Sulfonamides (Systemic)

This monograph includes information on the following:

1) Sulfadiazine
2) Sulfamethizole  
3) Sulfamethoxazole
4) Sulfisoxazole


INN:
Sulfisoxazole —Sulfafurazole

BAN:
Sulfadiazine—Sulphadiazine
Sulfamethizole —Sulphamethizole
Sulfamethoxazole—Sulphamethoxazole
Sulfisoxazole—Sulphafurazole


JAN:
Sulfamethoxazole—Acetylsulfamethoxazole
Sulfamethoxazole—Sulfamethoxazole sodium

VA CLASSIFICATION
Primary: AM650

Commonly used brand name(s): Apo-Sulfamethoxazole3; Apo-Sulfisoxazole4; Gantanol3; Gantrisin4; Novo-Soxazole4; Sulfizole4; Thiosulfil Forte2; Urobak3.

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

Not commercially available in Canada.



Category:


Antibacterial (urinary)—Sulfamethizole;  

Antibacterial (systemic)—Sulfadiazine; Sulfamethoxazole; Sulfisoxazole;

Antiprotozoal—Sulfadiazine; Sulfamethoxazole; Sulfisoxazole;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
Sulfonamides are active in vitro against a broad spectrum of gram-positive and gram-negative bacteria. They also have activity in vitro against Actinomyces , Chlamydia trachomatis , Nocardia asteroides , Plasmodium falciparum , and Toxoplasma gondii . Susceptibility of an organism to sulfonamides is variable; many bacteria have become resistant to sulfonamides, with resistance occurring in more than 20% of community and nosocomial bacterial isolates. Resistance has developed in strains of staphylococci, Neisseria gonorrhoeae , N. meningitidis , Enterbacteriaceae, and Pseudomonas species. {20} {22}

Accepted

Chancroid (treatment)—Sulfonamides are indicated in the treatment of chancroid caused by Haemophilus ducreyi . However, other agents, such as erythromycin and ceftriaxone, are considered to be first line agents. {03} {06} {34} {38} {48} {49} {50} {51}

Chlamydial infections, endocervical and urethral (treatment)1—Sulfonamides are indicated in the treatment of endocervical and urethral infections caused by Chlamydia trachomatis . However, other agents, such as doxycycline and azithromycin, are considered to be first line agents. {20} {38} {50} {51}

Conjunctivitis, inclusion (treatment)—Sulfonamides are indicated in the treatment of neonatal inclusion conjunctivitis caused by Chlamydia trachomatis . However, other agents, such as erythromycin, are considered to be first line agents. {03} {06} {20} {34} {48} {49} {50}

Malaria (treatment)—Sulfonamides are indicated as adjunctive therapy in the treatment of chloroquine-resistant Plasmodium falciparum . {03} {06} {34} {38} {48} {49}

Meningitis (prophylaxis)1—Sulfonamides are indicated in the prophylaxis of meningitis caused by susceptible strains of Neisseria meningitidis . However, other agents, such as rifampin, are considered to be first line agents. {03} {06} {34} {38} {51}

Nocardiosis (treatment)—Sulfonamides are indicated in the treatment of nocardiosis caused by Nocardia asteroides . {03} {06} {34} {38} {48} {49}

Otitis media (treatment)1—Sulfonamides are indicated in combination with other antibacterials in the treatment of otitis media caused by susceptible strains of H. influenzae , streptococci, and pneumococci. {03} {06} {34} {38}

Rheumatic fever (prophylaxis)1—Sulfadiazine, [sulfamethoxazole] , and [sulfisoxazole] are indicated in the prophylaxis of rheumatic fever associated with group A beta-hemolytic streptococcal infections. However, other agents, such as penicillin, are considered to be first line agents. {20} {34} {38} {50} {51}

Toxoplasmosis (treatment)1—Sulfonamides are indicated in combination with pyrimethamine in the treatment of toxoplasmosis caused by Toxoplasma gondii . {03} {06} {34} {38}

Trachoma (treatment)—Sulfonamides are indicated in the treatment of ocular trachoma caused by Chlamydia trachomatis . However, other agents, such as doxycycline and azithromycin, are considered to be first line agents. {03} {06} {20} {34} {48} {49} {50} {51}

