Telithromycin Integrated Summary of Safety Anti-Infective Drugs Advisory Committee January 8, 2003 Charles Cooper, M.D. Medical Officer Division of Anti-Infective Drug Products Center for Drug Evaluation and Research U.S. Food and Drug Administration
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Telithromycin Integrated Summary of Safety Anti-Infective Drugs Advisory Committee January 8, 2003 Charles Cooper, M.D. Medical Officer Division of Anti-Infective.
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Telithromycin Integrated Summary of Safety
Anti-Infective Drugs Advisory Committee
January 8, 2003
Charles Cooper, M.D.
Medical Officer
Division of Anti-Infective Drug Products
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
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Outline
• Description of safety database
• Overview of safety-related events
• Cardiac risk profile
• Hepatic risk profile
• Visual risk profile
• Summary
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Phase 3 safety database*
Telithromycin Comparators
Controlledstudies
Uncontrolledstudies
Allstudies
ControlledStudies
Initial NDA 2045 1220 3265 1672
New Studies 657 550 1207 467
Total 2702 1770 4472 2139
• Treatment groups balanced for age, sex, race, weight
• 15.8% telithromycin pts were 65 yo, vs. 19.4% of comparator pts
• 59 telithromycin pts were <18 yo for NDA* Does not include data from study 3014
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Deaths in Phase 3 trials
Telithromycin Comparators
Indication n/N (%) n/N (%)
Any 17/4472 (0.4%) 9/2139 (0.4%)
Controlled studies 7/2702 (0.3%) 9/2139 (0.4%)
CAP 5/916 (0.5%) 5/723 (0.7%)
AECB 2/609 (0.3%) 3/626 (0.5%)
Tonsillopharyngitis 0/427 (0.0%) 1/424 (0.2%)
Uncontrolled studies 10/1437 (0.7%) 33 (1.5%)
CAP 10/1437 (0.7%) --
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Nonfatal serious AEs in controlled Phase 3 trials
Telithromycin(N=2702)
Comparators(N=2139)
Any serious AE 59 (2.2%) 61 (2.9%)
AECB NOS 3 (0.1%) 3 (0.1%)
Pleural effusion 3 (0.1%) 1 (<0.1%)
Pneumonia aggravated 2 (0.1%) 11 (0.5%)
Hepatocellular damage 2 (0.1%) 0 (0.0%)
Lung abscess 2 (0.1%) 2 (0.1%)
Bronchospasm 2 (0.1%) 1 (<0.1%)
Empyema 2 (0.1%) 1 (<0.1%)
Hypersensitivity NOS 2 (0.1%) 1 (<0.1%)
COPD 2 (0.1%) 0 (0.0%)
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AEs in controlled Phase 3 trials
Telithromycin(N=2702)
Comparators(N=2139)
Any AE 1348 (49.9%) 1035 (48.5%)
Diarrhea NOS 292 (10.8%) 184 (8.6%)
Nausea 213(7.9%) 99 (4.6%)
Headache NOS 148 (5.5%) 125 (5.8%)
Dizziness 99 (3.7%) 57 (2.7%)
Vomiting NOS 79 (2.9%) 48 (2.2%)
Loose stools 63 (2.3%) 33 (1.5%)
Dyspepsia 46 (1.7%) 31 (1.4%)
Dysgeusia 43 (1.6%) 77 (3.6%)
Blurred Vision 17 (0.6%) 2 (0.1%)
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AEs resulting in discontinuation in controlled Phase 3 trials
Telithromycin(N=2702)
Comparators(N=2139)
Any AE 119 (4.4%) 92 (4.3%)
Diarrhea NOS 23 (0.9%) 13 (0.6%)
Vomiting NOS 21 (0.8%) 10 (0.5%)
Nausea 19 (0.7%) 10 (0.5%)
Abdominal pain NOS 5 (0.2%) 2 (0.1%)
LFT abnormal 5 (0.2%) 5 (0.2%)
Dizziness 5 (0.2%) 1 (<0.1%)
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Cardiac Risk Profile
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Cardiac toxicity: Pre-clinical/Phase 1
• Blocks IKr (major repolarization current)• Prolongs action potentials in isolated fibers• Prolongs QT and increases HR in dogs• Concentration-dependent in QTc in
Patient 502/1069 (cont.)D23 Hospitalized for hepatitis
Hepatitis A, B, C serologies negativeD29 Liver bx: centrilobular necrosis and
eosinophilic infiltrationD94 LFTs virtually normalAt follow up, 9 mos after event, on routine testing:
ALT 1331, tot. bili. 25 uM (nl < 20). Hep A, B, C neg. Anti-smooth muscle Ab + (1:1000). No eosinophilia. Patient asymptomatic.
Second liver bx: Zone 3 and portal fibrosis, piecemeal necrosis, plasma cell infiltrate; consistent with autoimmune hepatitis
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Incidence of ALT increases in controlled CAP trials*
ALT from entry to 7 dpost-therapy
Telithromycin(N=688)
Comparators(N=523)
Normal 550 (79.9%) 431 (82.4%)
>1x ULN 114 (16.6%) 80 (15.3%)
>2x ULN 15 (2.2%) 9 (1.7%)
>3x ULN 8 (1.2%) 2 (0.4%
>5x ULN 1 (0.1%) 1 (0.2%)
>8x ULN 0 (0.0%) 0 (0.0%)
* Patients with normal ALT at baseline
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Visual Risk Profile
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Blurred vision in Phase 3 trialsTelithromycin Comparators
All studies 20/4472 (0.4%) 2/2139 (0.1%)
Uncontrolled studies 3/1770 (0.2%) --
Controlled studies 17/2702 (0.6%) 2/2139 (0.1%)
Male 5/1317 (0.4%) 0/1031 (0.0%)
Female 12/1385 (0.9%) 2/1108 (0.2%)
-3A4 inhibitor* 8/2218 (0.4%) 2/1715 (0.1%)
+3A4 inhibitor* 9/484 (1.9%) 0/424 (0.0%)
* Patients not randomized by 3A4 inhibitor intake
• 15/20 telithromycin-treated patients with mild blurring; 4 with moderate blurring; 1 with severe blurring
• Median duration 2d (range1-10d); median onset 2nd d (range1-6 )
•4 discontinuations due to visual adverse events
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Blurred vision in Phase 1 studies
• Two studies (1059 and 1064) of telithromycin-associated visual blurring
• 13-50% incidence of blurring in subjects receiving 2400 mg telithromycin
• Higher incidence in younger subjects
• Median onset 3 h (range 1-5 h)
• Median duration 2.8 h (range 0.9-20.3 h)
• Likely due to interference with accommodation
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Serious visual adverse events
• One telithromycin-treated subject with SAE of “unable to accommodate.”
– AE determined to be “significantly disabling”– Began 2 hours after study drug administered– Patient seen by ophthalmologist who gave
diagnosis of “unable to accommodate.”– AE was initially assessed as related to study drug– Telithromycin was discontinued and AE resolved– 5 months later, causality of AE changed to “not
• Hepatic– Hepatotoxicity in pre-clinical studies– Cluster of pts with transaminases in Phase 3 incidence of low-level ALT elevations in Phase 3– One patient with eosinophillic hepatitis in Phase 3
• Visual– Incidence of blurred vision 0.6% in controlled studies– Possibly due to interference with accommodation