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Cannabidiol Oral Solution

DEA Controlled Substance Schedule C- (pending controlled substance scheduling)

TABLE OF CONTENTS

 

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. DRUG ABUSE AND DEPENDENCE
3. DOSAGE AND ADMINISTRATION 11. MECHANISM OF ACTION
4. CONTRAINDICATIONS 12. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 13. PHARMACOKINETICS
6. ADVERSE REACTIONS 14. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS  

 

1. DESCRIPTION

Cannabidiol is a cannabinoid designated chemically as 2-[(1R,6R)-3-Methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol (IUPAC/CAS). The chemical structure is:

Empirical formula: C21H30O2- Molecular weight: 314.46 g/mol

Cannabidiol, the active ingredient in cannabidiol, is a cannabinoid that naturally occurs in the Cannabis sativa L. plant.

Cannabidiol is a white to pale yellow crystalline solid. It is insoluble in water and is soluble in organic solvents.

Cannabidiol oral solution is a clear, colorless to yellow liquid containing cannabidiol at a concentration of 100 mg/mL. Inactive ingredients include dehydrated alcohol, sesame seed oil, strawberry flavor, and sucralose. Cannabidiol contains no ingredient made from a gluten-containing grain (wheat, barley, or rye).

2. INDICATIONS AND USAGE

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

3. DOSAGE AND ADMINISTRATION

3.1 Assessments Prior to Initiating Cannabidiol

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 cannabidiol [see Warnings and Precautions (5.1)].

3.2 Dosage Information

 Cannabidiol is to be administered orally.

 The starting dosage is 2.5 mg/kg twice daily (5 mg/kg/day).

 After one week, the dosage can be increased to a maintenance dosage of 5 mg/kg twice daily (10 mg/kg/day).

 Patients who are tolerating cannabidiol at 5 mg/kg twice daily and require further reduction of seizures may benefit from a dosage increase up to a maximum recommended maintenance dosage of 10 mg/kg twice daily (20 mg/kg/day), in weekly increments of 2.5 mg/kg twice daily (5 mg/kg/day), as tolerated. For patients in whom a more rapid titration from 10 mg/kg/day to 20 mg/kg/day is warranted, the dosage may be increased no more frequently than every other day. Administration of the 20 mg/kg/day dosage resulted in somewhat greater reductions in seizure rates than the recommended maintenance dosage of 10 mg/kg/day, but with an increase in adverse reactions.

3.3 Administration Instructions

Food may affect cannabidiol levels [see Clinical Pharmacology].

A calibrated measuring device (either 5 mL or 1 mL oral syringe) will be provided and is 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.

Discard any unused cannabidiol remaining 12 weeks after first opening the bottle [see How Supplied/ Storage and Handling].

3.4 Discontinuation of Cannabidiol

When discontinuing cannabidiol, the dose should be decreased gradually. As with all 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)].

3.5 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 (5.1), Use in Specific Populations (8.6), 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).

Cannabidiol does not require dose adjustment in patients with mild (Child-Pugh A) hepatic impairment.

Table 1: Dose Adjustments in Patients with Hepatic Impairment

4. CONTRAINDICATIONS

Cannabidiol 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)].

5. WARNINGS AND PRECAUTIONS

5.1 Hepatocellular Injury

Cannabidiol causes dose-related elevations of liver transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). In controlled studies for LGS and DS, the incidence of ALT elevations above 3 times the upper limit of normal (ULN) was 13% in cannabidiol-treated patients compared with 1% in patients on placebo. Less than 1% of cannabidiol-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 cannabidiol. 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 cannabidiol or reduction of cannabidiol 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 cannabidiol, without dose reduction.

Risk Factors for Transaminase Elevation

Concomitant Valproate and Clobazam

The majority of ALT elevations 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 cannabidiol-treated patients, 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. Consider discontinuation or dose adjustment of valproate or clobazam if liver enzyme elevations occur.

Dose

Transaminase elevations are dose-related. Overall, ALT elevations greater than 3 times the ULN were reported in 17% of patients taking cannabidiol 20 mg/kg/day compared with 1% in patients taking cannabidiol 10 mg/kg/day.

Baseline Transaminase Elevations

Patients with baseline transaminase levels above the ULN had higher rates of transaminase elevations when taking cannabidiol. In controlled trials (Studies 1, 2, and 3) in patients taking cannabidiol 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 cannabidiol 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.

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 cannabidiol treatment.