Urinary tract infections, bacterial (treatment)—Sulfonamides are indicated in the treatment of acute, uncomplicated urinary tract infections caused by susceptible bacteria. Because sulfamethizole produces low plasma levels and is rapidly eliminated, it is recommended only for use in urinary tract infections, not systemic infections. Sulfadiazine is not recommended for the treatment of urinary tract infections because of its relatively lower urine solubility and the increased chance of crystalluria; other, more soluble agents, such as sulfisoxazole, are generally preferred. {03} {06} {20} {34} {38} {48} {49}

[Lymphogranuloma venereum (treatment)]1—Sulfonamides are used in the treatment of lymphogranuloma venereum caused by Chlamydia species. However, other agents, such as doxycycline and erythromycin, are considered to be first line agents. {20} {38} {50} {51}

[Paracoccidioidomycosis (treatment)]1—Sulfadiazine is used in the treatment of paracoccidioidomycosis caused Paracoccidioides brasiliensis . {20} {38}

—Not all species or strains of a particular organism may be susceptible to a specific sulfonamide.

Unaccepted
Sulfonamides should not be used in the treatment of Group A beta-hemolytic streptococcal tonsillopharyngitis since they may not eradicate streptococci and therefore may not prevent sequelae such as rheumatic fever. {03} {06} {21} {34} {38}

Sulfonamides are also not effective in treating rickettsial, viral, tuberculous, actinomycotic, fungal, or mycoplasmal infections. They are also not effective in the treatment of shigellosis. {48}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Sulfadiazine: 250.28 {07}
    Sulfamethizole: 270.34 {07}
    Sulfamethoxazole: 253.28 {07}
    Sulfisoxazole: 267.31 {07}
    Sulfisoxazole acetyl: 309.35 {07}

Mechanism of action/Effect:

Sulfonamides are broad-spectrum, bacteriostatic anti-infectives. They are structural analogs of para-aminobenzoic acid (PABA) and competitively inhibit a bacterial enzyme, dihydropteroate synthetase, that is responsible for incorporation of PABA into dihydrofolic acid, the immediate precursor of folic acid. {21} This blocks the synthesis of dihydrofolic acid and decreases the amount of metabolically active tetrahydrofolic acid, a cofactor for the synthesis of purines, thymidine, and DNA. {21}

Susceptible bacteria are those that must synthesize folic acid. Mammalian cells require preformed folic acid and cannot synthesize it. {20} {38} The action of sulfonamides is antagonized by PABA and its derivatives (e.g., procaine and tetracaine) and by the presence of pus or tissue breakdown products, which provide the necessary components for bacterial growth. {21}

Absorption:

All sulfonamides are rapidly and well absorbed (70–100%). {03} {06} {34}

Distribution:

Widely distributed throughout body tissues and fluids, including pleural, peritoneal, synovial, and ocular fluids, as well as the vagina and middle ear {06}. Sulfadiazine is distributed throughout total body water {20} {21}, while sulfisoxazole is distributed primarily to extracellular fluid (ECF) {03} {20} {21}. Sulfadiazine, sulfamethoxazole, and sulfisoxazole penetrate into the cerebrospinal fluid (CSF) {20} {21}; sulfadiazine reaches 32 to 65% {34}, sulfamethoxazole reaches 14 to 30% {06} {38}, and sulfisoxazole reaches 30 to 50% of corresponding blood concentrations. {38} Sulfonamides may be detected in the urine in approximately 30 minutes. {21} They readily cross the placenta and are distributed into breast milk, also. {06} {20} {21}


Urine solubility:

Sulfadiazine: Less soluble in urine; increased risk of crystalluria. {20}

Sulfamethizole: Highly soluble in urine. {20} {32}

Sulfamethoxazole: Acetylated metabolite less soluble in urine; increased risk of crystalluria. {20}

Sulfisoxazole: Highly soluble in urine. {20}



Vol D:

Sulfamethoxazole: Approximately 0.15 L per kg of body weight (L/kg). {20}

Sulfisoxazole: Approximately 0.21 L/kg. {20}


Protein binding:

Variable; acetylated metabolites are more highly protein bound than the free drug. Sulfonamides compete with bilirubin for binding to albumin. Kernicterus may develop in premature infants or neonates. {06} {34} Binding is decreased in patients with severely impaired renal function. {38} Only free, unbound drug has antibacterial activity. {06}

