DRUG INTERACTIONS- (summary)

 Moderate or strong inhibitors of CYP3A4 or CYP2C19: Consider dose reduction of EPIDIOLEX

 Strong inducer of CYP3A4 or CYP2C19: Consider dose increase of EPIDIOLEX. (7.1) ? Consider a dose reduction of substrates of UGT1A9, UGT2B7, CYP2C8, CYP2C9, and CYP2C19 (e.g., clobazam)

Substrates of CYP1A2 and CYP2B6 may also require dose adjustment

 DRUG INTERACTIONS-(details)

1 Effect of Other Drugs on EPIDIOLEX Moderate or Strong Inhibitors of CYP3A4 or CYP2C19 EPIDIOLEX is metabolized by CYP3A4 and CYP2C19.

Therefore, coadministration with a moderate or strong inhibitor of CYP3A4 or CYP2C19 will increase cannabidiol plasma concentrations, which may result in a greater risk of adverse reactions..

Consider a reduction in EPIDIOLEX dosage when coadministered with a moderate or strong inhibitor of CYP3A4 or CYP2C19. Strong CYP3A4 or CYP2C19 Inducers

Coadministration with a strong CYP3A4 or CYP2C19 inducer will decrease cannabidiol plasma concentrations, which may lower the efficacy of EPIDIOLEX..

Consider an increase in EPIDIOLEX dosage (based on clinical response and tolerability) when coadministered with a strong CYP3A4 or CYP2C19 inducer.

2 Effect of EPIDIOLEX on Other Drugs-                                                                       UGT1A9, UGT2B7, CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 Substrates In vitro data predict drug-drug interactions with CYP1A2 substrates (e.g., theophylline, caffeine), CYP2B6 substrates (e.g., bupropion, efavirenz), uridine 5' diphospho-glucuronosyltransferase 1A9 (UGT1A9) (e.g., diflunisal, propofol, fenofibrate), and UGT2B7 (e.g., gemfibrozil, lamotrigine, morphine, lorazepam) when coadministered with EPIDIOLEX.

Coadministration of EPIDIOLEX is also predicted to cause clinically significant interactions with CYP2C8 and CYP2C9 (e.g., phenytoin) substrate

Because of potential inhibition of enzyme activity, consider a reduction in dosage of substrates of UGT1A9, UGT2B7, CYP2C8, and CYP2C9, as clinically appropriate, if adverse reactions are experienced when administered  concomitantly with EPIDIOLEX.

Because of potential for both induction and inhibition of enzyme activity, consider adjusting dosage of substrates of CYP1A2 and CYP2B6, as clinically appropriate. Sensitive CYP2C19 Substrates In vivo data show that coadministration of EPIDIOLEX increases plasma concentrations of drugs that are metabolized by (i.e., are substrates of) CYP2C19 (e.g., diazepam) and may increase the risk of adverse reactions with these substrates 

Consider a reduction in dosage of sensitive CYP2C19 substrates, as clinically appropriate, when coadministered with EPIDIOLEX. Clobazam Coadministration of EPIDIOLEX produces a 3-fold increase in plasma concentrations of Ndesmethylclobazam, the active metabolite of clobazam (a substrate of CYP2C19) 

This may increase the risk of clobazam-related adverse reactions

Consider a reduction in dosage of clobazam if adverse reactions known to occur with clobazam are experienced when co-administered with EPIDIOLEX.

3. Effect of Concomitant use of EPIDIOLEX and valproate-                                          increases the incidence of liver enzyme elevations .

Discontinuation or reduction of EPIDIOLEX and/or concomitant valproate should be considered. Insufficient data are available to assess the risk of concomitant administration of other hepatotoxic drugs and EPIDIOLEX.

4. CNS Depressants and Alcohol Concomitant use of EPIDIOLEX with other CNS depressants may increase the risk of sedation and somnolence 

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                              EPIDIOLEX® safely and effectively.

