1. 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

2. 2 Outline Description of safety database Overview of safety-related events Cardiac risk profile Hepatic risk profile Visual risk profile Summary

3. 3 Phase 3 safety database* 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

4. 4 Deaths in Phase 3 trials

5. 5 Nonfatal serious AEs in controlled Phase 3 trials

6. 6 AEs in controlled Phase 3 trials

7. 7 AEs resulting in discontinuation in controlled Phase 3 trials

8. 8 Cardiac Risk Profile

9. 9 Cardiac toxicity: Pre-clinical/Phase 1 Blocks IK r (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

10. 10 Cardiac AEs in controlled Phase 3 trials

11. 11 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

12. 12 ECG data in Phase 3 trials ECG data from 3013 added to previous NDA * Mean on-therapy  QT C (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

13. 13 Hepatic Risk Profile

14. 14 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

15. 15 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

16. 16 Hepatic AEs in controlled Phase 3 trials

17. 17 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

18. 18 Patient 502/1069 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

19. 19 Patient 502/1069 (cont.) D23Hospitalized for hepatitis Hepatitis A, B, C serologies negative D29Liver bx: centrilobular necrosis and eosinophilic infiltration D94LFTs virtually normal At 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

20. 20 Incidence of ALT increases in controlled CAP trials* * Patients with normal ALT at baseline

21. 21 Visual Risk Profile

22. 22 Blurred vision in Phase 3 trials * 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 2 nd d (range1-6 ) 4 discontinuations due to visual adverse events

23. 23 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

24. 24 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”

25. 25 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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