Cannabidiol

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 )

Cannabidiol oral solution: 100 mg/mL of a strawberry-flavored, clear, colorless to yellow solution. Oral solution: 100 mg/mL ( 3 )

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 )

• Hepatic Injury: EPIDIOLEX can cause transaminase elevations. Concomitant use of valproate and higher doses of EPIDIOLEX increase the risk of transaminase elevations. See Full Prescribing Information for serum transaminase and bilirubin monitoring recommendations. ( 5.1 )
• Somnolence and Sedation: Monitor for somnolence and sedation and advise patients not to drive or operate machinery until they have gained sufficient experience on EPIDIOLEX. ( 5.2 )
• Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and thoughts. ( 5.3 )
• Hypersensitivity Reactions: Advise patients to seek immediate medical care. Discontinue and do not restart EPIDIOLEX if hypersensitivity occurs. ( 5.4 )
• Withdrawal of Antiepileptic Drugs: EPIDIOLEX should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus. ( 5.5 )

5.1 Hepatic Injury EPIDIOLEX can cause dose-related elevations of liver transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). In controlled studies for LGS and DS (10 and 20 mg/kg/day dosages) and TSC (25 mg/kg/day), the incidence of ALT elevations above 3 times the upper limit of normal (ULN) was 13% (10 and 20 mg/kg/day dosages) and 12% (25 mg/kg/day dosage) in EPIDIOLEX-treated patients compared with 1% in patients on placebo. Less than 1% of EPIDIOLEX-treated patients had ALT or AST levels greater than 20 times the ULN. There were cases of transaminase elevations associated with hospitalization in patients taking EPIDIOLEX. In clinical trials, serum transaminase elevations typically occurred in the first two months of treatment initiation; however, there were some cases observed up to 18 months after initiation of treatment, particularly in patients taking concomitant valproate. Resolution of transaminase elevations occurred with discontinuation of EPIDIOLEX or reduction of EPIDIOLEX and/or concomitant valproate in about two-thirds of the cases. In about one-third of the cases, transaminase elevations resolved during continued treatment with EPIDIOLEX, without dose reduction. In the postmarketing setting, cases of cholestatic or mixed patterns of liver injury (i.e., based on calculated ratio of [ALT/ULN]/[ALP/ULN] less than 2 and between 2-5, respectively) were reported in patients treated with EPIDIOLEX. Risk Factors for Transaminase Elevation Concomitant Valproate and Clobazam The majority of ALT elevations in the controlled studies occurred in patients taking concomitant valproate [see Drug Interactions ( 7.3 )] . Concomitant use of clobazam also increased the incidence of transaminase elevations, although to a lesser extent than valproate [see Drug Interactions ( 7.2 )] . In EPIDIOLEX-treated patients with LGS or DS (10 and 20 mg/kg/day dosages), the incidence of ALT elevations greater than 3 times the ULN was 30% in patients taking both concomitant valproate and clobazam, 21% in patients taking concomitant valproate (without clobazam), 4% in patients taking concomitant clobazam (without valproate), and 3% in patients taking neither drug. In EPIDIOLEX-treated patients with TSC (25 mg/kg/day), 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. In the postmarketing setting, cases of elevated ammonia levels were reported in some EPIDIOLEX-treated