1 A review of the safety of Moxifloxacin Hydrochloride Leonard Sacks MD Medical officer/DSPIDP

2 Moxifloxacin safety review General safety Cardiac safety –in vitro –animal studies –clinical studies phase 1+ 2 –clinical studies phase 3

3 Patients valid for safety (worldwide) Moxifloxacin 400mg QD 4370 Moxifloxacin 200mg QD 557 Comparator3415

4 Drug related adverse events occurring in >= 3% of patients treated with Moxifloxacin or comparator agents

5 Quinolone related toxicities

6 Treatment-emergent abnormally elevated liver function tests (Abnormalities defined categorically according to each study)

7 Patients with a  2 fold increase in AST ALT and BR (and at least AST>3ULN or ALT>3ULN or BR>1.5ULN)

8 Overall death rates: moxifloxacin 0.45% comparator 0.47%

9 Moxifloxacin safety review General safety Cardiac safety –in vitro –animal studies –clinical studies phase 1+ 2 –clinical studies phase 3

10 In vitro models

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12 Mean serum concentration after 400mg oral dose = 2165 mcg/l SD 588

13 Mean prolongation of QTc

14 Definition of outliers Normal: <430mS males <450mS females Borderline: mS males mS females Prolonged: >450mS males >470mS females

15 Outlier shift analysis (Phase 1 and 2 studies)

16 Cardiac adverse events (Phase 1 &2)

17 ECG protocol May 97 - baseline and 2-6hr ECGs required exclusion of patients with baseline prolongations exclusion of concomitant medications: amiodarone, sotalol, disopyramide, quinidine, procainamide and terfenadine

18 Patients with ECGs

19 ECGs excluded

20 Mean changes of QTcB (QT) in mS for patients with valid paired ECGs

21 Outlier shift analysis (Phase 3 studies)

22 Extreme outliers in phase 3 trials

23 Effect of hypokalemia on QTc prolongation

24 Cardiac adverse events

25 Summary Blocked Ikr at 3x concentration of sparfloxacin prolonged APD at 50  M vs 3  M for sparfloxacin Dose related prolongation in animals and humans Mean prolongation 5mS (oral 400mg) 12mS (IV 400mg) outliers increased changes with hypokalemia

26 Moxifloxacin Question 1

27 Moxifloxacin Question 2 If the answer to question 1 is yes for one or more indications, do you believe that the labeling proposed by the firm regarding the prolongation of the Q-T interval produced by moxifloxacin is adequate? If not, what modifications would you suggest?

28 Moxifloxacin Question 3 If Moxifloxacin is approved, do you have any recommendations regarding Phase IV studies or data collection that the applicant should be requested to perform?

29 Moxifloxacin Question 4 Do you have any recommendations regarding the parameters both qualitative and quantitative that may be most useful in assessing the significance of the Q-T prolongation caused by anti-infective products?

30 Extract from Label WARNINGS Moxifloxacin as with some other quinolones and macrolides, has been shown to prolong the QTc interval of the electrocardiogram. The degree of mean (+/- standard deviation) QTc prolongation with moxifloxacin in clinical trials was 4 (+/-28) msec compared with 2 (=/-23) msec in patients treated with clarithromycin. Consequently, moxifloxacin should be used with caution in patients with congenital or acquired syndromes of QTc prolongation or in patients taking concomitant medication known to prolong the QTc interval (e.g. class 1a and class III antiarrhythmics).

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