A review of the safety of Moxifloxacin Hydrochloride

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
• Comparator 3415

4
Drug related adverse events occurring in gt 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 ASTgt3ULN or ALTgt3ULN or
BRgt1.5ULN)
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
11
(No Transcript)
12
Mean serum concentration after 400mg oral dose
2165 mcg/l SD 588
13
Mean prolongation of QTc
14
Definition of outliers

• Normal lt430mS males
• lt450mS females
• Borderline 430-450mS males
• 450-470mS females
• Prolonged gt450mS males
• gt470mS 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).

31
(No Transcript)
32
(No Transcript)