8.6 ) 2.1 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 [see Warnings and Precautions ( 5.1 )]. 2.2 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. 2.3 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. 2.4 Administration Instructions Food may affect EPIDIOLEX levels [see Clinical Pharmacology ( 12.3 )]. Consistent dosing of EPIDIOLEX with respect to...Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in labeling:
Hepatic Injury [see Warnings and Precautions ( 5.1 )] Somnolence and Sedation [see Warnings and Precautions ( 5.2 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions ( 5.5 )] The most common adverse reactions (10% or more for EPIDIOLEX and greater than placebo) in patients with Lennox-Gastaut syndrome or Dravet syndrome are: somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections. ( 6.1 ) The most common adverse reactions (10% or more for EPIDIOLEX and greater than placebo) in patients with tuberous sclerosis complex are: diarrhea; transaminase elevations; decreased appetite; somnolence; pyrexia; and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In controlled and uncontrolled trials in patients with LGS and DS, 689 patients were treated with EPIDIOLEX, including 533 patients treated for more than 6 months, and 391 patients treated for more than 1 year. In controlled and uncontrolled trials in patients with TSC, 223 patients were treated with EPIDIOLEX, including 151 patients treated for more than 6 months, 88 patients treated for more than 1 year, and 15 patients treated for more than 2 years. In an expanded access program and other compassionate use programs, 271 patients with DS, LGS, or TSC were treated with EPIDIOLEX, including 237 patients treated for more than 6 months, 204 patients treated for more than 1 year, and 140 patients treated for more than 2 years. Patients with LGS or DS In placebo-controlled trials of patients with LGS or DS (includes Studies 1, 2, 3, and a Phase 2 controlled study in DS), 323 patients received EPIDIOLEX [see Clinical Studies ( 14.1 , 14.2 )] . Adverse reactions are presented below; the duration of treatment in these trials was up to 14 weeks. Approximately 46% of patients were female, 83% were Caucasian, and the mean age was 14 years (range 2 to 48 years). All patients were taking other AEDs. In controlled trials in LGS or DS, the rate of discontinuation as a result of any adverse reaction was 2.7% for patients taking EPIDIOLEX 10 mg/kg/day, 11.8% for patients taking EPIDIOLEX 20 mg/kg/day, and 1.3% for patients on placebo. The most frequent cause of discontinuations was transaminase elevation. Discontinuation for transaminase elevation occurred at an incidence of 1.3% in patients taking EPIDIOLEX 10 mg/kg/day, 5.9% in patients taking EPIDIOLEX 20 mg/kg/day, and 0.4% in patients on placebo. Somnolence, sedation, and lethargy led to discontinuation in 3% of patients taking EPIDIOLEX 20 mg/kg/day compared to 0% of patients taking EPIDIOLEX 10 mg/kg/day or on placebo. The most common adverse reactions that occurred in EPIDIOLEX-treated patients with LGS or DS (incidence at least 10% and greater than placebo) were somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections. Table 3 lists the adverse reactions that were reported in at least 3% of EPIDIOLEX-treated patients, and at a rate greater than those on placebo, in the placebo-controlled trials in LGS and DS. Table 3: Adverse Reactions in Patients Treated with EPIDIOLEX in Controlled Trials of LGS and DS (Studies 1, 2, and 3) Adverse Reactions EPIDIOLEX Placebo...Drug Interactions
7 DRUG INTERACTIONS
Strong inducer of CYP3A4 or CYP2C19: Consider dose increase of EPIDIOLEX. ( 7.1 ) Consider a dose reduction of substrates of CYP1A2, CYP2C8, UGT1A9, and orally administered P-gp substrates. ( 7.2 ) A lower starting dose of orally administered everolimus is recommended. ( 7.2 ) Consider dose modification of CYP2B6 or CYP2C19 substrates. ( 7.2 ) 7.1 Effect of Other Drugs on EPIDIOLEX Strong CYP3A4 or CYP2C19 Inducers Concomitant use 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 is not known [see Clinical Pharmacology ( 12.3 )] . Consider an increase in EPIDIOLEX dosage (based on clinical response and tolerability) up to 2‑fold, when concomitantly used with a strong CYP3A4 and/or CYP2C19 inducer. 