Sulfadiazine—38 to 48%. {20} {34}

Sulfamethizole—Approximately 90%. {33}

Sulfamethoxazole—60 to 70%. {06} {14} {15} {16} {17}

Sulfisoxazole—85 to 90%. {03} {18} {20}

Biotransformation:

Hepatic; primarily by acetylation to inactive metabolites, which retain the toxicity of the parent compound. {21} {41} Some hepatic glucuronide conjugation may occur. Metabolism is increased with renal function impairment and decreased with hepatic failure. {21}

Half-life:


Sulfadiazine:

Normal renal function: Approximately 10 hours. {21} {22}

Renal failure: Approximately 34 hours. {21} {22}



Sulfamethizole:

Normal renal function: Approximately 1.5 hours. {33}



Sulfamethoxazole:

Normal renal function: 6 to 12 hours. {20} {22}

Renal failure: 20 to 50 hours. {20} {22}



Sulfisoxazole:

Normal renal function: 3 to 7 hours. {20} {22}

Renal failure: 6 to 12 hours. {20} {22}


Time to peak concentration:

Sulfadiazine—3 to 6 hours. {21}

Sulfamethoxazole—2 to 4 hours. {21}

Sulfisoxazole—2 to 4 hours. {21}

Peak serum concentration:


Free unbound sulfonamide:

Sulfadiazine: Single 2-gram dose—Approximately 30 to 60 mcg/mL. {38}

Sulfamethoxazole: Single 2-gram dose—Approximately 80 to 100 mcg/mL. {38}

Sulfisoxazole: Single 2-gram dose—40 to 50 mcg/mL. {38}


Duration of action:

Sulfadiazine—Short-acting sulfonamide. {20}

Sulfamethizole—Short-acting sulfonamide. {20}

Sulfamethoxazole—Intermediate-acting sulfonamide. {20}

Sulfisoxazole—Short-acting sulfonamide. {20}

Elimination:
    Renal, by glomerular filtration, with some tubular secretion {06} {20} and reabsorption of both active medication and metabolites. Excretion is increased in alkaline urine; small amounts are excreted in the feces, bile, and other body secretions. {20}


Percent of medication unchanged in the urine—
        Sulfadiazine: 60 to 85% in 48 to 72 hours. {20} {34}
        Sulfamethizole: Approximately 95%. {20} {32}
        Sulfamethoxazole: 20 to 40%. {06} {20} {29}
        Sulfisoxazole: Approximately 52% in 48 hours. {03} {20}
        Sulfisoxazole acetyl: Approximately 58% in 72 hours. {03} {20}



In dialysis—
        Peritoneal dialysis is not effective and hemodialysis is only moderately effective in removing sulfonamides. {03}



Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to one sulfonamide may be allergic to other sulfonamides also. {06} {34}

Patients allergic to furosemide, thiazide diuretics, sulfonylureas, or carbonic anhydrase inhibitors may be allergic to sulfonamides also. {35} {48}

Carcinogenicity


Sulfamethoxazole:

Long-term studies to evaluate the carcinogenic potential of sulfamethoxazole have not been done. {06}



Sulfisoxazole:

Studies in mice given daily oral doses of up to 18 times the highest recommended human daily dose for 103 weeks, and rats given 4 times the highest recommended human daily dose have not shown that sulfisoxazole is carcinogenic in either male or female mice or rats. {03}


Mutagenicity


Sulfamethizole:

No long-term mutagenicity studies have been done in animals or humans. {32}



Sulfamethoxazole:

Bacterial mutagenicity studies with sulfamethoxazole have not been done. Studies in human leukocytes cultured in vitro with sulfamethoxazole using concentrations that exceeded therapeutic serum concentrations have not shown that sulfamethoxazole causes chromosomal damage. {06}



Sulfisoxazole:

Bacterial mutagenicity studies with sulfisoxazole have not been done. However, sulfisoxazole has not been shown to be mutagenic when tested in Escherichia coli Sd-4-73 strains in the absence of a metabolic activating system. {03}


Pregnancy/Reproduction
Fertility—

Sulfamethizole

No long-term fertility studies have been done in animals or humans. {32}



Sulfamethoxazole

Studies in rats, given oral doses of 350 mg of sulfamethoxazole per kg of body weight daily, have not shown that it causes any adverse effects on fertility or general reproductive performance. {06}



