DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
Food and Drug Administration
Rockville, MD 20857
NDA 19-384/S-040, S-042, S-043
Merck & Co., Inc.
Attention: Mary Beth Wigley
Manager, Regulatory Affairs
P.O. Box 4
Sumneytown Pike, BLA-20
West Point, PA 19486-0004
Dear Ms. Wigley:
Please refer to your following supplemental new drug applications submitted under section 505(b) of
the Federal Food, Drug, and Cosmetic Act for NOROXIN™ (norfloxacin) Tablets, 400 mg.
Supplement Date submitted Date received
040 November 27, 2002 November 29, 2002
042 January 26, 2004 January 27, 2004
043 January 29, 2004 January 30, 2004
We acknowledge receipt of your amendments for NDA 19-384/S-040 dated October 3, 2003, October
17, 2003, January 20, 2004, and for NDA 19-384/S-040, S-042, S-043 dated March 19, 2004, May 6,
2004 and July 19, 2004.
NDA 19-384/S-040 provides for the following revisions:
• WARNINGS to add information on peripheral neuropathy and include revisions to the tendon
rupture statement
• PRECAUTIONS, General and ADVERSE REACTIONS, Post Marketing, Cardiovascular to
include information on QTc prolongation and torsades de pointes
• PRECAUTIONS, Drug Interactions, to include an interaction with glyburide.
• ADVERSE REACTIONS, Post Marketing to include elevated creatine kinase.
Your submission of March 19, 2004 constitutes a complete response to our September 30, 2003 action
letter.
NDA 19-384/S-042 provides for revisions to the package insert under PRECAUTIONS, Drug
Interactions concerning warfarin, ADVERSE REACTIONS, Post Marketing, Hematologic adding
agranulocytosis, and ADVERSE REACTIONS, Post Marketing, Special Senses adding hearing loss.
NDA 19-384/S-043 was submitted as Changes Being Effected (CBE) and provides for antibacterial
drug resistance labeling revisions as specified in the Division’s September 11, 2003 letter. This CBE
request letter was sent per the Final Rule entitled “Labeling Requirements for Systemic
Antibacterial Drug Products Intended for Human Use “(68FR 6062, February 6, 2003).
NDA 19-384/S-040. S-042, S-043
Page 2
These supplemental new drug applications provide for the following revisions to the package insert
(additions are double underlined and deletions are strikethrough):
NDA 19-384/S-040
1. The following revisions were made under the WARNINGS section:
Safety in Children, Adolescents, Nursing Mothers, and during Pregnancy: THE SAFETY
AND EFFICACY OF ORAL NORFLOXACIN IN PEDIATRIC PATIENTS,
ADOLESCENTS (UNDER THE AGE OF 18), PREGNANT WOMEN, AND NURSING
MOTHERS HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS, Pediatric Use,
Pregnancy, and Nursing Mothers subsections.) The oral administration of single doses of
norfloxacin, 6 times *** the recommended human clinical dose (on a mg/kg basis), caused lameness
in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed
permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in
weight-bearing joints and other signs of arthropathy in immature animals of various species. (See
ANIMAL PHARMACOLOGY.)
Seizures: Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased
intracranial pressure, and toxic psychoses have been reported in patients receiving drugs in this
class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to
tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in
patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted.
The effects of norfloxacin on brain function or on the electrical activity of the brain have not
been tested. Therefore, until more information becomes available, norfloxacin, like all other
quinolones, should be used with caution in patients with known or suspected CNS disorders, such as
severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures. (See
ADVERSE REACTIONS.)
Hypersensitivity/anaphylaxis: Serious and occasionally fatal hypersensitivity (anaphylactoid or
anaphylactic) reactions, some following the first dose, have been reported in patients receiving
quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of
consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria and itching. Only a few
patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs,
discontinue the drug. Serious acute hypersensitivity reactions may require immediate emergency
treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor
amines, and airway management, including intubation, should be administered as indicated.
Pseudomembranous colitis: Pseudomembranous colitis has been reported with nearly all
antibacterial agents, including norfloxacin, and may range in severity from mild to life-threatening.
Therefore, it is important to consider this diagnosis in patients who present with
diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit
overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one
primary cause of “antibiotic-associated colitis”.
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures
should be initiated. Mild cases of pseudomembranous colitis usually respond to drug
discontinuation alone. In moderate to severe cases, consideration should be given to management
*** Based on a patient weight of 50 kg.
NDA 19-384/S-040. S-042, S-043
Page 3
with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug
clinically effective against C. difficile colitis.
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 norfloxacin. Norfloxacin should be
discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling,
numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position
sense, vibratory sensation, and/or motor strength in order to prevent the development of an
irreversible condition.
Tendon effects: Ruptures of the shoulder, hand,and Achilles tendons or other tendons that
required surgical repair or resulted in prolonged disability have been reported with in patients
receiving quinolones, including norfloxacin. Post-marketing surveillance reports indicate that this
risk may be increased in patients receiving concomitant corticosteroids, especially in the elderly.