Prior to starting treatment with cannabidiol, 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 cannabidiol, and periodically thereafter or as clinically indicated. Serum transaminases and total bilirubin levels should also be obtained within 1 month following changes in cannabidiol 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 cannabidiol, as appropriate. Discontinue cannabidiol 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 co-administered medication that is known to affect the liver (e.g., valproate and clobazam).

5.2 Somnolence and Sedation

Cannabidiol can cause somnolence and sedation. In controlled studies for LGS and DS, the incidence of somnolence and sedation (including lethargy) was 32% in cannabidiol-treated patients, compared with 11% in patients on placebo and was dose-related (34% of patients taking cannabidiol 20 mg/kg/day, compared with 27% in patients taking cannabidiol 10 mg/kg/day). The rate was higher in patients on concomitant clobazam (46% in cannabidiol-treated patients taking clobazam compared with 16% in cannabidiol-treated patients not on clobazam). In general, these effects were more common early in treatment and may diminish with continued treatment. Other CNS depressants, including alcohol, could potentiate the somnolence and sedation effect of cannabidiol. Prescribers should monitor patients for somnolence and sedation and should advise patients not to drive or operate machinery until they have gained sufficient experience on cannabidiol to gauge whether it adversely affects their ability to drive or operate machinery.

5.3 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including cannabidiol, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono-and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27863 AED-treated patients was 0.43%, compared to 0.24% among 16029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2: Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis

The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing cannabidiol or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

5.4 Hypersensitivity Reactions

Cannabidiol can cause hypersensitivity reactions. One subject in the cannabidiol clinical trials had pruritus, erythema, and angioedema requiring treatment with antihistamines. Patients with known or suspected hypersensitivity to any ingredients of cannabidiol were excluded from the clinical trials. If a patient develops hypersensitivity reactions after treatment with cannabidiol, the drug should be discontinued. Cannabidiol is contraindicated in patients with a prior hypersensitivity reaction to cannabidiol or any of the ingredients in the product, which includes sesame seed oil [see Description (1)].

5.5 Withdrawal of Antiepileptic Drugs (AEDs)

As with most antiepileptic drugs, cannabidiol should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [see Dosage and Administration (3.4) and Clinical Studies]. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

6. ADVERSE REACTIONS

The following important adverse reactions are described elsewhere in labeling:

 Hepatocellular 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)]

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 cannabidiol, including 533 patients treated for more than 6 months, and 391 patients treated for more than 1 year. In an expanded access program and other compassionate use programs, 161 patients with DS and LGS were treated with cannabidiol, including 109 patients treated for more than 6 months, 91 patients treated for more than 1 year, and 50 patients treated for more than 2 years.

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 cannabidiol. 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, the rate of discontinuation as a result of any adverse reaction was 2.7% for patients taking cannabidiol 10 mg/kg/day, 11.8% for patients taking cannabidiol 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 cannabidiol 10 mg/kg/day, 5.9% in patients taking cannabidiol 20 mg/kg/day, and 0.4% in patients on placebo. Somnolence, sedation, and lethargy led to discontinuation in 3% of patients taking cannabidiol 20 mg/kg/day compared to 0% of patients taking cannabidiol 10 mg/kg/day or on placebo.

The most common adverse reactions that occurred in cannabidiol-treated patients (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 ≥3% of cannabidiol-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 Cannabidiol in Controlled Trials

Adverse reactions were similar across LGS and DS in pediatric and adult patients.

Decreased Weight

Cannabidiol can cause weight loss. In the controlled trials of patients with LGS or DS, based on measured weights, 16% of cannabidiol-treated patients had a decrease in weight of ≥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 cannabidiol 20 mg/kg/day experiencing a decrease in weight ≥5%, compared to 9% in patients on cannabidiol 10 mg/kg/day. In some cases, the decreased weight was reported as an adverse event (see Table 3).

Hematologic Abnormalities

Cannabidiol 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 cannabidiol-treated patients 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 cannabidiol-treated patients, and -0.4% in patients on placebo. There was no effect on red blood cell indices. Thirty percent (30%) of cannabidiol-treated patients 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 on placebo.

Increases in Creatinine

Cannabidiol can cause elevations in serum creatinine. The mechanism has not been determined. In controlled studies in healthy adults and in patients with LGS and DS, an increase in serum creatinine of approximately 10% was observed within 2 weeks of starting cannabidiol. The increase was reversible in healthy adults. Reversibility was not assessed in studies in LGS and DS.

