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One Year Post Exclusivity Adverse One Year Post Exclusivity Adverse Event Review:Event Review:SibutramineSibutramine

Pediatric Advisory Committee Meeting Pediatric Advisory Committee Meeting

March 22, 2006March 22, 2006

Hari Cheryl Sachs, MD, FAAPMedical OfficerDivision of Pediatric Drug DevelopmentCenter for Drug Evaluation and Research Food and Drug Administration

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Background Drug InformationBackground Drug Information

• Drug: Drug: MeridiaMeridia® ® (sibutramine)(sibutramine)

• Therapeutic Category: Therapeutic Category: Anti-obesityAnti-obesity

• Sponsor: Sponsor: AbbottAbbott

• Original Market Approval: Original Market Approval: Nov 22, 1997Nov 22, 1997

• Pediatric Exclusivity Granted: Pediatric Exclusivity Granted: Oct 6, 2004Oct 6, 2004

• Mechanism of action: Mechanism of action: norepinephrine, serotonin norepinephrine, serotonin and dopamine reuptake inhibitorand dopamine reuptake inhibitor

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Background Drug InformationBackground Drug Information

• Indication:Indication: management of obesity in adults management of obesity in adults– In conjunction with reduced calorie dietIn conjunction with reduced calorie diet– Body mass index (BMI) Body mass index (BMI) >> 30 kg/m 30 kg/m22 OR OR >> 27 kg/m 27 kg/m22

with risk factors (diabetes, dyslipidemia, controlled with risk factors (diabetes, dyslipidemia, controlled hypertension)hypertension)

• Dosage:Dosage:– Adults: 5-15 mg qdAdults: 5-15 mg qd

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Analysis of Adverse Events: Analysis of Adverse Events: SibutramineSibutramine

19961996• Endocrinology and Metabolic Advisory committee- clinically Endocrinology and Metabolic Advisory committee- clinically

important effect BP and HR, effective weight loss, split on important effect BP and HR, effective weight loss, split on benefit/riskbenefit/risk

19971997• Sibutramine approvalSibutramine approval

20032003• ODS Analysis of AERS database regarding death and other serious ODS Analysis of AERS database regarding death and other serious

cardiovascular and stroke- unable to attribute causalitycardiovascular and stroke- unable to attribute causality• ODS Analysis fetal toxicity - Category CODS Analysis fetal toxicity - Category C• Sibutramine Cardiovascular Outcomes (SCOUT) study initiated- Sibutramine Cardiovascular Outcomes (SCOUT) study initiated-

as of 4/05 approximately 9000 patients enrolledas of 4/05 approximately 9000 patients enrolled

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Analysis of Adverse Events: Analysis of Adverse Events: SibutramineSibutramine

20042004• Updated analysis of both cardiovascular and fetal adverse eventsUpdated analysis of both cardiovascular and fetal adverse events• Updated Risk Management Plan- Dear Healthcare professional Updated Risk Management Plan- Dear Healthcare professional

letter, educational outreach and revision to the labelingletter, educational outreach and revision to the labeling• Pediatric Exclusivity AwardedPediatric Exclusivity Awarded

20052005 • One-year post-exclusivity Adverse Event ReportingOne-year post-exclusivity Adverse Event Reporting

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Drug Use Trends (Outpatient Settings): Drug Use Trends (Outpatient Settings): sibutraminesibutramine

• Outpatient prescriptions for oral antiobesity agents Outpatient prescriptions for oral antiobesity agents decreased by 10 % and sibutramine by 36 % (Oct 2002-decreased by 10 % and sibutramine by 36 % (Oct 2002-Sep 2005)Sep 2005)11

• Sibutramine represented approximately 9 % of total Sibutramine represented approximately 9 % of total antiobesity agents (486,000 prescriptions/year during antiobesity agents (486,000 prescriptions/year during Oct 2004- Sep 2005)Oct 2004- Sep 2005)11

• Pediatric use < 1 % (approximately 4000 Pediatric use < 1 % (approximately 4000 prescriptions/year)prescriptions/year)11

