EPIDIOLEX- cannabidiol_solution

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. Cardiac Electrophysiology Concentration-dependent QTc prolongation was observed for EPIDIOLEX. At exposures obtained when administered as monotherapy at recommended doses with a high fat meal, EPIDIOLEX did not prolong the QTc interval greater than 10 msec. Other factors such as food intake, certain concomitant medications (e. , clobazam), and alcohol consumption may increase the exposure of EPIDIOLEX and the potential effect on QTc prolongation in this scenario is not known. Cannabidiol demonstrated an increase in exposure that was less than dose-proportional over the range of 5 to 25 mg/kg/day in patients. Absorption Cannabidiol has a time to maximum plasma concentration (T max ss Effect of Food Coadministration of EPIDIOLEX (750 or 1500 mg) with a high-fat/high-calorie meal increased C max [see Dosage and Administration ( 2. 4 max max max Distribution The apparent volume of distribution in healthy volunteers was 20963 L to 42849 L. Protein binding of the cannabidiol and its metabolites was > 94% in vitro. Elimination The half-life of cannabidiol in plasma was 56 to 61 hours after twice-daily dosing for 7 days in healthy volunteers. The plasma clearance of cannabidiol following a single EPIDIOLEX 1500 mg dose (approximately equal to the 20 mg/kg/day dosage) is 1111 L/h. Metabolism Cannabidiol is metabolized in the liver and the gut (primarily in the liver) by CYP2C19 and CYP3A4 enzymes, and UGT1A7, UGT1A9, and UGT2B7 isoforms. After repeat dosing, the active metabolite of cannabidiol, 7-OH-CBD, has a 38% lower AUC than the parent drug. The 7-OH-CBD metabolite is converted to 7‑COOH-CBD, which has an approximately 40‑fold higher AUC than the parent drug. Based on preclinical models of seizure, the 7-OH-CBD metabolite is active; however, the activity of the 7‑COOH-CBD metabolite is inconclusive. Excretion EPIDIOLEX is excreted in feces, with minor renal clearance. Specific Populations Patients with Hepatic Impairment No effects on the exposures of cannabidiol or metabolite exposures were observed following administration of a single dose of EPIDIOLEX 200 mg in patients with mild (Child-Pugh A) hepatic impairment. Patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment had an approximately 2. 2-fold higher AUC, compared with healthy volunteers with normal hepatic function [see Dosage and Administration ( 2. 6 Drug Interaction Studies In Vitro Assessment of Drug Interactions Drug Metabolizing Enzymes [see Drug Interactions ( 7. 2 )] Cannabidiol is a substrate for CYP3A4 and CYP2C19. Cannabidiol may induce or inhibit CYP2B6 at clinically relevant concentrations. Cannabidiol inhibits uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes UGT1A9 and UGT2B7, but does not inhibit the UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B17 isoforms. Transporters Cannabidiol and the cannabidiol metabolite, 7-OH-CBD, are not anticipated to interact with BCRP, BSEP, MDR1/P-gp, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, OATP1B1, or OATP1B3. However, due to limitations of the in vitro In vivo [see In Vivo Assessment of Drug Interactions] The cannabidiol metabolite, 7-COOH-CBD, is not a substrate of BCRP, OATP1B1, OATP1B3, or OCT1. However, 7-COOH-CBD is a substrate for P-gp. 7-COOH-CBD is an inhibitor of transport mediated via BCRP and BSEP at clinically relevant concentrations. In Vivo Assessment of Drug Interactions Drug Interaction Studies with AEDs Clobazam and Valproate The interaction potential with other AEDs (clobazam and valproate) was evaluated in dedicated clinical studies following coadministration of EPIDIOLEX (750 mg twice daily in healthy volunteers and 20 mg/kg/day in patients). Coadministration with clobazam in healthy volunteers increased the cannabidiol active metabolite 7-OH-CBD mean C max max [see Drug Interactions ( 7. 