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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
EPIDIOLEX (NDA-210365)
(CANNABIDIOL)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
03/04/2024 (SUPPL-21)
5 Warnings and Precautions
5.1 Hepatic InjurySubsection title revised
Additions and revisions underlined:
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)].
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.
8 Use in Specific Populations
8.1 PregnancyAdditions and revisions underlined:
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:
EPIDIOLEX Pregnancy Surveillance Program
1-855-272-7158
https://www.epidiolexpregnancystudy.com
North American Antiepileptic Drug (NAAED) Pregnancy Registry
1-888-233-2334
https://www.aedpregnancyregistry.org/
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication GuideAdditions and revisions underlined:
If you become pregnant while taking EPIDIOLEX, talk to your healthcare provider about registering for both the EPIDIOLEX Pregnancy Surveillance Program and the North American Antiepileptic Drug (NAAED) registry. The purpose of the surveillance program and exposure registry is to collect information about the safety of EPIDIOLEX and other antiepileptic drugs during pregnancy.
You can enroll in the EPIDIOLEX Pregnancy Surveillance Program by calling the toll free number 1- 855-272-7158 or visiting https://www.epidiolexpregnancystudy.com.
You can enroll in the North American Antiepileptic Drug Pregnancy Registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org.
Additions and revisions underlined:
Pregnancy Surveillance Program and Pregnancy Exposure 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 both the EPIDIOLEX Pregnancy Surveillance Program and the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. The surveillance program and exposure registry are collecting information about the safety of EPIDIOLEX and other antiepileptic drugs during pregnancy[see Use in Specific Populations (8.1)].
02/24/2022 (SUPPL-15)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions underlined
…
Administration Information
Advise patients who are prescribed EPIDIOLEX to use the adapter and oral dosing syringes provided [see Dosage and Administration (2.4) and Instructions for Use]. Provide instructions regarding which syringe to use and how to administer the specified dose, since EPIDIOLEX is supplied with 1 mL and 5 mL oral dispensing syringes.
Instruct patients to discard any unused EPIDIOLEX oral solution after 12 weeks of first opening the bottle [see Dosage and Administration (2.4)].
…
09/30/2021 (SUPPL-12)
6 Adverse Reactions
6.1 Clinical Trials ExperienceNewly added information to end of subsection:
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).
7 Drug Interactions
7.2 Effect of EPIODIOLEX on Other DrugsNewly added information to end of subsection:
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 (12.3)]. 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.
09/30/2021 (SUPPL-13)
6 Adverse Reactions
6.1 Clinical Trials ExperienceNewly added information to end of subsection:
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).
7 Drug Interactions
7.2 Effect of EPIODIOLEX on Other DrugsNewly added information to end of subsection:
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 (12.3)]. 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.
10/22/2020 (SUPPL-8)
7 Drug Interactions
7.2 Effect of EPIDIOLEX on Other Drugs(Additions underlined)
UGT1A9, UGT2B7, CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 Substrates
Cannabidiol is a weak inhibitor of CYP1A2 [see Clinical Pharmacology (12.3)]. Increases in exposure of sensitive CYP1A2 substrates (e.g., caffeine, theophylline, or tizanidine) may be observed when co- administered with cannabidiol.
… 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.
…
Stiripentol
Concomitant use of EPIDIOLEX and stiripentol causes an elevation in exposure to stiripentol [see Clinical Pharmacology (12.3)]. 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.
07/31/2020 (SUPPL-5)
5 Warnings and Precautions
5.2 Somnolence and Sedation
Additions and/or revisions underlined:
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 …
5.4 Hypersensitivity Reactions
Additions and/or revisions underlined:
EPIDIOLEX can cause hypersensitivity reactions. Some subjects in the EPIDIOLEX clinical trials had pruritus, erythema, and angioedema requiring treatment, including corticosteroids and antihistamines.
Additions and/or revisions underlined:
5.1 Hepatocellular 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 …
… 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 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.
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 … 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.
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
… 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, 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 (14.1, 14.2)] …
… In controlled trials in LGS or DS, the rate of discontinuation as a result of any adverse reaction was 2.7% …
… The most common adverse reactions that occurred in EPIDIOLEX-treated patients with LGS or DS (incidence at least 10% and greater than placebo)
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 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)]. 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) Newly added table; please refer to label for complete information.
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 greater than or equal to5%, 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-treatment 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 trial of patients with TSC, the mean decrease in hemoglobin from baseline to end 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.