– 85 % of this use in patients 12-16 years85 % of this use in patients 12-16 years11

– Typical diagnosis: Polycystic ovaries and ObesityTypical diagnosis: Polycystic ovaries and Obesity22

11Verispan LLC, VONA Vector One October 2002- Sept 2005, Data extracted 12-2005Verispan LLC, VONA Vector One October 2002- Sept 2005, Data extracted 12-200522IMS National Disease and Therapeutic IndexIMS National Disease and Therapeutic Index™, MAT6yr Oct 2002-Sep 2005, Data extracted 12-2005™, MAT6yr Oct 2002-Sep 2005, Data extracted 12-2005

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http://www.fda.gov/cder/pediatric/Summaryreview.htmhttp://www.fda.gov/cder/pediatric/Summaryreview.htm

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Pediatric Exclusivity Studies: Pediatric Exclusivity Studies: sibutraminesibutramine

• Single dose pharmacokinetic (pK) and safety Single dose pharmacokinetic (pK) and safety studystudy

• Efficacy and safety in obese adolescentsEfficacy and safety in obese adolescents

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Pediatric Exclusivity Study: Pediatric Exclusivity Study: Pharmacokinetics and SafetyPharmacokinetics and Safety

• Single dose 15 mg pK studySingle dose 15 mg pK study• n = 91 adolescents, age 12-16 years (subset of n = 91 adolescents, age 12-16 years (subset of

efficacy trial)efficacy trial)• pK parameters for sibutramine and two active pK parameters for sibutramine and two active

metabolitesmetabolites• pK findingspK findings

– Exposure of active metabolites similar between adults Exposure of active metabolites similar between adults and adolescentsand adolescents

– Trough levels similar for adults and adolescentsTrough levels similar for adults and adolescents

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Pediatric Exclusivity Study: EfficacyPediatric Exclusivity Study: Efficacy

• Placebo-controlled trial of obese adolescents with Placebo-controlled trial of obese adolescents with BMI > 2 units above 95 % (n = 498, randomized BMI > 2 units above 95 % (n = 498, randomized 3:1 treatment: placebo)3:1 treatment: placebo)

• Primary endpoint: absolute change in BMIPrimary endpoint: absolute change in BMI

• Detailed review of serial height measurements Detailed review of serial height measurements raised concerns about reliability or accuracy of raised concerns about reliability or accuracy of data (e.g., 12 % patients “lost height”)data (e.g., 12 % patients “lost height”)

• Labeling change: “data are inadequate to Labeling change: “data are inadequate to recommend use”recommend use”

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Pediatric Exclusivity Study: SafetyPediatric Exclusivity Study: Safety

• Ambulatory Blood Pressure MonitoringAmbulatory Blood Pressure Monitoring– Increase from baseline in SBP (3-5 mm Hg) and DBP Increase from baseline in SBP (3-5 mm Hg) and DBP

(1-3 mm Hg) vs. decrease in placebo group(1-3 mm Hg) vs. decrease in placebo group– Increase in treatment-emergent hypertension (11 vs. 8 Increase in treatment-emergent hypertension (11 vs. 8

%, treatment vs. placebo)%, treatment vs. placebo)

• Note: Bolded warning in labeling regarding Note: Bolded warning in labeling regarding substantial increase in BP and HRsubstantial increase in BP and HR*patients did not take medication day of measurement*patients did not take medication day of measurement

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Pediatric Exclusivity Study: SafetyPediatric Exclusivity Study: Safety

• Echocardiography- 105 treated, 34 placeboEchocardiography- 105 treated, 34 placebo– No abnormalities in valvular structure or functionNo abnormalities in valvular structure or function– No increased LV hypertrophy detectedNo increased LV hypertrophy detected

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Pediatric Exclusivity Study: SafetyPediatric Exclusivity Study: Safety

PsychiatricPsychiatric– Suicide attempt (1 each treatment and placebo, 0.3 vs. Suicide attempt (1 each treatment and placebo, 0.3 vs.

