One Year PostExclusivity Adverse Event Review: Oxcarbazepine Pediatric Advisory Committee Meeting No

1
One Year Post-Exclusivity Adverse Event Review
Oxcarbazepine Pediatric Advisory Committee
Meeting November 16, 2006
Felicia L. Collins, MD, MPH, FAAPMedical
Officer Pediatric and Maternal Health
StaffOffice of New Drugs Center for Drug
Evaluation and Research Food and Drug
Administration
2
Background Drug InformationOxcarbazepine

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

3
Background Drug InformationOxcarbazepine

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

4
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

Verispan, LLC, April 200 3 March 2006, Data
Extracted May 2006
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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)

1Verispan, LLC, April 200 3 March 2006, Data
Extracted May 2006 2IMS Health, National Disease
and Therapeutic Index CD-ROM, NDTI 3 year. April
2003-March 2006 Data extracted May 2006
6
Pediatric Exclusivity Studies Oxcarbazepine

• 4 PK studies in a total of 218 patients, aged 1
  month to lt 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 lt 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 lt 17 years, utilizing oxcarbazepine
  monotherapy or adjunctive therapy for 4-5 days, lt
  30 days, or 6 months

7
Pediatric Exclusivity Studies PK (n218)

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

8
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

9
Pediatric Exclusivity Studies Monotherapy (n92)

• 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
  duration of at least 5 minutes

11
Monotherapy Exclusivity Study Efficacy Results

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

12
Pediatric Exclusivity Studies Adjunctive
Therapy Efficacy (n128)

• 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 StudiesAdjunctive 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)

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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 groups
• 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

15
Pediatric Exclusivity Studies Safety Studies
(n337)

• 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

16
Safety Exclusivity Studies Deaths (n5)

• 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)

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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 60
  mg/kg/day concomitant meds)

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Safety Exclusivity Studies (n337) 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

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Safety Exclusivity Studies (n337)
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

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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

21
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

22
Labeling Changes

• Clinical Studies Efficacy of adjunctive
  treatment in children 2 years and above
• Indications Adjunctive therapy in children aged
  2 years and above

23
Labeling Changes

• Dosage and Administration Pediatric Patients
• In pediatric patients 2 to lt 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 lt 4 years old may require up to
  twice the oxcarbazepine dose per body weight
  compared to adults
• Children 4 to lt 12 years old may require a 50
  higher oxcarbazepine dose per body weight
  compared to adults

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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)

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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 lt 4 Years Old
  Previously Treated or not Previously Treated with
  Other AEDs
• Most commonly observed (gt 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

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Adverse Event Reports Since Market Approval
01/14/00 04/02/06
May include duplicates and unknown ages Crude
count is 21 with 13 unduplicated cases
Source Adverse Event Reporting System, FDA
28
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

Source Adverse Event Reporting System, FDA
29
Deaths During the Post-Exclusivity Period
03/02/05 04/02/06 (n1)

• 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

Source Adverse Event Reporting System, FDA
30
Deaths Prior to the Post-Exclusivity Period
(n12)

• 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

Source Adverse Event Reporting System, FDA
31
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

Source Adverse Event Reporting System, FDA
32
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

Source Adverse Event Reporting System, FDA
33
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

Source Adverse Event Reporting System, FDA
34
Pediatric Hypersensitivity Reactions Since Market
Approval (n7)

• 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.

Source Adverse Event Reporting System, FDA
35
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).

Source Adverse Event Reporting System, FDA
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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).

Source Adverse Event Reporting System, FDA
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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

38
Adverse Event Reports During the
Post-Exclusivity Period 03/02/05 04/02/06
may include duplicates and unknown ages
Source Adverse Event Reporting System, FDA
39
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

Source Adverse Event Reporting System, FDA
40
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
Source Adverse Event Reporting System, FDA
41
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
42
Unlabeled/Unexpected Adverse Events (n52)

• Neurologic (10)
• Psychiatric (9)
• Endocrine (8)
• Hematologic (4)
• In utero (4)
• Hepatobiliary (3)
• General (3)
• Musculoskeletal (3)

• Ophthalmic (2)
• Cardiac (1)
• Renal (1)
• Immunologic (1)
• Vascular (1)
• Dental (1)
• Electrolyte (1)

Includes serious and non-serious cases
Source Adverse Event Reporting System, FDA
43
Neurologic Unlabeled Adverse Events (n10)

• 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
Source Adverse Event Reporting System, FDA
44
Psychiatric Unlabeled Adverse Events (n9)

• 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
Source Adverse Event Reporting System, FDA
45
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).

Source Adverse Event Reporting System, FDA
46
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.

Source Adverse Event Reporting System, FDA
47
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)

48
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 ( gt 5) seen
  during the exclusivity studies in pediatric
  patients 1 month to lt 4 years old were
  similar to those seen in older children and
  adults.
• FDAs 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?

50
Acknowledgements

• DNP
• Norman Hershkowitz
• John Feeney
• Alice Hughes
• Evelyn Mentari
• Russell Katz
• OCP
• John Duan
• Ramana Uppoor
• Jogarao Gobburu

• OSE
• Kendra Worthy
• Laura Governale
• Sigal Kaplan
• Andrea Feight
• Solomon Iyasu
• Charlene Flowers
• Rosemary Johann-Liang

51
Update Oxcarbazepine

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