7 Drug Interactions
7.1 Effect of Other Drugs on EPIDIOLEX
Additions and/or revisions underlined:
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 [see Clinical Pharmacology (12.3)]. 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.
7.2 Effect of EPIDIOLEX on Other Drugs
Additions and/or revisions underlined:
… 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)]. The increase in N-desmethylclobazam may increase the risk of clobazam-related adverse reactions [see Warnings and Precautions (5.1, 5.2)].
7.3 Concomitant Use of EPIDIOLEX and Valproate
Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations [see Warnings and Precautions (5.1)]. If such elevations occur, discontinuation or reduction of EPIDIOLEX and/or concomitant valproate should be considered …
Newly added subsection:
7.4 Concomitant Use of EPIDIOLEX and Mammalian Target of Rapamycin (mTOR) or Calcineurin Inhibitors
No dedicated drug-drug interaction studies have been conducted with mTOR inhibitors (e.g., everolimus) or calcineurin inhibitors (e.g., tacrolimus). Reports in the literature suggest that cannabidiol administration resulted in increased serum levels of everolimus, sirolimus, or tacrolimus. The mechanism of increase in mTOR or calcineurin inhibitors concentrations is not clearly understood. Consider a reduction in dosage of everolimus, sirolimus, or tacrolimus, if adverse reactions known to occur with those medications are experienced when co-administered with EPIDIOLEX.
Additions and/or revisions underlined:
7.5 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 (5.2)].
8 Use in Specific Populations
8.1 Pregnancy
… 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 …
… 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.
8.4 Pediatric Use
Additions and/or revisions underlined:
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 (14.1, 14.2, 14.3)].
Safety and effectiveness of EPIDIOLEX in pediatric patients below 1 year of age have not been established.
Juvenile Animal Data
… 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.
8.5 Geriatric Use
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 …
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAdditions and/or revisions underlined:
What is EPIDIOLEX?
EPIDIOLEX is a prescription medicine that is used to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in people 1 year of age and older.
It is not known if EPIDIOLEX is safe and effective in children under 1 year of age.
Additions and/or revisions underlined:
Hepatocellular Injury
… Advise patients of the 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) and to contact a healthcare provider promptly if these signs or symptoms occur.
Other
EPIDIOLEX is no longer a controlled substance.
07/31/2020 (SUPPL-6)
5 Warnings and Precautions
5.2 Somnolence and Sedation
Additions and/or revisions underlined:
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 …
5.4 Hypersensitivity Reactions
Additions and/or revisions underlined:
EPIDIOLEX can cause hypersensitivity reactions. Some subjects in the EPIDIOLEX clinical trials had pruritus, erythema, and angioedema requiring treatment, including corticosteroids and antihistamines.
Additions and/or revisions underlined:
5.1 Hepatocellular 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 …
… 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 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.
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 … 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.
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
… 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, 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 (14.1, 14.2)] …
… In controlled trials in LGS or DS, the rate of discontinuation as a result of any adverse reaction was 2.7% …
… The most common adverse reactions that occurred in EPIDIOLEX-treated patients with LGS or DS (incidence at least 10% and greater than placebo)
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 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)]. 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) Newly added table; please refer to label for complete information.
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 greater than or equal to5%, 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-treatment 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 trial of patients with TSC, the mean decrease in hemoglobin from baseline to end 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.
7 Drug Interactions
7.1 Effect of Other Drugs on EPIDIOLEX
Additions and/or revisions underlined:
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 [see Clinical Pharmacology (12.3)]. 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.
7.2 Effect of EPIDIOLEX on Other Drugs
Additions and/or revisions underlined:
… 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)]. The increase in N-desmethylclobazam may increase the risk of clobazam-related adverse reactions [see Warnings and Precautions (5.1, 5.2)].
7.3 Concomitant Use of EPIDIOLEX and Valproate
Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations [see Warnings and Precautions (5.1)]. If such elevations occur, discontinuation or reduction of EPIDIOLEX and/or concomitant valproate should be considered …
Newly added subsection:
7.4 Concomitant Use of EPIDIOLEX and Mammalian Target of Rapamycin (mTOR) or Calcineurin Inhibitors
No dedicated drug-drug interaction studies have been conducted with mTOR inhibitors (e.g., everolimus) or calcineurin inhibitors (e.g., tacrolimus). Reports in the literature suggest that cannabidiol administration resulted in increased serum levels of everolimus, sirolimus, or tacrolimus. The mechanism of increase in mTOR or calcineurin inhibitors concentrations is not clearly understood. Consider a reduction in dosage of everolimus, sirolimus, or tacrolimus, if adverse reactions known to occur with those medications are experienced when co-administered with EPIDIOLEX.