1%), suicidal ideation (2- treatment)1%), suicidal ideation (2- treatment)– Depression (3- treatment)Depression (3- treatment)– Accidental injury (11 vs. 6 %, treatment vs. placebo)Accidental injury (11 vs. 6 %, treatment vs. placebo)

Labeling updated to describe these results and Labeling updated to describe these results and similarity between mechanism of action and that similarity between mechanism of action and that of antidepressants, recommend monitoringof antidepressants, recommend monitoring

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Pediatric Use:Pediatric Use:““Efficacy of sibutramine in adolescents who are obese has not Efficacy of sibutramine in adolescents who are obese has not

been adequately studied.been adequately studied.Sibutramine’s mechanism of action inhibiting the reuptake of Sibutramine’s mechanism of action inhibiting the reuptake of

serotonin and norepinephrine is similar to the mechanism serotonin and norepinephrine is similar to the mechanism of action of some antidepressants….of action of some antidepressants….

……In the study of adolescents with obesity in which 368 In the study of adolescents with obesity in which 368 patients were treated with sibutramine and 130 patients patients were treated with sibutramine and 130 patients with placebo, one patient in [each] group attempted with placebo, one patient in [each] group attempted suicide. Suicidal ideation was reported by 2 sibutramine-suicide. Suicidal ideation was reported by 2 sibutramine-treated patients and none of the placebo patients. It is treated patients and none of the placebo patients. It is unknown if sibutramine increases the rate of suicidal unknown if sibutramine increases the rate of suicidal behavior or thinking in pediatric patientsbehavior or thinking in pediatric patients

Data are inadequate to recommend the use of sibutramine for Data are inadequate to recommend the use of sibutramine for the treatment of obesity in pediatric patients” the treatment of obesity in pediatric patients”

Labeling Changes Resulting fromLabeling Changes Resulting fromExclusivity StudiesExclusivity Studies

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• Contraindications: MAO-inhibitors, Contraindications: MAO-inhibitors, hypersensitivity and major eating disorderhypersensitivity and major eating disorder

• Warning: Warning: – Bolded: substantial increase BP and HRBolded: substantial increase BP and HR– Avoid use in patients with cardiovascular risk Avoid use in patients with cardiovascular risk

factorsfactors– Use with caution in glaucomaUse with caution in glaucoma– Exclude secondary causes of obesityExclude secondary causes of obesity

– Drug interactions: cytochrome P450(3ADrug interactions: cytochrome P450(3A44))

Additional Relevant Safety LabelingAdditional Relevant Safety Labeling

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• Precautions:Precautions:– Unknown if related to pulmonary hypertensionUnknown if related to pulmonary hypertension– Seizures reported in < 0.1 %- use cautiouslySeizures reported in < 0.1 %- use cautiously– Use cautiously in patients with bleeding Use cautiously in patients with bleeding

predispositionpredisposition– May precipitate or exacerbate gallstones (weight loss)May precipitate or exacerbate gallstones (weight loss)– Not recommended in patients with renal/hepatic Not recommended in patients with renal/hepatic

toxicitytoxicity– Potential to affect judgment, thinking or motor skillsPotential to affect judgment, thinking or motor skills

• Pregnancy Category CPregnancy Category C

Relevant Safety LabelingRelevant Safety Labeling

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Adverse Event Reports* since Market Adverse Event Reports* since Market Approval (Nov 1997- Oct 2005): Approval (Nov 1997- Oct 2005):

sibutraminesibutramine

All reports (US)All reports (US) Serious (US)Serious (US) Death (US)Death (US)

All AgesAll Ages 5788 (5071)5788 (5071) 1032(544)1032(544) 118 (58)118 (58)

Adults (> 17)Adults (> 17) 4969 (4374)4969 (4374) 848 (446)848 (446) 75 (38)75 (38)

Pediatrics (0-16)Pediatrics (0-16) 56 (45)56 (45) 31 (22)31 (22) 5 (0)5 (0)

*includes duplicates and unknown ages

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Fatal Serious AEs since Market Fatal Serious AEs since Market Approval: sibutramine (n= 5)Approval: sibutramine (n= 5)

