Pill Identifier App

Nalidixic Acid (Systemic)


VA CLASSIFICATION
Primary: AM401

Commonly used brand name(s): NegGram.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antibacterial (systemic)—
Note: Nalidixic acid is a synthetic narrow-spectrum quinolone antibacterial. It is bacteriostatic or bactericidal depending on the concentration. At urine concentrations normally found clinically, it is bactericidal against most gram-negative bacilli (except Pseudomonas species) that commonly cause urinary tract infections. {11}



Indications

Accepted

Urinary tract infections, bacterial (treatment)—Nalidixic acid is indicated in the treatment of urinary tract infections caused by susceptible strains of gram-negative organisms, including Proteus species, Klebsiella species, Enterobacter species, and Escherichia coli . {08} {27}
—Since nalidixic acid achieves only low concentrations in the serum and is concentrated in the urine, it is indicated only in the treatment of urinary tract infections. {11}

—Not all species or strains of a particular organism may be susceptible to nalidixic acid.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    232.24 {12}

Mechanism of action/Effect:

Nalidixic acid appears to act by inhibiting bacterial DNA synthesis, probably by interfering with DNA polymerization. Resistance may develop rapidly during treatment. {03} {15}

Absorption:

Rapidly and almost completely absorbed from the gastrointestinal tract; bioavailability is approximately 96%. {11} {19} Absorption may be delayed if taken with antacids.

Distribution:

Parent drug and active metabolite are distributed to most tissues, {15} especially to the kidneys and to urine; serum concentrations are low; traces of drug cross the placenta. {11} Distributed into breast milk, also. {17} Drug does not penetrate into prostatic fluid.

Protein binding:

Nalidixic acid—Very high (93%). {15}

Hydroxynalidixic acid—Moderate (63%) {15}

Biotransformation:

Hepatic; 30% metabolized to the active metabolite, hydroxynalidixic acid; {11} rapid conjugation of parent drug and active metabolite to inactive metabolites. Metabolism may vary widely among individuals. In the urine, hydroxynalidixic acid represents 80 to 85% of the antibacterial activity. {11}

Half-life:


Serum:


Adults—

Normal renal function—1.1 to 2.5 hours. {11}

Impaired renal function—Up to 21 hours. {16}



Elderly (n = 6, 70 to 89 years old)—

11.5 hours (6.9 to 25.6 hours). {25}




Urine:

6 hours. {11}


Time to peak serum concentration

1 to 2 hours (normal renal function). {11}

Time to peak urine concentration

3 to 4 hours. {11}

Peak serum concentration:

Approximately 20 to 40 micrograms per mL (mcg/mL) following a 1 gram dose administered in a fasting state {27}.

Elimination:
    Renal—2 to 3% excreted unchanged, 13% as active metabolite and more than 80% as inactive metabolites; {15} rapidly and almost completely excreted within 24 hours; active drug does not accumulate in patients with impaired renal function, but inactive metabolites accumulate and may be toxic.
    Fecal—Approximately 4%. {11}


Precautions to Consider

Cross-sensitivity and/or related problems

Since nalidixic acid is closely related chemically to other quinolone derivatives (e.g., cinoxacin and fluoroquinolones), patients hypersensitive to other quinolones may also be hypersensitive to this medication.

Carcinogenicity

In lifetime studies in rats given nalidixic acid in their diets, an increased incidence of preputial gland neoplasms in males and clitoral gland neoplasms in females was observed. Results concerning carcinogenic activity were ambiguous in studies in mice in which nalidixic acid was administered in their feed for either 2 years or for 76 weeks followed by no treatment for 9 weeks. {27}

Mutagenicity

Nalidixic acid was negative for mutagenicity in the Ames test (maximum dose 33 mcg per plate) and in a mouse lymphoma assay (L5178/TK; maximum dose 100 mcg/mL) with and without metabolic activation. {27}

Pregnancy/Reproduction

Pregnancy—
Nalidixic acid crosses the placenta. Adequate and well-controlled studies in humans have not been done. However, since nalidixic acid and other related compounds have been shown to cause arthropathy in immature animals, use is not recommended in pregnancy. {20} {21}

