1 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

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 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 – 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 period 1 –Neurology: 26% (726,000) –Pediatrics: 3% (77,000) Diagnoses most frequently associated with Trileptal ® use in the pediatric population 2 –Convulsions: 30% (100,000) –Bipolar affective disorder: 22% (73,000) 1 Verispan, LLC, April – March 2006, Data Extracted May IMS 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 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

7 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

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 (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 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 (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 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)

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 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

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)

17 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)

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 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 < 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

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 Raw Counts* All Reports (US) Serious (US) Death (US) All Ages2482 (1346)2164 (1037)156 (76) Adults (> 17) 1653 (834)1465 (654)123 (66) Pediatrics (0-16) 409 (242)344 (177)21 † (5) *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 (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 Source: Adverse Event Reporting System, FDA

30 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 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 (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. 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

36 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

37 Related Labeling Warnings - History of Hypersensitivity Reaction to Carbamazepine – % 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 Raw Counts*All Reports (US) Serious (US) Death (US) All Ages493 (307)471 (289)38 (29) Adults (> 17) 308 (182)299 (176)33 (27) Pediatrics (0-16) 88 (59)82 (53)1 (0) * 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 Source: Adverse Event Reporting System, FDA * A report may have more than one outcome

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

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

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

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 ( >= 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.

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 suicidality in controlled clinical trials of all antiepileptic drugs