Cardiac (n = 2)Cardiac (n = 2)– Myoplastic left heart syndrome, died at 1 monthMyoplastic left heart syndrome, died at 1 month– Hypoplastic left ventricle, died at 2 monthsHypoplastic left ventricle, died at 2 months

Preterm Birth (n =3)Preterm Birth (n =3)– 6 month premature birth, died age unknown6 month premature birth, died age unknown– 6 month premature birth with intracranial 6 month premature birth with intracranial

bleeding, died 36 hoursbleeding, died 36 hours– 26 week premature birth, intrauterine growth 26 week premature birth, intrauterine growth

retardation secondary to pre-eclampsia, died at retardation secondary to pre-eclampsia, died at 12 hours12 hours

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Pediatric Non Fatal Serious Adverse Event Pediatric Non Fatal Serious Adverse Event Reports since Market Approval: sibutramine Reports since Market Approval: sibutramine

(n= 24 unduplicated)(n= 24 unduplicated)

Overdose (n=9)Overdose (n=9)

QTc prolongation (n=1)QTc prolongation (n=1)

Seizure (1)Seizure (1)

noninsulin-dependent diabetes (1)noninsulin-dependent diabetes (1)

granulomatous uveitis (1)granulomatous uveitis (1)

CongenitalCongenital, no pattern (n=11) , no pattern (n=11)

UnderlinedUnderlined events are not specifically labeled events are not specifically labeled

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Adverse Event Reports* One Year Adverse Event Reports* One Year Post Exclusivity Period Post Exclusivity Period

(Oct 2004- Oct 2005):(Oct 2004- Oct 2005): sibutramine sibutramine

Raw countsRaw counts All reports (US)All reports (US) Serious (US)Serious (US) Death (US)Death (US)

All agesAll ages 154 (33)154 (33) 140 (25)140 (25) 18 (2)18 (2)

Adults (Adults (>> 17) 17) 102 (14)102 (14) 96 (12)96 (12) 4 (0)4 (0)

Pediatrics (0-16)Pediatrics (0-16) 1 (1)1 (1) 1 (1)1 (1) 00

* Includes duplicates and unknown ages

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Adverse Event Reports during Adverse Event Reports during One-Year Post Exclusivity Period: One-Year Post Exclusivity Period:

sibutraminesibutramine

• 14 year old obese male (88.3 kg) during phase III 14 year old obese male (88.3 kg) during phase III studystudy

• Baseline EKG- sinus rhythm with non-specific Baseline EKG- sinus rhythm with non-specific intraventricular conduction delay and QTc- 436 msecintraventricular conduction delay and QTc- 436 msec

• After 10 mg sibutramine for 1 year, QTc - 465 msecAfter 10 mg sibutramine for 1 year, QTc - 465 msec

• Note: QTc guideline: QTc Note: QTc guideline: QTc >> 450 or change 450 or change >> 30 30 msec potentially of concern.msec potentially of concern.

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Summary: sibutramineSummary: sibutramine• Labeling updated after exclusivity studies Labeling updated after exclusivity studies • No new pediatric AEs identifiedNo new pediatric AEs identified• ODS reviews did not reveal additional ODS reviews did not reveal additional

cardiovascular risk or underlying pattern of cardiovascular risk or underlying pattern of congenital anomaliescongenital anomalies

• SCOUT study ongoing for formal evaluation of SCOUT study ongoing for formal evaluation of cardiac riskcardiac risk

• Agency proposes monitoring for additional yearAgency proposes monitoring for additional year

Does the Advisory Committee concur?Does the Advisory Committee concur?

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AcknowledgementsAcknowledgements

ODSODSAndrea FeightAndrea Feight

Rosemary Johann-LiangRosemary Johann-Liang

Toni Piazza- HeppToni Piazza- Hepp

Joslyn SwannJoslyn Swann

Kendra WorthyKendra Worthy

DPMEPDPMEPHae-Young AhnHae-Young Ahn

Patricia BeastonPatricia Beaston

Eric ColmanEric Colman

David OrloffDavid Orloff

Wei QiuWei Qiu