Nalidixic acid has been shown to be teratogenic and embryocidal in rats when given in oral doses six times the human dose. In addition, nalidixic acid, particularly at four times the clinical dose, prolonged the duration of pregnancy. {27}

FDA Pregnancy Category C. {27}

Breast-feeding

Nalidixic acid is distributed into breast milk. The milk:plasma ratio has been reported to be 0.08 to 0.13. One case of hemolytic anemia occurred in a nursing infant with glucose-6-phosphate dehydrogenase deficiency; however, nalidixic acid is considered to be compatible with breast-feeding. {22} {23}

Pediatrics

Nalidixic acid produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of most species tested. Although the potential for nalidixic acid to cause arthropathy in humans has not been determined, nalidixic acid should only be used in patients under 18 years of age when the potential benefit justifies the potential risk. {27} Use is not recommended in infants up to 3 months of age. {20} {21}



Adolescents

Nalidixic acid produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of most species tested. Although the potential for nalidixic acid to cause arthropathy in humans has not been determined, nalidixic acid should only be used in patients under 18 years of age when the potential benefit justifies the potential risk. {27}


Geriatrics


Studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of nalidixic acid in the elderly. However, elderly patients are more likely to have an age-related decrease in renal function, resulting in a prolonged half-life and decreased drug clearance. {25} {26}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Antacids, aluminum-, calcium-, and/or magnesium-containing or
» Iron or
» Multivitamin preparations, zinc-containing or
» Sucralfate    (these medications substantially interfere with the absorption of quinolones, resulting in much lower urine concentrations; concomitant administration should be avoided; the doses of these medications should be separated by 2 hours from the dosing of nalidixic acid {27})


» Anticoagulants, coumarin- or indanedione-derivative    (coumarin- or indanedione-derivative anticoagulants, especially warfarin and dicumarol, may be displaced from protein-binding sites by nalidixic acid, resulting in increased anticoagulant effect; dosage adjustments may be necessary during and after nalidixic acid therapy {11} {27})


» Caffeine    (nalidixic acid reduces the clearance and extends the half-life of caffeine {27})


» Cyclosporine    (concurrent use may cause elevation of cyclosporine plasma concentrations; cyclosporine plasma concentrations should be monitored and the dose adjusted as necessary {27})


Nitrofurantoin    (nitrofurantoin interferes with the therapeutic effects of nalidixic acid {08} {18} {27})


» Theophylline    (concurrent use may lead to increased plasma concentrations of theophylline; plasma theophylline concentrations should be monitored during treatment with nalidixic acid and the dosage adjusted as necessary {27})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Glucose determinations, urine    (may give false-positive test results with copper sulfate tests, such as Benedict's or Fehling's solutions, because of liberation of glucuronic acid, a reducing agent; glucose enzymatic tests, such as Clinistix Reagent Strips or Tes-Tape, are not affected {11} {27})


17-ketogenic steroid (17-KGS), urine and
17-ketosteroid (17-KS), urine    (false increase in concentration may occur because of interaction between nalidixic acid and m-dinitrobenzene; use Porter-Silber method for 17-hydroxycorticosteroid [17-OHCS] determinations {11} {27})


Metyrapone    (nalidixic acid may interfere with the assay for urine 17-ketosteroids or 17-ketogenic steroids {05})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Cerebral arteriosclerosis, severe or
» Seizure disorders, history of    (patients with severe cerebral arteriosclerosis or a history of seizure disorders may be at increased risk of toxicity {11} {21} {24} {27}, especially seizures {27})


Glucose-6-phosphate dehydrogenase (G6PD) deficiency    (hemolytic anemia may occur {11} {21} {27} {24})


» Hepatic function impairment    (patients with hepatic function impairment may be at increased risk of toxicity {11} {21} {24} {27})


» Hypersensitivity to nalidixic acid or other quinolone derivatives (cinoxacin, fluoroquinolones){11}{21}{24}
Renal function impairment, severe    (patients with severe renal function impairment [creatinine clearance of < 10 mL/min (0.17 mL/second)] may be at increased risk of toxicity {11} {21} {24} {27})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Complete blood counts (CBCs) and
Hepatic function determinations and
Renal function determinations    (may be required periodically during therapy if nalidixic acid is continued for more than 2 weeks {27}; patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe [creatinine clearance of < 10 mL/min] {11} {27})


