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

Phase 1 studies (2 msec/mg/L)• Increased exposure w/ CrCl <30 mL/min

and/or concomitant CYP 3A4 inhibitor/ substrate

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Cardiac AEs in controlled Phase 3 trials

Telithromycin(N=2702)

Comparators(N=2139)

Any cardiac AE 23 (0.9%) 32 (1.5%)

Palpitations 4 (0.1%) 9 (0.4%)

Sinus arrhythmia 3 (0.1%) 2 (0.1%)

Cardiac failure NOS 2 (0.1%) 2 (0.1%)

Tachycardia NOS 2 (0.1%) 3 (0.1%)

Bundle branch block 2 (0.1%) 0 (0.0%)

Sinus tachycardia 2 (0.1%) 0 (0.0%)

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Serious cardiac AEs in all Phase 3 trials

• Telithromycin patients:

– 3 / 2702 (0.1%) in controlled studies

– 5 / 1770 (0.3%) in uncontrolled studies

• Comparator patients: – 8 /2139 (0.4%)

• No serious cardiac AEs related to study drug

• Serious cardiac AEs in telithromycin patients:– Cardiac arrest– Cardiac failure NOS– LV failure (drug discont.)– Acute MI (drug discont.)– Angina pectoris– Cardiac failure aggrav.– Cardiomyopathy NOS– LV failure

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ECG data in Phase 3 trials

• ECG data from 3013 added to previous NDA*

• Mean on-therapy QTC (Bazett’s formula):– 1.5 22.3 msec in telithromycin-treated patients for

all Phase 3 trials combined

– 3.8 19.3 msec for telithromycin vs. 3.3 19.6 msec for clarithromycin in controlled studies (3006, 3008, 3013)

* ECG data not consistently collected for new studies 4003 and 3012

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Hepatic Risk Profile

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Hepatic toxicity: pre-clinical

• Hepatotoxicity in rats, dogs, monkeys– Increased AST and ALT– Hepatic necrosis in 4-week rat study– Hepatocellular hypertrophy and multinucleated

hepatocytes

• Hepatic effects of telithromycin greater than those of clarithromycin in animals

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Hepatic toxicity: Phase 1

Study 1030 • 8 elderly subjects• Single doses of 1200, 1600, 2000 mg telithromycin or

placebo• 3 subjects with ALT/AST to 100-300 U/L (ALT>AST)

– 72 yo F - 7 days post 2000 mg – 69 yo M - 17 days post 2000 mg – 62 yo M - 7 days post placebo (14 days post 2000 mg)– Patients asymptomatic

• Possible drug effect with 7-17 day latency period

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Hepatic AEs in controlled Phase 3 trials

Telithromycin(N=2702)

Comparators(N=2139)

Any hepatic AE 91 (3.4%) 69 (3.2%)LFTs abnormal NOS 28 (1.0%) 26 (1.2%)ALT increased 21 (0.8%) 17 (0.8%)AST increased 10 (0.4%) 6 (0.3%)Transaminase increased NOS 6 (0.2%) 3 (0.1%)Alkaline phosphatase increased 6 (0.2%) 3 (0.1%)LDH increased 5 (0.2%) 3 (0.1%)GGT increased 5 (0.2%) 4 (0.2%)Hepatocellular damage 2 (0.1%) 0 (0.0%)Hepatitis NOS 2 (0.1%) 1 (<0.1%)Cholestasis 2 (0.1%) 0 (0.0%)Hepatic function abnormal NOS 1 (<0.1%) 1 (<0.1%)Bilirubinemia 1 (<0.1%) 1 (<0.1%)Jaundice NOS 0 (0.0%) 1 (<0.1%)

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Serious hepatic AEs in all Phase 3 clinical trials

• Four patients with serious hepatic AEs (3 telithromycin, 1 comparator)

• Drug effect unlikely in comparator patient and 1 telithromycin patient

• Drug effect plausible in 2 telithromycin-treated patients– 76 yo F on allopurinol/pravastatin; asympto-

matic in ALT/AST on telithromycin– 53 yo M with eosinophilic hepatitis

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Patient 502/1069

Analyte Normal Range Day 1 Day 21 Day 24 Day 35AST (<49 U/L) 38 - - -ALT (<49 U/L) 81 354 1529 518T. Bili. (2-20 umol/L) 9 nl 29 15Alk. Phos. (60-275 U/L) nl nl 169 261Eosinophils (<500 cells/uL) 774 960 1062 2856

PMH: 53 yo M w/ asthma, DM

Meds: Inhaled salbutamol, fluticasone, Atrovent, Nasonex, po Ca++, ? DM medication

Course: D1-10 Telithromycin 800 mg po qd for CAP

D13 -? Acetaminophen (500 mg x 6 over 1 wk)

D14 fever/vomiting/diarrhea - fever persists

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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

related to study medication”

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Summary of ISS• Overall

– Most common AEs are GI

• Cardiac– Concentration-dependent QT – No drug-related serious cardiac adverse events

• 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

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