Sulfisoxazole

Studies in rats given daily doses of 7 times the highest recommended daily dose have not shown that sulfisoxazole causes adverse effects on mating behavior, conception rate, or fertility index (percent of animals pregnant). {03}


Pregnancy—

Sulfadiazine

FDA Pregnancy Category C. {34}



Sulfamethizole

FDA Pregnancy Category C. {32}



Sulfamethoxazole

Sulfamethoxazole crosses the placenta. Large, adequate, and well-controlled studies in humans have not been done. {06}

Studies in rats given oral doses of 533 mg of sulfamethoxazole per kg of body weight have shown that it causes teratogenic effects (primarily cleft palates). However, doses of 512 mg of sulfamethoxazole per kg of body weight did not cause cleft palates in rats. {06}

Studies in rabbits given doses of 150 to 350 mg of sulfamethoxazole per kg of body weight daily have shown that sulfamethoxazole causes increased maternal mortality but has no adverse effects on the fetus. {06}

FDA Pregnancy Category C.



Sulfisoxazole

Sulfisoxazole crosses the placenta and enters the fetal circulation. Adequate and well-controlled studies in humans have not been done. {03}

Studies in rats and rabbits given daily doses of 7 times the highest recommended human daily dose have not shown that sulfisoxazole is teratogenic. However, in studies in rats and mice given doses of 9 times the highest recommended human daily dose, sulfisoxazole caused cleft palates in both mice and rats and skeletal defects in rats. {03}

FDA Pregnancy Category C.



Labor and delivery—

Sulfonamides are not recommended at term since sulfonamides may cause kernicterus in the newborn. {03} {06} {34} {48}

Breast-feeding

Sulfonamides are distributed into breast milk. {03} {06} Use is not recommended in nursing women since sulfonamides may cause kernicterus in nursing infants. {03} {06} {34} Also, sulfonamides may cause hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD)–deficient infants. {03} {34}

Pediatrics

Except as concurrent adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis, use of sulfonamides is contraindicated in infants up to 2 months of age. Sulfonamides compete for bilirubin binding sites on plasma albumin, increasing the risk of kernicterus in the newborn. Also, because the acetyltransferase system is not fully developed in the newborn, increased blood concentrations of the free sulfonamide can further increase the risk of kernicterus. {03} {06} {34} {38} {48}


Geriatrics


Elderly patients may be at increased risk of severe side/adverse effects. Severe skin reactions, generalized bone marrow depression, and decreased platelet count (with or without purpura) are the most frequently reported severe side/adverse effects in the elderly. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients who are receiving diuretics, primarily thiazides, concurrently with sulfamethoxazole. {06} The potential for these problems should also be considered for elderly patients taking other sulfonamide medications. {06}


Pharmacogenetics

Sulfonamides are metabolized primarily by acetylation. {41} Patients can be divided into 2 groups, slow and fast acetylators. Slow acetylators have a higher incidence of severe sulfonamide reactions, although a slow acetylator phenotype is not thought to be the sole reason for sulfonamide toxicity. {41} {42} {43} {44} The incidence of the slow acetylator phenotype is approximately 50% in North American blacks and whites. {41} {42} {45} Approximately 30% of the Hispanic population {43} and 10% of the Asian population {42} are slow acetylators. Also, acquired immunodeficiency syndrome (AIDS) patients with acute illness, but not AIDS patients who are stable or human immunodeficiency virus (HIV)–infected patients without AIDS, have an increased incidence of slow acetylation. {43}


Dental

The leukopenic and thrombocytopenic effects of sulfonamides may result in an increased incidence of certain microbial infections, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

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.

» Anticoagulants, coumarin- or indandione-derivative or{03}{18}{27}{34}
» Anticonvulsants, hydantoin or{27}
» Antidiabetic agents, oral{03}{27}{34}    (these medications may be displaced from protein binding sites and/or their metabolism may be inhibited by some sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy)


Bone marrow depressants (See Appendix II )    (concurrent use of bone marrow depressants with sulfonamides may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered)


Contraceptives, estrogen-containing, oral{23}    (concurrent long-term use of sulfonamides may result in increased incidence of breakthrough bleeding and pregnancy)


Cyclosporine{24}{25}{26}{27}    (concurrent use with sulfonamides may increase the metabolism of cyclosporine, resulting in decreased plasma concentrations and potential transplant rejection, and additive nephrotoxicity; plasma cyclosporine concentrations and renal function should be monitored)


