Review Update: QT Prolongation with Citalopram and Escitalopram

1
Review Update QT Prolongation with Citalopram
and Escitalopram

• Pediatric Advisory Committee Meeting
• November 16, 2006
• Prepared by M. Lisa Jones, MD
• Division of Psychiatry Products (DPP)

2
Summary of Past Review

• 3-4 msec QT prolongation for both CT (citalopram)
  and SCT (escitalopram) compared to placebo in
  Phase 3 trials
• AERS reviews found cases suggestive of
  QT-prolonging effect
• Study 92104 (DB, PC Phase 1 CT study) found QTcF
  of 7-9 msec
• CT-Pimozide interaction study with elements
  supportive of an association between CT and QT
  prolongation

3
Labeling Request

• Current CT/SCT labeling on the QT interval
  describes the Phase 3 study data
• Based on the findings in other data sources
  (previous slide), in 5/06 the Division requested
  the addition of an expanded labeling statement
  regarding QT interval prolongation

4
Ongoing Review Overview

• Sponsor June-July 2006 Submissions
• Rebuttal of Points in the DPP Letter
• Medicaid Analysis
• GPRD Analysis
• Post-marketing (AERS) Data Analysis
• Updated FDA AERS Search
• Additional FDA review of previously submitted
  data

5
Sponsor June-July 2006 Submissions
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Sponsor 2006 SubmissionsSponsor Response to DPP
Labeling Letter

1. Disagreed with FDA conclusions on CT-pimozide
   interaction study
2. Reiterated belief that Study 92104 was unreliable
   due to QT data collection methods (manual read)
3. Characterized post-marketing cases as confounded
   by concomitant drugs and medical conditions

7
Sponsor 2006 SubmissionsMedicaid Analysis

• Sponsor examined TdP-related adverse events in
  the Medicaid claims database
• Compared patients treated with CT or SCT to
  patients treated with other SSRI/SNRIs
• Found similar rates of TdP-related events for CT
  0.99 (0.92-1.06) and SCT 1.04 (0.96-1.12)
  relative to other SSRI/SNRIs

8
Sponsor 2006 SubmissionsGPRD Analysis

• General Practice Research Database UK primary
  care records (35 million PYs)
• Searched for QT-related events in depressed
  patients (age 18-70) treated with at least one
  antidepressant
• Found adjusted OR of 0.9 (0.6-1.4) for CT
  compared to other SSRIs

9
Sponsor 2006 SubmissionsAERS Data

• Searched AERS MedWatch database for cases with
  QT-related MedDRA terms (e.g. QT prolonged,
  cardiac arrest) and a SSRI/SNRI as a suspect drug
• Found increased risk with CT (OR 1.58) and SCT
  (OR 1.56) use relative to SSRI/SNRIs
• Sponsor cited preferential use in medically
  compromised patients

10
FDA AERS Search Update
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AERS Search Pediatric Pts.

• Searched for cases in pts. ? 17 years old from
  8/03 to 8/06
• Used QT-related preferred terms
• QT c prolonged, Sudden Death, Death,
  Ventricular Arrhythmia, Cardiac Arrest
• Search resulted in 3 cases

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Pediatric AERS Case 1

• Literature report of a 12-year-old female who
  concomitantly took an unknown dose of CT with 4-5
  grams of diphenhydramine (treatment details
  unavailable)
• Treated in ER for altered mental status, followed
  by bradycardia, wide complex rhythm on ECG and
  cardiac arrest
• Patient died as a result of cardiac arrest

13
Pediatric AERS Case 2

• 17-year-old male hospitalized for seizures,
  intermittent tachyarrhythmias and wide QRS
  complex rhythms on ECG following an intentional
  overdose (2400 mg) of CT
• Resolved with supportive care
• Patients medical history included marijuana use
  and asthma
• No information on concomitant drugs

14
Pediatric AERS Case 3

• 14-year-old male developed QT prolongation while
  taking CT (40 mg/day) for depression and anxiety
• Six months after beginning treatment, he was
  diagnosed by a cardiologist with QT prolongation
  (QTc interval 445 msec)
• The pt.s drugs were discontinued (CT,
  atomoxetine) and QTc decreased to 408 msec (No
  re-challenge)

15
Ongoing Review
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Ongoing FDA Review

• Further analysis of Study 92104 and CT-Pimozide
  interaction study
• Review of the sponsors Medicaid and GPRD
  analyses
• AERS datamining analysis of SCT/CT compared to
  other antidepressants, including non-SSRIs

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Summary of Update

• This update on Celexa provides information on the
  recent pediatric-related labeling changes and on
  the ongoing analysis of QT interval data within
  the Division of Psychiatry Products
• Does the Committee have any comments?
• The FDA suggests that this product return to
  routine monitoring
• Does the Committee agree?