The Fluoroquinolone Toxicity Research Foundation

 
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Tequin Lable Changes Research   See downloads for: Adobe Files



DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
Food and Drug Administration
Rockville, MD 20857
NDA 21-061/S-023, S-024
NDA 21-062/S-026, S-037
Bristol Myers-Squibb Company
Attention: Amy A. Jennings, Ph.D.
Senior Regulatory Associate, Global Regulatory Sciences
5 Research Parkway
P.O. Box 5100
Wallingford, CT 06492-7660
Dear Dr. Jennings:
Please refer to your supplemental new drug applications, which were submitted under section
505(b) of the Federal Food, Drug, and Cosmetic Act for the following:
NDA # Drug Product Supplement
Number
Letter Date Receipt Date
S-023 March 18, 2004 March 19, 2004 21-061 Tequin ® (gatifloxacin)
Tablets, 200 mg and 400 mg S-024 March 29, 2004 March 30, 2004
S-026 March 18, 2004 March 19, 2004
21-062
Tequin ® (gatifloxacin in 5%
dextrose) Injection S-027 March 29, 2004 March 30, 2004
Please refer to your amendments dated March 29, 2004, and August 5, 2004 to NDA 21-061/S-023
and NDA 21-062/S-026. Please also refer to your amendments dated August 26, 2004 to
NDA 21-061/S-023, S-024 and NDA 21-062/S-026, S-037.
NDA 21-061/S-023 (Tablets) and NDA 21-062/S-026 (Injection) were submitted as “Special
Supplements- Changes Being Effected” (CBEs) and provide for the addition of quinolone class
labeling as was requested in the Division’s supplement request letter on November 26, 2003 and
the facsimiles from the Division dated March 10, and July 26, 2004. The WARNINGS: QTc
Interval Prolongation, WARNINGS: Tendon Effects, WARNINGS: Peripheral
Neuropathy and PRECAUTIONS: Information for Patients sections were revised.
NDA 21-061/S-024 (Tablets) and NDA 21-062/ S-027 (Injection) were submitted as “Special
Supplements- Changes Being Effected” (CBEs) and provide for labeling changes to the Patient
Information About: and What are the possible side effects of TEQUIN? sections of the patient
package insert.
NDA 21-061/S-023, S-024
NDA 21-062/S-026, S-027
Page 2
These supplements provide for the following changes to the Tequin ® (gatifloxacin) Tablets, 200
mg and 400 mg and Tequin ® (gatifloxacin) Injection, 200 mg and 400 mg label. Deleted text is
noted by strikethrough and added text is noted by double underline:
1. The following revisions were made under the WARNINGS section:
Prolongation of the QTc Interval
GATIFLOXACIN HAS THE POTENTIAL TO PROLONG THE QTc INTERVAL OF
THE ELECTROCARDIOGRAM IN SOME PATIENTS. DUE TO THE LACK OF
CLINICAL EXPERIENCE IN PATIENTS WITH KNOWN PROLONGATION OF
THE QTc INTERVAL, PATIENTS WITH UNCORRECTED HYPOKALEMIA, AND
PATIENTS RECEIVING CLASS IA (EG, QUINIDINE, PROCAINAMIDE) OR
CLASS III (EG, AMIODARONE, SOTALOL) ANTIARRHYTHMIC AGENTS,
GATIFLOXACIN SHOULD BE AVOIDED IN THESE PATIENT POPULATIONS.
QTc Interval Prolongation
Gatifloxacin has the potential to prolong the QTc interval of the electrocardiogram in some
patients. QTc prolongation may lead to an increased risk for ventricular arrhythmias
including torsades de pointes. Rare cases of torsades de pointes have been spontaneously
reported during postmarketing surveillance in patients receiving quinolones, including
gatifloxacin. Nearly all of these rare cases were associated with one or more of the following
factors: age over 60, female gender, underlying cardiac disease, and/or use of multiple
medications. No cardiovascular morbidity or mortality attributable to QTc prolongation has
occurred in over 44,000 patients treated with gatifloxacin in clinical trials; these include 118
patients concurrently receiving drugs known to prolong the QTc interval and 139 patients
known to have uncorrected hypokalemia (ECG monitoring was not performed). Gatifloxacin
should be avoided in patients with known prolongation of the QTc interval, patients with
uncorrected hypokalemia, and patients receiving class IA (quinidine, procainamide), or class
III (amiodarone, sotalol) antiarrhythmic agents. (See CLINICAL PHARMACOLOGY:
Electrocardiogram.)
Pharmacokinetic and pharmacodynamic studies between gatifloxacin and drugs that
prolong the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic
antidepressants have not been performed. Gatifloxacin should be used with caution when
given concurrently with these drugs, as well as in patients with ongoing proarrhythmic
conditions, such as clinically significant bradycardia or acute myocardial ischemia.
The magnitude of QTc prolongation increases with increasing concentrations of the
drug;QTc prolongation may lead to an increased risk for ventricular arrhythmias including
NDA 21-061/S-023, S-024
NDA 21-062/S-026, S-027
Page 3
torsades de pointes (see CLINICAL PHARMACOLOGY: Electrocardiogram);
therefore, the recommended dose and the recommended intravenous infusion rate should not
be exceeded (see DOSAGE AND ADMINISTRATION for dosing recommendations for
patients with or without renal impairment).
No cardiovascular morbidity or mortality attributable to QTc prolongation has occurred in
over 44,000 patients treated with gatifloxacin in clinical trials; these include 118 patients
concurrently receiving drugs known to prolong the QTc interval and 139 patients known to
have uncorrected hypokalemia (ECG monitoring was not performed). During postmarketing
surveillance, rare cases of torsades de pointes have been reported in patients taking
gatifloxacin. These cases have occurred primarily in elderly patients with underlying
medical problems for which they were receiving concomitant medications known to prolong
the QTc interval; the contribution, if any, of gatifloxacin to the development of torsades de
pointes in these patients is unknown.
Tendon Effects
Ruptures of the shoulder, hand, and Achilles tendon or other tendons that required surgical
repair or resulted in prolonged disability have been reported in patients receiving quinolones,
including gatifloxacin. Postmarketing surveillance reports indicate that this risk may be
increased in patients receiving concomitant corticosteroids, especially the elderly.
Gatifloxacin should be discontinued if the patient experiences pain, inflammation, or rupture
of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendonitis or
tendon rupture has been excluded. Tendon rupture can occur during or after therapy with
quinolones, including gatifloxacin.
Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted
in prolonged disability have been reported in patients receiving quinolones. TEQUIN should
be discontinued if the patient experiences pain, inflammation, or rupture of a tendon.
Patients should rest and refrain from exercise until the diagnosis of tendonitis or tendon
rupture has been confidently excluded. Tendon rupture can occur during or after therapy
with quinolones.
Peripheral Neuropathy
Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large
axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported
in patients receiving quinolones.
NDA 21-061/S-023, S-024
NDA 21-062/S-026, S-027
Page 4
2. The following revisions were made under the PRECAUTIONS section, Information for
Patients subsection:
• that TEQUIN may producecause changes in the electrocardiogram (QTc interval
prolongation);
• that TEQUIN should be avoided in patients receiving Classclass IA (eg, quinidine,
procainamide) or Classclass III (eg, amiodarone, sotalol) antiarrhythmic agents;
• that TEQUIN should be used with caution in patientssubjects receiving drugs that may
effectaffect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic
antidepressants;
• to inform their physicians of any personal or family history of QTc prolongation or
proarrhythmic conditions such asrecent hypokalemia,significant bradycardia, or recent
myocardial ischemia;
• to discontinue treatment and contact their physician if symptoms of peripheral
neuropathy including pain, burning, tingling, numbness and/or weakness develop;
3. The following typographical error was made in the patient package insert and will be
corrected in the final printed labeling:
Patient Information About:
TEQGUIN