» Hemolytics, other (See Appendix II )    (concurrent use with sulfonamides may increase the potential for toxic side effects)


» Hepatotoxic medications, other (See Appendix II )    (concurrent use with sulfonamides may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with a history of liver disease, should be carefully monitored)


» Methenamine{20}{38}    (in acid urine, methenamine breaks down into formaldehyde, which may form an insoluble precipitate with certain sulfonamides, especially those that are less soluble in urine, and may also increase the danger of crystalluria; concurrent use is not recommended)


» Methotrexate or{03}{30}{34}
Phenylbutazone or{20}{34}
Sulfinpyrazone{34}    (the effects of methotrexate may be potentiated during concurrent use with sulfonamides because of displacement from plasma protein binding sites; phenylbutazone and sulfinpyrazone may displace sulfonamides from plasma protein binding sites, increasing sulfonamide concentrations)


Penicillins{13}    (since bacteriostatic drugs may interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations where a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy)



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
Benedict's test{20}{28}{38}    (sulfonamides may produce a false-positive Benedict's test for urine glucose)


Jaffé alkaline picrate reaction assay{06}    (sulfamethoxazole may interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of approximately 10% in the normal values for creatinine)


Sulfosalicylic acid test{20}{28}{38}    (sulfonamides may produce a false-positive sulfosalicylic acid test for urine protein)


Urine urobilinogen test strip (e.g., Urobilistix){28}    (sulfonamides may interfere with the urine urobilinogen [Urobilistix] test for urinary urobilinogen)

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]), serum and
Aspartate aminotransferase (AST [SGOT]), serum and
Bilirubin, serum    (values may be increased {03} {06})


Blood urea nitrogen (BUN) and
Creatinine, serum    (concentrations may be increased {06} {34})


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).


Except under special circumstances, this medication should not be used when the following medical problems exist:
Allergy to sulfonamides, furosemide, thiazide diuretics, sulfonylureas, or carbonic anhydrase inhibitors{35}{48}
Risk-benefit should be considered when the following medical problems exist
» Blood dyscrasias or
» Megaloblastic anemia due to folate deficiency    (sulfonamides may cause blood dyscrasias {06} {34})


» Glucose-6-phosphate dehydrogenase (G6PD) deficiency    (hemolysis may occur {03} {06} {34} {48})


» Hepatic function impairment    (sulfonamides are metabolized in the liver; delayed metabolism may increase the risk of toxicity; also, sulfonamides may cause fulminant hepatic necrosis {03} {34})


» Porphyria    (sulfonamides may precipitate an acute attack of porphyria {28} {48})


» Renal function impairment    (sulfonamides are renally excreted; delayed elimination may increase the risk of toxicity; also, sulfonamides may cause tubular necrosis or interstitial nephritis {03} {06} {34})



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)    (may be required prior to and monthly during treatment to detect blood dyscrasias in patients on prolonged therapy; therapy should be discontinued if a significant decrease in the count of any formed blood elements occurs {03} {06} {34})


Urinalyses    (may be required prior to and periodically during treatment to detect crystalluria and/or urinary calculi formation in patients on long-term or high-dose therapy and in patients with impaired renal function {03} {06} {34})




Side/Adverse Effects

Note: Fatalities have occurred, although rarely, due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Therapy should be discontinued at the first appearance of skin rash or any serious side/adverse effects. {03}
Patients with acquired immunodeficiency syndrome (AIDS) may have a greater incidence of side/adverse effects, especially rash, fever, and leukopenia, than do non-AIDS patients. {43}
The multiorgan toxicity of sulfonamides is thought to be the result of the way sulfonamides are metabolized in certain patients. It is probably due to the inability of the body to detoxify reactive metabolites. Sulfonamides are metabolized primarily by acetylation. {41} Patients can be divided into slow and fast acetylators. Slow acetylation of sulfonamides makes more of the medication available for metabolism by the oxidative pathways of the cytochrome P-450 system. {44} {45} These pathways produce reactive toxic metabolites, such as hydroxylamine and nitroso compounds. {43} {44} {45} The metabolites are normally detoxified by scavengers, such as glutathione. However, some populations, such as human immunodeficiency virus (HIV)–infected patients, have low concentrations of glutathione and these metabolites accumulate, producing toxicity. {43} {46} Patients who are slow acetylators have a higher incidence of sulfonamide hypersensitivity reactions {41} {42} {43} {44}, although severe toxicity has also been seen in fast acetylators. {41} Acetylation status alone cannot fully explain sulfonamide toxicity since approximately 50% of North American blacks and whites are slow acetylators and severe reactions occur in less than 1% of patients treated with sulfonamides. {45} However, decreased acetylation may increase the amount of sulfonamide metabolized to toxic metabolites. {45}
Crytalluria is more likely to occur with a less soluble sulfonamide, such as sulfadiazine. It occurs most often with the administration of high doses, and can be minimized by maintaining a high urine flow and alkalinizing the urine. {38} {39} {40}

