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A review of the safety of Moxifloxacin Hydrochloride

Leonard Sacks MD

Medical officer/DSPIDP

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Moxifloxacin safety review

• General safety

• Cardiac safety– in vitro– animal studies– clinical studies phase 1+ 2– clinical studies phase 3

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Patients valid for safety (worldwide)

• Moxifloxacin 400mg QD 4370

• Moxifloxacin 200mg QD 557

• Comparator 3415

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

agents

Moxifloxacin(n=4301)

Comparator(n=3415)

Any event 1377 (32%) 1020 (30%)Nausea 324 (8%) 212 (6%)Diarrhea 283 (7%) 171 (5%)Headache 115 (3%) 89 (3%)Dizziness 137 (3%) 54 (2%)Taste perversion 44 (1%) 86 (3%)

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Quinolone related toxicities

Moxifloxacin ComparatorPhototoxicity <1% (4/4926) Not reportedHUS syndrome 0 0Tendon rupture 0/4301 (Achilles tendon

pain in 2 patients)0 ( 0/3415)

Hypoglycemia 5% (157/2879) 4% (79/1945)CNS effects Dizziness convulsions

4% (166/4301)<1% ( 2/4301)

2% (77/3415)<1% (2/3415)

Abnormal liverfunction

2% (73/4301) 2% (69/3415)

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Treatment-emergent abnormally elevated liver function tests

All moxifloxacin Control

Incidence % Incidence %

AST 243/3663 7 239/2918 8ALT 320/3711 9 273/2919 9AlkPhos 132/3610 4 98/2875 3

BR(tot) 117/3793 3 69/2964 2

(Abnormalities defined categorically according to each study)

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Patients with a 2 fold increase in AST ALT and BR

(and at least AST>3ULN or ALT>3ULN or BR>1.5ULN)

Patients Rx AST ALT Bilirubin Outcome

Pre-Rx

Post-Rx

Pre-Rx

Post-Rx

Pre-Rx

Post-Rx

1 Moxi 400 25 302 17 194 5.2 Resolved

2 Moxi 400 35 117 40 152 0.2 0.7 Resolved

3 Moxi 400 108 684 42 150 0.6 1.6 Improved

4 Moxi 400 45 190 60 366 0.8 7.2 BR 2.2 mg/dl 5days post Rx

5 Cephalexin 26 109 18 135 0.54 1.12 Resolved

6 Cephalexin& metronid

63 191 59 179 0.4 0.8 -

7 Clarithro 59 402 81 592 0.8 1.6 -

8

0

1

2

3

4

5

6

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15-30 >30

day post Rx

Deaths on and after treatment

Moxifloxacin

comparators

Overall death rates: moxifloxacin 0.45% comparator 0.47%

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Moxifloxacin safety review

• General safety

• Cardiac safety– in vitro– animal studies– clinical studies phase 1+ 2– clinical studies phase 3

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In vitro models

Ikr Iks APDGuinea pig papillarymuscle (intracellularelectrodes)

No effect -Prolonged 50uM Moxi 3uM Spar

Guinea pig ventricmyocytes(whole cell voltageclamp)

No effectBlocked Moxi50uM

-

Mouse atrial cells(whole cell patchclamp)

Blocked Moxi0.75uM Spar 0.23uM

- -

CHO transfectedline (Depolarizationor mefanemic acininduced ion flux)

-

No effect Neithermoxi nor Spar

-

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Summary of preclinical animal dataSpecies &study design

Route ofadmin

Dose range(mg/kg)

Increase in mean QTc

Ventricarrhythmias

Beagles Intraduodenal 10-100 2 ms -

Beagles (4weeks)

Oral 0-90 25 ms at highdose *

-

Monkeys Intraduodenal 10-100 0 -

Beagles IV bolus 1-30 8-69ms -

Beagles IV infusion 30 over 30 min <21ms -

Beagles IV varyinginfusion rates

30 over 15 to60 min

64 ms athighest rate

-

Beagles(Hypokalemia)

IV infusion 30 over 30 min 20ms -

Dogs(+sotalol)

IV infusion 30 over 30 min 113ms -

Beagles(vs Sparflox)