Glucose-6-phosphate dehydrogenase (G6PD) concentration{24}    (determination recommended in patients at high risk prior to treatment; if a deficiency is found, nalidixic acid should be given with extreme caution since hemolytic effects may be exaggerated)




Side/Adverse Effects

Note: Serious and occasionally fatal hypersensitivity reactions, some following the first dose, have occurred in patients receiving quinolone therapy. Of these patients, only a few had a history of hypersensitivity. {27}
Photosensitivity reactions consisting of erythema and bullae usually resolve completely within 2 weeks to 2 months once 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 drug discontinuation. {27}
Sixth cranial nerve palsy has been reported rarely. {27}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Skin rash{27}

Incidence less frequent {08}
    
Central nervous system (CNS) stimulation{27} (confusion; lightheadedness; restlessness; tremor)
    
visual disturbances{27} (blurred or decreased vision; change in color vision; double vision; halos around lights; overbright appearance of lights)

Incidence rare {08} {20}
    
Blood dyscrasias, specifically thrombocytopenia, leukopenia, and hemolytic anemia{27} (chills; pale skin; sore throat and fever; unusual bleeding or bruising; unusual tiredness or weakness)
    
cholestatic jaundice (dark or amber urine; pale stools; stomach pain, severe; yellow eyes or skin)
    
CNS toxicity, specifically hallucinations, mood or other mental changes, increased intracranial pressure{27} (bulging of fontanel [soft spot] on top of head of an infant{27}; visual changes{27}; headache, severe{27})
    
hypersensitivity{27} (skin rash, itching, or hives; sudden trouble in swallowing or breathing; swelling of face, mouth, hands, or feet; hoarseness; joint pain, stiffness, or swelling; shortness of breath; changes in facial skin color)
    
metabolic acidosis{27} (increased frequency of breathing; nausea or vomiting; unusual tiredness)
    
paresthesia{27} (burning or tingling skin sensation)
    
pseudomembranous colitis{27} (abdominal or stomach cramps or pain, severe; diarrhea, watery and severe, which may also be bloody; fever)
    
seizures —usually with excessive doses
    
skin rash, severe, including erythema multiforme{27} (fever; general feeling of discomfort or illness; red skin lesions, often with a purple center), and Stevens-Johnson syndrome{27} (blistering, peeling, or loosening of skin and mucous membranes; fever; general feeling of discomfort or illness)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent {08}
    
CNS toxicity{27} (dizziness; feeling of constant movement of self or surroundings; drowsiness; headache; weakness)
    
gastrointestinal disturbance{27} (abdominal pain; diarrhea; nausea; vomiting)

Incidence less frequent {08}
    
Photosensitivity{27} (increased sensitivity of skin to sunlight)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Increased intracranial pressure{27} (bulging anterior fontanel; papilledema; headache)
    
lethargy{27} (unusual tiredness or weakness, extreme)
    
metabolic acidosis{27} (increased frequency of breathing; nausea and vomiting; unusual tiredness)
    
nausea or vomiting{27}
    
seizures{27}
    
toxic psychosis{27} (hallucinations; aggressive and violent behavior)


Note: Reactions from nalidixic acid overdose usually are short-lived, lasting approximately 2 to 3 hours, due to rapid excretion of the medication. {27}


Treatment of overdose
Recommended treatment consists of the following: {06} {27}

To decrease absorption—Performing gastric lavage if overdose is noted early.

Specific treatment—Administering anticonvulsants if needed for seizures.