Additions and/or revisions underlined:
7.5 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 (5.2)].
8 Use in Specific Populations
8.1 Pregnancy
… 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 …
… 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.
8.4 Pediatric Use
Additions and/or revisions underlined:
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 (14.1, 14.2, 14.3)].
Safety and effectiveness of EPIDIOLEX in pediatric patients below 1 year of age have not been established.
Juvenile Animal Data
… 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.
8.5 Geriatric Use
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 …
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAdditions and/or revisions underlined:
What is EPIDIOLEX?
EPIDIOLEX is a prescription medicine that is used to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in people 1 year of age and older.
It is not known if EPIDIOLEX is safe and effective in children under 1 year of age.
Additions and/or revisions underlined:
Hepatocellular Injury
… Advise patients of the 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) and to contact a healthcare provider promptly if these signs or symptoms occur.
Other
EPIDIOLEX is no longer a controlled substance.
07/31/2020 (SUPPL-7)
5 Warnings and Precautions
5.2 Somnolence and Sedation
Additions and/or revisions underlined:
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 …
5.4 Hypersensitivity Reactions
Additions and/or revisions underlined:
EPIDIOLEX can cause hypersensitivity reactions. Some subjects in the EPIDIOLEX clinical trials had pruritus, erythema, and angioedema requiring treatment, including corticosteroids and antihistamines.
Additions and/or revisions underlined:
5.1 Hepatocellular 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 …
… 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 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.
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 … 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.
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
… 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, 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 (14.1, 14.2)] …
… In controlled trials in LGS or DS, the rate of discontinuation as a result of any adverse reaction was 2.7% …
… The most common adverse reactions that occurred in EPIDIOLEX-treated patients with LGS or DS (incidence at least 10% and greater than placebo)
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 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)]. 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) Newly added table; please refer to label for complete information.
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 greater than or equal to5%, 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-treatment 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 trial of patients with TSC, the mean decrease in hemoglobin from baseline to end 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.
7 Drug Interactions
7.1 Effect of Other Drugs on EPIDIOLEX
Additions and/or revisions underlined:
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 [see Clinical Pharmacology (12.3)]. 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.
7.2 Effect of EPIDIOLEX on Other Drugs
Additions and/or revisions underlined:
… 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)]. The increase in N-desmethylclobazam may increase the risk of clobazam-related adverse reactions [see Warnings and Precautions (5.1, 5.2)].
7.3 Concomitant Use of EPIDIOLEX and Valproate
Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations [see Warnings and Precautions (5.1)]. If such elevations occur, discontinuation or reduction of EPIDIOLEX and/or concomitant valproate should be considered …
Newly added subsection:
7.4 Concomitant Use of EPIDIOLEX and Mammalian Target of Rapamycin (mTOR) or Calcineurin Inhibitors
No dedicated drug-drug interaction studies have been conducted with mTOR inhibitors (e.g., everolimus) or calcineurin inhibitors (e.g., tacrolimus). Reports in the literature suggest that cannabidiol administration resulted in increased serum levels of everolimus, sirolimus, or tacrolimus. The mechanism of increase in mTOR or calcineurin inhibitors concentrations is not clearly understood. Consider a reduction in dosage of everolimus, sirolimus, or tacrolimus, if adverse reactions known to occur with those medications are experienced when co-administered with EPIDIOLEX.
Additions and/or revisions underlined:
7.5 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 (5.2)].
8 Use in Specific Populations
8.1 Pregnancy
… 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 …
… 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.
8.4 Pediatric Use
Additions and/or revisions underlined:
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 (14.1, 14.2, 14.3)].
Safety and effectiveness of EPIDIOLEX in pediatric patients below 1 year of age have not been established.
Juvenile Animal Data
… 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.
8.5 Geriatric Use
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 …
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAdditions and/or revisions underlined:
What is EPIDIOLEX?
EPIDIOLEX is a prescription medicine that is used to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in people 1 year of age and older.
It is not known if EPIDIOLEX is safe and effective in children under 1 year of age.
Additions and/or revisions underlined:
Hepatocellular Injury
… Advise patients of the 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) and to contact a healthcare provider promptly if these signs or symptoms occur.