2 When EPIDIOLEX was coadministered with valproate in a healthy-volunteer trial, there was no effect on the systemic exposure to valproate. In a separate study in epilepsy patients investigating the effect of EPIDIOLEX on valproate exposure, there were decreases in both the plasma C max In the healthy-volunteer trial, coadministration with valproate resulted in no clinically relevant changes in exposure to cannabidiol or its major metabolites (cannabidiol C max max Effect of EPIDIOLEX on Midazolam Coadministration of EPIDIOLEX with midazolam (a sensitive CYP3A4 substrate) did not result in changes in plasma concentrations of midazolam compared to midazolam administered alone. Effect of EPIDIOLEX on Stiripentol When EPIDIOLEX was coadministered with stiripentol in a healthy volunteer trial, C max max [see Drug Interactions ( 7. 2 Effect of EPIDIOLEX on Caffeine In vivo data from steady-state dosing with cannabidiol (750 mg twice daily) when coadministered with a single dose of caffeine (200 mg), a sensitive CYP1A2 substrate, showed increased caffeine exposure by 15% for C max [see Drug Interactions ( 7. 2 Effect of CYP3A4 and CYP2C19 Inducers and Inhibitors Coadministered with EPIDIOLEX on Exposure to Cannabidiol Coadministration of EPIDIOLEX with potent inhibitors of CYP3A4 and CYP2C19 had the following effects on exposure to cannabidiol and its metabolites. The potent CYP3A4 inhibitor, itraconazole, increased exposure by < 10% for cannabidiol and < 20% for 7-OH-CBD and 7-COOH-CBD for both AUC and C max max max max Coadministration with the potent CYP3A4 and CYP2C19 inducing agent rifampin caused a decrease in cannabidiol exposure of 32% and 34% for AUC and C max [see Drug Interactions ( 7. 1 max max Effect of EPIDIOLEX on Everolimus Coadministration of EPIDIOLEX (12. 5 mg/kg twice daily) with the P-gp and CYP3A4 substrate everolimus (5 mg) in healthy volunteers led to an approximately 2. 5-fold increase in everolimus mean C max [see Drug Interactions ( 7.

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.

3 Seizures Associated with Lennox-Gastaut Syndrome or Dravet Syndrome 2. 2 Seizures Associated with Tuberous Sclerosis Complex 2. 3 ) Patients with Impaired Hepatic Function 2. 6 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 Food may affect EPIDIOLEX levels [see Clinical Pharmacology ( 12. 3 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 ( 16. 1 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. , 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 ( 16. 2 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 [see Warnings and Precautions ( 5. 5 Dose adjustment is recommended in patients with moderate (Child-Pugh B) hepatic impairment or severe (Child-Pugh C) hepatic impairment [see Warnings and Precautions ( 5. EPIDIOLEX does not require dose adjustment in patients with mild (Child-Pugh A) hepatic impairment. Table 1: Dose Adjustments in Patients with Hepatic Impairment 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 to 10 mg/kg twice daily 12. 5 mg/kg twice daily Moderate 1. 25 mg/kg twice daily (2. 5 mg/kg/day) 2. 5 to 5 mg/kg twice daily 6. 25 mg/kg twice daily Severe 0. 5 mg/kg twice daily 1 to 2 mg/kg twice daily 2. 5 mg/kg twice daily.