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
    
Hypersensitivity (fever; itching; skin rash){03}{06}{34}
    
photosensitivity (increased sensitivity of skin to sunlight){06}{34}

Incidence less frequent
    
Blood dyscrasias (fever and sore throat; pale skin; unusual bleeding or bruising; unusual tiredness or weakness){03}{06}{34}
    
hepatitis (yellow eyes or skin){03}{06}{47}
    
Lyell's syndrome (difficulty in swallowing; redness, blistering, peeling, or loosening of skin){03}{06}{34}
    
Stevens-Johnson syndrome (aching joints and muscles; redness, blistering, peeling, or loosening of skin; unusual tiredness or weakness){03}{06}{34}

Incidence rare
    
Central nervous system toxicity (confusion; disorientation; euphoria; hallucination; mental depression){37}
    
Clostridium difficilecolitis (severe abdominal or stomach cramps and pain; abdominal tenderness; watery and severe diarrhea, which may also be bloody; fever){03}
    
crystalluria or hematuria (blood in urine; lower back pain; pain or burning while urinating){34}
    
goiter or thyroid function disturbance (swelling of front part of neck){03}{34}
    
interstitial nephritis or tubular necrosis (greatly increased or decreased frequency of urination or amount of urine; increased thirst; loss of appetite; nausea; vomiting){34}

Note: C. difficile colitis may occur up to several weeks after discontinuation of these medications.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Central nervous system effects (dizziness; headache; lethargy){06}{34}
    
gastrointestinal disturbances (diarrhea; loss of appetite; nausea or vomiting){06}{34}





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

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

Before using this medication
»   Conditions affecting use, especially:
Allergy to sulfonamides, furosemide, thiazide diuretics, sulfonylureas, carbonic anhydrase inhibitors

Pregnancy—Sulfonamides cross the placenta; not recommended at term since sulfonamides may cause kernicterus in newborn





Breast-feeding—Sulfonamides are distributed into breast milk; may cause kernicterus in nursing infants





Use in children—Sulfonamides are contraindicated in infants up to 2 months of age since sulfonamides may cause kernicterus in neonates






Use in the elderly—Elderly patients may be at increased risk of severe side/adverse effects
Other medications, especially coumarin- or indandione-derivative anticoagulants, hydantoin anticonvulsants, oral antidiabetic agents, other hemolytics, other hepatotoxic medications, methenamine, or methotrexate
Other medical problems, especially blood dyscrasias, G6PD deficiency, hepatic function impairment, megaloblastic anemia, porphyria, and renal function impairment

Proper use of this medication
» Not giving to infants under 2 months of age

» Maintaining adequate fluid intake

Proper administration technique for oral liquids

» Compliance with full course of therapy

» Importance of not missing doses and taking at evenly spaced times

» 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 blood counts

Checking with physician if no improvement within a few days

Using caution in use of regular toothbrushes, dental floss, and toothpicks; deferring dental work until blood counts have returned to normal; checking with physician or dentist concerning proper oral hygiene

» Possible photosensitivity reactions

» Caution if dizziness occurs


Side/adverse effects
Severe skin problems and blood problems may be more likely to occur in the elderly who are taking sulfamethoxazole, especially if taking diuretics concurrently

Signs of potential side effects, especially hypersensitivity, photosensitivity, blood dyscrasias, hepatitis, Lyell's syndrome, Stevens-Johnson syndrome, central nervous system toxicity, C. difficile colitis, crystalluria or hematuria, goiter or thyroid function disturbance, and interstitial nephritis or tubular necrosis


General Dosing Information
Fluid intake should be sufficient to maintain urine output of at least 1200 mL per day in adults. {48}

SULFADIAZINE

Summary of Differences
Indications: Because of its relatively low urine solubility and the increased chance of crystalluria, sulfadiazine is not recommended for the treatment of urinary tract infections. Sulfadiazine is used for the prophylaxis of rheumatic fever and, in combination with pyrimethamine, for the treatment of toxoplasmosis and malaria caused by chloroquine-resistant P. falciparum .


