Included as part of the PRECAUTIONS section.
EPIDIOLEX 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 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.
Risk Factors For Transaminase Elevation
Concomitant Valproate And Clobazam
The majority of ALT elevations occurred in patients
taking concomitant valproate [see DRUG INTERACTIONS]. Concomitant use of
clobazam also increased the incidence of transaminase elevations, although to a
lesser extent than valproate [see DRUG INTERACTIONS]. In
EPIDIOLEX-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.
Transaminase elevations are dose-related. Overall, ALT
elevations greater than 3 times the ULN were reported in 17% of patients taking
EPIDIOLEX 20 mg/kg/day compared with 1% in patients taking EPIDIOLEX 10
Baseline Transaminase Elevations
Patients with baseline transaminase levels above the ULN
had higher rates of transaminase elevations when taking EPIDIOLEX. In
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 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
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 co-administered medication that is known to affect the liver
(e.g., valproate and clobazam).
Somnolence And Sedation
EPIDIOLEX can cause somnolence and sedation. In
controlled studies for LGS and DS, the incidence of somnolence and sedation
(including lethargy) was 32% in EPIDIOLEX-treated patients, compared with 11%
in patients on placebo and was dose-related (34% of patients taking EPIDIOLEX
20 mg/kg/day, compared with 27% in patients taking EPIDIOLEX 10 mg/kg/day). 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 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.
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
||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
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.
EPIDIOLEX can cause hypersensitivity reactions. One
subject in the EPIDIOLEX clinical trials had pruritus, erythema, and angioedema
requiring treatment with 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 [see DESCRIPTION].
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 [see DOSAGE AND ADMINISTRATION and Clinical
Studies]. But if withdrawal is needed because of a serious adverse event,
rapid discontinuation can be considered.
Patient Counseling Information
Advise the caregiver or patient to read the FDA-approved
patient labeling (Medication Guide and Instructions for Use).
Advise patients who are prescribed EPIDIOLEX to use the
adapter and oral dosing syringes provided [see DOSAGE AND ADMINISTRATION
and Instructions for Use].
Advise patients to take EPIDIOLEX consistently either in
the fasted or fed state [see DOSAGE AND ADMINISTRATION].
Instruct patients to discard any unused EPIDIOLEX oral
solution after 12 weeks of first opening the bottle [see DOSAGE AND
Inform patients about the potential for elevations of
liver enzymes. Discuss with the patient the importance of measuring hepatic
laboratory values and having them evaluated by the healthcare provider before
treatment with EPIDIOLEX and periodically during treatment [see WARNINGS AND
PRECAUTIONS]. Advise patients of the clinical signs or symptoms suggestive
of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain,
fatigue, anorexia, or jaundice and/or dark urine) and to contact a healthcare
provider promptly if these signs or symptoms occur.
Somnolence And Sedation
Caution patients about operating hazardous machinery,
including motor vehicles, until they are reasonably certain that EPIDIOLEX does
not affect them adversely (e.g., impair judgment, thinking or motor skills) [see
WARNINGS AND PRECAUTIONS].
Suicidal Thinking And Behavior
Counsel patients, their caregivers, and their families
that antiepileptic drugs, including EPIDIOLEX, may increase the risk of
suicidal thoughts and behavior and advise them to be alert for the emergence or
worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts of self-harm.
Instruct patients, caregivers, and families to report behaviors of concern immediately
to healthcare providers [see WARNINGS AND PRECAUTIONS].
Withdrawal Of Antiepileptic Drugs (AEDs)
Advise patients not to discontinue use of EPIDIOLEX
without consulting with their healthcare provider. EPIDIOLEX should normally be
gradually withdrawn to reduce the potential for increased seizure frequency and
status epilepticus [see DOSAGE AND ADMINISTRATION, WARNINGS AND
Advise patients to notify their healthcare provider if
they become pregnant or intend to become pregnant during EPIDIOLEX therapy.
Encourage women who are taking EPIDIOLEX to enroll in the North American
Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs
during pregnancy [see Use In Specific Populations].
Advise patients of the potential for positive cannabis
Carcinogenesis And Mutagenesis
Adequate studies of the carcinogenic potential of
cannabidiol have not been conducted.
Cannabidiol was negative for genotoxicity in in vitro (Ames)
and in vivo (rat Comet and bone marrow micronucleus) assays.
Impairment Of Fertility
Oral administration of cannabidiol (0, 75, 150, or 250
mg/kg/day) to male and female rats, prior to and throughout mating and
continuing in females during early gestation, produced no adverse effects on
fertility. The highest dose tested was associated with plasma exposures
approximately 60 times that in humans at the maximum recommended human dose (20
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as
EPIDIOLEX, during pregnancy. Encourage women who are taking EPIDIOLEX during
pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry by calling the toll free number 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.
There are no adequate data on the developmental risks
associated with the use of EPIDIOLEX in pregnant women. Administration of
cannabidiol to pregnant animals produced evidence of developmental toxicity
(increased embryofetal mortality in rats and decreased fetal body weights in
rabbits; decreased growth, delayed sexual maturation, long-term neurobehavioral
changes, and adverse effects on the reproductive system in rat offspring) at
maternal plasma exposures similar to (rabbit) or greater than (rat) that in
humans at therapeutic doses (see Animal Data). In the U.S. general
population, the estimated background risk of 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.
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
There are no data on the presence of cannabidiol or its
metabolites in human milk, the effects on the breastfed infant, or the effects
on milk production. The developmental and health benefits of breastfeeding
should be considered along with the mother's clinical need for EPIDIOLEX and
any potential adverse effects on the breastfed infant from EPIDIOLEX or from
the underlying maternal condition.
Safety and effectiveness of EPIDIOLEX for the treatment
of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome have
been established in patients 2 years of age and older.
Safety and effectiveness of EPIDIOLEX in pediatric
patients below 2 years of age have not been established.
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.
Clinical trials of EPIDIOLEX in the treatment of LGS and
DS did not include any patients aged above 55 years to determine whether or not
they respond differently from younger patients. In general, dose selection for
an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy [see DOSAGE
AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and CLINICAL
Because of an increase in exposure to EPIDIOLEX, dosage
adjustments are necessary in patients with moderate or severe hepatic
impairment [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS,
and CLINICAL PHARMACOLOGY]. EPIDIOLEX does not require dosage
adjustments in patients with mild hepatic impairment.