7.2 Effect of EPIDIOLEX on Other Drugs Antiepileptic Drugs Clobazam Concomitant use of EPIDIOLEX with clobazam increases plasma concentrations of N‑desmethylclobazam, the active metabolite of clobazam [see Clinical Pharmacology ( 12.3 )], which may increase the risk of clobazam-related adverse reactions [see Adverse Reactions ( 6.1 ) and Warnings and Precautions ( 5.1 , 5.2 )]. Consider a reduction in dosage of clobazam if adverse reactions known to occur with clobazam are experienced when concomitantly used with EPIDIOLEX. Stiripentol Concomitant use of EPIDIOLEX with stiripentol increases plasma exposures of stiripentol [see Clinical Pharmacology ( 12.3 )] . Monitor for stiripentol-related adverse reactions when concomitantly used with EPIDIOLEX. Orally Administered P-gp Substrates Concomitant use of EPIDIOLEX with orally administered everolimus results in an approximately 2.5‑fold increase in plasma exposures of everolimus [see Clinical Pharmacology ( 12.3 )] . When initiating EPIDIOLEX in patients taking everolimus, monitor therapeutic drug levels of everolimus and adjust the dosage accordingly. In patients on a stable dosage of EPIDIOLEX, it is recommended to initiate everolimus at a lower starting dosage and titrate the dose based on therapeutic drug monitoring. Increases in exposure of other orally administered P‑gp substrates (e.g., sirolimus, tacrolimus, digoxin) may be observed when concomitantly used with EPIDIOLEX. Consider therapeutic drug monitoring and dosage reduction of other P‑gp substrates when given orally with EPIDIOLEX. CYP1A2, CYP2B6, CYP2C8, CYP2C19, and UGT1A9 Substrates CYP1A2 Substrates Cannabidiol is a weak inhibitor of CYP1A2 [see Clinical Pharmacology ( 12.3 )] . Increases in exposure of certain CYP1A2 substrates (e.g., theophylline, tizanidine) may be observed when concomitantly used with EPIDIOLEX. Consider dosage reduction of CYP1A2 substrates where minimal concentration changes may lead to serious adverse reactions, as clinically appropriate, when concomitantly used with EPIDIOLEX. CYP2B6 Substrates Cannabidiol is an inducer and...Contraindications
4 CONTRAINDICATIONS EPIDIOLEX is contraindicated in patients with a history of hypersensitivity to cannabidiol or any of the ingredients in the product [see Description ( 11 ) and Warnings and Precautions ( 5.4 )]. Hypersensitivity to cannabidiol or any of the ingredients in EPIDIOLEX ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Pregnancy Surveillance Program and Pregnancy Exposure Registry There are two programs, an EPIDIOLEX pregnancy surveillance program and an antiepileptic drug (AED) pregnancy exposure registry, that monitor pregnancy outcomes. Encourage women who are taking EPIDIOLEX during pregnancy to enroll in both, by calling the toll free numbers or visiting the websites below:
EPIDIOLEX Pregnancy Surveillance Program o 1-855-272-7158 o https://www.epidiolexpregnancystudy.com North American Antiepileptic Drug (NAAED) Pregnancy Registry o 1-888-233-2334 o https://www.aedpregnancyregistry.org/ Risk Summary There are no adequate data on the developmental risks associated with the use of EPIDIOLEX in pregnant women. 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 (see Animal Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. The background risks of major birth defects and miscarriage for the indicated populations are unknown. Data Animal Data Oral administration of cannabidiol (0, 75, 150, or 250 mg/kg/day) to pregnant rats throughout the period of organogenesis resulted in embryofetal mortality at the highest dose tested. There were no other drug-related maternal or developmental effects. The highest no-effect dose for embryofetal toxicity in rats was associated with maternal plasma cannabidiol exposures (AUC) approximately 16 and 9 times that in humans at the recommended human doses (RHD) of 20 and 25 mg/kg/day, respectively. Oral administration of cannabidiol...How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied EPIDIOLEX is a strawberry-flavored, clear, colorless to yellow solution supplied in an amber glass bottle with a child-resistant closure. EPIDIOLEX is available in bottles containing 60 mL (NDC 70127-100-06) or 100 mL of oral solution (NDC 70127-100-01). Each mL contains 100 mg of cannabidiol. EPIDIOLEX is packaged in a carton with two 1 mL calibrated oral dosing syringes, two 5 mL calibrated oral dosing syringes, and bottle adapters (NDC 70127-100-60 or NDC 70127‑100‑10). 16.2 Storage and Handling Store EPIDIOLEX in an upright position at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . Do not freeze. Keep the cap tightly closed. Use within 12 weeks of first opening the bottle, then discard any remainder. 16.1 How Supplied EPIDIOLEX is a strawberry-flavored, clear, colorless to yellow solution supplied in an amber glass bottle with a child-resistant closure. EPIDIOLEX is available in bottles containing 60 mL (NDC 70127-100-06) or 100 mL of oral solution (NDC 70127-100-01). Each mL contains 100 mg of cannabidiol. EPIDIOLEX is packaged in a carton with two 1 mL calibrated oral dosing syringes, two 5 mL calibrated oral dosing syringes, and bottle adapters (NDC 70127-100-60 or NDC 70127‑100‑10).
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.