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Nalidixic Acid Label Changes  Research   See downloads for: Adobe Files



DEPARTMENT OF HEALTH & HUMAN SERVICES
_______________________________________________________________________
Food and Drug Administration
Rockville, MD 20857
NDA 14-214/S-053, S-055, S-056
Sanofi-Synthelabo
Attention: Michelle A. McGuinness
Senior Manager, Regulatory Operations, DRA
90 Park Ave.
New York, NY 10016
Dear Ms. McGuinness:
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-053 April 8, 2003 April 16, 2003
S-055 May 7, 2004 May 11, 2004 14-214 NegGram  (nalidixic acid)
Caplets, 500mg S-056 May 7, 2004 May 11, 2004
We acknowledge receipt of your submissions dated May 22, 2003, March 10, 2004, and August 27,
2004 to S-053, and May 7, 2004, and August 27, 2004 to S-055 and S-056.
Your submission of August 27, 2004 constituted a complete response to the Division’s October 10,
2003 action letter.
These supplemental new drug applications provide for the following revisions to the package insert
(additions are double underlined and deletions are in strikethrough):
1. Caplets was added after the drug name.
2. The following sentence was added under the drug name:
To reduce the development of drug-resistant bacteria and maintain the effectiveness of NegGram
(nalidixic acid, USP) and other antibacterial drugs, NegGram should be used only to treat or prevent
infections that are proven or strongly suspected to be caused by bacteria.
3. The following was added as the second paragraph of the INDICATIONS AND USAGE section:
To reduce the development of drug-resistant bacteria and maintain effectiveness of NegGram and
other antibacterial drugs, NegGram 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 when selecting or modifying antibacterial
therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute
to the empiric selection of therapy.
NDA 14-214/S-053, S-055, S-056
Page 2
4. The CONTRAINDICATIONS section was revised as follows:
NegGram is contraindicated in patients with known hypersensitivity to nalidixic acid or to related
compounds, infants less than three months of age, and in patients with porphyria or a history of
convulsive disorders. NegGram is contraindicated in patients undergoing concomitant therapy with
melphalan or other related cancer chemotherapeutic alkylating agents because of serious
gastrointestinal toxicity such as hemorrhagic ulcerative colitis or intestinal necrosis.
5. The following two paragraphs were added at the end 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 nalidixic acid. Nalidixic acid 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, Achilles tendon or other tendons that required
surgical repair or resulted in prolonged disability have been reported in patients receiving
quinolones, including nalidixic acid. Post-marketing surveillance reports indicate that this risk may
be increased in patients receiving concomitant corticosteroids, especially in the elderly. Nalidixic
acid 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
nalidixic acid.
6. The following information was added at the end of the PRECAUTIONS section, General
subsection:
Cross-resistance between nalidixic acid and other quinolone derivatives such as oxolinic
acid and cinoxacin has been observed.
Caution should be observed in patients with glucose-6-phosphate dehydrogenase deficiency.
(See ADVERSE REACTIONS).
Prescribing NegGram 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.
7. The following information was added at the end of the PRECAUTIONS section, Information for
Patients subsection:
Patients should be advised NegGram may be taken with or without meals. Patients should be
advised to drink fluids liberally and not take antacids.
Patients should be advised that quinolones may be associated with hypersensitivity reactions,
even following a single dose, and to discontinue the drug at the first sign of a skin rash or other
allergic reactions.
NDA 14-214/S-053, S-055, S-056
Page 3
Quinolones may cause dizziness and light-headedness, therefore, patients should know how
they react to NegGram before they operate an automobile or machinery or engage in activities
requiring mental alertness or coordination.
Patients should be advised that quinolones may increase the effects of theophylline and
caffeine. There is a possibility of caffeine accumulation when products containing caffeine are
consumed while taking quinolones. Patients should be advised to avoid excessive sunlight or
artificial ultraviolet light while receiving nalidixic acid and to discontinue therapy if phototoxicity
occurs.
Patients should be advised that convulsions have been reported in patients taking quinolones,
including nalidixic acid, and to notify their physician before taking this drug if there is a history of
this condition. Patients should be advised that mineral supplements, vitamins with iron or minerals,
calcium-, aluminum-, magnesium-based antacids, sucralfate or Videx® , (didanosine),
chewable/buffered tablets of the pediatric powder for oral solution should not be taken within the
two-hour period before or within the two-hour period after taking nalidixic acid (see Drug
Interactions).
Patients should be advised:
−that nalidixic acid may cause changes in the electrocardiogram (QTc interval
prolongation)
−that nalidixic acid should be avoided in patients receiving class IA (e.g. quinidine,
Procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic agents
−that nalidixic acid 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 nalidixic acid use. If
symptoms of peripheral neuropathy including pain, burning, tingling, numbness,
and/or weakness develop, they should discontinue treatment and contact their
physicians.
Patients should be counseled that antibacterial drugs including NegGram should only be
used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).
When NegGram 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 NegGram or other antibacterial drugs in the
future.
8. The PRECAUTIONS section, Drug Interactions subsection was revised as follows:
Elevated plasma levels of theophylline have been reported with concomitant quinolone use.
