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QTc and Quinolones:recent regulatory actions

Joyce Korvick M.D., M.P.H.Office of Drug Evaluation IV

Division of Special Pathogens

FDA

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Overview:Quinolone Antibiotics

• Background

• Recent approvals

• Comparison of Selected Characteristics

• Considerations & Approach to Regulatory Actions

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Background

• Antibiotics-– Short term use (<14 days)

• Track record of macrolides– Erythromycin post-marketing experience

• Quinolones– Sparfloxacin (approved 1995, low volume use)– Grepafloxacin (approved 1997,low volume use)

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Background

• Spontaneous withdrawal of Grepafloxacin (Raxar) by Glaxo (11/99)– Original labeling: contraindication– Post-marketing QT experience

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Moxifloxacin(Avelox)

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Anti-infectives Advisory Committee (10/99)

• Moxifloxacin (Avelox)– Pre-clinical data– Phase I/II QT studies– Electrocardiographic studies in Phase III– OPDRA presentation re: post-marketing

experience in approved antibiotics

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Pre-Clinical Animal Data: Moxifloxacin

• Significant changes in animal models with – rapid infusion– extreme dose

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

N Mean change 95% CI

Moxi 200mg 37 4(3)

-1 to 10(-6 to 11)

Moxi 400mg 611 5(12)

3 to 7(9 to 15)

Clari 136 2(12)

-2 to 6(6 to 18)

All comparators 515 0(7)

-2 to 2(4 to 10)

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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 Moxifloxacin 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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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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Gatifloxacin (Tequin)

• Pre-clinical data

• Phase I/II QT studies

• Electrocardiographic studies in phase III– patients with QT prolonging drugs not excluded

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Gatifloxacin

Delta QTc versus Concentration of Gatifloxacin 1 Hour After the End of an IV Infusion at Steady State (1 Hour after Expected Cmax)

-60

-40

-20

0

20

40

60

0 2000 4000 6000 8000

Concentation (mcg/L)

De

lta

QT

c (m

Se

c)

200 mg (n=11)

400 mg (n=6)

600 mg (n=6)

800 mg (n=3)

Placebo (n=10)

y = 0.0042 - 11.84

R2 = 0.113(without placebo)

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Selected Characteristics

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Quinolone CharacteristicsMoxifloxacin Gatifloxacin Grepafloxacin Sparfloxacin

EliminationPathways

Renal / Hepatic Renal Hepatic /Biliary Hepatic/Biliary

Effect onCYP450

Invitro: NONEInvivo: UNKN

Invitro: NONEInvivo: NONE

Invitro: YESCYP1A2/ 3A4Invivo: YESCYP1A2

Invitro: NONEInvivo: NONE

Delta QTc(mean)

5-(12) msec Est’d. 3 msec No phase III data 7-11 msec

Dose Relation YES YES YES YES

Outliers 0.5% (3/559) 0% (0/56) Post-marketing 0.7% (10/1489)

Labeling Warning - Info for pts.

Warning- Info for pts.

Contraindication -sponsor

Contraindication -cases

* Outliers defined as QTc on drug > 500 msec

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Considerations at Approval

• Unique characteristics

• Spectrum of indications

• Metabolic pathways– Potential for drug-drug interactions

• Short-term vs. chronic administration

• Route of administration

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Approach to Regulatory Action

• Labeling within drug class– Warning– Information to Patient Section

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Gatifloxacin (Tequin ) LabelWARNINGS:

GATIFLOXACIN MAY HAVE THE POTENTIAL TO PROLONG THE QTc INTERVAL OF THE ELECTROCARDIOGRAM IN SOME PATIENTS. DUE TO THE LACK OF CLINICAL EXPERIENCE, GATIFLOXACIN SHOULD BE AVOIDED IN PATIENTS WITH KNOWN PROLONGATION OF THE QTc INTERVAL, PATIENTS WITH UNCORRECTED HYPOKALEMIA, AND PATIENTS RECEIVING CLASS IA (E.G. QUINIDINE, PROCAINAMIDE) OR CLASS III (E.G. AMIODARONE, SOTALOL) ANTIARRHYTHMIC AGENTS.

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Approach to Regulatory Action

• Phase IV Commitments– pK/pD: ECG Monitoring

• Controlled studies within quinolone/macrolide classes

• Dose escalation to at least 2X recommended dose

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Approach to Regulatory Action

• Phase IV Commitments– Post-Marketing

• Adverse Event Surveillance Protocol*

• MedWatch

• Pharmaceutical Company Reports

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ODE IV Continuing Response

• Commitment to Anti-infective AC– Assess class labeling approach for all approved

• Quinolones

• Macrolides

• Current Activities– Office level QT working group– Letter to all current NDA holders re: QT data– Coordination within Office: review of NDAs

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Patient Information About:TEQUIN

200 mg and 400 mg Tablets

• Who should not take TEQUIN?• You should avoid TEQUIN if you have a rare condition known as congenital

prolongation of the QTc interval. If any of your family members have this condition, you should inform your health care professional.

• You should avoid TEQUIN if you are being treated for heart rhythm disturbances with certain medicines such as quinidine, procainamide, amiodarone, or sotalol. Inform your healthcare professional if you are taking a heart rhythm drug.

• TEQUIN should be avoided in patients with a condition known as hypokalemia (low blood potassium).

• Hypokalemia may be caused by medicines called diuretics such as furosemide and hydrochlorothiazide. If you are taking a diuretic you should speak with your healthcare professional

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Patient Information About:TEQUIN

200 mg and 400 mg Tablets• What are the possible side effects of TEQUIN?

• TEQUIN is generally well tolerated. The most common side effects that can occur when taking TEQUIN are usually mild, and include nausea, vomiting, stomach pain, diarrhea, dizziness, and headache. …….

• In a few people, TEQUIN, like some other antibiotics, may produce a small effect on the heart that is seen on an electrocardiogram test. Although this has not caused any problems in more than 4000 patients who have taken TEQUIN in clinical trials, in theory, it could result in extremely rare cases of abnormal heartbeat, that may be dangerous. Contact your healthcare professional if you develop heart palpitations (fast beating), or have fainting spells.