Supportive care—Administering fluids and supportive measures such as oxygen and artificial respiration if absorption has occurred. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Nalidixic Acid (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to nalidixic acid or other quinolone derivatives (cinoxacin, fluoroquinolones)

Pregnancy—Nalidixic acid crosses the placenta and is not recommended during pregnancy





Breast-feeding—Nalidixic acid is distributed into breast milk





Use in children—Nalidixic acid is not recommended in infants up to 3 months of age since it has been found to cause arthropathy in young animals; caution is recommended in children up to 18 years of age since these medications have been shown to cause arthropathy in immature animals




Use in adolescents—
Caution is recommend in children up to 18 years of age since these medications have been shown to cause arthropathy in immature animals

Other medications, especially aluminum-, calcium-, and/or magnesium-containing antacids, caffeine-containing products, cyclosporine, iron, multivitamin preparations containing zinc, coumarin- and indanedione-derivative anticoagulants, sucralfate, and theophylline
Other medical problems, especially a history of severe cerebral arteriosclerosis, seizure disorders, or severe hepatic impairment

Proper use of this medication
» Not giving to infants up to 3 months of age; has caused arthropathy in immature animals

Taking with full glass (240 mL) of water; maintaining adequate fluid intake

Taking on an empty stomach, or with food or milk if gastrointestinal irritation occurs

Proper administration technique for oral liquids

» Compliance with full course of therapy

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress if therapy lasts longer than 2 weeks

Checking with physician if no improvement within 2 days

» Not taking medications that interfere with the absorption of nalidixic acid at the same time as nalidixic acid; separating the administration of these medications and nalidixic acid by 2 hours

» Caution if blurred vision or other vision problems, dizziness, or drowsiness occur

Caution in eating or drinking large amounts of caffeine-containing foods or beverages during therapy with this medication

» Possible skin photosensitivity; avoiding unprotected exposure to sun; using protective clothing; using a sun block product that includes protection against both UVA-caused photosensitivity reactions and UVB-caused sunburn reactions; avoiding use of sunlamp, tanning bed, or tanning booth

» Patients with diabetes: False-positive reactions with copper sulfate urine glucose tests may occur


Side/adverse effects
Signs of potential side effects, especially skin rash; CNS stimulation; visual disturbances; blood dyscrasias; cholestatic jaundice; CNS toxicity; hypersensitivity; metabolic acidosis; paresthesia; pseudomembranous colitis; seizures; severe skin rash, including erythema multiforme and Stevens-Johnson syndrome


General Dosing Information
Nalidixic acid should preferably be taken with a full glass (240 mL) of water on an empty stomach (either 1 hour before or 2 hours after meals) to obtain optimum urine concentrations. However, if gastrointestinal irritation occurs, this medication may be taken with food or milk.

For treatment of adverse effects
Recommended treatment consists of the following:

• For serious anaphylactoid reactions requiring immediate emergency treatment {27}—    • Parenteral epinephrine
   • Oxygen
   • Intravenous corticosteroids
   • Airway management (including intubation)



• For antibiotic-associated pseudomembranous colitis (AAPMC) {27}—    • Some patients may develop antibiotic-associated pseudomembranous colitis (AAPMC), caused by Clostridium difficile toxin, during or after administration of nalidixic acid. Mild cases may respond to discontinuation of the drug alone. Moderate to severe cases may require fluid, electrolyte, and protein replacement. {27}
   • In cases not responding to the above measures or in more severe cases, oral doses of an antibacterial medication effective against C. difficile should be administered. {27}




Oral Dosage Forms

NALIDIXIC ACID ORAL SUSPENSION USP

Usual adult and adolescent dose
Antibacterial
Initial: Oral, 1 gram every six hours (four times a day) for one to two weeks. {08} {27} {28}

Maintenance: Oral, 500 mg every six hours. {16} {17} {27} {28}

Note: Underdosing during the initial treatment may increase the likelihood of bacterial resistance {28}.



Usual adult prescribing limits
4 grams daily. {08} {27}

Note: Doses up to 6 grams daily have been used in severe urinary tract infections, although side effects may be increased at high dosage.


Usual pediatric dose
Antibacterial
Infants up to 3 months of age: Use is not recommended in infants up to 3 months of age since nalidixic acid causes arthropathy in immature animals. {04} {05} {06} {27} {28}

Children 3 months to 12 years of age: Oral, 55 mg per kg of body weight per day in four equally divided doses for one to two weeks initially, followed by a maintenance dose of 33 mg per kg of body weight per day in four equally divided doses. {20} {21} {27} {28}

Children 12 years of age and over: See Usual adult and adolescent dose .