IV infusion 30 over 30 min 28ms (vs58ms)

-

Rabbits (vsSparflox)

IV infusion 120 50ms (vs 140) 1/6 PVC (vs4/6 PVC, 1/6VT)

Beagles(overdose)

IV infusion Up to 360over 60-90min

600ms VEs & TdP

*QT rather than QTc

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Delta QTc versus Concentration of BAY 12-8039 at 2 Hours Following a Single Oral Dose of > 200 mg (N=181)

y = 0.0061x - 7.3R2 = 0.0832p < 0.001

-80

-60

-40

-20

0

20

40

60

0 1000 2000 3000 4000 5000

Concentration (mcg/L)

De

lta

QT

c (m

Se

c) -

au

tom

atic

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

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Mean prolongation of QTc

NMean prolongation of QTc(msec) +/- SE Mat Cmax

Range

Moxifloxacin 400mg(PO)

112 6.9 +/- 2.1 -70.4 to 89.4

Moxifloxacin 400mg(IV over 15-60min)

28 12.1 +/- 3.8 -48.4 to 43

Placebo 27 3.5 +/- 4.7 -64.8 to 60

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Definition of outliers

• Normal: <430mS males

<450mS females

• Borderline: 430-450mS males

450-470mS females

• Prolonged: >450mS males

>470mS females

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Outlier shift analysis (Phase 1 and 2 studies)

Moxifloxacin 400mg PO

At C max

normal borderline Prolonged Total

Normal 94(88%)

10(9%)

3(2.8%)

107

Border-line 9 3 0 12

Pro-longed

0 0 0 0

base

line

Total 103 13 3 119

Placebo

normal borderline Prolonged Total

Normal 39(95%)

1(2.4%)

1(2.4%)

41

Border-line 3 1 1(20%)

5

Pro-longed

0 0 0 0

base

line

Total 42 2 2 46

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Cardiac adverse events (Phase 1 &2)

Elderly woman given a single 200mg PO dose of moxifloxacin, Subjective complaintof irregular heartbeat 12 hours after dosing.ECG performed after the event was normal and relationship to drug listed as remote.

Young healthy male.Tolerated a 33 minute infusion of Moxifloxacin 400mg.11 minutes after drug was stopped patient developed weakness, nausea and sinusbradycardia ( 35-40 bpm).Patient fainted with an asystole of “several seconds”.Cardiac resuscitation ventricular rhythm junctional rhythm

sinus rhythm. No sequelae.2 cardiologists evaluated the event as “vasovagal syncope”

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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

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Patients with ECGs

5 5 9 m oxi 4 0 0 m g 3 7 m oxi 2 0 0 m g 5 1 5 com p ara to r

1 1 1 1 "p a ired va lid E C G s"

1 0 0 2 exc lu d ed fo r tech n ica l reason s

2 1 1 3 w ith E C G s(1 1 3 9 m oxifloxac in )

8 3 4 1 va lid fo r sa fe ty

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ECGs excludedMoxifloxacin Comparator

Non paired 104 91Relative time notknown

131 132

Not within timewindow

122 101

Poor quality 101 75Missing scale 65 74VPCs 83 53Atrial fibrillation 24 19other 51 43total 681 588

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

N Mean change 95% CI max

Moxi 200mg 37 4(3)

-1 to 10(-6 to 11)

41(50)

Moxi 400mg 611 5(12)

3 to 7(9 to 15)

218(277)

Clari 136 2(12)

-2 to 6(6 to 18)

56(140)

All comparators 515 0(7)

-2 to 2(4 to 10)

80(140)

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Outlier shift analysis (Phase 3 studies)

Moxifloxacin 400mgAt C max

normal borderline prolonged Totalnormal 350 64 (15.1%) 10 (2.4%) 424borderline 32 42 26 (26%) 100prolonged 8 8 19 35

base

line

Total 390 114 55 559

ComparatorsAt C max

normal borderline prolonged Totalnormal 343 39 (10%) 10 (2.6%) 392borderline 39 32 19 (21%) 90prolonged 7 9 16 32

base

line

Total 389 80 45 514

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Extreme outliers in phase 3 trials

Treatmentgroup

Pre dose QTc (mS) Post dose QTc (mS) Associated factors

Moxi 400 365 583 HypokalemiaMoxi 400 439 535 RBBBMoxi 400 452 519 -Comparator >500 <500 -Comparator >500 <500 -Comparator >500 <500 -Comparator 494 >500 -

3/559 patients treated with Moxifloxacin developed treatment emergent QTc’s >500mScompared with 1/515 among comparator treated patients.

