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SulfADIAZINE

Pronunciation

(sul fa DYE a zeen)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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Tablet, Oral:

Generic: 500 mg

Pharmacologic Category

  • Antibiotic, Sulfonamide Derivative

Pharmacology

Interferes with bacterial growth by inhibiting bacterial folic acid synthesis through competitive antagonism of PABA

Absorption

Well absorbed

Distribution

Throughout body tissues and fluids including pleural, peritoneal, synovial, and ocular fluids; throughout total body water; readily diffused into CSF

Metabolism

Via N-acetylation

Excretion

Urine (43% to 60% as unchanged drug, 15% to 40% as metabolites)

Time to Peak

Within 3-6 hours

Half-Life Elimination

10 hours

Protein Binding

38% to 48%

Use: Labeled Indications

Treatment of the following conditions (per product labeling): Chancroid, trachoma, inclusion conjunctivitis, nocardiosis, urinary tract infections, toxoplasmosis encephalitis, malaria, meningococcal meningitis, acute otitis media, rheumatic fever (prophylaxis), meningitis (adjunctive)

Refer to current guidelines for appropriate use.

Contraindications

Hypersensitivity to any sulfa drug or any component of the formulation; infants <2 months of age unless indicated for the treatment of congenital toxoplasmosis; pregnancy (at term); breast-feeding

Dosage

Oral:

General dosing guidelines:

Children >2 months of age: Initial: 75 mg/kg; Maintenance: 150 mg/kg/day in 4 to 6 divided doses (maximum: 6 g/24 hours)

Adults: 2 to 4 g/day in 3 to 6 divided doses

Rheumatic fever prophylaxis: Children and Adults:

<30 kg: 0.5 g/day

≥30 kg: 1 g/day

Toxoplasmosis (HIV-exposed/-infected patients) (off-label dose):

Congenital toxoplasmosis: Infants: 100 mg/kg/day in divided doses every 12 hours for 12 months in combination with pyrimethamine plus leucovorin calcium (HHS [OI pediatric 2013])

Acquired toxoplasmosis: Infants and Children:

Acute induction therapy: 25 to 50 mg/kg/dose given 4 times/day (maximum: 1 to 1.5 g/dose) in combination with pyrimethamine and leucovorin calcium. Continue acute induction therapy for ≥6 weeks, then follow with chronic suppressive therapy (HHS [OI pediatric 2013]).

Chronic maintenance therapy (prior to encephalitis): 85 to 120 mg/kg/day divided every 6 to 12 hours (maximum: 2 to 4 g/day) in combination with pyrimethamine plus leucovorin calcium (HHS [OI pediatric 2013])

Toxoplasma gondii encephalitis: Adolescents and Adults:

Treatment: 1,000 mg (<60 kg) or 1,500 mg (≥60 kg) every 6 hours in combination with pyrimethamine plus leucovorin calcium (preferred) or alternatively, may give 1,000 mg (<60 kg) or 1,500 mg (≥60 kg) every 6 hours in combination with atovaquone; treat for ≥6 weeks; longer duration may be necessary if clinical or radiographic disease is extensive or if response is incomplete at 6 weeks. (HHS [OI adult 2015])

Chronic maintenance therapy: 2,000 to 4,000 mg/day in 2 to 4 divided doses in combination with pyrimethamine and leucovorin calcium (preferred) or alternatively, may give 2,000 to 4,000 mg/day in 2 to 4 divided doses in combination with atovaquone; may discontinue if successfully completed initial treatment, remain asymptomatic of toxoplasmic encephalitis, and CD4 count >200 cells/mm3 for 6 months in response to ART (HHS [OI adult 2015])

Extemporaneously Prepared

A 200 mg/mL oral suspension may be made with sulfadiazine powder and sterile water. Place 50 g sulfadiazine powder in a glass mortar. Add small portions of sterile water and mix to a uniform paste; mix while incrementally adding sterile water to almost 250 mL; transfer to a calibrated bottle, rinse mortar with sterile water, and add sufficient quantity of sterile water to make 250 mL. Label "shake well" and "refrigerate". Stable for 3 days refrigerated. Note: Suspension may also be prepared by crushing one-hundred 500 mg tablets; however, it is stable for only 2 days.

Pathmanathan U, Halgrain D, Chiadmi F, et al, "Stability of Sulfadiazine Oral Liquids Prepared From Tablets and Powder," J Pharm Pharm Sci, 2004, 7(1):84-7.15144740

Administration

Administer with at least 8 ounces of water and around-the-clock to promote less variation in peak and trough serum levels. Oral sodium bicarbonate may be used to alkalinize the urine of patients unable to maintain adequate fluid intake (in order to prevent crystalluria, azotemia, oliguria) (Lerner, 1996).

Dietary Considerations

Supplemental leucovorin calcium should be administered to reverse symptoms or prevent problems due to folic acid deficiency.

Storage

Store at controlled room temperature of 20°C to 25°C (68°F to 77°F). Protect from light.