Note: Underdosing during the initial treatment may increase the likelihood of bacterial resistance {28}.



Strength(s) usually available
U.S.—


250 mg per 5 mL (Rx) [NegGram{27} (parabens) (saccharin sodium) (sorbitol)]

Canada—
Not commercially available.

Packaging and storage:
Store at room temperature up to 25 °C (77 °F). {27} Store in a tight container. Protect from freezing.

Auxiliary labeling:
   • Shake well.
   • May cause blurred vision, dizziness, or drowsiness.
   • Avoid too much sun or use of sunlamp.
   • Continue medicine for full time of treatment.

Note: When dispensing, include a calibrated liquid-measuring device.



NALIDIXIC ACID TABLETS USP

Usual adult and adolescent dose
See Nalidixic Acid Oral Suspension USP .

Usual adult prescribing limits
See Nalidixic Acid Oral Suspension USP .

Usual pediatric dose
See Nalidixic Acid Oral Suspension USP .

Strength(s) usually available
U.S.—


250 mg (Rx) [NegGram{27} (scored)][Generic]


500 mg (Rx) [NegGram{27} (scored)][Generic]


1 gram (Rx) [NegGram{27} (scored)][Generic]

Canada—


500 mg (Rx) [NegGram{28} (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • May cause blurred vision, dizziness, or drowsiness.
   • Avoid too much sun or use of sunlamp.
   • Continue medicine for full time of treatment.



Revised: 06/14/1999



References
  1. Indications Index review, 1986.
  1. PDR 1986, NegGram (Winthrop), pp 1922-3.
  1. Panel comments, Nalidixic Acid (Systemic), 6/22/84.
  1. Package insert, Cipro (Miles), Rev 10/87, Rec 11/87.
  1. Davies DM, editor. Textbook of adverse drug reactions. 3rd ed. New York: Oxford University Press, 1985: 340-1.
  1. PDR 1988, NegGram (Winthrop), p 2241.
  1. USP DI 1989, VA Medication Classification System, p 2472.
  1. Package insert, NegGram (Winthrop), Rev 7/86, Rec 2/89.
  1. CPS 1988, NegGram (Winthrop), p 594.
  1. Redbook 1989, Nalidixic acid (generic), p 495.
  1. Package insert, Nalidixic acid (Danbury), Rev 9/87, Rec 2/89.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1997. p. 496.
  1. Reference not used.
  1. Reference not used.
  1. Gleckman R, et al. Drug therapy reviews: nalidixic acid. Am J Hosp Pharm August 1979; 36(8): 1071-6.
  1. Goodman and Gilman, editors. The pharmacological basis of therapeutics. 7th ed. New York: Macmillan. 1985: 1109-10.
  1. AHFS 1989, pp 400-1.
  1. AMA Drug Evaluations. 6th ed. Chicago: American Medical Association, 1986: 1480-1.
  1. Mandell, Douglas, Bennett, editors. Principles and practice of infectious diseases. 3rd ed. NY: Churchill Livingstone, 1990: 338.
  1. PDR 1991, NegGram (Winthrop), p. 2342-3.
  1. CPS 1990, NegGram (Winthrop), p 685.
  1. Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in pregnancy and lactation. 3rd ed. Baltimore: Williams and Wilkins, 1990: 441-2.
  1. American Academy of Pediatrics. Transfer of drugs and other chemicals into human milk. Pediatrics November 1989; 84(5): 924-36.
  1. Beutler E. Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med January 1991; 324(3): 169-74.
  1. Barbeau G, Belanger P-M. Pharmacokinetics of nalidixic acid in old and young volunteers. J Clin Pharmacol 1982; 22: 490-6.
  1. Niinisto L, et al. Pipemidic acid and nalidixic acid in recurrent urinary tract infections of elderly patients. Curr Therap Res January 1984; 35(1): 57-63.
  1. NegGram (Sanofi). In: PDR Physicians' desk reference. 53rd ed. 1999. Montvale, NJ: Medical Economics Company; 1999. p. 2792-3.
  1. NegGram (Sanofi). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 1083-4.
Hide
(web3)