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One Year Post-Exclusivity

Adverse Event Review:
Oxcarbazepine

Pediatric Advisory Committee Meeting
November 16, 2006

Felicia L. Collins, MD, MPH, FAAP
Medical Officer
Pediatric and Maternal Health Staff
Office of New Drugs
Center for Drug Evaluation and Research
Food and Drug Administration 1
Background Drug Information:
Oxcarbazepine

• Drug: Trileptal® (oxcarbazepine)
• Therapeutic Category: Anticonvulsant
• Sponsor: Novartis
• Original Market Approval: January 14, 2000
• Pediatric Exclusivity Granted: March 2, 2005

2
Background Drug Information:
Oxcarbazepine

• Indications:
– Monotherapy and adjunctive therapy in
the treatment of partial seizures in adults and
children ages 4-16 with epilepsy

3
Drug Use Trends in Outpatient Settings:
Oxcarbazepine
• 2.75 million dispensed prescriptions for all age groups
during the 12-month post-exclusivity period
– 763,000 (28%) for the pediatric population 0 - 16
years old

• 2% increase in prescriptions for all age groups between
the 12-month pre and post-exclusivity periods
– 1% increase for the pediatric population

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Verispan, LLC, April 200 3 – March 2006, Data Extracted May 2006
Drug Use Trends in Outpatient Settings:
Oxcarbazepine
• Neurology was the most frequent prescriber specialty
during the 12-month post-exclusivity period1
– Neurology: 26% (726,000)
– Pediatrics: 3% (77,000)
• Diagnoses most frequently associated with Trileptal® use
in the pediatric population2
– Convulsions: 30% (100,000)
– Bipolar affective disorder: 22% (73,000)
Verispan, LLC, April 200 3 – March 2006, Data Extracted May 2006
1

IMS Health, National Disease and Therapeutic Index™ CD-ROM, NDTI 3 year. April 2003-March 2006
2
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Data extracted May 2006
Pediatric Exclusivity Studies:
Oxcarbazepine
• 4 PK studies in a total of 218 patients, aged 1 month
to < 17 years, utilizing oxcarbazepine monotherapy or
adjunctive therapy
• 1 monotherapy efficacy and safety study in 92
patients, aged 1 month to 16 years old, utilizing low
and high dose oxcarbazepine for 5 days
• 1 adjunctive therapy efficacy and safety study in
128 patients, aged 1 month to < 4 years old, utilizing
low dose (9 days) or high dose (35 day) oxcarbazepine
• 7 safety studies in a total of 337 patients, aged 1
month to < 17 years, utilizing oxcarbazepine
monotherapy or adjunctive therapy for 4-5 days, < 30
days, or 6 months 6
Pediatric Exclusivity Studies:
PK (n=218)

• Design:
– 2 open-label, age-stratified, pilot PK
studies
– Population PK sampling employed in the
2 efficacy and safety studies

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PK Exclusivity Studies:
Results

• Younger pediatric patients required a greater
weight based dose to produce the same
concentration
• Proposed adjunctive therapy dosing regimens
were adequate
• Data could not be interpreted for proposed
monotherapy dosing regimens

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Pediatric Exclusivity Studies:
Monotherapy (n=92)

• Design: Multi-center, parallel-group,
rater-blinded, randomized comparison
of low dose (10 mg/kg/day) vs. high
dose (titrated up to 60 mg/kg/day with
2400 mg/day maximum)
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Pediatric Exclusivity Studies:
Monotherapy Efficacy
• Endpoints:
– Primary: time to meet specified exit criteria based
upon a central rater blinded reading of a 72-hour
video-EEG
– Secondary: percent of patients meeting exit criteria
and number of partial seizures as determined by
electrographic manifestations alone

• Exit criteria:
– Three study seizures with or without secondarily
generalized seizures; or
– A prolonged study seizure with an electrographic
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duration of at least 5 minutes
Monotherapy Exclusivity Study:
Efficacy Results

• No difference in the primary endpoint
between the low and high dose groups

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Pediatric Exclusivity Studies:
Adjunctive Therapy Efficacy (n=128)