Norfloxacin 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 at any time during or after therapy
with quinolones, including norfloxacin.
Syphilis treatment: Norfloxacin has not been shown to be effective in the treatment of syphilis.
Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or
delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test
for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up
serologic test for syphilis after three months.
2. The following text was added as the first five bullets in the PRECAUTIONS, Information for
Patients subsection:
−that norfloxacin may cause changes in the electrocardiogram (QTc interval prolongation).
−that norfloxacin should be avoided in patients receiving class IA (e.g., quinidine,
procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents.
— that norfloxacin should be used with caution in subjects receiving drugs that affect 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 as hypokalemia, bradycardia or recent myocardial ischemia.
−that peripheral neuropathies have been associated with norfloxacin use. If symptoms of
peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop,
they should discontinue treatment and contact their physicians.
3. The following text was added in the PRECAUTIONS, Drug Interactions subsection:
The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea
agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood
glucose is recommended when these agents are co-administered.
4. The following text was revised in the PRECAUTIONS, Geriatric Use subsection:
Of the 340 subjects in one large clinical study of NOROXIN for treatment of urinary tract
infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in
safety and effectiveness were evident between these subjects and younger subjects. In clinical
NDA 19-384/S-040. S-042, S-043
Page 4
practice, no difference in the type of reported adverse experiences have been observed between the
elderly and younger patients; however,patients except for a possible increased risk of tendon rupture
in elderly patients receiving concomitant corticosteroids (see WARNINGS). In addition, increased
risk for other adverse experiences in some older individuals cannot be ruled out (see ADVERSE
REACTIONS).
This drug is known to be substantially excreted by the kidney, and 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 (see DOSAGE AND ADMINISTRATION).
A pharmacokinetic study of NOROXIN in elderly volunteers (65 to 75 years of age with normal
renal function for their age) was carried out (see CLINICAL PHARMACOLOGY).
5. The following text was added under the ADVERSE REACTIONS, Post Marketing subsection:
Cardiovascular
On rare occasions, prolonged QTc interval and ventricular arrhythmia including torsades de pointes.
Musculoskeletal
Tendonitis, tendon rupture; exacerbation of myasthenia gravis (see PRECAUTIONS) ; elevated
creatine kinase (CK).
NDA 19-384/S-042
1. The following revisions were made under the PRECAUTIONS, Drug Interactions subsection:
Quinolones, including norfloxacin, may enhance the effects of the oral anticoagulant oral
anticoagulants, including warfarin or its derivatives or similar agents. When these products are
administered concomitantly, prothrombin time or other suitable coagulation tests should be closely
monitored.
2. The following revisions were made under the ADVERSE REACTIONS, Post Marketing,
subsection:
Hematologic
Neutropenia; leukopenia; agranulocytosis; hemolytic anemia, sometimes associated with glucose-6-
phosphate dehydrogenase deficiency; thrombocytopenia.
Special Senses
Transient hearing loss (rare),Hearing loss, tinnitus, diplopia, dysgeusia.
Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria,
crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol,
elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis,
symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time,
and vaginal candidiasis.
NDA 19-384/S-043
1. The following sentence was added at the beginning of the label under the Product Name:
NDA 19-384/S-040. S-042, S-043
Page 5
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent
infections that are proven or strongly suspected to be caused by bacteria.
2. The following was added as the last paragraph in the INDICATIONS AND USAGE section:
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
NOROXIN and other antibacterial drugs, NOROXIN should be used only to treat or prevent
infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture
and susceptibility information are available, they should be considered in selecting or modifying
antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns
may contribute to the empiric selection of therapy.
3. The following was added as the last paragraph in the PRECAUTIONS, General subsection:
Prescribing NOROXIN in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
4. The following was added as the last paragraph in the PRECAUTIONS, Information for Patients
subsection:
Patients should be counseled that antibacterial drugs including NOROXIN should only be used to
treat bacterial infections. They do not treat viral infections (e.g., the common cold). When
NOROXIN is prescribed to treat a bacterial infection, patients should be told that although it is
common to feel better early in the course of therapy, the medication should be taken exactly as
directed. Skipping doses or not completing the full course of therapy may (1) decrease the
effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop
resistance and will not be treatable by NOROXIN or other antibacterial drugs in the future.
We have completed the review of these supplemental 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, these supplemental
applications are approved effective on the date of this letter.
The final printed labeling (FPL) must be identical to the submitted draft labeling (package insert
submitted July 19, 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 supplements
NDA 19-384/S-040. S-042, S-043
Page 6
NDA 19-384/S-040, S-042, S-043." Approval of these submissions by FDA is not required before the
labeling is used.
If a letter communicating important information about this drug product (i.e., a "Dear Health Care
Professional" letter) is issued to physicians and others responsible for patient care, we request that you
submit a copy of the letter to this NDA and a copy to the following address:
MEDWATCH, HF-2
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 Robin Anderson, R.N., M.B.A., 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