Epidiolex Side Effects Center

SIDE EFFECTS

The following important adverse reactions are described elsewhere in labeling:

• Hepatocellular Injury [see WARNINGS AND PRECAUTIONS]
• Somnolence and Sedation [see WARNINGS AND PRECAUTIONS]
• Suicidal Behavior and Ideation [seeWARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
• Withdrawal of Antiepileptic Drugs [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In controlled and uncontrolled trials in patients with LGS and DS, 689 patients were treated with EPIDIOLEX, including 533 patients treated for more than 6 months, and 391 patients treated for more than 1 year. In controlled and uncontrolled trials in patients with TSC, 223 patients were treated with EPIDIOLEX, including 151 patients treated for more than 6 months, 88 patients treated for more than 1 year, and 15 patients treated for more than 2 years.

In an expanded access program and other compassionate use programs, 271 patients with DS, LGS, or TSC were treated with EPIDIOLEX, including 237 patients treated for more than 6 months, 204 patients treated for more than 1 year, and 140 patients treated for more than 2 years.

Patients with LGS Or DS

In placebo-controlled trials of patients with LGS or DS (includes Studies 1, 2, 3, and a Phase 2 controlled study in DS), 323 patients received EPIDIOLEX [see Clinical Studies] Adverse reactions are presented below; the duration of treatment in these trials was up to 14 weeks. Approximately 46% of patients were female, 83% were Caucasian, and the mean age was 14 years (range 2 to 48 years). All patients were taking other AEDs.

In controlled trials in LGS or DS, the rate of discontinuation as a result of any adverse reaction was 2.7% for patients taking EPIDIOLEX 10 mg/kg/day, 11.8% for patients taking EPIDIOLEX 20 mg/kg/day, and 1.3% for patients on placebo. The most frequent cause of discontinuations was transaminase elevation. Discontinuation for transaminase elevation occurred at an incidence of 1.3% in patients taking EPIDIOLEX 10 mg/kg/day, 5.9% in patients taking EPIDIOLEX 20 mg/kg/day, and 0.4% in patients on placebo. Somnolence, sedation, and lethargy led to discontinuation in 3% of patients taking EPIDIOLEX 20 mg/kg/day compared to 0% of patients taking EPIDIOLEX 10 mg/kg/day or on placebo.

The most common adverse reactions that occurred in EPIDIOLEX-treated patients with LGS or DS (incidence at least 10% and greater than placebo) were somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections.

Table 3 lists the adverse reactions that were reported in at least 3% of EPIDIOLEX-treated patients, and at a rate greater than those on placebo, in the placebo-controlled trials in LGS and DS.

Table 3: Adverse Reactions in Patients Treated with EPIDIOLEX in Controlled Trials of LGS and DS (Studies 1, 2, and 3)

Adverse Reactions	EPIDIOLEX		Placebo
	10 mg/kg/day	20 mg/kg/day
	N=75 %	N=238 %	N=227 %
Hepatic Disorders
Transaminases elevated	8	16	3
Gastrointestinal Disorders
Decreased appetite	16	22	5
Diarrhea	9	20	9
Weight decreased	3	5	1
Gastroenteritis	0	4	1
Abdominal pain, discomfort	3	3	1
Nervous System Disorders
Somnolence	23	25	8
Fatigue, malaise, asthenia	11	12	4
Lethargy	4	8	2
Sedation	3	6	1
Irritability, agitation	9	5	2
Aggression, anger	3	5	<1
Insomnia, sleep disorder, poor quality sleep	11	5	4
Drooling, salivary hypersecretion	1	4	<1
Gait disturbance	3	2	<1
Infections
Infection, all	41	40	31
Infection, other	25	21	24
Infection, viral	7	11	6
Pneumonia	8	5	1
Infection, fungal	1	3	0
Other
Rash	7	13	3
Hypoxia, respiratory failure	3	3	1

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

Patients With TSC

In a placebo-controlled trial of patients with TSC (Study 4), 148 patients received EPIDIOLEX [see Clinical Studies] Adverse reactions are presented below; the duration of treatment in this trial was up to 16 weeks. Approximately 42% of patients were female, 90% were Caucasian, and the mean age was 14 years (range 1 to 57 years). All patients but one (25 mg/kg/day group) were taking other AEDs.

In the controlled trial in TSC, the rate of discontinuation as a result of any adverse reaction was 11% for patients taking EPIDIOLEX 25 mg/kg/day and 3% for patients on placebo. The most frequent cause of discontinuation was rash (5%).

The most common adverse reactions that occurred in EPIDIOLEX-treated patients with TSC (incidence at least 10% at the recommended dosage and greater than placebo) were diarrhea; transaminase elevations; decreased appetite; somnolence; pyrexia; and vomiting.

Table 4 lists the adverse reactions that were reported in at least 3% of EPIDIOLEX-treated patients, and at a rate greater than those on placebo, in the placebo-controlled trial in TSC.

