us food and drug administration: 2006-4254s 07 collins oxcarbazepine

8/14/2019 US Food and Drug Administration: 2006-4254s 07 Collins Oxcarbazepine

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1

One Year Post-Exclusivity

Adverse Event Review:

Oxcarbazepine

Pediatric Advisory Committee MeetingNovember 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



2

Background Drug Information:

Oxcarbazepine

• Drug: Trileptal® (oxcarbazepine)

• Therapeutic Category: Anticonvulsant

• Sponsor: Novartis

• Original Market Approval: January 14, 2000

• Pediatric Exclusivity Granted: March 2, 2005



3

Background Drug Information:

Oxcarbazepine

• 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



5

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 20062IMS 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 < 17 years, utilizing oxcarbazepine monotherapy or adjunctive therapy

• 1 monotherapy efficacy and safety study in 92patients, aged 1 month to 16 years old, utilizing lowand high dose oxcarbazepine for 5 days

• 1 adjunctive therapy efficacy and safety study in128 patients, aged 1 month to < 4 years old, utilizinglow dose (9 days) or high dose (35 day) oxcarbazepine

• 7 safety studies in a total of 337 patients, aged 1month to < 17 years, utilizing oxcarbazepinemonotherapy or adjunctive therapy for 4-5 days, < 30

days, or 6 months



7


PK (n=218)

• 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


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)



10


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 criteriaand number of partial seizures as determined byelectrographic 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


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



13


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 electrographicseizures compared to baseline

• Response to treatment (e.g., patients with a 50%

response reduction in seizures)



14

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



15


Safety Studies (n=337)• Design:

– 2 efficacy studies: multi-center, parallel-group,

rater-blinded, randomized comparisons of lowdose vs. high dose monotherapy and adjunctivetherapy

– 2 pilot PK studies: open-label, age-stratified

– 4 extension studies: 6-month open-labelextension of efficacy and PK studies

– 1 additional open-label, multi-center, active-control, flexible-dose monotherapy



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 lunginfections, died from “pneumopathy secondary to anincrease in seizures” 2 days after discontinuingoxcarbazepine (OXC) (2 month treatment; 60 mg/kg/daywith 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 onOXC monotherapy (4.5 month treatment; 60 mg/kg/day;no other meds at initial presentation of adverse event)



17

Safety Exclusivity Studies: Deaths(continued)

– 13 m.o. female, with developmental delay and staticencephalopathy, died due to “progression of seizuredisorder” approximately 8.5 months after discontinuingOXC (2 month treatment; 78 mg/kg/day at time of

adverse event; concomitant meds) – 10 m.o. male, with history of bronchitis and corticaldysplasia, died of “sudden death” 2 ½ weeks after elective cortical resection surgery while on OXC (5.5month treatment; 18 mg/kg/day at death; concomitantmeds)

– 40 m.o. female, with developmental delay and cerebralinfarction, died due to “bronchoaspiration” after a4-hour seizure while on OXC (8 month treatment;

60 mg/kg/day; concomitant meds)



18

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



19

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



20

Labeling Changes

• Clinical Pharmacology – Pediatric Use

– Weight-adjusted MHD clearancedecreases 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 < 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 toadults

– Children 4 to <= 12 years old may require a 50%higher oxcarbazepine dose per body weight compared

to adults



24

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)



25

Labeling Changes

• Precautions – Pediatric use:

– Controlled clinical trials involved 898 patients between the ages of 1 month – 17 years old

(332 treated as monotherapy)



26

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%



27

Adverse Event Reports Since

Market Approval

01/14/00 – 04/02/06

21† (5)344 (177)409 (242)Pediatrics

(0-16)

123 (66)1465 (654)1653 (834)Adults

(> 17)

156 (76)2164 (1037)2482 (1346)All Ages

Death

(US)

Serious

(US)

All Reports

(US)

Raw

Counts*

*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 Approval01/14/00 – 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




30

Deaths Prior to the

Post-Exclusivity Period (n=12)

• Cases confounded by other suspectmedications, 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 at300 mg QD and titrated to 1200 mg QD). Developed

psychosis described as periods of confusion prior todeath. No prior suicide attempts and no concomitantdrugs per autopsy. Family history positive for depression, schizophrenia, and drug abuse




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




32

Deaths Prior to the


– 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, andhad restarted the drug for a year prior to death

• 2 d.o. male whose mother had received multiplemedications during pregnancy including fluoxetine,nadolol, codeine-acetaminophen, and Neurontin




33

Deaths Prior to the


– 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 (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 treatmentwith epinephrine, dexamethasone, and

diphenhydramine.