The following important adverse reactions are described elsewhere in labeling: [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 4 [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. 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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. 2 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 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. In the trial of patients with TSC, the mean decrease in hemoglobin from baseline to end of treatment was -0. 37 g/dL in EPIDIOLEX-treated patients receiving 25 mg/kg/day and 0. 07 g/dL in patients on placebo. 2% in EPIDIOLEX-treated patients, and -0. 2% in patients on placebo. There was no effect on red blood cell indices. Thirty percent (30%) of EPIDIOLEX-treated patients with LGS and DS and 38% of EPIDIOLEX-treated patients with TSC developed a new laboratory-defined anemia during the course of the study (defined as a normal hemoglobin concentration at baseline, with a reported value less than the lower limit of normal at a subsequent time point), versus 13% of patients with LGS and DS on placebo and 15% of patients with TSC on placebo. Increases in Creatinine EPIDIOLEX can cause elevations in serum creatinine. The mechanism has not yet been determined. In controlled studies in healthy adults and in patients with LGS, DS, and TSC, an increase in serum creatinine of approximately 10% was observed within 2 weeks of starting EPIDIOLEX. The increase was reversible in healthy adults. Reversibility was not assessed in studies in LGS, DS, or TSC. Increases in Pneumonia with Concomitant Clobazam Pneumonia has been observed in controlled trials in patients with LGS and DS more frequently with clobazam (7 of 41 [17%] in patients receiving 10 mg/kg/day EPIDIOLEX, 13 of 125 [10%] in patients receiving 20 mg/kg/day EPIDIOLEX, and 1 of 123 [1%] receiving placebo) than without concomitant clobazam (0% in patients receiving 10 mg/kg/day EPIDIOLEX, 4 of 113 [4%] in patients receiving 20 mg/kg/day EPIDIOLEX, and 1 of 104 [1%] receiving placebo). In the controlled trial in patients with TSC, pneumonia was observed more frequently with concomitant clobazam (3 of 18 [17%] in patients receiving 25 mg/kg/day EPIDIOLEX and 0 of 25 [0%] receiving placebo) than without clobazam (0 of 57 [0%] in patients receiving 25 mg/kg/day EPIDIOLEX and 1 of 51 [2%] receiving placebo).

EPIDIOLEX is contraindicated in patients with a history of hypersensitivity to cannabidiol or any of the ingredients in the product [see Description ( 11 5. 4 Hypersensitivity to cannabidiol or any of the ingredients in EPIDIOLEX ( 4.

Pregnancy: Based on animal data, may cause fetal harm. 1 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: o o https://www. epidiolexpregnancystudy. com o 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). 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 the major human metabolite of cannabidiol, 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. The highest no‑effect dose for embryofetal toxicity in rats was associated with maternal plasma 7-COOH-CBD exposures (AUC) approximately 10 times that in humans at the RHDs of 20 and 25 mg/kg/day. 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 the RHDs. 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 5 times that in humans at the RHDs 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 was well tolerated and no adverse effects were observed on maternal animals or subsequent offspring until adulthood. The no-effect dose for pre- and post-natal developmental toxicity in rats was associated with maternal plasma 7-COOH-CBD exposure approximately 15 or 16 times that in humans at the RHDs of 20 or 25 mg/kg/day, respectively. 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. 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. 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 15 and 8 times that in humans at the RHDs of 20 and 25 mg/kg/day, respectively. 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. 3 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.

2 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 is not known [see Clinical Pharmacology ( 12. 3 UGT1A9, UGT2B7, CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 Substrates Cannabidiol is a weak inhibitor of CYP1A2 [see Clinical Pharmacology ( 12. 3 In vitro data predict drug-drug interactions with CYP2B6 substrates (e. , bupropion, efavirenz), uridine 5'-diphospho-glucuronosyltransferase 1A9 (UGT1A9) substrates (e. , diflunisal, propofol, fenofibrate), and UGT2B7 substrates (e. , gemfibrozil, lamotrigine, morphine, lorazepam) when coadministered with EPIDIOLEX. Coadministration of EPIDIOLEX is also predicted to cause clinically significant interactions with CYP2C8 and CYP2C9 (e. , phenytoin) substrates. Because of potential inhibition of enzyme activity, consider a reduction in dosage of substrates of UGT1A9, UGT2B7, CYP1A2, CYP2C8, and CYP2C9, as clinically appropriate, if adverse reactions are experienced when administered concomitantly with EPIDIOLEX. Because of the potential for both induction and inhibition of enzyme activity, consider adjusting dosage of substrates of 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. , are substrates of) CYP2C19 (e. , diazepam) and may increase the risk of adverse reactions with these substrates [see Clinical Pharmacology ( 12. 3 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 [see Clinical Pharmacology ( 12. 3 [see Adverse Reactions ( 6. 2 Stiripentol Concomitant use of EPIDIOLEX and stiripentol causes an elevation in exposure to stiripentol [see Clinical Pharmacology ( 12. 3 Sensitive P-gp Substrates Given Orally Coadministration of EPIDIOLEX with orally administered everolimus, a P-gp and CYP3A4 substrate, results in an approximately 2. 5-fold increase in mean C max [see Clinical Pharmacology ( 12. 3 Increases in exposure of other orally administered P-gp substrates (e. , sirolimus, tacrolimus, digoxin) may be observed on coadministration with EPIDIOLEX. Therapeutic drug monitoring and dose reduction of other P-gp substrates should be considered when given orally and concurrently with EPIDIOLEX. Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations [see Warnings and Precautions ( 5. 1 Concomitant use of EPIDIOLEX with other CNS depressants (including alcohol) may increase the risk of sedation and somnolence [see Warnings and Precautions ( 5.

