CANNABIDIOL Drug Interactions: What You Need to Know

INTERACTIONS

• Strong inducer of CYP3A4 or CYP2C19: Consider dose increase of EPIDIOLEX. ( 7.1 )
• Consider a dose reduction of substrates of CYP1A2, CYP2C8, UGT1A9, and orally administered P-gp substrates. ( 7.2 )
• A lower starting dose of orally administered everolimus is recommended. ( 7.2 )
• Consider dose modification of CYP2B6 or CYP2C19 substrates. ( 7.2 )

7.1 Effect of Other Drugs on EPIDIOLEX Strong CYP3A4 or CYP2C19 Inducers Concomitant use with a strong CYP3A4 and CYP2C19 inducer (rifampin 600 mg once daily) decreased cannabidiol and 7‑OH‑CBD plasma concentrations by approximately 32% and 63%. The impact of such changes on efficacy of EPIDIOLEX is not known <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Consider an increase in EPIDIOLEX dosage (based on clinical response and tolerability) up to 2‑fold, when concomitantly used with a strong CYP3A4 and/or CYP2C19 inducer.

7.2 Effect of EPIDIOLEX on Other Drugs Antiepileptic Drugs Clobazam Concomitant use of EPIDIOLEX with clobazam increases plasma concentrations of N‑desmethylclobazam, the active metabolite of clobazam <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>, which may increase the risk of clobazam-related adverse reactions <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ) and Warnings and Precautions ( 5.1 , 5.2 )]</span>. Consider a reduction in dosage of clobazam if adverse reactions known to occur with clobazam are experienced when concomitantly used with EPIDIOLEX.

Stiripentol

Concomitant use of EPIDIOLEX with stiripentol increases plasma exposures of stiripentol [see Clinical Pharmacology ( 12.3 )] . Monitor for stiripentol-related adverse reactions when concomitantly used with EPIDIOLEX.

Orally

Administered P-gp Substrates Concomitant use of EPIDIOLEX with orally administered everolimus results in an approximately 2.5‑fold increase in plasma exposures of everolimus [see Clinical Pharmacology ( 12.3 )] . When initiating EPIDIOLEX in patients taking everolimus, monitor therapeutic drug levels of everolimus and adjust the dosage accordingly. In patients on a stable dosage of EPIDIOLEX, it is recommended to initiate everolimus at a lower starting dosage and titrate the dose based on therapeutic drug monitoring. Increases in exposure of other orally administered P‑gp substrates (e.g., sirolimus, tacrolimus, digoxin) may be observed when concomitantly used with EPIDIOLEX. Consider therapeutic drug monitoring and dosage reduction of other P‑gp substrates when given orally with EPIDIOLEX. CYP1A2, CYP2B6, CYP2C8, CYP2C19, and UGT1A9 Substrates CYP1A2 Substrates Cannabidiol is a weak inhibitor of CYP1A2 [see Clinical Pharmacology ( 12.3 )] . Increases in exposure of certain CYP1A2 substrates (e.g., theophylline, tizanidine) may be observed when concomitantly used with EPIDIOLEX. Consider dosage reduction of CYP1A2 substrates where minimal concentration changes may lead to serious adverse reactions, as clinically appropriate, when concomitantly used with EPIDIOLEX. CYP2B6 Substrates Cannabidiol is an inducer and inhibitor of CYP2B6 [see Clinical Pharmacology ( 12.3 )]. No clinically significant reduction in exposures of CYP2B6 substrates are observed when concomitantly used with EPIDIOLEX at 7.5 mg/kg twice daily. Changes in exposures of CYP2B6 substrates are unknown when concomitantly used with EPIDIOLEX at doses above 7.5 mg/kg twice daily. Consider dosage modification of CYP2B6 substrates, as clinically appropriate, when concomitantly used with EPIDIOLEX at doses above 7.5 mg/kg twice daily. CYP2C8 Substrates Concomitant use of EPIDIOLEX may cause clinically significant interactions with CYP2C8 substrates. Consider a reduction in dosage of CYP2C8 substrates, as clinically appropriate, if adverse reactions are experienced when concomitantly used with EPIDIOLEX. CYP2C19 Substrates Cannabidiol is a moderate inhibitor of CYP2C19 [see Clinical Pharmacology ( 12.3 )] . Concomitant use of EPIDIOLEX increases plasma concentrations of CYP2C19 substrates and may increase the risk of adverse reactions. Consider a dosage reduction of CYP2C19 substrates, as clinically appropriate, when concomitantly used with EPIDIOLEX. For CYP2C19 substrates (e.g., clopidogrel) where efficacy is mainly due to their active metabolite(s), concomitant use of EPIDIOLEX may decrease plasma concentration of the active metabolite(s) and may therefore decrease efficacy. Consider a dosage increase of such CYP2C19 substrates, as clinically appropriate, when concomitantly used with EPIDIOLEX. UGT1A9 Substrates Cannabidiol is an inhibitor of UGT1A9 [see Clinical Pharmacology ( 12.3 )] . Increases in exposure of UGT1A9 substrates may be observed when concomitantly used with EPIDIOLEX. Consider a reduction in dosage of UGT1A9 substrates where minimal concentration changes may lead to serious adverse reactions, as clinically appropriate, when concomitantly used with EPIDIOLEX.