See full prescribing information for EPIDIOLEX. EPIDIOLEX® (cannabidiol) oral solution, CX [pending DEA scheduling action]

Initial U.S. Approval: XXXX [pending controlled substance scheduling]

INDICATIONS AND USAGE-

­ EPIDIOLEX is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older (1) ----------------------

DOSAGE AND ADMINIS TRATION----------------------­ ? Obtain serum transaminases (ALT and AST) and total bilirubin levels in all patients prior to starting treatment. (2.1, 5.1) ? EPIDIOLEX is to be administered orally. (2.2) ? The recommended starting dosage is 2.5 mg/kg taken 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). See Full Prescribing Information for titration. (2.2) ? Dosage adjustment is recommended for patients with moderate or severe hepatic impairment. (2.5, 8.6) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ Oral solution: 100 mg/mL (3)

-------------------------------CONTRAINDICATIONS-----------------------------­ Hypersensitivity to cannabidiol or any of the ingredients in EPIDIOLEX (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ ? Hepatocellular 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)

ADVERS E REACTIONS-

­ The most common adverse reactions (10% or more for EPIDIOLEX and greater than placebo) are: somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections.

CONTRAINDICATIONS-

­ Hypersensitivity to cannabidiol or any of the ingredients in EPIDIOLEX

WARNINGS AND PRECAUTIONS-

 Hepatocellular 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. 

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.

 Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and thoughts.

 Hypersenstivity Reactions: Advise patients to seek immediate medical care. Discontinue and do not restart EPIDIOLEX if hypersensitivity occurs

Withdrawal of Antiepileptic Drugs: EPIDIOLEX should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus.

DOSAGE AND ADMINIS TRATION-

 Obtain serum transaminases (ALT and AST) and total bilirubin levels in all patients prior to starting treatment. 

 EPIDIOLEX is to be administered orally.

 The recommended starting dosage is 2.5 mg/kg taken 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).

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). See Full Prescribing Information for titration.

 Dosage adjustment is recommended for patients with moderate or severe hepatic impairment.

DOSAGE FORMS AND STRENGTHS-

­ Oral solution: 100 mg/mL 

17 PATIENT COUNSELING INFORMATION -

Advise the caregiver or patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Administration-

Information Advise patients who are prescribed EPIDIOLEX to use the adapter and oral dosing syringes provided [see Dosage and Administration (2.3) and Instructions for Use].

Advise patients to take EPIDIOLEX consistently either in the fasted or fed state

Instruct patients to discard any unused EPIDIOLEX oral solution after 12 weeks of first opening the bottle 

Hepatocellular Injury-                                                                                              Inform patients about the potential for elevations of liver enzymes.

Discuss with the patient the importance of measuring hepatic laboratory values and having them evaluated by the healthcare provider before treatment with EPIDIOLEX and periodically during treatment 

Advise patients of the clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine) and to contact a healthcare provider promptly if these signs or symptoms occur.

Somnolence and Sedation-                                                                                           Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that EPIDIOLEX does not affect them adversely (e.g., impair judgment, thinking or motor skills) 

Suicidal Thinking and Behavior-                                                                         Counsel patients, their caregivers, and their families that antiepileptic drugs, including EPIDIOLEX, may increase the risk of suicidal thoughts and behavior and advise them to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to healthcare providers

 Withdrawal of Antiepileptic Drugs (AEDs) Advise patients not to discontinue use of EPIDIOLEX without consulting with their healthcare provider.

EPIDIOLEX should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus.

Pregnancy Registry-                                                                                                  Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during EPIDIOLEX therapy. Encourage women who are taking EPIDIOLEX to enroll in the North American Antiepileptic Drug (NAAED)

Pregnancy Registry-                                                                                                         if they become pregnant. This registry is Reference ID: 4282447 collecting information about the safety of antiepileptic drugs during pregnancy.