7. DRUG INTERACTIONS

7.1 Effect of Other Drugs on Cannabidiol

Moderate or Strong Inhibitors of CYP3A4 or CYP2C19

Cannabidiol 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 [see Clinical Pharmacology]. Consider a reduction in cannabidiol 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 cannabidiol [see Clinical Pharmacology]. Consider an increase in cannabidiol dosage (based on clinical response and tolerability) when coadministered with a strong CYP3A4 or CYP2C19 inducer.

7.2 Effect of Cannabidiol 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 cannabidiol. Coadministration of cannabidiol is also predicted to cause clinically significant interactions with CYP2C8 and CYP2C9 (e.g., phenytoin) substrates. 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 cannabidiol. 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 cannabidiol 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 [see Clinical Pharmacology]. Consider a reduction in dosage of sensitive CYP2C19 substrates, as clinically appropriate, when coadministered with cannabidiol.

Clobazam

Coadministration of cannabidiol produces a 3-fold increase in plasma concentrations of N-desmethylclobazam, the active metabolite of clobazam (a substrate of CYP2C19) [see Clinical Pharmacology]. This may increase the risk of clobazam-related adverse reactions [see 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 co-administered with cannabidiol.

7.3 Concomitant Use of Cannabidiol and Valproate

Concomitant use of cannabidiol and valproate increases the incidence of liver enzyme elevations [see Warnings and Precautions (5.1)]. Discontinuation or reduction of cannabidiol and/or concomitant valproate should be considered. Insufficient data are available to assess the risk of concomitant administration of other hepatotoxic drugs and cannabidiol.

7.4 CNS Depressants and Alcohol

Concomitant use of cannabidiol with other CNS depressants may increase the risk of sedation and somnolence [see Warnings and Precautions (5.2)].

8. USE IN SPECIFIC POPULATIONS

8.1 Usage in Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as cannabidiol, during pregnancy. Encourage women who are taking cannabidiol 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 cannabidiol 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 times that in humans at the recommended human dose (RHD) of 20 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 RHD.

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 postnatal developmental toxicity in rats was associated with maternal plasma cannabidiol exposures approximately 9 times that in humans at the RHD.

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 cannabidiol and any potential adverse effects on the breastfed infant from cannabidiol or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of cannabidiol 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 cannabidiol in pediatric patients below 2 years 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 approximately 30 times that in humans at the recommended dose of 20 mg/kg/day.

8.5 Geriatric Use

Clinical trials of cannabidiol 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 [see Dosage and Administration (3.5), Warnings and Precautions (5.1), and Clinical Pharmacology].

8.6 Hepatic Impairment

Because of an increase in exposure to cannabidiol, dosage adjustments are necessary in patients with moderate or severe hepatic impairment [see Dosage and Administration (3.5), Warnings and Precautions (5.1), and Clinical Pharmacology]. Cannabidiol does not require dosage adjustments in patients with mild hepatic impairment.

9. DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

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

9.2 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.

9.3 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.

11. MECHANISM OF ACTION

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

12. PHARMACODYNAMICS

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

13. 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 (Css).

Effect of Food

Coadministration of cannabidiol 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 [see Dosage and Administration (3.2)].

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 cannabidiol 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

Cannabidiol 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 cannabidiol 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 [see Dosage and Administration (3.5), Warnings and Precautions(5.1), Use in SpecificPopulations (8.7)].

Drug Interaction Studies

In Vitro Assessment of Drug Interactions

Drug Metabolizing Enzymes [see Drug Interactions (7.1, 7.2)]

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 cannabidiol (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 cannabidiol was coadmininistered with valproate, there was no effect on valproate exposure.

Effect of Cannabidiol on Midazolam

Coadministration of cannabidiol with midazolam (a sensitive CYP3A4 substrate) did not result in changes in plasma concentrations of midazolam compared to midazolam administered alone.

14. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

EPIDIOLEX is a strawberry flavored clear, colorless to yellow solution supplied in a 105mL amberglass bottle with a child-resistant closure containing 100 mL of oral solution (NDC 70127-100-01). Each mL contains 100 mg of cannabidiol. EPIDIOLEX is packaged in a carton with two 5 mL calibrated oral dosing syringes and a bottle adapter (NDC 70127-100-10). The pharmacy will provide 1 mL calibrated oral dosing syringes when doses less than 1 mL are required.

Storage:

Store EPIDIOLEX in its original bottle in an upright position at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature].

Do not refrigerate or freeze. Keep the cap tightly closed. Use within 12 weeks of first opening the bottle, then discard any remainder.

Rx only

Rev 06/18