7.3 Concomitant Use of EPIDIOLEX and Valproate Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>. If such elevations occur, consider discontinuation or reduction of EPIDIOLEX and/or concomitant valproate. Insufficient data are available to assess the risk of concomitant administration of other hepatotoxic drugs and EPIDIOLEX.

7.4 CNS Depressants and Alcohol Concomitant use of EPIDIOLEX with other CNS depressants (including alcohol) may increase the risk of sedation and somnolence <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> .

EPIDIOLEX is contraindicated in patients with a history of hypersensitivity to cannabidiol or any of the ingredients in the product [see Description ( 11 ) and Warnings and Precautions ( 5.4 )]. Hypersensitivity to cannabidiol or any of the ingredients in EPIDIOLEX ( 4 )

AND PRECAUTIONS

• Hepatic Injury: EPIDIOLEX can cause transaminase elevations. Concomitant use of valproate and higher doses of EPIDIOLEX increase the risk of transaminase elevations.

See Full Prescribing

Information for serum transaminase and bilirubin monitoring recommendations. ( 5.1 )

• Somnolence and Sedation: Monitor for somnolence and sedation and advise patients not to drive or operate machinery until they have gained sufficient experience on EPIDIOLEX. ( 5.2 )
• Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and thoughts. ( 5.3 )
• Hypersensitivity Reactions: Advise patients to seek immediate medical care. Discontinue and do not restart EPIDIOLEX if hypersensitivity occurs. ( 5.4 )
• Withdrawal of Antiepileptic Drugs: EPIDIOLEX should be gradually withdrawn to minimize the risk of increased seizure frequency and status epilepticus. ( 5.5 )

5.1 Hepatic Injury EPIDIOLEX can cause dose-related elevations of liver transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). In controlled studies for LGS and DS (10 and 20 mg/kg/day dosages) and TSC (25 mg/kg/day), the incidence of ALT elevations above 3 times the upper limit of normal (ULN) was 13% (10 and 20 mg/kg/day dosages) and 12% (25 mg/kg/day dosage) in EPIDIOLEX-treated patients compared with 1% in patients on placebo. Less than 1% of EPIDIOLEX-treated patients had ALT or AST levels greater than 20 times the ULN. There were cases of transaminase elevations associated with hospitalization in patients taking EPIDIOLEX. In clinical trials, serum transaminase elevations typically occurred in the first two months of treatment initiation; however, there were some cases observed up to 18 months after initiation of treatment, particularly in patients taking concomitant valproate. Resolution of transaminase elevations occurred with discontinuation of EPIDIOLEX or reduction of EPIDIOLEX and/or concomitant valproate in about two-thirds of the cases. In about one-third of the cases, transaminase elevations resolved during continued treatment with EPIDIOLEX, without dose reduction. In the postmarketing setting, cases of cholestatic or mixed patterns of liver injury (i.e., based on calculated ratio of [ALT/ULN]/[ALP/ULN] less than 2 and between 2-5, respectively) were reported in patients treated with EPIDIOLEX.

Risk

Factors for Transaminase Elevation Concomitant Valproate and Clobazam The majority of ALT elevations in the controlled studies occurred in patients taking concomitant valproate [see Drug Interactions ( 7.3 )] . Concomitant use of clobazam also increased the incidence of transaminase elevations, although to a lesser extent than valproate [see Drug Interactions ( 7.2 )] . In EPIDIOLEX-treated patients with LGS or DS (10 and 20 mg/kg/day dosages), the incidence of ALT elevations greater than 3 times the ULN was 30% in patients taking both concomitant valproate and clobazam, 21% in patients taking concomitant valproate (without clobazam), 4% in patients taking concomitant clobazam (without valproate), and 3% in patients taking neither drug. In EPIDIOLEX-treated patients with TSC (25 mg/kg/day), the incidence of ALT elevations greater than 3 times the ULN was 20% in patients taking both concomitant valproate and clobazam, 25% in patients taking concomitant valproate (without clobazam), 0% in patients taking concomitant clobazam (without valproate), and 6% in patients taking neither drug. Consider discontinuation or dose adjustment of valproate or clobazam if liver enzyme elevations occur. In the postmarketing setting, cases of elevated ammonia levels were reported in some EPIDIOLEX-treated patients who also had transaminase elevations; where data were available, most cases reported concomitant use of valproate, clobazam, or both. Consider discontinuation or dose adjustment of valproate or clobazam if ammonia level elevations occur.