Additional Dosing Information
Fluid intake should be sufficient to maintain urine output of at least 1200 mL per day in adults.

Patients with impaired renal function may require a reduction in dose.


Oral Dosage Forms

SULFADIAZINE TABLETS USP

Usual adult and adolescent dose
Antibacterial (systemic) or
Antiprotozoal
Oral, 2 to 4 grams initially, then 1 gram every four to six hours. {34}


Meningitis (prophylaxis):
Oral, 1 gram every twelve hours for two days. {38}



Rheumatic fever (prophylaxis):
Oral, 1 gram once a day. {38} {52}



Toxoplasmosis:
AIDS patients: Oral, 1 to 2 grams of sulfadiazine every 6 hours with 50 to 100 mg of pyrimethamine per day and 10 to 25 mg of leucovorin per day. {36} {38}

Pregnant women: Oral, 1 gram of sulfadiazine every 6 hours with 25 mg of pyrimethamine per day after week 16 of the pregnancy. With this regimen, 5 to 15 mg of leucovorin per day is administered. {38}



Usual pediatric dose
Antibacterial (systemic) or
Antiprotozoal {34}
Infants up to 2 months of age: Use is not recommended.

Infants 2 months of age and over: Oral, 75 mg per kg of body weight initially, then 37.5 mg per kg of body weight every six hours or 25 mg per kg of body weight every four hours.

Toxoplasmosis: Oral, 50 mg of sulfadiazine per kg of body weight two times a day, administered concurrently with 2 mg of pyrimethamine per kg of body weight per day for two days, then 1 mg of pyrimethamine per kg of body weight per day for two to six months, then of 1 mg pyrimethamine per kg of body weight per day three times per week. With this regimen, 5 mg of leucovorin is administered three times a week. The three medications should be given for a total of twelve months. {38}


Note: The maximum dose for children should not exceed 6 grams daily. {34}


Strength(s) usually available
U.S.—


500 mg (Rx)[Generic]

Canada—


500 mg (Rx)[Generic]

Packaging and storage:
Store below 30 °C (86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from light.

Auxiliary labeling:
   • Take with a full glass of water.
   • Avoid too much sun or use of sunlamp.
   • May cause dizziness.
   • Continue medicine for full time of treatment.


SULFAMETHIZOLE

Summary of Differences
Indications: Sulfamethizole is recommended for use only in the treatment of urinary tract infections, not systemic infections.


Additional Dosing Information
Fluid intake should be sufficient to maintain urine output of at least 1200 mL per day in adults.

Patients with impaired renal function may require a reduction in dose.


Oral Dosage Forms

SULFAMETHIZOLE TABLETS USP

Usual adult and adolescent dose
Antibacterial
Oral, 500 mg to 1 gram every six to eight hours. {32}


Usual pediatric dose
Antibacterial
Infants up to 2 months of age: Use is not recommended.

Infants 2 months of age and over: Oral, 7.5 to 11.25 mg per kg of body weight every six hours. {32}


Strength(s) usually available
U.S.—


500 mg (Rx) [Thiosulfil Forte]

Canada—
Not commercially available.

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

Auxiliary labeling:
   • Take with a full glass of water.
   • Avoid too much sun or use of sunlamp.
   • May cause dizziness.
   • Continue medicine for full time of treatment.


SULFAMETHOXAZOLE


Additional Dosing Information
Fluid intake should be sufficient to maintain urine output of at least 1200 mL per day in adults.

Although sulfamethoxazole has a greater tendency to cause crystalluria than sulfisoxazole because of slower absorption and excretion, alkalinization of the urine is usually unnecessary.

Therapy should be continued for at least 7 to 10 days in urinary tract infections.

