1. 1 Telithromycin (Ketek™): General Safety Profile Anti-Infective Drugs Advisory Committee April 26, 2001 David Ross, M.D., Ph.D. Division of Anti-Infective Drug Products Center for Drug Evaluation and Research U.S. Food and Drug Administration

2. 2 Ketek Phase 3 safety database

3. 3 Extent of exposure - phase 3

4. 4 Deaths No deaths in phase I trials 11 deaths in phase III (10 CAP, 1 pharyngitis) –7 deaths in telithromycin pts, 4 in comparator pts –None directly attributed to drug –6 deaths (4 Ketek, 2 comp) scored as tx failures –6/7 Ketek-treated patients who died had CV cause –0/4 comparator patients who died had CV cause Most CAP deaths occurred in high-risk patients (Fine category III or higher)

5. 5 Serious AEs - Phase 3 4 drug-related SAEs in uncontrolled trials: gastroenteritis, vasculitis, hepatitis, leukopenia

6. 6 AEs - Phase 3

7. 7 AEs by 3A4 inhibitor intake

8. 8 Telithromycin (Ketek™): Cardiac Effects

9. 9 Telithromycin: Cardiac Effects In vitro and preclinical data Phase 1 data Phase 3 data Conclusions

10. 10 QT c vs. QT n

11. 11 QT c effects: in vitro and preclinical data Inhibits IK r channel (major repolarization current) –K i 42.5 µM (moxifloxacin 129 µM) –Mean serum C max 2.4 µM; max C max 12 µM –Rat myocardial:serum conc. ratio = 6 Prolongs action potentials in isolated fibers –>75% increase in APD 90 at K i –Potentiates sotalol-induced APD prolongation Prolongs QT c and increases HR in dogs –30 ms  1 min after single IV dose (17 ms for clari) –27-30 ms after multiple oral doses (100 mg/kg/d)

12. 12  QTc with telithromycin: Phase 1 * p<0.05 vs. placebo

13. 13  QTc in Phase 1 subjects with CV disease Source: Study 1049

14. 14  QTc vs. telithromycin concentration (Phase 1 studies) ΔQTc = -1.30 + 3.90 * concentration (p < 0.0001)

15. 15 Telithromycin vs. Cisapride

16. 16 3A4 inhibitor interactions Telithromycin C max increased by 52% with ketoconazole Telithromycin AUC increased by 95% with ketoconazole *comparison with placebo

17. 17 Telithromycin: PK variability Phase 1 –Nonlinear pharmacokinetics    predictability –Single dose (800 mg) mean C max : 1.99 mg/L maximum C max : 5.13 mg/L (renally impaired subject) –Multiple dose (800 mg) mean C max : 2.07 mg/L maximum C max : 6.66 mg/L (elderly subject) Phase 3 –Maximum observed concentration: 7.6 - 9.9 mg/L

18. 18 Telithromycin pharmacokinetics in special populations Elderly subjects: C max and AUC  by 100% Hepatic impairment –Single-dose study: t 1/2  by 40% –Mult. dose: AUC and C max ~ healthy subjects, but renal clearance increases to compensate –Potential accumulation if  CrCl with hepatic impairment Renal impairment (single dose study) –Moderate impairment (CrCl 40-80 mL/min): C max  by 33%; AUC  by 42% –Severe impairment (CrCl <40 mL/min): C max  by 44%; AUC  by 59%

19. 19 Phase 1 conclusions Concentration- and dose-dependent  in QT c QT c increase comparable to cisapride QT c increase enhanced by 3A4 inhibitor Concentration increased by 3A4 inhibitor PK variability seen  exposure with age, renal impairment Potential  exposure in hepatic impairment with decreased CrCl

20. 20 Issues in  QT c assessment Rare related clinical events (e.g., cisapride) Variability –Inter-individual –Inter-observer –Inter-measurement Significance of ΔQTc –Small  may lead to torsade (e.g., terfenadine) –Increase in risk for given  not clear

21. 21 Limitations of phase 3 EKG data EKG data not collected on all patients –Controlled trials: 1515 Ketek, 1276 comparator Few data from high risk patients –2 telithromycin-treated pts with low baseline K + –5 telithromycin-treated pts on anti-arrhythmics EKG timing  peak QTc effect EKGs obtained at different times after dosing EKGs obtained at 25 mm/sec No data on Mg 2+

22. 22 Exclusion criteria for telithromycin phase 3 trials Long QTc syndrome Severe hypokalemia QTc >450 msec* Sick sinus syndrome* Bradycardia <50 bpm* ALT  3x ULN AST  3x ULN Bilirubin > 2x ULN PT  1.3x control Encephalopathy CrCl  50 mL/min AIDS Concomitant: –ergot alkaloid derivatives –terfenadine –astemizole –cisapride –pimozide –cholinesterase inhibitors –ketamine –digoxin* –itraconazole* –fluconazole* –quinidine –diisopyramide* –procainamide* –bretylium* –sotalol* *criterion dropped 2/99