Dose

Transaminase elevations are generally dose-related. In patients with DS or LGS (10 and 20 mg/kg/day) or TSC (25 mg/kg/day), ALT elevations greater than 3 times the ULN were reported in 17% and 12% of patients taking EPIDIOLEX 20 or 25 mg/kg/day, respectively, compared with 1% in patients taking EPIDIOLEX 10 mg/kg/day. The risk of ALT elevations was higher (25%) in patients with TSC receiving a dosage above the recommended maintenance dosage of 25 mg/kg/day in Study 4.

Baseline Transaminase Elevations

Patients with baseline transaminase levels above the ULN had higher rates of transaminase elevations when taking EPIDIOLEX. In the DS and LGS controlled trials (Studies 1, 2, and 3) in patients taking EPIDIOLEX 20 mg/kg/day, the frequency of treatment-emergent ALT elevations greater than 3 times the ULN was 30% when ALT was above the ULN at baseline, compared to 12% when ALT was within the normal range at baseline. No patients taking EPIDIOLEX 10 mg/kg/day experienced ALT elevations greater than 3 times the ULN when ALT was above the ULN at baseline, compared with 2% of patients in whom ALT was within the normal range at baseline. In the TSC controlled trial (Study 4) in patients taking EPIDIOLEX 25 mg/kg/day, the frequency of treatment-emergent ALT elevations greater than 3 and 5 times the ULN were both 11% when ALT was above the ULN at baseline, compared to 12% and 6%, respectively, when ALT was within the normal range at baseline. Monitoring In general, transaminase elevations of greater than 3 times the ULN in the presence of elevated bilirubin without an alternative explanation are an important predictor of severe liver injury. Early identification of elevated liver enzymes may decrease the risk of a serious outcome. Patients with elevated baseline transaminase levels above 3 times the ULN, accompanied by elevations in bilirubin above 2 times the ULN, should be evaluated prior to initiation of EPIDIOLEX treatment. Prior to starting treatment with EPIDIOLEX, obtain serum transaminases (ALT and AST) and total bilirubin levels. Serum transaminases and total bilirubin levels should be obtained at 1 month, 3 months, and 6 months after initiation of treatment with EPIDIOLEX, and periodically thereafter or as clinically indicated. Serum transaminases and total bilirubin levels should also be obtained within 1 month following changes in EPIDIOLEX dosage and addition of or changes in medications that are known to impact the liver. Consider more frequent monitoring of serum transaminases and bilirubin in patients who are taking valproate or who have elevated liver enzymes at baseline. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with EPIDIOLEX, as appropriate. Discontinue EPIDIOLEX in any patients with elevations of transaminase levels greater than 3 times the ULN and bilirubin levels greater than 2 times the ULN. Patients with sustained transaminase elevations of greater than 5 times the ULN should also have treatment discontinued. Patients with prolonged elevations of serum transaminases should be evaluated for other possible causes. Consider dosage adjustment of any coadministered medication that is known to affect the liver (e.g., valproate and clobazam).

5.2 Somnolence and Sedation EPIDIOLEX can cause somnolence and sedation. In controlled studies for LGS and DS (10 and 20 mg/kg/day dosages), the incidence of somnolence and sedation (including lethargy) was 32% in EPIDIOLEX-treated patients (27% and 34% of patients taking EPIDIOLEX 10 or 20 mg/kg/day, respectively), compared with 11% in patients on placebo and was generally dose-related. The rate was higher in patients on concomitant clobazam (46% in EPIDIOLEX-treated patients taking clobazam compared with 16% in EPIDIOLEX-treated patients not on clobazam). In the controlled study for TSC, the incidence of somnolence and sedation (including lethargy) was 19% in EPIDIOLEX-treated patients (25 mg/kg/day), compared with 17% in patients on placebo. The rate was higher in patients on concomitant clobazam (33% in EPIDIOLEX-treated patients taking clobazam compared with 14% in EPIDIOLEX-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 EPIDIOLEX. 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 EPIDIOLEX to gauge whether it adversely affects their ability to drive or operate machinery.

5.3 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including EPIDIOLEX, 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 Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5

2.4 Psychiatric 5.7 8.5 1.5

2.9 Other 1.0 1.8 1.9

0.9 Total 2.4 4.3 1.8

1.9 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 EPIDIOLEX 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 EPIDIOLEX can cause hypersensitivity reactions. Some subjects in the EPIDIOLEX clinical trials had pruritus, erythema, and angioedema requiring treatment, including corticosteroids and antihistamines. Patients with known or suspected hypersensitivity to any ingredients of EPIDIOLEX were excluded from the clinical trials. If a patient develops hypersensitivity reactions after treatment with EPIDIOLEX, the drug should be discontinued. EPIDIOLEX is contraindicated in patients with a prior hypersensitivity reaction to cannabidiol or any of the ingredients in the product, which includes sesame seed oil <span class="opacity-50 text-xs">[see Description ( 11 )]</span>.

5.5 Withdrawal of Antiepileptic Drugs (AEDs) As with most antiepileptic drugs, EPIDIOLEX should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ) and Clinical Studies ( 14 )]</span>. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.