 Drug Testing Advise patients of the potential for positive cannabis drug screens.

Marketed by Greenwich Biosciences, Inc., Carlsbad, CA 92008 USA © 2018 Greenwich Biosciences, Inc. All rights reserved.

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

 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.

2. Pharmacodynamics-                                                                                                  There are no relevant data on the pharmacodynamic effects of cannabidiol.

3. Pharmacokinetics -                                                                                              Cannabidiol demonstrated an increase in exposure that was less than dose-proportional over the range of 5 to 20 mg/kg/day in patients.

Absorption- Cannabidiol has a time to maximum plasma concentration (Tmax) of 2.5 to 5 hours at steady state

 Effect of Food -                                                                                                     Coadministration of EPIDIOLEX with a high-fat/high-calorie meal increased Cmax by 5-fold, AUC by 4-fold, and reduced the total variability, compared with the fasted state in healthy volunteers

 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 (1.1 times the maximum recommended daily 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 7-COOH-CBD metabolite is not active.

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 2.5 to 5.2-fold higher AUC, compared with healthy volunteers with normal hepatic function

Drug Interaction Studies -

In Vitro Assessment of Drug Interactions Drug Metabolizing Enzymes-

 Cannabidiol is a substrate for cytochrome p450 (CYP) enzymes CYP3A4 and CYP2C19. Cannabidiol has the potential to inhibit CYP2C8, CYP2C9, and CYP2C19 at clinically relevant concentrations.

Cannabidiol may induce or inhibit CYP1A2 and 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-pg, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, OATP1B1, or OATP1B3. 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).

Coadmininistration with clobazam in healthy volunteers increased the cannabidiol active metabolite 7-OH CBD mean Cmax by 73% and AUC by 47%; and increased the clobazam active metabolite, N-desmethylclobazam, Cmax and AUC by approximately 3-fold [see Drug Interactions (7.2)]. When EPIDIOLEX was coadmininistered with valproate, there was no effect on valproate exposure.

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.

 USE IN SPECIFIC POPULATIONS-

1. Pregnancy Pregnancy-                                                                                    Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as EPIDIOLEX, during pregnancy.

Encourage women who are taking EPIDIOLEX during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

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 Reference ID: 4282447 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.

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.

3. Pediatric Use-

Safety and effectiveness of EPIDIOLEX for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome have been established in patients 2 years of age and older.

Safety and effectiveness of EPIDIOLEX in pediatric patients below 2 years of age have not been established.

4. Geriatric Use -                                                                                                              Clinical trials of EPIDIOLEX in the treatment of LGS and DS did not include any 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

5 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 (2.5), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

EPIDIOLEX does not require dosage adjustments in patients with mild hepatic impairment.

6.DRUG ABUSE AND DEPENDENCE-

1 Controlled Substance [A statement in this section cannot be finalized until a scheduling action is completed by DEA]

2. Drug Abuse- Animal abuse-related studies show that cannabidiol does not produce cannabinoid-like behavioral responses, including generalization to delta-9-tetrahydrocannabinol (THC) in a drug discrimination study.

Cannabidiol also does not produce animal self-administration, suggesting it does not produce rewarding effects. In a human abuse potential study, acute administration of cannabidiol to non-dependent adult recreational drug users at therapeutic and supratherapeutic doses of 750, 1500, and 4500 mg in the fasted state (equivalent respectively to 10, 20, and 60 mg/kg in a 75 kg adult) produced responses on positive subjective measures such as Drug Liking and Take Drug Again that were within the acceptable placebo range. In contrast, 10 and 30 mg of dronabinol (synthetic THC, Schedule III) and 2 mg alprazolam (Schedule IV) produced large increases on positive subjective measures compared to placebo that were statistically significantly greater than those produced by cannabidiol. In other Phase 1 clinical studies conducted with cannabidiol, there were no reports of abuse-related adverse events. Reference ID: 4282447

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