NONCLINICAL TOXICOLOGY
Carcinogenesis In a carcinogenicity study in mice, oral administration of cannabidiol (0 [water], 0 [vehicle], 30, 100, or 300 mg/kg/day) for 2 years resulted in an increased incidence of hepatocellular adenomas in male mice at the highest dose tested. At the mid dose (100 mg/kg/day), plasma exposures (AUC) were approximately 5 and 3 times that at the recommended human doses (RHDs) of 20 and 25 mg/kg/day, respectively. The carcinogenic potential of cannabidiol has not been assessed in rats. Mutagenesis Cannabidiol was negative for genotoxicity in in vitro in vivo in vitro in vivo in vitro Impairment of Fertility Oral administration of cannabidiol (0, 75, 150, or 250 mg/kg/day) to male and female rats, prior to and throughout mating and continuing in females during early gestation, produced no adverse effects on fertility. The highest dose tested was associated with plasma exposures (AUC) approximately 60 and 34 times that in humans at the RHDs of 20 and 25 mg/kg/day, respectively.
CLINICAL STUDIES
The effectiveness of EPIDIOLEX for the treatment of seizures associated with LGS was established in two randomized, double-blind, placebo-controlled trials in patients aged 2 to 55 years (Study 1, NCT02224690; and Study 2, NCT02224560). Study 1 (N=171) compared a dose of EPIDIOLEX 20 mg/kg/day with placebo. Study 2 (N=225) compared a 10 mg/kg/day dose and a 20 mg/kg/day dose of EPIDIOLEX with placebo. In both studies, patients had a diagnosis of LGS and were inadequately controlled on at least one AED, with or without vagal nerve stimulation and/or ketogenic diet. Both trials had a 4-week baseline period, during which patients were required to have a minimum of 8 drop seizures (>= 2 drop seizures per week). The baseline period was followed by a 2-week titration period and a 12-week maintenance period. In Study 1, 94% of patients were taking at least 2 concomitant AEDs. The most frequently used concomitant AEDs (greater than 25%) in Study 1 were clobazam (49%), valproate (40%), lamotrigine (37%), levetiracetam (34%), and rufinamide (27%). In Study 2, 94% of patients were taking at least 2 concomitant AEDs. The most frequently used concomitant AEDs (greater than 25%) in Study 2, were clobazam (49%), valproate (38%), levetiracetam (31%), lamotrigine (30%), and rufinamide (29%). The primary efficacy measure in both studies was the percent change from baseline in the frequency (per 28 days) of drop seizures (atonic, tonic, or tonic-clonic seizures) over the 14-week treatment period. Key secondary endpoints in both studies included analyses of change in total seizure frequency and changes from baseline in the Subject/Caregiver Global Impression of Change (S/CGIC) score at the last visit. For the S/CGIC, the following question was rated on a 7-point scale: “Since [you/your child] started treatment, please assess the status of [your/your child’s] overall condition (comparing [your/their] condition now to [your/their] condition before treatment) using the scale below. ” The 7-point scale was as follows: “Very Much Improved” (1); “Much Improved” (2); “Slightly Improved” (3); “No Change” (4); “Slightly Worse” (5); “Much Worse” (6); “Very Much Worse” (7). In Studies 1 and 2, the median percent change from baseline (reduction) in the frequency of drop seizures was significantly greater for both dosage groups of EPIDIOLEX than for placebo (Table 5). A reduction in drop seizures was observed within 4 weeks of initiating treatment with EPIDIOLEX, and the effect remained generally consistent over the 14-week treatment period. Table 5: Change in Drop Seizure Frequency in Lennoxen dashGastaut Syndrome during the Treatment Period (Studies 1 and 2) Drop Seizure Frequency (per 28 Days) Placebo EPIDIOLEX 10 mg/kg/day EPIDIOLEX 20 mg/kg/day Study 1 N=85 em dash N=86 Baseline Period Median Seizure Frequency 75 em dash 71 Median Percentage Change from Baseline During Treatment −22 em dash −44 p-value compared to placebo a 0. 