Cannabidiol
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Dosing in kidney impairment
This label has no separate kidney-impairment dosing section. Check warnings and clinical pharmacology in the full label.
Dosing in liver impairment
Patients with Hepatic Impairment Dose adjustment is recommended in patients with moderate (Child-Pugh B) hepatic impairment or severe (Child-Pugh C) hepatic impairment [see Warnings and Precautions, Use in Specific Populations, and Clinical Pharmacology]. 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. [See table below.] 5 to 10 mg/kg twice daily (10 to 20 mg/kg/day) 12.5 mg/kg twice daily (25 mg/kg/day) Moderate 1.25 mg/kg twice daily (2.5 mg/kg/day) 2.5 to 5 mg/kg twice daily (5 to 10 mg/kg/day) 6.25 mg/kg twice daily (12.5 mg/kg/day) Severe 0.5 mg/kg twice daily (1 mg/kg/day) 1 to 2 mg/kg twice daily (2 to 4 mg/kg/day) 2.5 mg/kg twice daily (5 mg/kg/day)
| Hepatic Impairment | Starting Dosage | In Patients with LGS or DS | In Patients with TSC |
| Maintenance Dosage Range | Maintenance Dosage | ||
| Mild | 2.5 mg/kg twice daily (5 mg/kg/day) | 5 to 10 mg/kg twice daily (10 to 20 mg/kg/day) | 12.5 mg/kg twice daily (25 mg/kg/day) |
| Moderate | 1.25 mg/kg twice daily (2.5 mg/kg/day) | 2.5 to 5 mg/kg twice daily (5 to 10 mg/kg/day) | 6.25 mg/kg twice daily (12.5 mg/kg/day) |
| Severe | 0.5 mg/kg twice daily (1 mg/kg/day) | 1 to 2 mg/kg twice daily (2 to 4 mg/kg/day) | 2.5 mg/kg twice daily (5 mg/kg/day) |
Preparation and administration
Administration Instructions Food may affect EPIDIOLEX levels [see Clinical Pharmacology]. Consistent dosing of EPIDIOLEX with respect to meals is recommended to reduce variability in cannabidiol plasma exposure. Calibrated measuring devices (1 mL and 5 mL oral syringes) will be provided and are recommended to measure and deliver the prescribed dose accurately [see How Supplied/Storage and Handling].
A household teaspoon or tablespoon is not an adequate measuring device. Oral administration is recommended. When necessary, EPIDIOLEX can be enterally administered via silicone feeding tubes, such as nasogastric or gastrostomy tubes. The recommended volume for flushing (with room temperature drinking water) after each dose is approximately 5 times the priming volume of the tube.
The flushing volume may need to be modified in patients with fluid restrictions. Do not use with tubes made of polyvinyl chloride (PVC) or polyurethane and avoid use of silicone nasogastric tubes with short lengths and narrow diameters (e.g., less than 50 cm and less than 5 FR). Discard any unused EPIDIOLEX remaining 12 weeks after first opening the bottle [see How Supplied/Storage and Handling].
Drug interactions
Check cannabidiol against a medication listLabel text (11 paragraphs)
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-hydroxy-cannabidiol (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 inhibitor of CYP2B6 [see Clinical Pharmacology ( 12.3 )]. No clinically significant reduction in exposures of CYP2B6 substrates are observed when concomitantly used with EPIDIOLEX at 7.5 mg/kg twice daily. Changes in exposures of CYP2B6 substrates are unknown when concomitantly used with EPIDIOLEX at doses above 7.5 mg/kg twice daily.
Consider dosage modification of CYP2B6 substrates, as clinically appropriate, when concomitantly used with EPIDIOLEX at doses above 7.5 mg/kg twice daily. CYP2C8 Substrates Concomitant use of EPIDIOLEX may cause clinically significant interactions with CYP2C8 substrates. Consider a reduction in dosage of CYP2C8 substrates, as clinically appropriate, if adverse reactions are experienced when concomitantly used with EPIDIOLEX. CYP2C19 Substrates Cannabidiol is a moderate inhibitor of CYP2C19 [see Clinical Pharmacology ( 12.3 )] . Concomitant use of EPIDIOLEX increases plasma concentrations of CYP2C19 substrates and may increase the risk of adverse reactions.
Consider a dosage reduction of CYP2C19 substrates, as clinically appropriate, when concomitantly used with EPIDIOLEX. For CYP2C19 substrates (e.g., clopidogrel) where efficacy is mainly due to their active metabolite(s), concomitant use of EPIDIOLEX may decrease plasma concentration of the active metabolite(s) and may therefore decrease efficacy. Consider a dosage increase of such CYP2C19 substrates, as clinically appropriate, when concomitantly used with EPIDIOLEX. UGT1A9 Substrates Cannabidiol is an inhibitor of UGT1A9 [see Clinical Pharmacology ( 12.3 )] . Increases in exposure of UGT1A9 substrates may be observed when concomitantly used with EPIDIOLEX.
Consider a reduction in dosage of UGT1A9 substrates where minimal concentration changes may lead to serious adverse reactions, as clinically appropriate, when concomitantly used with EPIDIOLEX.
7.3 Concomitant Use of EPIDIOLEX and Valproate Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations [see Warnings and Precautions ( 5.1 )]. If such elevations occur, consider discontinuation or reduction of EPIDIOLEX and/or concomitant valproate. Insufficient data are available to assess the risk of concomitant administration of other hepatotoxic drugs and EPIDIOLEX.
7.4 CNS Depressants and Alcohol Concomitant use of EPIDIOLEX with other CNS depressants (including alcohol) may increase the risk of sedation and somnolence [see Warnings and Precautions ( 5.2 )] .
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 lactation
Pregnancy
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 13 times that in humans at the maximum recommended human doses (MRHD) of 20 and 25 mg/kg/day, respectively.
Oral administration of the major human cannabidiol metabolite, 7-COOH-CBD (0, 25, 50 or 100 mg/kg/day), to pregnant rats throughout the period of organogenesis resulted in embryofetal malformations and variations at the highest dose tested, which was not maternally toxic. The highest no‑effect dose for embryofetal developmental toxicity in rats (50 mg/kg/day) was associated with maternal plasma 7-COOH-CBD exposures (AUC) approximately 5 and 4 times that in humans at the MRHDs of 20 and 25 mg/kg/day cannabidiol, respectively. Oral administration of cannabidiol (0, 50, 80, or 125 mg/kg/day) to pregnant rabbits…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
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