patients who also had transaminase elevations; where data were available, most cases reported concomitant use of valproate, clobazam, or both. Consider discontinuation or dose adjustment of valproate or clobazam if ammonia level elevations occur. Dose Transaminase elevations are generally dose-related. In patients with DS or LGS (10 and 20 mg/kg/day) or TSC (25 mg/kg/day), ALT elevations greater than 3 times the ULN were reported in 17% and 12% of patients taking EPIDIOLEX 20 or 25 mg/kg/day, respectively, compared with 1% in patients taking EPIDIOLEX 10 mg/kg/day. The risk of ALT elevations was higher (25%) in patients with TSC receiving a dosage above the recommended maintenance dosage of 25 mg/kg/day in Study 4. Baseline Transaminase Elevations Patients with baseline transaminase levels above the ULN had higher rates of transaminase elevations when taking EPIDIOLEX. In the DS and LGS controlled trials (Studies 1, 2, and 3) in patients taking EPIDIOLEX 20 mg/kg/day, the frequency of treatment-emergent ALT elevations greater than 3 times the ULN was 30% when ALT was above the ULN at baseline, compared to 12% when ALT was within the normal range at baseline. No patients taking EPIDIOLEX 10 mg/kg/day experienced ALT elevations greater than 3 times the ULN when ALT was above the ULN at baseline, compared with 2% of patients in whom ALT was within the normal range at baseline. In the TSC controlled trial (Study 4) in patients taking EPIDIOLEX 25 mg/kg/day, the frequency of treatment-emergent ALT elevations greater than 3 and 5 times the ULN were both 11% when ALT was above the ULN at baseline, compared to 12% and 6%, respectively, when ALT was within the normal range at baseline. Monitoring In general, transaminase elevations of greater than 3 times the ULN in the presence of elevated bilirubin without an alternative explanation are an important predictor of severe liver injury. Early identification of elevated liver enzymes may decrease the risk of a serious outcome. Patients with elevated baseline transaminase levels above 3 times the ULN, accompanied by elevations in bilirubin above 2 times the ULN, should be evaluated prior to initiation of EPIDIOLEX treatment. Prior to starting treatment with EPIDIOLEX, obtain serum transaminases (ALT and AST) and total bilirubin levels. Serum transaminases and total bilirubin levels should be obtained at 1 month, 3 months, and 6 months after initiation of treatment with EPIDIOLEX, and periodically thereafter or as clinically indicated. Serum transaminases and total bilirubin levels should also be obtained within 1 month following changes in EPIDIOLEX dosage and addition of or changes in medications that are known to impact the liver. Consider more frequent monitoring of serum transaminases and bilirubin in patients who are taking valproate or who have elevated liver enzymes at baseline. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with EPIDIOLEX, as appropriate. Discontinue EPIDIOLEX in any patients with elevations of transaminase levels greater than 3 times the ULN and bilirubin levels greater than 2 times the ULN. Patients with sustained transaminase elevations of greater than 5 times the ULN should also have treatment discontinued. Patients with prolonged elevations of serum transaminases should be evaluated for other possible causes. Consider dosage adjustment of any coadministered medication that is known to affect the liver (e.g., valproate and clobazam).

