NegGram (Nalidixic Acid)

NegGram®

Sanofi

Nalidixic Acid

Urinary Antibacterial

Action And Clinical Pharmacology: Nalidixic acid has bactericidal activity against gram-negative rods such as Escherichia, Klebsiella, Aerobacter and Proteus. It is relatively inactive against gram-positive bacteria. The mode of action is believed to be interference with the replication of genetic information by the blocking of the synthesis of bacterial DNA.

Bacterial cross-resistance between nalidixic acid and other quinolone antimicrobials has been observed only with oxolinic acid. Even in patients treated for prolonged periods, no fungal overgrowth has been reported during therapy with nalidixic acid.

Following oral administration, nalidixic acid 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 hydroxynalidixic acid, and the dicarboxylic acid derivative.

The hydroxy metabolite represents 30% of the biologically active drug in the blood and 85% in the urine. Peak serum levels of active drug average approximately 20 to 40 g/mL (90% protein bound), 1 to 2 hours after administration of a 1 g dose to a fasting normal individual, with a half-life of about 90 minutes. Peak urine levels of active drug average approximately 150 to 200 g/mL, 3 to 4 hours after administration with a half-life of about 6 hours.

Approximately 4% of nalidixic acid is excreted in the feces.

Indications And Clinical Uses: Acute or chronic urinary tract infections due to one or more species of nalidixic acid-sensitive gram-negative pathogenic organisms, in particular Proteus species, E. coli, Aerobacter and Klebsiella (disc sensitivity testing with the 30 g disc is recommended). It is useful in mixed urinary tract infection when the nalidixic acid-sensitive gram-negative rods predominate.

When urinary tract pathogens which are resistant to other types of antibacterial drugs are found to be sensitive to nalidixic acid, the use of nalidixic acid should be considered.

Contra-Indications: Known hypersensitivity to nalidixic acid and in patients with a history of convulsive disorders. Until further experience is gained, the drug should not be administered to infants under 3 months of age.

Manufacturers’ Warnings In Clinical States: CNS effects, including brief convulsions, increased intracranial pressure, and toxic psychosis, have been reported with nalidixic acid therapy. Convulsive seizures have been reported with other drugs in this class. Therefore, nalidixic acid should be used with caution in patients with known or suspected CNS disorders such as cerebral arteriosclerosis or other factors which predispose to seizures (see Adverse Effects). Quinolones may also cause CNS stimulation which may lead to tremor, restlessness, lightheadedness, confusion and hallucinations. If these reactions occur in patients receiving nalidixic acid, the drug should be discontinued and appropriate measures instituted.

Serious and occasionally fatal hypersensitivity (anaphylactoid) 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. Serious anaphylactoid reactions required immediate emergency treatment with epinephrine. Oxygen, i.v. steroids, and airway management, including intubation, should be administered as indicated.

Precautions: Although prolonged treatment with nalidixic acid has been generally well tolerated, it is advisable to carry out blood counts and renal and liver function tests periodically if treatment is continued for more than 2 weeks.

Nalidixic acid should only be used with caution in patients with liver disease. While caution should be used in patients with severe renal failure, therapeutic concentrations of nalidixic acid in the urine, without increased toxicity due to drug accumulation in the blood, have been observed in patients on full dosage, with creatinine clearances as low as 2 to 8 mL/min.

Microorganisms may develop resistance to nalidixic acid. It is also possible that resistant bacteria, not previously present or identified, may emerge. Conventional chromosomal resistance to nalidixic acid taken in full dosage has been reported to emerge in approximately 2 to 14% of patients during treatment; however, bacterial resistance to nalidixic acid has not been shown to be transferable via R factor. If bacterial resistance to nalidixic acid emerges during treatment, it usually does so within 48 hours, necessitating change to another antimicrobial. Therefore, if the clinical response is unsatisfactory or if relapse occurs, cultures and sensitivity tests should be repeated. Underdosage with nalidixic acid during initial treatment (with less than 4 g/day for adults) or during maintenance treatment (with less than 2 g/day for adults), may predispose a patient to emergence of bacterial resistance. It should be recognized that apparent relapse or bacterial resistance may frequently be due to obstruction of the urinary tract.

Drug Interactions: Active proliferation of the organism is a necessary condition for the antibacterial action of nalidixic acid and it is possible that the presence of bacteriostatic substances may inhibit its action. Such an effect has been demonstrated in vitro with nitrofurantoin, tetracycline and chloramphenicol.

Quinolones, including nalidixic acid may enhance the effect of oral anticoagulants, warfarin or bishydroxycoumarin, by displacing significant amounts from serum albumin binding sites. When concomitant administration of these products cannot be avoided, daily measurements of prothrombin time or other suitable coagulation tests are essential.

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 and plasma levels should be considered and dosage of theophylline adjusted, as required.