(gatifloxacin)
200 mg and 400 mg Tablets
4. The following revisions were made in the patient package insert, under the
What are the possible side effects of TEQUIN? section, second paragraph:
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 causeddid not cause any
problems in more than 4000 patients who have taken took TEQUIN in premarketing clinical
trials, in theory, it could result in extremely rare cases of abnormal heartbeat, which may be
dangerous. Contact your healthcare professional if you develop heart palpitations (fast
beating) or have fainting spells.
We have completed the review of these supplemental new drug applications, as amended, and
have concluded that adequate information has been presented to demonstrate that the drug
NDA 21-061/S-023, S-024
NDA 21-062/S-026, S-027
Page 5
product is safe and effective for use as recommended in the agreed upon labeling text (enclosed).
Accordingly, this supplemental application is approved effective on the date of this letter.
The final printed labeling (FPL) must be identical to the submitted draft labeling (package insert
submitted August 26, 2004).
The electronic labeling rule published December 11, 2003, (68 FR 69009) requires submission of
labeling content in electronic format effective June 8, 2004. For additional information, consult
the following guidances for industry regarding electronic submissions: Providing Regulatory
Submissions in Electronic Format - NDAs (January 1999) and Providing Regulatory Submissions
in Electronic Format – Content of Labeling (February 2004). The guidances specify that
labeling to be submitted in pdf format. To assist in our review, we request that labeling also be
submitted in MS Word format. If formatted copies of all labeling pieces (i.e., package insert,
patient package insert, container labels, and carton labels) are submitted electronically, labeling
does not need to be submitted in paper. For administrative purposes, these submissions should be
designated “FPL for approved supplement NDA 21-061/S-023, S-024 and NDA 21-062/S-026,
S-027." Approval of this submission by FDA is not required before the labeling is used.
If you issue a letter communicating important information about these drug products (i.e., a
“Dear Health Care Professional” letter), we request that you submit a copy of the letter to each
NDA and a copy to the following address:
MEDWATCH, HFD-410
FDA
5600 Fishers Lane
Rockville, MD 20857
We remind you that you must comply with the requirements for an approved NDA set forth
under 21 CFR 314.80 and 314.81.
If you have any questions, call Christine Lincoln, Labeling Reviewer, at (301) 827-2127.
Sincerely,
{See appended electronic signature page}
Renata Albrecht, M.D.
Director
Division of Special Pathogen and Immunologic
Drug Products
Office of Drug Evaluation IV
Center for Drug Evaluation and Research