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Effect of hypokalemia on QTc prolongation

Delta QTc 30-60mSMoxiflox Comparator

K >=3.5 12.1 %(147/1211)

8%(84/1044)

K < 3.5 18.9%(7/37)

7.3%(3/41)

Delta QTc >60Moxiflox Comparator

K >=3.5 1.7%(20/1211)

1.1%(12/1044)

K < 3.5 8.1%(3/37) p=0.002

0%(0/41)

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Cardiac adverse eventsMoxifloxacin 400(n=3745)

Control(n=3415)

Death 1 2Tachycardia 16 15Palpitation 11 9Syncope 8 6Arrhythmia 3 3Atrial fib 12 2 (p=0.014)Bradycardia 3 3Shock 4 1Ventricextrasystoles

1 1

CVA 2 1Atrial flutter 1 1Ventricarrhythmia

1 0

Ventric tachy 0 2Ventric fib 1 0

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Summary

• Blocked Ikr at 3x concentration of sparfloxacin• prolonged APD at 50M vs 3M for sparfloxacin• Dose related prolongation in animals and humans• Mean prolongation 5mS (oral 400mg) 12mS (IV

400mg)• outliers• increased changes with hypokalemia

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Moxifloxacin Question 1

1. Has moxifloxacin been shown to be safe and effective for the treatment of: Uncomplicated skin and skin structure infections Community acquired pneumonia Acute exacerbation of chronic bronchitis Acute maxillary sinusitis

a. If the answer is no for one or more indications, what additional information wouldbe required?

b. If the answer is yes for any or all the indications, are there any caveats regarding itsuse that you would recommend be included in the product labeling? As part of yourdiscussion of the community acquired pneumonia indication please address theapplicant’s request that the “Indications and Usage” include PRSP. Should yourecommend inclusion of PRSP, should any mention also be made of PISP in thissection?

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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?

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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?

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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?

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Extract from LabelWARNINGS

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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Drug Mean change inQTcB (mS)

Recommendeddose

On treatmentQTc >500mS

Effect onIKr/APD

DoseRelation with

QTcprolongation

Potential fordrug interaction

via p450

Regulatoryaction

Sparfloxacin 7-14 11/1489 Yes/Yes yes No ApprovedGrepafloxacin 10 1/48 - 1A2 ?3A4 ApprovedOfloxacin 1 - ApprovedCiprofloxacin - ?1A2 ApprovedLevofloxacin ?/no effect No ApprovedMoxifloxacin 5 po 3/559 Yes/yes Yes No Pending

Erythromycin 13.8 (51 iv) yes/yes 3A4 ApprovedClarithromycin 2-3 0/84 3A4 ApprovedBepridil 30-40 yes/yes ApprovedDofetilide 40 yes/yes 3A4 ApprovedAntipsychotic X 3.8 -10 (160 per

day)(or change >

75mS) (13?)1/1544 *

yes/? Yes ? Not approvable

Sertindole ?21 yes/? Yes 2D6 Withdrawn(deaths)

Sotolol 10-40 yes/yes No ApprovedAntihistamine X 4-10 yes/yes 3A4 Not approvedCisapride yes/yes 3A4 ApprovedTerfenadine 6 ms at 60 bid. yes/yes 3A4 Withdrawn

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Delta QTc versus Concentration of BAY 12-8039 at the End of a15 minute or 60 minute IV Infusion of 400 mg

(Young N=6, Elderly N=12)

-10

0

10

20

30

40

50

0 2000 4000 6000 8000 10000 12000

Concentration (mcg/L)

Delta

QTc

(mSe

c) SD over 15 min in Young

SD over 15 min in Elderly

MD over 60 min in Elderly

y = 0.0025x + 2.63

R2 = 0.1428p = 0.04