23. 23  QT c : controlled phase 3 trials

24. 24  QT c : telithromycin vs. clarithromycin

25. 25  QT c with CYP substrates

26. 26  QT c vs. clarithromycin with CYP substrates

27. 27

28. 28

29. 29 QT c : In vitro/preclinical conclusions Telithromycin inhibits repolarization in vitro –Effect seen in cell culture and isolated fibers –myocardial concentration may approximate K i Telithromycin significantly increased QT c in dogs –Effect seen with both oral and IV dosing –IV telithromycin  QT c > IV clarithromycin  QT c

30. 30 QT c : phase 1 conclusions Telithromycin increased QT c in phase 1 –Controlled cross-over studies show consistent effect –Concentration- and dose-dependent increase –Comparable to cisapride; additive with cisapride –Increased by 3A4 inhibitor (ketoconazole) Telithromycin PK variability –Nonlinear pharmacokinetics –Increased exposure in special populations

31. 31 QT c : phase 3 conclusions Telithromycin increased QTc in phase 3 –Small but consistent increase in controlled trials –  larger than comparators –  larger than clarithromycin –Possible interactions with 3A4 and 2D6 substrates Mean with 3A4 + 2D6: 11.5 msec (clarithromycin 5.4 msec)

32. 32 Telithromycin (Ketek™): Risk/benefit issues

33. 33 S. pneumoniae resistance 1995-1998 Whitney CG et al. N Engl J Med 2000;343:1917-24.

34. 34 Risk factors for mortality in pneumococcal pneumonia Pallares R et al. N Engl J Med 1995; 333:474-80

35. 35 Resistance and mortality in pneumococcal pneumonia Pallares R et al. N Engl J Med 1995; 333:474-80

36. 36 Assessing benefits of resistance claims Public health impact –benefit in cases due to resistant pathogens –benefit in outpatients with mild to moderate disease Seriousness of infection (e.g., CAP vs. AECB) Mechanism of action –out-of-class vs. in-class resistance –in-class: potential for concurrent resistance Evidence for clinical efficacy vs. resistant isolates –Evidence for susceptible and resistant isolates –Evidence for resistant isolates –Evidence in invasive disease due to resistant isolates

37. 37 Telithromycin-ketoconazole interaction * *p=0.004, compared to placebo

38. 38 Drugs associated with  QTc/TdP Amiodarone Amitriptyline Astemizole Aresenic trioxide Azelastine Bepridil Chlorpromazine Cisapride Clarithromycin Desimpramine Disopyramide Dofetilide Doxepin Droperidol Erythromycin Felbamate Flecainide Fluoxetine Foscarnet Fosphenytoin Gatifloxacin Grepafloxacin Halofantrine Haloperidol Ibutilide Imipramine Indapamide Isradipine Levomethadyl Mesoridazine Moexipril/HCTZ Moxifloxacin Naratriptan Nicardipine Octreotide Pentamidine Pimozide Probucol Procainamide Quetiapine Quinidine Risperidone Salmeterol Sotalol Sparfloxacin Sumatriptan Tacrolimus Tamoxifen Terfenadine Thioridazine Tizanidine Trimethoprim/ Sulfamethoxazole Venlafaxine Zolmitriptan

39. 39 Telithromycin effects on co- administered drugs

40. 40 Mibefradil (Posicor) Ca 2+ -channel blocker CYP 3A4 inhibitor –In vitro, inhibited metabolism of simvastatin, lovastatin, atorvastatin, cerivastatin (K i < 1 µM) –No statin-associated events seen in phase III

41. 41 Mibefradil regulatory history 8/97: Approved for angina, HTN –Warnings re: astemizole, cisapride, terfenadine 12/97: Additional warnings re: –Use of lovastatin or simvastatin –Use of any statin AND tacrolimus or cyclosporine 6/98: Withdrawal from market –>25 interacting drugs identified –Continued reports of AEs from interacting drugs –Further labeling changes impractical –No special benefits relative to other agents

42. 42 Ketek safety concerns Potential confluence of multiple risk factors –(1) QTc prolongation –(2) Concentration dependence of QTc effect –(3) Pharmacokinetic variability –(4) Potential for hepatotoxicity –(5)  exposure in elderly pts, hepatic/renal disease –(6)  exposure with concomitant medications (1) - (6) may lead to clinically significant ΔQTc Very limited data on at-risk subjects –Few patients in any given risk group –Limited range of concentration data in phase III

43. 43 Ketek safety concerns (cont.) Potential hepatotoxicity Uncertainty re: dosing in special populations –Altered pharmacokinetics in special populations –Nonlinearity of pharmacokinetics Potential effects on concomitant medications Potentially wide exposure

44. 44 Outpatient Antimicrobial Therapy, U.S. (millions of courses in 1992) McCaig LF and Hughes JM. JAMA 1995; 273:214-9 Otitis media URI (non-specific) Bronchitis Pharyngitis Sinusitis All other diagnoses 23.6 17.9 16.3 13.1 12.9 26.5