There have been reports of theophylline-related side effects in patients on concomitant therapy with
quinolones and theophylline. Therefore, monitoring of theophylline plasma levels should be
considered and dosage of theophylline adjusted, as required.
NDA 14-214/S-053, S-055, S-056
Page 4
Quinolones have been shown to interfere with the metabolism of caffeine. This may lead to
reduced clearance of caffeine and the prolongation of its plasma half-life.
Quinolones, including nalidixic acid, may enhance the effects of the oral anticoagulant
warfarin or its derivatives. When these products are administered concomitantly, prothrombin time
or other suitable coagulation test should be closely monitored.
Nitrofurantoin interferes with the therapeutic Since active proliferation of organisms is a
necessary condition for its antibacterial activity, the action of nalidixic acid may be inhibited by the
presence of other antibacterial substances, especially bacteriostatic agents such as tetracycline,
chloramphenicol, or nitrofurantoin, which is antagonistic to nalidixic acid in vitro.
Probenecid inhibits the tubular secretion of nalidixic acid and may reduce its efficacy in the
treatment of urinary tract infections while increasing the risk of systemic side effects.
Serious gastrointestinal toxicity has been associated with the concomitant use of nalidixic
acid and the anti-cancer drug melphalan. (see CONTRAINDICATIONS)
Antacids containing magnesium, aluminum, or calcium; sucralfate or divalent or trivalent
cations such as iron; multivitamins containing zinc; and Videx®, (Didanosine), chewable/buffered
tablets or the pediatric powder for oral solution may substantially interfere with the absorption of
quinolones, resulting in systemic levels considerably lower than desired. These agents should not be
taken within the two-hour period before or within the two-hour period after nalidixic acid
administration.
Elevated serum levels of cyclosporine have been reported with the concomitant use of some
quinolones and cyclosporine. Therefore, cyclosporine serum levels should be monitored and
appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly.
9. The PRECAUTIONS section, Nursing Mothers subsection was revised as follows:
It is not known whether NegGram is excreted in human milk. Because other drugs are
excreted in human milk and because Since nalidixic acid is excreted in breast milk, it is
contraindicated during lactation.1 Because of the potential for serious adverse reactions in nursing
infants from NegGram, a decision should be made whether to discontinue nursing or to discontinue
the drug taking into account the importance of the drug to the mother.
10. The PRECAUTIONS section, Usage in Patients Under 18 Years of Age subsection had the
following sentence added:
Toxicological studies have shown that nalidixic acid and related drugs can produce erosions of the
cartilage in weight-bearing joints and other signs of arthropathy in immature animals of most
species tested. No such joint lesions have been reported in humans to date. Nevertheless, until the
significance of this finding is clarified, this drug should only be used in patients under 18 years of
age when the potential benefit justifies the potential risk. If arthralgia occurs, treatment with
nalidixic acid should be stopped. (See WARNINGS and ANIMAL PHARMACOLOGY.)
NDA 14-214/S-053, S-055, S-056
Page 5
11. Anaphylactic shock was added to the ADVERSE REACTIONS section, Allergic subsection and
Peripheral neuropathy was added to the ADVERSE REACTIONS section, Other subsection:
Allergic: rash, pruritus, urticaria, angioedema, eosinophilia, arthralgia with joint stiffness
and swelling, and anaphylactoid reaction, including anaphylactic shock. Erythema Multiforme and
Stevens-Johnson syndrome have been reported with nalidixic acid and other drugs in this class.
Rash was the most frequently reported adverse reaction. Photosensitivity reactions consisting of
erythema and bullae on exposed skin surfaces usually resolve completely in 2 weeks to 2 months
after NegGram is discontinued; however, bullae may continue to appear with successive exposures
to sunlight or with mild skin trauma for up to 3 months after discontinuation of drug. (See
PRECAUTIONS.)
Other: rarely, cholestasis, paresthesia, metabolic acidosis, thrombocytopenia, leukopenia,
or hemolytic anemia, sometimes associated with glucose 6-phosphate dehydrogenase deficiency and
peripheral neuropathy.
12. The OVERDOSAGE section, Treatment subsection had the following deletion:
Treatment: Reactions are short-lived (two to three hours) because the drug is rapidly
excreted. If overdosage is noted early, gastric lavage is indicated. If absorption has occurred,
increased fluid administration is advisable and supportive measures such as oxygen and means of
artificial respiration should be available. Although anticonvulsant therapy has not been used in the
few instances of overdosage reported, it may be indicated in a severe case.
13. The HOW SUPPLIED section was revised as follows:
Caplets of 1 g, light buff-colored capsule-shaped tablets,
bottles of 100 (NDC 0024-1323-04) NegGram (nalidixic acid, USP) is supplied as:
Caplets of 500 mg, light buff-colored capsule-shaped tablets,
bottles of 56 (NDC 0024-1322-03)
500 (NDC 0024-1322-06)
Caplets of 250 mg, light buff-colored capsule-shaped tablets,
bottles of 56 (NDC 0024-1321-03)
Store at room temperature, up to 30° C (86° F).
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.
NDA 14-214/S-053, S-055, S-056
Page 6
The final printed labeling (FPL) must be identical to the submitted draft labeling (package insert
submitted August 27, 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 14-214/S-053, S-055, S-056." Approval of this submission 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 Christine Lincoln, RN, 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