To reduce the development of drug-resistant bacteria and maintain the effectiveness of NegGram. (nalidixic acid, USP) and other antibacterial drugs, NegGram

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NDA 14-214/S-058 Page 3 NegGram® Caplets (nalidixic acid, USP) To reduce the development of drug-resistant bacter ia and maintain the effectiveness of NegGram (nalidixic acid, USP) and other an tibacterial drugs, NegGram should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION NegGram, brand of nalidixic acid, is a quinolone antib acterial agent for oral administration. Nalidixic acid is 1-ethyl-1, 4-dihydro-7-methyl-4-oxo-1, 8-napht hyridine-3-carboxylic acid. It is a pale yellow, crystalline substance and a very weak organic acid. Nalidixic acid has the following structural formula: Inactive Ingredients – Hydrogenated Vegetable Oil, Methylcellulose, Microcrystalline Cellulose, Sodium Lauryl Sulfate, Yellow Ferric Oxide. CLINICAL PHARMACOLOGY Following oral administration, NegGram is rapidly absorbed from the gastrointestinal tract, partially metabolized in the liver, and rapidly excreted through the kidneys. Unchanged nalidixic acid appears in the urine along with an active metabolite, hydroxynalidixic acid, which has antibacterial activity similar to that of nalidixic acid. Other metabolites include glucuronic acid conjugates of nalidixic acid and hydroxy nalidixic acid, and the dicarboxylic acid derivative. The hydroxy metabolite represents 30 percent of the biologically active drug in the bl ood and 85 percent in the urine. Peak serum levels of active drug average approximately 20 mcg to 40 mcg per mL (90 percent protein bound), one to two hours after administration of a 1 g dose to a fastin g normal individual, with a half-life of about 90 minutes. Peak urine levels of active drug averag e approximately 150 mcg to 200 mcg per mL, three to four hours after administration, with a half-life of about six hours. Approximately four percent of NegGram is excreted in the feces. Traces of nalid ixic acid were found in blood and urine of an infant whose mother had received the drug during the last trimester of pregnancy. (See PRECAUTI Drug Interactions.) Microbiology NegGram has marked antibacterial activity against gram-negative bacteria including Enterobacter species, Escherichia coli , Morganella Morganii; Proteus Mirabilis , Proteus vulgaris , and Providencia 3

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NDA 14-214/S-058 Page 4 rettgeri . Pseudomonas species are generally resistant to the drug. NegGram is bactericidal and is effective over the entire urinary pH range. Conven tional chromosomal resistance to NegGram taken in full dosage has been reported to emerge in approx imately 2 to 14 percent of patients during treatment; however, bacterial resistance to NegGram has not been shown to be transferable via R factor. Susceptibility Test Diffusion Techniques: Quantitative methods that require measur ement of zone diameters give the most precise estimates of antibacterial susceptibilit y. One such procedure recommended for use with a disc containing 30 mcg of nalidixic acid is the National Committee for Clinical Laboratory Standards (NCCLS) approved procedure. Only organisms from urinary tract infections should be tested. Results of laboratory tests using 30 mcg nalid ixic acid discs should be interpreted using the following criteria: Zone Diameter (mm) Interpretation 19 (S) Susceptible 14-18 (I) Intermediate 13 (R) Resistant Dilution Techniques: Broth and agar dilution methods, such as those recommended by the NCCLS, may be used to determine the minimum inhibitory concentration (MIC) of nalidixic acid. MIC test results should be interpreted according to the following criteria: MIC (mcg/mL) Interpretation 16 (S) Susceptible 32 (R) Resistant For any susceptibility test, a report of “susceptible” i ndicates that the pathogen is likely to respond to nalidixic acid therapy. A report of “resistant” indicat es that the pathogen is not likely to respond. A report of “intermediate” generally indicat es that the test result is equivocal. The Quality Control strains should have the followi ng assigned daily ranges for nalidixic acid: QC Strains E. Coli (ATCC 25922) Disc Zone Diameter 22-28 MIC (mcg/mL) 1.0-4.0 4