5.2 Somnolence and Sedation EPIDIOLEX can cause somnolence and sedation. In controlled studies for LGS and DS (10 and 20 mg/kg/day dosages), the incidence of somnolence and sedation (including lethargy) was 32% in EPIDIOLEX-treated patients (27% and 34% of patients taking EPIDIOLEX 10 or 20 mg/kg/day, respectively), compared with 11% in patients on placebo and was generally dose-related. The rate was higher in patients on concomitant clobazam (46% in EPIDIOLEX-treated patients taking clobazam compared with 16% in EPIDIOLEX-treated patients not on clobazam). […]

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 10 mg/kg/day 20 mg/kg/day N=75 % N=238 % N=227 % Hepatic Disorders Transaminases elevated 8 16 3 Gastrointestinal Disorders Decreased appetite 16 22 5 Diarrhea 9 20 9 Weight decreased 3 5 1 Gastroenteritis 0 4 1 Abdominal pain, discomfort 3 3 1 Nervous System Disorders Somnolence 23 25 8 Fatigue, malaise, asthenia 11 12 4 Lethargy 4 8 2 Sedation 3 6 1 Irritability, agitation 9 5 2 Aggression, anger 3 5 <1 Insomnia, sleep disorder, poor quality sleep 11 5 4 Drooling, salivary hypersecretion 1 4 <1 Gait disturbance 3 2 <1 Infections Infection, all 41 40 31 Infection, other 25 21 24 Infection, viral 7 11 6 Pneumonia 8 5 1 Infection, fungal 1 3 0 Other Rash 7 13 3 Hypoxia, respiratory failure 3 3 1 Adverse reactions were similar across LGS and DS in pediatric and adult patients. Patients with TSC In a placebo-controlled trial of patients with TSC (Study 4), 148 patients received EPIDIOLEX [see Clinical Studies ( 14.3 )] . Adverse reactions are presented below; the duration of treatment in this trial was up to 16 weeks. Approximately 42% of patients were female, 90% were Caucasian, and the mean age was 14 years (range 1 to 57 years). All patients but one (25 mg/kg/day group) were taking other AEDs. In the controlled trial in TSC, the rate of discontinuation as a result of any adverse reaction was 11% for patients taking EPIDIOLEX 25 mg/kg/day and 3% for patients on placebo. The most frequent cause of discontinuation was rash (5%). The most common adverse reactions that occurred in EPIDIOLEX-treated patients with TSC (incidence at least 10% at the recommended dosage and greater than placebo) were diarrhea; transaminase elevations; decreased appetite; somnolence; pyrexia; and vomiting. Table 4 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 trial in TSC. Table 4: Adverse Reactions in Patients Treated with EPIDIOLEX in Controlled Trial of TSC (Study 4) Adverse Reactions EPIDIOLEX Placebo 25 mg/kg/day N=75 % N=76 % Hematological changes Anemia 7 1 Platelet count decreased 5 1 Eosinophil count increased 5 0 Hepatic Disorders Transaminases elevated 25 0 Gastrointestinal Disorders Diarrhea 31 25 Decreased appetite 20 12 Vomiting 17 9 Nausea 9 3 Gastroenteritis 8 7 Weight decreased 7 0 Nervous System Disorders Somnolence 13 9 Gait disturbance 9 5 Fatigue, malaise, asthenia 5 1 Infections Ear infection 8 3 Urinary tract infection 5 0 Pneumonia 4 1 Other Pyrexia 19 8 Rash 8 4 Rhinorrhea 4 0 Adverse reactions were similar in pediatric and adult patients with TSC. Additional Adverse Reactions in Patients with LGS, DS, or TSC Decreased Weight EPIDIOLEX can cause weight loss. In the controlled trials of patients with LGS or DS (10 and 20 mg/kg/day), based on measured weights, 16% of EPIDIOLEX-treated patients had a decrease in weight of at least 5% from their baseline weight, compared to 8% of patients on placebo. The decrease in weight appeared to be dose-related, with 18% of patients on EPIDIOLEX 20 mg/kg/day experiencing a decrease in weight at least 5%, compared to 9% in patients on EPIDIOLEX 10 mg/kg/day. In the controlled trial of patients with TSC (25 mg/kg/day), 31% of EPIDIOLEX-treated patients had a decrease in weight of at least 5% from their baseline weight, compared to 8% of patients on placebo. In some cases, the decreased weight was reported as an adverse event (see Tables 3 and 4 ). Hematologic Abnormalities EPIDIOLEX can cause decreases in hemoglobin and hematocrit. In controlled trials of patients with LGS or DS, the mean decrease in hemoglobin from baseline to end of treatment was -0.42 g/dL in EPIDIOLEX-treated patients receiving 10 or 20 mg/kg/day and -0.03 g/dL in patients on placebo. A corresponding decrease in hematocrit was also observed, with a mean change of -1.5% in EPIDIOLEX-treated patients, and -0.4% in patients on placebo. […]

• 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 )] .

Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 )

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 throughout organogenesis resulted in decreased fetal body weights and increased fetal structural variations at the highest dose tested, which was also associated with maternal toxicity. Maternal plasma cannabidiol exposures at the no-effect level for embryofetal developmental toxicity in rabbits were less than that in humans at both MRHDs. When cannabidiol (75, 150, or 250 mg/kg/day) was orally administered to rats throughout pregnancy and lactation, decreased growth, delayed sexual maturation, neurobehavioral changes (decreased activity), and adverse effects on male reproductive organ development (small testes in adult offspring) and fertility were observed in the offspring at the mid and high dose. These effects occurred in the absence of maternal toxicity. The no-effect dose for pre- and post-natal developmental toxicity in rats was associated with maternal plasma cannabidiol exposures approximately 9 and 7 times that in humans at the MRHDs of 20 and 25 mg/kg/day, respectively. Oral administration of 7-COOH-CBD (0, 20, 40, or 75 mg/kg/day) to rats throughout pregnancy and lactation resulted in adverse effects on neurobehavioral function (locomotor activity) in offspring when tested in adulthood at the mid and high doses, and on reproductive function (increased preimplantation loss) in offspring at all doses. The lowest dose tested, a no-effect dose for pre- and postnatal developmental toxicity in rats (20 mg/kg/day), was associated with maternal plasma 7-COOH-CBD exposures approximately 2 times that in humans at both MRHDs of 20 or 25 mg/kg/day cannabidiol.

8.2 Lactation Risk Summary 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.

8.4 Pediatric Use Safety and effectiveness of EPIDIOLEX for the treatment of seizures associated with LGS, DS, or TSC have been established in patients 1 year of age and older. The use of EPIDIOLEX in these indications is supported by adequate and well-controlled studies in patients 2 years of age and older with LGS and DS and in patients 1 year of age and older with TSC [see Clinical Studies ( 14.1 , 14.2 , 14.3 )]. Safety and effectiveness of EPIDIOLEX in pediatric patients below 1 year of age have not been established. Juvenile Animal Data Administration of cannabidiol (subcutaneous doses of 0 or 15 mg/kg on Postnatal Days (PNDs) 4-6 followed by oral administration of 0, 100, 150, or 250 mg/kg on PNDs 7-77) to juvenile rats for 10 weeks resulted in increased body weight, delayed male sexual maturation, neurobehavioral effects (decreased locomotor activity and auditory startle habituation), increased bone mineral density, and liver hepatocyte vacuolation. A no-effect dose was not established. The lowest dose causing developmental toxicity in juvenile rats (15 sc/100 po mg/kg) was associated with cannabidiol exposures (AUC) approximately 4 times that in humans at both MRHDs of 20 and 25 mg/kg/day. Administration of the major human cannabidiol metabolite 7-COOH-CBD (0, 20, 40, or 80 mg/kg/day) to juvenile rats by subcutaneous injection on PNDs 4-6 followed by oral gavage on PNDs 7-77, for a total of 10 weeks, resulted in mortality, ophthalmic abnormalities, and accelerated female sexual maturation at the mid and high doses, and long-term neurobehavioral (increased locomotor activity, decreased auditory startle response habituation and prepulse inhibition, delayed maze learning) and reproductive functional impairment (disrupted estrous cyclicity, decreased sperm concentration and increased abnormal sperm; decreased mating, fertility, and fecundity indices; increased preimplantation loss), decreased brain weight, and decreased bone density at the high dose. The no-effect dose for developmental toxicity in juvenile rats (20 mg/kg/day) was associated with 7-COOH-CBD exposures (AUC) that were approximately equivalent to that in humans at the MRHDs of 20 and 25 mg/kg/day.

8.5 Geriatric Use Clinical trials of EPIDIOLEX in the treatment of LGS, DS, and TSC did not include a sufficient number of patients aged above 55 years to determine whether or not they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 )] .

8.6 Hepatic Impairment Because of an increase in exposure to EPIDIOLEX, dosage adjustments are necessary in patients with moderate or severe hepatic impairment [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 )] . EPIDIOLEX does not require dosage adjustments in patients with mild hepatic impairment.

The precise mechanisms by which EPIDIOLEX exerts its anticonvulsant effect in humans are unknown. Cannabidiol does not appear to exert its anticonvulsant effects through interaction with cannabinoid receptors.