Table 4: Adverse Reactions in Patients Treated with EPIDIOLEX in Controlled Trial of TSC (Study 4)

Adverse Reactions	EPIDIOLEX	Placebo
	25 mg/kg/day
	N = 75 %	N = 76 %
Hematological changes
Anemia	7	1
Platelet count decreased	5	1
Eosinophil count increased	5	0
Hepatic Disorders
Transaminases elevated	25	0
Gastrointestinal Disorders
Diarrhea	31	25
Decreased appetite	20	12
Vomiting	17	9
Nausea	9	3
Gastroenteritis	8	7
Weight decreased	7	0
Nervous System Disorders
Somnolence	13	9
Gait disturbance	9	5
Fatigue, malaise, asthenia	5	1
Infections
Ear infection	8	3
Urinary tract infection	5	0
Pneumonia	4	1
Other
Pyrexia	19	8
Rash	8	4
Rhinorrhea	4	0

Adverse reactions were similar in pediatric and adult patients with TSC.

Additional Adverse Reactions In Patients With LGS, DS, Or TSC

Decreased Weight

EPIDIOLEX can cause weight loss. In the controlled trials of patients with LGS or DS (10 and 20 mg/kg/day), based on measured weights, 16% of EPIDIOLEX-treated patients had a decrease in weight of at least 5% from their baseline weight, compared to 8% of patients on placebo. The decrease in weight appeared to be dose-related, with 18% of patients on EPIDIOLEX 20 mg/kg/day experiencing a decrease in weight at least 5%, compared to 9% in patients on EPIDIOLEX 10 mg/kg/day. In the controlled trial of patients with TSC (25 mg/kg/day), 31% of EPIDIOLEX-treated patients had a decrease in weight of at least 5% from their baseline weight, compared to 8% of patients on placebo. In some cases, the decreased weight was reported as an adverse event (see Tables 3 and 4).

Hematologic Abnormalities

EPIDIOLEX can cause decreases in hemoglobin and hematocrit. In controlled trials of patients with LGS or DS, the mean decrease in hemoglobin from baseline to end of treatment was -0.42 g/dL in EPIDIOLEX-treated patients receiving 10 or 20 mg/kg/day and -0.03 g/dL in patients on placebo. A corresponding decrease in hematocrit was also observed, with a mean change of -1.5% in EPIDIOLEX-treated patients, and -0.4% in patients on placebo. 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. A corresponding decrease in hematocrit was also observed, with a mean change of -1.2% 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).

DRUG INTERACTIONS

Effect Of Other Drugs On EPIDIOLEX

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 are not known [seeCLINICAL PHARMACOLOGY.] Consider an increase in EPIDIOLEX dosage (based on clinical response and tolerability) up to 2-fold, when coadministered with a strong CYP3A4 and/or CYP2C19 inducer.

Effect Of EPIDIOLEX On Other Drugs

UGT1A9, UGT2B7, CYP1A2, CYP2B6, CYP2C8, CYP2C9, And CYP2C19 Substrates

Cannabidiol is a weak inhibitor of CYP1A2 [see CLINICAL PHARMACOLOGY] Increases in exposure of sensitive CYP1A2 substrates (e.g., caffeine, theophylline, or tizanidine) may be observed when coadministered with cannabidiol.

In vitro data predict drug-drug interactions with CYP2B6 substrates (e.g., bupropion, efavirenz), uridine 5'-diphospho-glucuronosyltransferase 1A9 (UGT1A9) substrates (e.g., diflunisal, propofol, fenofibrate), and UGT2B7 substrates (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) 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.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 EPIDIOLEX.

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] The increase in N-desmethylclobazam may increase the risk of clobazam-related adverse reactions [see ADVERSE REACTIONS and WARNINGS AND PRECAUTIONS]. Consider a reduction in dosage of clobazam if adverse reactions known to occur with clobazam are experienced when coadministered with EPIDIOLEX.

Stiripentol

Concomitant use of EPIDIOLEX and stiripentol causes an elevation in exposure to stiripentol [see CLINICAL PHARMACOLOGY] The mechanism of this interaction has not been determined. The clinical relevance of this effect is unknown, but patients should be monitored for stiripentol-related adverse drug reactions.

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 Cmax and AUC of everolimus [see CLINICAL PHARMACOLOGY] When initiating EPIDIOLEX in patients taking everolimus, monitor therapeutic drug levels of everolimus and adjust the dosage accordingly. When initiating everolimus in patients taking a stable dosage of EPIDIOLEX, a lower starting dose of everolimus is recommended, with therapeutic drug monitoring.

Increases in exposure of other orally administered P-gp substrates (e.g., 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

Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations [see WARNINGS AND PRECAUTIONS] If such elevations occur, 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.

CNS Depressants And Alcohol

Concomitant use of EPIDIOLEX with other CNS depressants (including alcohol) may increase the risk of sedation and somnolence [see WARNINGS AND PRECAUTIONS]

Drug Abuse And Dependence

Controlled Substance

EPIDIOLEX is not a controlled substance.

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) and 2 mg alprazolam 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.

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 assessment period beginning three days after drug discontinuation. This suggests that cannabidiol likely does not produce physical dependence.

Read the entire FDA prescribing information for Epidiolex (Cannabidiol Oral Solution)