01 Study 2 N=76 N=73 N=76 Baseline Period Median Seizure Frequency 80 87 86 Median Percentage Change from Baseline During Treatment −17 −37 −42 p-value compared to placebo a <0. 01 a Figure 1: Proportion of Patients by Category of Seizure Response for EPIDIOLEX and Placebo in Patients with Lennoxen dashGastaut Syndrome (Study 1) Figure 2 displays the percentage of patients by category of reduction from baseline in drop seizure frequency (per 28 days) during the treatment period in Study 2. Figure 2: Proportion of Patients by Category of Seizure Response for EPIDIOLEX and Placebo in Patients with Lennoxen dashGastaut Syndrome (Study 2) In Study 1, 3 of 85 (4%) patients in the EPIDIOLEX 20 mg/kg/day group reported no drop seizures during the maintenance period, compared to 0 patients in the placebo group. In Study 2, 3 of 73 (4%) patients in the EPIDIOLEX 10 mg/kg/day group, 5 of 76 (7%) patients in the EPIDIOLEX 20 mg/kg/day group, and 1 of 76 (1%) patients in the placebo group reported no drop seizures during the maintenance period. In LGS patients, EPIDIOLEX was associated with significant reductions in total seizure frequency (drop and non-drop seizures) versus placebo. During the treatment period in Study 1, the median percent reduction in total seizure frequency (per 28 days) was 41% in patients taking EPIDIOLEX 20 mg/kg/day compared to 14% in patients taking placebo (p<0. In Study 2, the median percent reduction in total seizure frequency (per 28 days) was 36% in the 10 mg/kg/day group, 38% in the 20 mg/kg/day group, and 18% in the placebo group (p<0. 01 for both groups). A greater improvement on the Subject/Caregiver Global Impression of Change (S/CGIC) was reported in patients treated with EPIDIOLEX compared with placebo in Studies 1 and 2. In Study 1, the mean S/CGIC score at last visit was 3. 0 in the 20 mg/kg/day EPIDIOLEX group (corresponding to “slightly improved”) compared with 3. 7 (most closely associated with “no change”) in the placebo group (p<0. In Study 2, the mean S/CGIC score at last visit was 3. 2 in the 10 mg/kg/day and 20 mg/kg/day EPIDIOLEX groups, respectively (“slightly improved”), compared with 3. 6 (“no change”) in the placebo group (p<0. 04, respectively). Figure 1: Proportion of Patients by Category of Seizure Response for EPIDIOLEX and Placebo in Patients with Lennoxen dashGastaut Syndrome (Study 1) Figure 2: Proportion of Patients by Category of Seizure Response for EPIDIOLEX and Placebo in Patients with Lennoxen dashGastaut Syndrome (Study 2) The effectiveness of EPIDIOLEX for the treatment of seizures associated with DS was demonstrated in a single randomized, double-blind, placebo-controlled trial in 120 patients aged 2 to 18 years (Study 3, NCT02091375). Study 3 compared a dose of EPIDIOLEX 20 mg/kg/day with placebo. Patients had a diagnosis of treatment-resistant DS and were inadequately controlled with at least one concomitant AED, with or without vagal nerve stimulation or ketogenic diet. During the 4-week baseline period, patients were required to have at least 4 convulsive seizures while on stable AED therapy. The primary efficacy measure was the percent change from baseline in the frequency (per 28 days) of convulsive seizures (all countable atonic, tonic, clonic, and tonic-clonic seizures) over the 14-week treatment period. In Study 3, 93% of patients were taking at least 2 concomitant AEDs during the trial. The most commonly used concomitant AEDs (greater than 25%) in Study 3 were clobazam (65%), valproate (57%), stiripentol (43%), levetiracetam (28%), and topiramate (26%). The median percent change from baseline (reduction) in the frequency of convulsive seizures was significantly greater for EPIDIOLEX 20 mg/kg/day than for placebo (Table 6). A reduction in convulsive seizures was observed within 4 weeks of initiating treatment with EPIDIOLEX and the effect remained generally consistent over the 14-week treatment period. Table 6: Change in Convulsive Seizure Frequency in Dravet Syndrome during the Treatment Period (Study 3) Total Convulsive Seizures (per 28 Days) Placebo EPIDIOLEX 20 mg/kg/day Study 3 N=59 N=61 Baseline Period Median Seizure Frequency 15 12 Median Percentage Change from Baseline During Treatment −13 −39 p-value compared to placebo a 0. 