Patients with impaired renal function may require a reduction in dose. {06}


Oral Dosage Forms

SULFAMETHOXAZOLE TABLETS USP

Usual adult and adolescent dose
Antibacterial (systemic) or
Antiprotozoal
Mild to moderate infections: Oral, 2 grams initially, then 1 gram every eight to twelve hours. {06} {48}

Severe infections: Oral, 4 grams initially, then 2 grams every eight to twelve hours. {06}


Usual pediatric dose
Antibacterial (systemic) or
Antiprotozoal {06}
Infants up to 2 months of age: Except as concurrent adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis, use is contraindicated since sulfonamides may cause kernicterus in neonates.

Infants and children 2 months of age and over: Oral, 50 to 60 mg per kg of body weight (maximum—2 grams) initially, then 25 to 30 mg per kg of body weight every twelve hours.


Note: The maximum dose for children should not exceed 75 mg per kg of body weight per day. {06}


Strength(s) usually available
U.S.—


500 mg (Rx) [Gantanol] [Urobak]

Canada—


500 mg (Rx) [Apo-Sulfamethoxazole (scored)][Generic]

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 well-closed, light-resistant container.

Auxiliary labeling:
   • Take with a full glass of water.
   • May cause dizziness.
   • Avoid too much sun or use of sunlamp.
   • Continue medicine for full time of treatment.


SULFISOXAZOLE


Additional Dosing Information
Fluid intake should be sufficient to maintain urine output of at least 1200 mL per day in adults.

Because of its relatively high solubility even in acid urine, the risk of crystalluria with sulfisoxazole is low and alkalinization of the urine is usually unnecessary.

Therapy should be continued for at least 7 to 10 days in urinary tract infections.

Patients with impaired renal function may require a reduction in dose.


Oral Dosage Forms

SULFISOXAZOLE TABLETS USP

Usual adult and adolescent dose
Antibacterial (systemic) or
Antiprotozoal
Oral, 2 to 4 grams initially, then 750 mg to 1.5 grams every four hours; or 1 to 2 grams every six hours. {03} {49}


Usual adult prescribing limits
Up to 8 grams daily. {49}

Usual pediatric dose
Antibacterial (systemic) or
Antiprotozoal
Infants up to 2 months of age: Except as concurrent adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis, use is contraindicated since sulfonamides may cause kernicterus in neonates. {03} {49}

Infants and children 2 months of age and over: Oral, 75 mg per kg of body weight or 2 grams per square meter of body surface initially, then 25 mg per kg of body weight or 667 mg per square meter of body surface every four hours; or 37.5 mg per kg of body weight or 1 gram per square meter of body surface every six hours. {03} {49}


Note: The maximum dose for children should not exceed 6 grams daily. {03} {49}


Strength(s) usually available
U.S.—


500 mg (Rx) [Gantrisin (scored)][Generic]

Canada—


500 mg (Rx) [Apo-Sulfisoxazole] [Novo-Soxazole] [Sulfizole]

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 well-closed, light-resistant container.

Auxiliary labeling:
   • Take with a full glass of water.
   • May cause dizziness.
   • Avoid too much sun or use of sunlamp.
   • Continue medicine for full time of treatment.


SULFISOXAZOLE ACETYL ORAL SUSPENSION USP

Usual adult and adolescent dose
See Sulfisoxazole Tablets USP .

Usual adult prescribing limits
See Sulfisoxazole Tablets USP .

Usual pediatric dose
See Sulfisoxazole Tablets USP .

Strength(s) usually available
U.S.—


500 mg per 5 mL (Rx) [Gantrisin (alcohol 0.3%) (parabens) (sucrose)][Generic]

Canada—
Not commercially available.

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, light-resistant container. Protect from freezing.

Auxiliary labeling:
   • Shake well.
   • Take with a full glass of water.
   • May cause dizziness.
   • Avoid too much sun or use of sunlamp.
   • Continue medicine for full time of treatment.

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



SULFISOXAZOLE ACETYL ORAL SYRUP

Usual adult and adolescent dose
See Sulfisoxazole Tablets USP .

Usual adult prescribing limits
See Sulfisoxazole Tablets USP .

Usual pediatric dose
See Sulfisoxazole Tablets USP .

Strength(s) usually available
U.S.—


500 mg per 5 mL (Rx) [Gantrisin]

Canada—
Not commercially available.

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, light-resistant container. Protect from freezing.

Auxiliary labeling:
   • Take with a full glass of water.
   • May cause dizziness.
   • Avoid too much sun or use of sunlamp.
   • Continue medicine for full time of treatment.

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




Revised: 08/25/1995



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