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NDA 14-214/S-058 Page 5 INDICATIONS AND USAGE NegGram (nalidixic acid, USP) is indicated for the treatment of urinary tract infections caused by susceptible gram-negative microorganisms, including the majority of E. Coli , Enterobacter species, Klebsiella species, and Proteus species. Disc susceptibility testing with the 30 mcg disc should be performed prior to administration of the drug, a nd during treatment if clinical response warrants. To reduce the development of drug-resistant bacteria and maintain effectiven ess 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 sele cting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS NegGram is contraindicated in pa tients 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 conc omitant therapy with melphalan or other related can cer chemotherapeutic alkylating agents because of serious gastrointestinal toxicity such as hemorrhagic ulcerative colitis or intestinal necrosis. WARNINGS Central Nervous System (CNS) ef fects including convulsions, increas ed intracranial pressure, and toxic psychosis have been reporte d with nalidixic acid therapy. Convulsive seizures have been reported with other drugs in this class. Quinolone s may also cause CNS stimulation which may lead to tremor, restlessness, lightheadedne ss, confusion, and hallucinations. Therefore, nalidixic acid should be used with caution in patients with known or suspected CNS disorders, such as, cerebral arteriosclerosis or epilepsy, or other fa ctors which predispose seizures. (See ADVERSE REACTIONS.) If these reactions occur in patie nts receiving nalidixic acid, the drug should be discontinued and appropriate measures instituted. Serious and occasionally fatal hype rsensitivity (anaphylactoid) reactions, some following the first dose, have been reported in patients receiving quino lone 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. Serious anaphylactoid reactions required immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated. Nalidixic acid and other me mbers of the quinolone drug class have been shown to cause arthropathy in juvenile animals. (See PRECAUTIONS and ANIMAL PHARMACOLOGY.) Clostridium difficile associated diarrhea (CDAD) has been repor ted with use of nearly all antibacterial agents, including NegGram, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all 5

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NDA 14-214/S-058 Page 6 patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrol yte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. Peripheral neuropathy: Rare cases of sensory or sensor imotor axonal polyneuropathy affe cting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including nalidixic acid. Na lidixic acid should be disc ontinued 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 se nse, 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 disab ility have been reported in patients recei ving quinolones, including nalidixic acid. Post-marketing surveillance re ports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especi ally in the elderly. Nalidixic acid should be discontinued if the patient experiences pain, inflammati on, or rupture of a tendon. Patie nts 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. PRECAUTIONS General Blood counts and renal and liver f unction tests should be performed periodically if treatment is continued for more than two weeks. NegGram s hould be used with caution in patients with liver disease, epilepsy, or severe cere bral arteriosclerosis. (See WARNINGS .) Caution should be used in patients with renal insufficiency. (See DOSAGE AND ADMINISTRATION.) Moderate to severe phototoxicity reactions have been observed in pa tients who are exposed to direct sunlight while receiving NegGram or other members of this drug class. Excessive sunlight should be avoided. Therapy should be disc ontinued if phototoxicity occurs. If bacterial resistance to NegGram emerges during treatment, it usually does so within 48 hours, permitting rapid change to another an timicrobial. Therefore, if the c linical response is unsatisfactory or if relapse occurs, cultures a nd sensitivity tests should be repeat ed. Underdosage with NegGram during initial treatment (with less than 4 g per day for adults) may predispose to emergence of bacterial resistance. (See DOSAGE AND ADMINISTRATION.) Cross-resistance between nalidixic acid and other quinolone derivatives such as oxolinic acid and cinoxacin has been observed. 6

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NDA 14-214/S-058 Page 7 Caution should be observed in patients with glucose-6-phosphate de hydrogenase 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 benef it to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be advised NegGram may be taken with or without m eals. Patients should be advised to drink fluids liberally and not take antacids. Patients should be advised that quinolones may be a ssociated 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. 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 sunlig ht or artificial ultraviolet light while receiving nalidixic acid and to disc ontinue therapy if phototoxicity occurs. Patients should be advised that convulsions have been reported in patients taking quinolones, including nalidixic acid, and to notify their phys ician before taking this drug if th ere is a history of this condition. Patients should be advised that mineral supplements, vitamins w ith 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 afte r 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 avoi ded 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 fa mily history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia -that peripheral neuropath ies have been associated with nalidixic acid use. If symptoms of peripheral neuropathy including pa in, burning, tingling, numbness, a nd/or weakness develop, they should discontinue treatment and contact their physicians. 7

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NDA 14-214/S-058 Page 8 -that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. 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 s hould 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 w ill not be treatable by NegGram or other antibacterial drugs in the future. Drug Interactions 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, monitori ng of theophylline plasma levels should be considered and dosage of theophylline adjusted, as required. Quinolones have been shown to inte rfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and the prol ongation of its plasma half-life. Quinolones, including nalidixic acid, may enhance the effects of the oral anticoagulant warfarin or its derivatives. When these products ar e administered concomitantly, prothrombin time or other suitable coagulation test should be closely monitored. 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 nalidix ic 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, alum inum, or calcium; sucralfate or di valent 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 consid erably 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. 8