01 a Figure 3: Proportion of Patients by Category of Seizure Response for EPIDIOLEX and Placebo in Patients with Dravet Syndrome (Study 3) In Study 3, 4 of 60 (7%) patients treated with EPIDIOLEX 20 mg/kg/day reported no convulsive seizures during the maintenance period, compared to 0 patients in the placebo group. Figure 3:Proportion of Patients by Category of Seizure Response for EPIDIOLEX and Placebo in Patients with Dravet Syndrome (Study 3) The effectiveness of EPIDIOLEX for the treatment of seizures associated with TSC was demonstrated in a randomized, double-blind, placebo-controlled trial in 224 patients aged 1 to 65 years (Study 4; NCT02544763). Study 4 (N=224) compared doses of EPIDIOLEX 25 mg/kg/day and 50 mg/kg/day (2 times the recommended maintenance dosage) with placebo. Patients had a diagnosis of TSC and seizures inadequately controlled with at least one concomitant AED, with or without vagal nerve stimulation or ketogenic diet. During the 4-week baseline period, patients had at least 8 seizures, with at least 1 seizure occurring in at least 3 of the 4 weeks (focal motor seizures without impairment of consciousness or awareness; focal seizures with impairment of consciousness or awareness; focal seizures evolving to bilateral generalized convulsive seizures and generalized seizures [tonicen dashclonic, tonic, clonic or atonic seizures]). The baseline period was followed by a 4-week titration period and a 12‑week maintenance period. In Study 4, all patients but 1 (in EPIDIOLEX 25 mg/kg/day group) were taking 1-5 concomitant AEDs during the trial. The most commonly used concomitant AEDs (greater than 25%) were valproate (45%), vigabatrin (33%), levetiracetam (29%), and clobazam (27%). The baseline median TSC-associated seizure frequency was 57 per 28 days for the combined groups. The primary efficacy measure was the change in seizure frequency of TSC-associated seizures over the 16-week treatment period compared with baseline. In Study 4, the percentage change from baseline (reduction) in the frequency of TSC-associated seizures was significantly greater for patients treated with EPIDIOLEX than for placebo (Table 7). A reduction in TSC-associated seizures was observed within 4 weeks of initiating treatment with EPIDIOLEX and the effect remained generally consistent over the 12-week maintenance period. Table 7: Change in TSC-Associated Seizure Frequency during the Treatment Period (Study 4) Total TSC-Associated Seizures (per 28 Days) Placebo EPIDIOLEX Study 4 N=76 N=75 Baseline Period Median Seizure Frequency 54 56 Median Percentage Change from Baseline During Treatment −20 −43 p-value compared to placebo a <0. 01 Percentage Change from Baseline During Treatment in Estimated Mean Seizure Frequency b −24 −48 p-value compared to placebo b <0. 01 a b Figure 4 displays the percentage of patients by category of reduction from baseline in TSC-associated seizure frequency (per 28 days) during the treatment period in Study 4. Figure 4: Proportion of Patients by Category of Seizure Response for EPIDIOLEX and Placebo in Patients with Tuberous Sclerosis Complex (Study 4) In Study 4, 4 of 71 (6%) patients treated with EPIDIOLEX 25 mg/kg/day reported no TSC-associated seizures during the maintenance period, compared to 0 patients in the placebo group.

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