• Design: Multi-center, parallel-group, rater-blinded,
randomized comparison of low dose (10 mg/kg/day
for 6 days) vs. high dose (10 mg/kg/day with slow
upward titration to 60 mg/kg/day, as tolerated, for 32
days) with subsequent 72-hour, inpatient video-EEG
evaluation
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Pediatric Exclusivity Studies:
Adjunctive Therapy Efficacy
• Endpoints
– Primary: absolute change in study seizure frequency
per 24 hours from baseline
– Secondary:
• Percentage change in study seizure frequency per
24 hours from baseline
• Absolute change in frequency of all electrographic
seizures compared to baseline
• Response to treatment (e.g., patients with a 50%
response reduction in seizures) 13
Adjunctive Therapy Exclusivity Study:
Efficacy Results
• Greater absolute reduction in the number of
study seizures in the high vs. low dose group
• Greater reduction in the high dose group’s
– Percentage change in study seizure frequency
– Absolute change in all electrographic seizures
• For patients under 24 months, no therapeutic
effect when baseline seizure frequency was
considered 14
Pediatric Exclusivity Studies:
Safety Studies (n=337)
• Design:
– 2 efficacy studies: multi-center, parallel-group,
rater-blinded, randomized comparisons of low
dose vs. high dose monotherapy and adjunctive
therapy
– 2 pilot PK studies: open-label, age-stratified
– 4 extension studies: 6-month open-label
extension of efficacy and PK studies
– 1 additional open-label, multi-center, active-
control, flexible-dose monotherapy
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Safety Exclusivity Studies: Deaths (n=5)
• Each case is confounded by medical conditions
(respiratory pathology and seizure disorder) and/or
concomitant medications
– 10 m.o. male, with encephalopathy and history of lung
infections, died from “pneumopathy secondary to an
increase in seizures” 2 days after discontinuing
oxcarbazepine (OXC) (2 month treatment; 60 mg/kg/day
with taper to lower dose; concomitant meds)
– 22 m.o. male, with history of influenza and oral Candida,
died due to “pneumonia” that led to sepsis while on
OXC monotherapy (4.5 month treatment; 60 mg/kg/day;
no other meds at initial presentation of adverse event)
Safety Exclusivity Studies: Deaths
(continued)
– 13 m.o. female, with developmental delay and static
encephalopathy, died due to “progression of seizure
disorder” approximately 8.5 months after discontinuing
OXC (2 month treatment; 78 mg/kg/day at time of
adverse event; concomitant meds)
– 10 m.o. male, with history of bronchitis and cortical
dysplasia, died of “sudden death” 2 ½ weeks after
elective cortical resection surgery while on OXC (5.5
month treatment; 18 mg/kg/day at death; concomitant
meds)
– 40 m.o. female, with developmental delay and cerebral
infarction, died due to “bronchoaspiration” after a
4-hour seizure while on OXC (8 month treatment;
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60 mg/kg/day; concomitant meds)
Safety Exclusivity Studies (n=337):
Non-Fatal Serious Adverse Reactions

• 18.4% (62) of patients experienced serious
adverse events (AEs)
• Most common serious AEs
– Convulsions: 5.9% (20)
– Status epilepticus: 3.9% (13)
– Pneumonia: 3.0% (10)
• These AEs are expected for this population
and listed in the drug labeling 18
Safety Exclusivity Studies (n=337):
Discontinuations
• 9.2% (31) of patients discontinued due to AEs
• Most common AEs leading to discontinuation
– Nervous system disorders: 6.5% (22)
• Seizure, tremor, somnolence, ataxia
– Skin and subcutaneous tissue disorders: 1.5% (5)
• No serious skin reactions

• Rates of discontinuation due to these AEs were no
greater than that in prior safety studies
• These AEs are listed in the drug labeling 19
Labeling Changes

• Clinical Pharmacology – Pediatric Use
– Weight-adjusted MHD clearance
decreases as age and weight increases
approaching that of adults for patients 13
years and older

20
Labeling Changes

• Clinical Studies:
– Pediatric monotherapy trial failed to demonstrate
efficacy
– Possible explanations
• Short treatment and assessment period
• Absence of a true placebo
• Likely persistence of plasma levels of previously
administered antiepileptic drugs (AEDs) during the
treatment period
21
Labeling Changes

• Clinical Studies: Efficacy of adjunctive
treatment in children 2 years and above

• Indications: Adjunctive therapy in children
aged 2 years and above

22
Labeling Changes
• Dosage and Administration – Pediatric Patients
– In pediatric patients 2 to < 4 years old, treatment
should be initiated at a daily dose of 8 – 10 mg/kg
generally not to exceed 600 mg/day in a BID regimen
– For patients under 20 kg, a starting dose of 16 – 20
mg/kg may be considered
– Children 2 to < 4 years old may require up to twice the
oxcarbazepine dose per body weight compared to
adults
– Children 4 to <= 12 years old may require a 50%
higher oxcarbazepine dose per body weight compared
to adults 23
Labeling Changes

