The Fluoroquinolone Toxicity Research Foundation

 
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Levaquin Label Changes Research   See downloads for: Adobe Files



DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
Food and Drug Administration
Rockville, MD 20857
NDA 20-634/S-033, S-034
NDA 20-635/S-033, S-034
R.W. Johnson Pharmaceutical Research Institute
Attention: Ms. Robyn S. Thomas
Regulatory Affairs
920 Route 202 South
P. O. Box 300
Raritan, NJ 08869-0602
Dear Ms. Thomas:
Please refer to your supplemental new drug applications dated March 16, 2004, received March 17,
2004, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for LEVAQUIN ®
(levofloxacin) Tablets and Injection.
We acknowledge receipt of your submissions dated April 9, 2004 to NDA 20-634/S-033 and NDA 20-
635/S-033. We also acknowledge the receipt of your submissions dated August 23, 2004 to NDA 20-
634/S-033, S-034 and NDA 20-635/S-033, S-034.
NDA 20-634/S-033 and NDA 20-635/S-033 were submitted as “Changes Being Effected” (CBE)
supplemental labeling applications and provide for the addition of quinolone class labeling
information to the package insert. These changes were requested in our supplement request letter
dated October 27, 2003, and in our facsimiles dated March 10, and July 12, 2004.
NDA 20-634/S-034 and NDA 20-635/S-034 were submitted as prior approval supplemental
applications and provide for revisions to the PRECAUTIONS: Geriatric Use section of the package
insert regarding QTc prolongation/torsades de pointes, and the Post-Marketing Adverse Reactions
section of the package insert providing for the addition of rhabdomyolysis.
These supplemental new drug applications provide for the following revisions to the package insert:
1. The following paragraph was added as the sixth paragraph of the WARNINGS section:
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, including levofloxacin. Levofloxacin should be
discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling,
numbness, and/or weakness or other alterations of sensation including light touch, pain,
temperature, position sense, and vibratory sensation in order to prevent the development of an
irreversible condition.

NDA 20-634/S-033, S-034
NDA 20-635/S-033, S-034
Page 2
2. The tenth paragraph of the WARNINGS section was revised as follows:
Tendon Effects: Ruptures of the shoulder, hand, or Achilles tendon, or other tendons that required
surgical repair or resulted in prolonged disability have been reported in patients receiving
quinolones, including levofloxacin. Post-marketing surveillance reports indicate that this risk may
be increased in patients receiving concomitant corticosteroids, especially in the elderly.
Levofloxacin 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 tendinitistendonitis or
tendon rupture has been confidently excluded. Tendon rupture can occur during or after therapy
with quinolones, including levofloxacin.
3. The last paragraph of the PRECAUTIONS section, General subsection was revised as follows:
Torsades de pointes: Some quinolones, including levofloxacin, have been associated with
prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia.
During post-marketing surveillance, rareRare cases of torsades de pointes have been reported in
patients taking levofloxacin. These reports generally involved patients withspontaneously reported
during post-marketing surveillance in patients receiving quinolones, concurrent medical conditions
or concomitant medications that may have been contributory. The risk of arrhythmias may be
reduced by avoiding concurrent use with other drugs that prolong the QT interval including class Ia
or class III antiarrhythmic agents; in addition, use of levofloxacin in the presence of risk factors for
torsades de pointes such as hypokalemia, significant bradycardia, and cardiomyopathy should be
avoided.
including levofloxacin. Levofloxacin should be avoided in patients with known prolongation of
the QT interval, patients with uncorrected hypokalemia, and patients receiving class IA (quinidine,
procainamide), or class III (amiodarone, sotalol) antiarrhythmic agents.
As with any potent antimicrobial drug, periodic assessment of organ system functions, including
renal, hepatic, and hematopoietic, is advisable during therapy. (See WARNINGS and ADVERSE
REACTIONS.)
4. The following was added as the second bullet in the PRECAUTIONS section, Information for
Patients subsection:
• that peripheral neuropathies have been associated with levofloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop,
they should discontinue treatment and contact their physicians;

NDA 20-634/S-033, S-034
NDA 20-635/S-033, S-034
Page 3
5. The following paragraph was added to the PRECAUTIONS section, Geriatric Use subsection:
In phase 3 clinical trials, 1,190 levofloxacin-treated patients (25%) were ≥65 years of age. Of
these, 675 patients (14%) were between the ages of 65 and 74 and 515 patients (11%) were 75
years or older. No overall differences in safety or effectiveness were observed between these
subjects and younger subjects, and other reported clinical experience has not identified differences
in responses between the elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore,
precaution should be taken when using levofloxacin with concomitant drugs that can result in
prolongation of the QT interval (e.g. class IA or class III antiarrhythmics) or in patients with risk
factors for Torsades de pointes (e.g. known QT prolongation, uncorrected hypokalemia). See
PRECAUTIONS: GENERAL: Torsades de Pointes.
The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ
significantly when creatinine clearance is taken into consideration. However since the drug is
known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be
greater in patients with impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection, and it may be useful to monitor
renal function.
6. The following revisions were made in the Post-Marketing Adverse Reactions section:
Additional adverse events reported from worldwide post-marketing experience with levofloxacin
include: allergic pneumonitis, anaphylactic shock, anaphylactoid reaction, dysphonia, abnormal
EEG, encephalopathy, eosinophilia, erythema multiforme, hemolytic anemia, multi-system organ
failure, increased International Normalized Ratio (INR)/prothrombin time, peripheral neuropathy,
rhabdomyolysis, Stevens-Johnson Syndrome, tendon rupture, torsades de pointes, vasodilation.
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 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 23, 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
NDA 20-634/S-033, S-034
NDA 20-635/S-033, S-034
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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 20-634/S-033, S-034 and NDA 20-635/S-033, S-034." Approval of this submission by FDA is
not required before the labeling is used.
If you issue a letter communicating important information about this drug product (i.e., a “Dear Health
Care Professional” letter), we request that you submit a copy of the letter to this 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 reporting requirements for an approved NDA (21 CFR
314.80 and 314.81).
If you have any questions, call Christine Lincoln, R.N., MS, MBA, 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