Source: FDA, National Drug Code (US) Revision Year: 2007
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.
Central Nervous System (CNS) effects including 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. Quinolones may also cause CNS stimulation which may lead to tremor, restlessness, lightheadedness, 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 factors which predispose seizures. (See ADVERSE REACTIONS.) 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. 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 members 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 reported 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 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 electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
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.
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.
Reactions reported after oral administration of NegGram include the following.
CNS effects: drowsiness, weakness, headache, dizziness and vertigo. Reversible subjective visual disturbances without objective findings have occurred infrequently (generally with each dose during the first few days of treatment). These reactions include overbrightness of lights, change in color perception, difficulty in focusing, decrease in visual acuity, and double vision. They usually disappeared promptly when dosage was reduced or therapy was discontinued. 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. 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, arthralgia with joint stiffness and swelling, and anaphylactoid reaction, including anaphylactic shock. Erythema Multiforme and StevensJohnson 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.
Blood counts and renal and liver function tests should be performed periodically if treatment is continued for more than two weeks. NegGram should be used with caution in patients with liver disease, epilepsy, or severe cerebral arteriosclerosis. (See WARNINGS.) While caution should be used in patients with severe renal failure, therapeutic concentrations of NegGram 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 mL/minute to 8 mL/minute.
Moderate to severe phototoxicity reactions have been observed in patients who are exposed to direct sunlight while receiving NegGram or other members of this drug class. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.
If bacterial resistance to NegGram emerges during treatment, it usually does so within 48 hours, permitting rapid change to another antimicrobial. Therefore, if the clinical response is unsatisfactory or if relapse occurs, cultures and sensitivity tests should be repeated. 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.
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.
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.
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:
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.
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.
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.
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.
Pregnancy Category C.
NegGram has been shown to be teratogenic and embryocidal in rats when given in oral doses six times the human dose. NegGram also prolonged the duration of pregnancy especially at four times the clinical dose. There are no adequate and well-controlled studies in pregnant women. Since nalidixic acid, like other drugs in this class, causes arthropathy in immature animals, NegGram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See WARNINGS and ANIMAL PHARMACOLOGY.)
Since nalidixic acid is excreted in breast milk, it is contraindicated during lactation.
Safety and effectiveness in infants below the age of three months have not been established.
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.)
Clinical studies of NegGram did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution should therefore be observed in using nalidixic 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 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 PRECAUTIONS, General.)
When Benedict’s or Fehling’s solution or Clinitest Reagent Tablets are used to test the urine of patients taking NegGram, 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 NegGram, because of an interaction between the drug and the m-dinitrobenzene used in the usual assay method. In such cases, the Porter-Silber test for 17-hydroxycorticoids may be used.
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