• Precautions – Pediatric patients:
– Study of pediatric patients 3 – 17 years old with
inadequately controlled seizures in which
Trileptal® was added to existing AEDs
• Cognitive adverse events: 5.8% drug group
and 3.1% placebo group
• Somnolence: 34.8% drug group and
14% placebo group
• Ataxia or gait disturbances: 23.2% drug group
(1.4% discontinuation) and 7% placebo group
(0.8% discontinuation) 24
Labeling Changes

• Precautions – Pediatric use:
– Controlled clinical trials involved 898 patients
between the ages of 1 month – 17 years old
(332 treated as monotherapy)

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Labeling Changes

• Adverse Reactions – Adjunctive Therapy/Monotherapy
in Pediatric Patients 1 Month to < 4 Years Old Previously
Treated or not Previously Treated with Other AEDs:
– Most commonly observed (>= 5%) adverse experiences were
similar to those seen in older children and adults
• Exceptions: infections and infestations
– 11% of these 241 patients discontinued treatment due to an
adverse experience
• Convulsions: 3.7%
• Status epilepticus: 1.2%
• Ataxia: 1.2% 26
Adverse Event Reports Since
Market Approval
01/14/00 – 04/02/06
Raw All Reports Serious Death
Counts* (US) (US) (US)
All Ages 2482 (1346) 2164 (1037) 156 (76)

Adults 1653 (834) 1465 (654) 123 (66)
(> 17)
Pediatrics 409 (242) 344 (177) 21† (5)
(0-16)
*May include duplicates and unknown ages

Crude count is 21 with 13 unduplicated cases
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Source: Adverse Event Reporting System, FDA
Pediatric Deaths Since Market Approval
01/14/00 – 04/02/06

• 21 crude count cases

• 13 (4 US) unduplicated cases
– 1 case during the post-exclusivity period
– 12 cases prior to the post-exclusivity period

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Source: Adverse Event Reporting System, FDA
Deaths During the Post-Exclusivity Period
03/02/05 – 04/02/06 (n=1)

• 6 year old male died in China due to
rhabdomyolysis
– Treated with oxcarbazepine for 9 days prior
(150 mg QD titrated to 300 mg QD)
– Hospitalized for fever and CPK = 100,000
(units unspecified)
– Insufficient information to assess the
possibility of drug causality

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Source: Adverse Event Reporting System, FDA
Deaths Prior to the
Post-Exclusivity Period (n=12)
• Cases confounded by other suspect
medications, underlying medical conditions,
family history, and/or insufficient details
– 1 suicide case
• 15 year old, US male with self-inflicted, fatal gunshot
wound after 8 months of oxcarbazepine (starting at
300 mg QD and titrated to 1200 mg QD). Developed
psychosis described as periods of confusion prior to
death. No prior suicide attempts and no concomitant
drugs per autopsy. Family history positive for
depression, schizophrenia, and drug abuse

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Source: Adverse Event Reporting System, FDA
Deaths Prior to the
Post-Exclusivity Period (continued)
– 4 seizure cases
• 11 y.o. male with h/o nocturnal seizures died due to
asphyxiation when he became wedged between the bed and
night stand during an evening seizure
• 9 y.o. year old patient who experienced status epilepticus
during the night and died
• 15 y.o. female who died due to cardiac arrest after seizure
activity had induced a comatose state
• 10 y.o. male with multiple organ system disorders who
experienced status epilepticus and subsequently died due to
multiple organ system failure
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Source: Adverse Event Reporting System, FDA
Deaths Prior to the
Post-Exclusivity Period (continued)
– 2 cardiac cases
• 16 y.o. patient experienced fatal cardiac arrest 9 days after
an increased Lamictal dose
• 11 y.o. female on multiple suspect medication and who
died due to myocarditis