H iti it R ti



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 timingof reaction).

– 5 y.o. male with periauricular edema and allergicexanthema 4 days after starting 300 mg/dayoxcarbazepine . Symptoms resolved within 7 days after oxcarbazepine discontinuance and IV corticosteroids.

– 7 y.o. female with urticarial rash, facial edema, andfeeling of suffocation 1 month after initiating 600mg/day oxcarbazepine . Symptoms resolved with

Urbason (unclear if oxcarbazepine discontinued).Source: Adverse Event Reporting System, FDA




36


Since Market Approval• Angioedema cases (continued)

– 9 y.o. female with rash, eyelid edema 3 days after decreased oxcarbazepine dose to 300 mg/day (haddizziness and diplopia on 450 mg/day). Concomitantvalproate. Symptoms resolved after oxcarbazepine

discontinuance and corticosteroids. – 12 y.o. male with face edema, allergic exanthema, and

conjunctivitis 3 days after initiating 600 mg/dayoxcarbazepine . 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 . Concomitantisoniazid (no information on symptom resolution and

unclear if oxcarbazepine discontinued).Source: Adverse Event Reporting System, FDA



37

Related Labeling

• Warnings - History of HypersensitivityReaction to Carbamazepine

– 25 - 30% of patients with hypersensitivity reactions to

carbamazepine will experience hypersensitivityreactions with Trileptal®

• Adverse Reactions – Other Events Observed inAssociation with Trileptal® Administration

– Skin and appendages: angioedema



38

Adverse Event Reports During the

Post-Exclusivity Period

03/02/05 – 04/02/06

1 (0)82 (53)88 (59)Pediatrics

(0-16)

33 (27)299 (176)308 (182)Adults

(> 17)

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

Death

(US)

Serious

(US)

All Reports

(US)

Raw Counts*

* may include duplicates and unknown ages


Ch t i ti f C R t d



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


Ch t i ti f C R t d



40

Characteristics of Cases Reported


• 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



41

Non-Fatal Adverse Events


• 83 total cases*

• 52 unlabeled/unexpected cases

• 31 cases of events listed or implied in

the drug labeling


* Includes serious and non-serious cases



42

Unlabeled/Unexpected Adverse Events(n=52*)

• 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

N l i U l b l d Ad E t



43

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 themyoclonus 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)

Source: Adverse Event Reporting System, FDA* Includes serious and non-serious cases

P hi i U l b l d Ad E



44

Psychiatric Unlabeled Adverse Events(n=9*)

• Cases confounded by underlying medicalconditions 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 medicationsexperienced anger, agitation, and frustration that continued after

oxcarbazepine discontinued. Later attempted suicide by

ingesting oxcarbazepine.

Source: Adverse Event Reporting System, FDA* Includes serious and non-serious cases

P hi t i U l b l d Ad E t



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 andincreased number of seizures. Oxcarbazepine wasdiscontinued. Patient recovered.

– 7 y.o. male experienced visual hallucinations of snakesfollowing increased doses of oxcarbazepine to 1500 mgand dexmethylphenidate use. Oxcarbazepine

discontinued. Patient recovered. – A patient on multiple drugs to treat ADHD experiencedhallucinations (outcome not reported).




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 Adderallexperienced tantrums, aggression, and weight gain.

Oxcarbazepine discontinued (no outcome reported). – 14 y.o. boy with severe learning disabilities experienced

breath holding spells.




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 ( >= 5%) seenduring 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.



49

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

OSE• Kendra Worthy• Laura Governale

• Sigal Kaplan

• Andrea Feight• Solomon Iyasu

• Charlene Flowers

• Rosemary Johann-Liang

DNP• Norman Hershkowitz

• John Feeney

• Alice Hughes• Evelyn Mentari

• Russell Katz

OCP• John Duan• Ramana Uppoor

• Jogarao Gobburu



51

Update: Oxcarbazepine

DNP Presentation

Independent analysis of suicidalityin controlled clinical trials of all

antiepileptic drugs

us food and drug administration: 2006-4254s 07 collins oxcarbazepine

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