QTc and Quinolones: recent regulatory actions

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QTc and Quinolonesrecent regulatory actions

• Joyce Korvick M.D., M.P.H.
• Office of Drug Evaluation IV
• Division of Special Pathogens
• FDA

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OverviewQuinolone Antibiotics

• Background
• Recent approvals
• Comparison of Selected Characteristics
• Considerations Approach to Regulatory Actions

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Background

• Antibiotics-
• Short term use (lt14 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
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Mean changes of QTcB (QT) in mS for patients with
valid paired ECGs
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Mean serum concentration after 400mg Moxifloxacin
oral dose 2165 mcg/l SD 588
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Mean prolongation of QTc
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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

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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
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Selected Characteristics
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Quinolone Characteristics
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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 ) Label

• WARNINGS
• 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 AboutTEQUIN 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 AboutTEQUIN 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.