– 2 unspecified death cases
• 11 y.o. male who had received oxcarbazepine for 5 – 6
years without incidence, had discontinued the drug when
diagnosed with lupus without patient improvement, and
had restarted the drug for a year prior to death
• 2 d.o. male whose mother had received multiple
medications during pregnancy including fluoxetine,
nadolol, codeine-acetaminophen, and Neurontin 32
Source: Adverse Event Reporting System, FDA
Deaths Prior to the
Post-Exclusivity Period (continued)
– 3 additional cases
• 15 y.o. patient who died of hepatic failure after experiencing
an inhalation pneumonia and subsequent hypoxemia,
hypotension, and compromised vascular circulation to the
liver
• 10 y.o. female receiving oxcarbazepine for an unspecified
disorder for 1.5 years prior to developing nephrotic
syndrome that did not improve with corticosteroids and
discontinuation of oxcarbazepine
• 4 y.o. male with h/o congenital hydrocephalus who died due
to infectious peritonitis and septicemia after experiencing an
intestinal perforation associated with the placement of an
indwelling gastric catheter 33
Source: Adverse Event Reporting System, FDA
Pediatric Hypersensitivity Reactions
Since Market Approval (n=7)
• All cases were non-fatal
• 1 anaphylaxis case
– 4 year old male with progressive stridor,
drooling, and croupy cough starting 30
minutes after first oxcarbazepine dose.
Recovered after hospitalization and treatment
with epinephrine, dexamethasone, and
diphenhydramine.
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Source: Adverse Event Reporting System, FDA
Hypersensitivity Reactions
Since Market Approval (continued)
• 6 angioedema cases
– 5 y.o. male with angioedema on 7 ml po oxcarbazepine
q 12 hours. Multiple concomitant meds (unclear timing
of reaction).
– 5 y.o. male with periauricular edema and allergic
exanthema 4 days after starting 300 mg/day
oxcarbazepine . Symptoms resolved within 7 days after
oxcarbazepine discontinuance and IV corticosteroids.
– 7 y.o. female with urticarial rash, facial edema, and
feeling of suffocation 1 month after initiating 600
mg/day oxcarbazepine . Symptoms resolved with
Urbason (unclear if oxcarbazepine discontinued). 35
Source: Adverse Event Reporting System, FDA
Hypersensitivity Reactions
Since Market Approval
• Angioedema cases (continued)
– 9 y.o. female with rash, eyelid edema 3 days after
decreased oxcarbazepine dose to 300 mg/day (had
dizziness and diplopia on 450 mg/day). Concomitant
valproate. Symptoms resolved after oxcarbazepine
discontinuance and corticosteroids.
– 12 y.o. male with face edema, allergic exanthema, and
conjunctivitis 3 days after initiating 600 mg/day
oxcarbazepine . Symptoms resolved within 5 days after
oxcarbazepine discontinuance and corticosteroids.
Assessed as probable oxcarbazepine causality.
– 16 y.o. female with hand and eyelid edema and rash after
8 doses of 300 mg BID oxcarbazepine . Concomitant
isoniazid (no information on symptom resolution and
unclear if oxcarbazepine discontinued). 36
Source: Adverse Event Reporting System, FDA
Related Labeling

• Warnings - History of Hypersensitivity
Reaction to Carbamazepine
– 25 - 30% of patients with hypersensitivity reactions to
carbamazepine will experience hypersensitivity
reactions with Trileptal®

• Adverse Reactions – Other Events Observed in
Association with Trileptal® Administration
– Skin and appendages: angioedema
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Adverse Event Reports During the
Post-Exclusivity Period
03/02/05 – 04/02/06
Raw Counts* All Reports Serious Death
(US) (US) (US)

All Ages 493 (307) 471 (289) 38 (29)

Adults 308 (182) 299 (176) 33 (27)
(> 17)
Pediatrics 88 (59) 82 (53) 1 (0)
(0-16)
* may include duplicates and unknown ages 38
Source: Adverse Event Reporting System, FDA
Characteristics of Cases Reported
During the Post-Exclusivity Period
• Indications - 63
– Seizure – 40
– Bipolar disorder – 6
– Affective disorder -5
– Attention deficit hyperactivity disorder (ADHD) – 4
– No indication for fetus in utero with passive
exposure – 4
– Abnormal behavior – 2
– Labile mood – 1
– Opposition defiant disorder -1
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Source: Adverse Event Reporting System, FDA
Characteristics of Cases Reported
During the Post-Exclusivity Period
• Outcomes - 86*
– Serious - 67
• Death – 1
• Life-threatening - 10
• Hospitalization - 23
• Disability – 11
• Congenital anomaly – 1
• Medically significant – 21
– Non-serious - 19
* A report may have more than one outcome
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Source: Adverse Event Reporting System, FDA
Non-Fatal Adverse Events
During the Post-Exclusivity Period

• 83 total cases*
• 52 unlabeled/unexpected cases
• 31 cases of events listed or implied in
the drug labeling