Interference with Laboratory Tests: When Benedict’s or Fehling’s solutions or Clinitest Reagent tablets are used to test the urine of patients taking nalidixic acid, a false-positive reaction for glucose may be obtained, due to the liberation of glucuronic acid from the metabolites excreted. However, a colorimetric test for glucose based on an enzyme reaction (e.g. with Clinistix Reagent Strips or Tes-Tape) does not give a false-positive reaction to the liberated glucuronic acid.

Incorrect values may be obtained for urinary 17-keto and ketogenic steroids in patients receiving nalidixic acid, because of an interaction between the drug and the m-dinitrobenzene used in the assay method. In such cases, the Porter-Silber test for 17-hydroxy-corticoids may be used.

Children: Recent toxicological studies have shown that high doses of nalidixic acid or other chemically related antibacterial agents 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 man to date. Nevertheless, until the significance of this finding is clarified, it should be carefully considered before prescribing this product for prepubertal children.

Pregnancy: There are no adequate and well controlled studies in pregnant women. Nalidixic acid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Caution should be used in administering nalidixic acid in the days prior to delivery because of the theoretical risk that exposure to maternal nalidixic acid in utero may lead to significant blood levels of nalidixic acid in the neonate immediately after birth. Patients using nalidixic acid during pregnancy should be advised to discontinue use at the first sign of labor.

Lactation: When treating women who are breast feeding, consideration should be given to the fact that traces of nalidixic acid are excreted in the milk. Because other drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from nalidixic acid, 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.

Information for the Patient: Patients should be advised that nalidixic acid may be taken with or without meals. Patients should be advised to drink fluids liberally and not take antacids within 2 hours of taking nalidixic acid, as antacids may interfere with its absorption. 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.

Since reversible photosensitivity reactions have been reported in a small number of cases, patients should be cautioned to avoid direct sunlight while on nalidixic acid therapy. Therapy should be discontinued if photosensitivity occurs.

Quinolones may cause dizziness and lightheadedness; therefore, patients should know how they react to nalidixic acid before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.

Patients should be advised to avoid excessive caffeine intake, as quinolones may increase the effects of caffeine containing compounds.

Adverse Reactions: Nalidixic acid is usually well tolerated. It is seldom necessary to discontinue treatment or to reduce the dosage. Gastrointestinal: abdominal pain, nausea, vomiting and diarrhea.

Hypensensitivity: rash, pruritus, urticaria, angioedema, arthralgia with joint stiffness and swelling and, rarely, anaphylactoid reactions. Photosensitivity reactions consisting of erythema and bullae on exposed skin surfaces, usually resolve completely in 2 weeks to 2 months after nalidixic acid 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).

CNS: drowsiness, weakness, headache, dizziness, vertigo and, rarely, paresthesia.

Toxic psychosis or brief convulsions have been reported rarely, usually following excessive doses. In general, the convulsions have occurred in patients with predisposing factors such as epilepsy or cerebral arteriosclerosis (see Dosage).

In infants and children receiving therapeutic doses of nalidixic acid, 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.

Hemotological: Eosinophilia, thrombocytopenia, leukopenia and hemolytic anemia (rare; observed in patients with and those without a deficiency in glucose-6-phosphate dehydrogenase activity). A single case of fatal acute immune hemolytic anemia has been reported, without a deficiency in glucose-6-phosphate dehydrogenase activity.

Ocular: Overbrightness of lights, change in color perception, difficulty in focusing, decrease in visual acuity and double vision. These visual disturbances were subjective and without objective findings, occurred infrequently (generally with each dose during the first few days of treatment), and were reversible (usually disappearing promptly when dosage was reduced or therapy was discontinued).

Other: rarely, cholestasis and metabolic acidosis. Erythema multiforme and Stevens-Johnson syndrome have been reported with nalidixic acid and other drugs in this class. A single case of non fatal pulmonary hypersensitivity to nalidixic acid has been reported in the literature.

Symptoms And Treatment Of Overdose: Symptoms: 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 generally short-lived (2 to 3 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.

Dosage And Administration: Adults: Initial therapy: 1 g administered 4 times daily for 1 or 2 weeks (total daily dose 4 g). For prolonged therapy, 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. Adjustment of urinary pH is not necessary.

Children: Dosage in children 12 years of age and under should be calculated on the basis of body weight. The recommended total daily dosage for initial therapy is 55 mg/kg/day, administered in 4 equally divided doses. For prolonged therapy, the total daily dose may be reduced to 33 mg/kg/day.

Note: In light of potential neurologic reactions, the recommended dose should not be increased except under the careful supervision of a physician. Until further experience is gained, the drug should not be administered to infants under 3 months of age.

Availability And Storage: Each scored, yellow caplet with “N” on one side of the score and “22” on the other, with the flying W on the reverse, contains: nalidixic acid 500 mg. Nonmedicinal ingredients: cellulose (microcrystalline), methylcellulose, sodium lauryl sulfate, vegetable oil (hydrogenated) and yellow iron oxide. Gluten-, lactose-, starch-, sucrose-, sulfite- and tartrazine-free. Bottles of 56 and 500. (Shown in Product Recognition Section)

NegGram® Sanofi Nalidixic Acid Urinary Antibacterial

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