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NDA 14-214/S-058 Page 10 Usage in Patients Under 18 Years of Age 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.) Geriatric Use Clinical studies of NegGram did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from youn ger subjects. Other repor ted clinical experience has not identified differences in responses between the elderly and younger pa tients. Caution shouldtherefore be observed in using nalidix ic acid in elderly patients. 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 el derly patients are more likely to ha ve decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See PRECAUTIONS, General.) ADVERSE REACTIONS Reactions reported after oral administra tion of NegGram include the following. CNS effects: drowsiness, weakness, headache, dizziness and vertig o. Reversible subjective visual disturbances without objective findings have occurred infrequently (generally with each dose during the first few days of treatment). These reactions include overb rightness of lights, change in color perception, difficulty in focusing, decrease in visual acuity, a nd double vision. They usually disappeared promptly when dosage was reduced or therapy was discontinue d. Toxic psychosis or brief convulsions have been reported rarely, usually following excessive dos es. In general, the convulsions have occurred in patients with predisposing factors such as epilepsy or cerebral arteriosclerosis. In infants and children receiving therapeutic doses of NegGram, increased intracranial pressure with bulging anterior fontanel, papilledema, and headache has occasionally been observed. A few cases of 6th cranial nerve palsy have been reported. Although the mechanisms of these reactions are unknown, the signs and symptoms usually disappeared rapidly with no sequelae when treatment was discontinued. Gastrointestinal: abdominal pain, nausea, vomiting, and diarrhea. Allergic: rash, pruritus, urticaria, angioedema, eosinophilia, arth ralgia with joint sti ffness and swelling, and anaphylactoid reaction, including anaphylactic shock. Erythe ma 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 cons isting of erythema and bullae on exposed skin surfaces usually resolve completely in 2 weeks to 2 months after NegGram is 10

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NDA 14-214/S-058 Page 11 discontinued; however, bullae may continue to appear with successive exposures to sunlight or with mild skin trauma for up to 3 months afte r discontinuation of drug. (See PRECAUTIONS.) Other: rarely, cholestasis, paresthesia, metabolic acidosis, thrombocytope nia, leukopenia, or hemolytic anemia, sometimes associated with glucose 6-phosphate dehydrogenase deficiency and peripheral neuropathy. OVERDOSAGE Manifestations: Toxic psychosis, convulsions, increased intracranial pressure, or metabolic acidosis may occur in patients taking more than the recommended dosage. Vomiting, nausea, and lethargy may also occur following overdosage. Treatment: Reactions are short-lived (two to three hours) becaus e the drug is rapidly excreted. If absorption has occurred, increased fluid administ ration is advisable and supportive measures such as oxygen and means of artificial respiration shoul d be available. Although anticonvul sant therapy has not been used in the few instances of overdosage reported, it may be indicated in a severe case. DOSAGE AND ADMINISTRATION Antacids containing calcium, magnesium, or aluminum; sucralfate; divalent or trivalent cations such as iron; multivitamins containing zinc; or Videx® (Didanosine), chewable/buffered tablets of the pediatric powder for oral solution should not be take n within the two-hour period before or within the two-hour period after ta king nalidixic acid. Adults. The recommended dosage for initial therapy in adults is 1 g administered four times daily for one or two weeks (total daily dose, 4 g). For prolonged th erapy, the total daily dose may be reduced to 2 g after the initial treatment period. Underdosage during initial treatment may predispose to emergence of bacterial resistance. Renal Insufficiency. The normal dosage of nalidixic acid may be employed in patients with plasma creatinine of less than 300 µmol/L (creatinine clearance more than 20 mL/mi nute). Dosage should be ha lved in patients with plasma creatinine of more than 300 µmol/L (creatinine clearance 20 mL/minute or less). Pediatric Patients. Until further experience is gained, NegGram should not be administered to infants younger than three months. Dosage in pediatric patients 12 years of age and under should be calculated on the basis of 11

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NDA 14-214/S-058 Page 12 body weight. The recommended total daily dosage for initial therapy is 25 mg/lb/day (55 mg/kg/day), administered in four equally divided doses. For pr olonged therapy, the total daily dose may be reduced to 15 mg/lb/day (33 mg/kg/day). NegGram Caplets of 250 mg may be used. HOW SUPPLIED NegGram (nalidixic acid, USP) is supplied as: Caplets of 500 mg, light buff-colored capsule- shaped tablets, bottle s of 56 (NDC 0024-1322-03) Store at room temperature, up to 30° C (86° F). ANIMAL PHARMACOLOGY NegGram (nalidixic acid) and relate d drugs have been shown to cause arthropathy in juvenile animals of most species tested. (See WARNINGS.) Long-term administration of nalidixic acid to rats resulted in retinal de generation and cataracts. Hydroxynalidixic acid, the principal metabolite of NegGram, did not produce any oculotoxic effects at any dosage level in seven species of animals including three primate species. However, oral administration of this metabolite in high doses has been shown to have oculotoxic potential, namely in dogs and cats where it produced retinal degenerati on upon prolonged administration leading, in some cases, to blindness. In experiments with NegGram itself, little if any such activity could be elicited in either dogs or cats. Sensitivity to CNS side effects in these species limited the doses of NegGram that could be used; this factor, together with a low conversion rate to the hydroxy metabolite in these species, may explain the absence of these effects. Rx Only Manufactured for: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 Revised September 2008 © 2008 sanofi-aventis U.S. LLC 12

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