* Includes serious and non-serious cases
Source: Adverse Event Reporting System, FDA 41
Unlabeled/Unexpected Adverse Events
(n=52*)
• Neurologic (10) • Ophthalmic (2)
• Psychiatric (9) • Cardiac (1)
• Endocrine (8) • Renal (1)
• Hematologic (4) • Immunologic (1)
• In utero (4) • Vascular (1)
• Hepatobiliary (3) • Dental (1)
• General (3) • Electrolyte (1)
• Musculoskeletal (3)
* Includes serious and non-serious cases
Source: Adverse Event Reporting System, FDA 42
Neurologic Unlabeled Adverse Events
(n=10*)
• Cases confounded by insufficient details and/or
alternative explanations for the adverse events
 13 m.o. female with an unknown genetic disorder on
oxcarbazepine and other drugs experienced “myoclonus without
EEG abnormality”. Dose of oxcarbazepine decreased and the
myoclonus disappeared (case lacking clinical details).
 2 seizure cases. One case linked to increased Wellbutrin dosing.
Other case without details or an outcome.
 7 other cases with events explained by alternative etiology or that
continued after oxcarbazepine was discontinued.
 2 – sedation, 1 – somnolence, 1 - forceful eyelid closure,
1 – dystonia, 1 – depression, 1 - mental retardation (case
lacking clinical details)
* Includes serious and non-serious cases 43
Source: Adverse Event Reporting System, FDA
Psychiatric Unlabeled Adverse Events
(n=9*)
• Cases confounded by underlying medical
conditions and/or concomitant medications
• 3 suicide attempt/suicidal ideation cases
– 14 y.o. male with bipolar disorder experienced suicidal and
homicidal ideation that was not new behavior.
– 15 y.o. female with multiple drug overdose, including
oxcarbazepine (unknown if patient was prescribed
oxcarbazepine).
– Patient with bipolar disorder on multiple medications
experienced anger, agitation, and frustration that continued after
oxcarbazepine discontinued. Later attempted suicide by
ingesting oxcarbazepine.
* Includes serious and non-serious cases 44
Source: Adverse Event Reporting System, FDA
Psychiatric Unlabeled Adverse Events
(continued)

• 3 hallucination cases
– 9 y.o. female on 1200 mg qd oxcarbazepine for 16 days
for seizures experienced visual hallucinations and
increased number of seizures. Oxcarbazepine was
discontinued. Patient recovered.
– 7 y.o. male experienced visual hallucinations of snakes
following increased doses of oxcarbazepine to 1500 mg
and dexmethylphenidate use. Oxcarbazepine
discontinued. Patient recovered.
– A patient on multiple drugs to treat ADHD experienced
hallucinations (outcome not reported).

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Source: Adverse Event Reporting System, FDA
Psychiatric Unlabeled Adverse Events
(continued)

• 3 other cases
– Patient with epilepsy and unknown duration of
oxcarbazepine treatment experienced ADHD.
– Patient on oxcarbazepine concomitantly with Adderall
experienced tantrums, aggression, and weight gain.
Oxcarbazepine discontinued (no outcome reported).
– 14 y.o. boy with severe learning disabilities experienced
breath holding spells.

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Source: Adverse Event Reporting System, FDA
Related Labeling
Cognitive/Neuropsychiatric Adverse Events
Most significant central nervous system-related adverse
events
• Cognitive symptoms (including psychomotor
slowing, difficulty with concentration, and speech or
language problems)
• Somnolence or fatigue
• Coordination abnormalities (including ataxia and
gait disturbances)

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Summary: Oxcarbazepine
• Deaths occurring during the exclusivity studies were
confounded by suspect medications, underlying
medical conditions, and/or insufficient details.

• The most common adverse events ( >= 5%) seen
during the exclusivity studies in pediatric patients
1 month to < 4 years old were similar to those seen in
older children and adults.

• FDA’s Division of Neurology Products (DNP) is
evaluating hypersensitivity reactions to further
consider if there is an association with oxcarbazepine.
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Summary: Oxcarbazepine
(continued)

• This completes the one-year post-exclusivity
adverse event reporting as mandated by
BPCA.

• FDA recommends routine monitoring of
oxcarbazepine for adverse events in all
populations.

• Does the Advisory Committee concur? 49
Acknowledgements
OSE DNP
• Kendra Worthy • Norman Hershkowitz
• Laura Governale • John Feeney
• Sigal Kaplan
• Andrea Feight • Alice Hughes
• Solomon Iyasu • Evelyn Mentari
• Charlene Flowers • Russell Katz
• Rosemary Johann-Liang
OCP
• John Duan
• Ramana Uppoor
• Jogarao Gobburu 50
Update: Oxcarbazepine

DNP Presentation
Independent analysis of suicidality
in controlled clinical trials of all
antiepileptic drugs

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