Drug Interactions

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Bosentan: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Cannabis: May increase the serum concentration of CYP2C9 Inhibitors (Strong). More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Carvedilol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Ceritinib: May increase the serum concentration of CYP2C9 Substrates. Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (e.g., warfarin, phenytoin) should be avoided when possible. Monitor therapy

CycloSPORINE (Systemic): Sulfonamide Derivatives may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Sulfonamide Derivatives may decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

CYP2C9 Substrates: CYP2C9 Inhibitors (Strong) may decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Monitor therapy

Diclofenac (Systemic): CYP2C9 Inhibitors (Strong) may increase the serum concentration of Diclofenac (Systemic). Management: Consider using a lower dose of diclofenac when used together with a strong CYP2C9 inhibitor. Arthrotec (diclofenac and misoprostol) labeling specifically recommends limiting the total daily dose to a maximum of 50 mg twice/day. Consider therapy modification

Dronabinol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Dronabinol. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates. Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Lacosamide: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates. Lumacaftor may increase the serum concentration of CYP2C9 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination

Methenamine: May enhance the adverse/toxic effect of Sulfonamide Derivatives. Specifically, the combination may result in the formation of an insoluble precipitate in the urine. Avoid combination

Methotrexate: Sulfonamide Derivatives may enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and either sulfamethoxazole or trimethoprim. If used concomitantly, monitor for the development of signs and symptoms of methotrexate toxicity (eg, bone marrow suppression). Consider therapy modification

Mifepristone: May increase the serum concentration of CYP2C9 Substrates. Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy

Ospemifene: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy

Parecoxib: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Potassium P-Aminobenzoate: May diminish the therapeutic effect of Sulfonamide Derivatives. Avoid combination

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Monitor therapy

Procaine: May diminish the therapeutic effect of Sulfonamide Derivatives. Avoid combination

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ramelteon: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Sulfonylureas: Sulfonamide Derivatives may enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Tetrahydrocannabinol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Sulfonamide Derivatives may enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Adverse Reactions

Frequency not defined.

Cardiovascular: Allergic myocarditis, periarteritis nodosa

Central nervous system: Ataxia, chills, convulsions, depression, fever, hallucinations, headache, insomnia, vertigo

Dermatologic: Epidermal necrolysis, erythema multiforme, exfoliative dermatitis, photosensitivity, pruritus, purpura, rash, skin eruptions, Stevens-Johnson syndrome, urticaria

Endocrine & metabolic: Hypoglycemia, thyroid function disturbance

Gastrointestinal: Abdominal pain, anorexia, diarrhea, nausea, pancreatitis, stomatitis, vomiting

Genitourinary: Crystalluria, stone formation, toxic nephrosis with oliguria and anuria

Hematologic: Agranulocytopenia, aplastic anemia, hemolytic anemia, hypoprothrombinemia, leukopenia, methemoglobinemia, thrombocytopenia

Hepatic: Hepatitis

Neuromuscular & skeletal: Arthralgia, peripheral neuritis

Ocular: Conjunctival/scleral injection, periorbital edema

Otic: Tinnitus

Renal: Diuresis

Miscellaneous: Anaphylactoid reactions, lupus erythematosus, serum sickness-like reactions

Warnings/Precautions

Concerns related to adverse effects:

• Blood dyscrasias: Fatalities associated with severe reactions including agranulocytosis, aplastic anemia and other blood dyscrasias have occurred; discontinue use at first sign of rash or signs of serious adverse reactions.

• Dermatologic reactions: Fatalities associated with severe reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred; discontinue use at first sign of rash.

• Hepatic necrosis: Fatalities associated with hepatic necrosis have occurred; discontinue use at first sign of rash.

• Sulfonamide (“sulfa”) allergy: Traditionally, concerns for cross-reactivity have extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur, or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides and antibiotic sulfonamides. A nonantibiotic sulfonamide compound which contains the arylamine structure and therefore may cross-react with antibiotic sulfonamides is sulfasalazine (Zawodniak 2010). T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Allergies/asthma: Use with caution in patients with allergies or asthma.

• Glucose 6-phosphate dehydrogenase (G6PD) deficiency: Use with caution in patients with G6PD deficiency; hemolysis may occur.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment; dosage modification required. Maintain adequate hydration to prevent crystalluria.

Special populations:

• Neonates: Sulfa antibiotics have been shown to displace bilirubin from protein binding sites which may potentially lead to hyperbilirubinemia and kernicterus in neonates and young infants; do not use in neonates; avoid use in infants <2 months unless other options are not available.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

Other warnings/precautions:

• Appropriate use: Not for the treatment of group A beta-hemolytic streptococcal infections.

Monitoring Parameters

Perform culture and sensitivity testing prior to initiating therapy; frequent CBC and urinalysis during therapy; signs of serious blood disorders (sore throat, fever, pallor, purpura, jaundice); CD4+ count in HIV-exposed/-positive patients treated for toxoplasmosis; sulfonamide blood concentrations may be monitored for severe infections (target: 12-15 mg/100 mL)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Sulfadiazine crosses the placenta (Speert, 1943). Available studies and case reports have failed to show an increased risk for congenital malformations after sulfadiazine use (Heinonen, 1977); however, studies with sulfonamides as a class have shown mixed results (ACOG, 2011).

Sulfadiazine is recommended for use in pregnant women to prevent T. gondii infection of the fetus, for the maternal treatment of Toxoplasmic gondii encephalitis, and as an alternative agent for the secondary prevention of rheumatic fever (CDC, 2009; DHHS, 2013; Gerber, 2009). Sulfonamides may be used to treat other infections in pregnant women when clinically appropriate for confirmed infections caused by susceptible organisms; use during the first trimester should be limited to situations where no alternative therapies are available (ACOG, 2011). Because safer options are available for the treatment of urinary tract infections in pregnant women, use of sulfonamide-containing products >32 weeks gestation should be avoided (Lee, 2008). Due to the theoretical increased risk for hyperbilirubinemia and kernicterus, sulfadiazine is contraindicated by the manufacturer for use near term. Neonatal healthcare providers should be informed if maternal sulfonamide therapy is used near the time of delivery (DHHS, 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, diarrhea, lack of appetite, or insomnia. Have patient report immediately to prescriber signs of pancreatitis, urinary retention, oliguria, skin discoloration, pallor, severe dizziness, syncope, angina, tachycardia, hallucinations, arthralgia, stomatitis, pharyngitis, vaginitis, mouth discoloration, signs of pseudomembranous colitis (rare), or signs of severe sulfonamide reaction (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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