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  • CLASSES

    Aminosalicyclic Acid and Related Intestinal Antiinflammatory Agents
    Other Specific Antirheumatics

    DEA CLASS

    Rx

    DESCRIPTION

    Oral prodrug; metabolized by intestinal bacteria to sulfapyridine and 5-aminosalicylate (5-ASA, also known as mesalamine)
    Used to treat ulcerative colitis, rheumatoid arthritis, and juvenille idiopathic arthritis (JIA)
    The sulfapyridine component is particularly associated with adverse reactions vs. 5-ASA use alone

    COMMON BRAND NAMES

    Azulfidine, Azulfidine En-Tabs, Sulfazine, Sulfazine EC

    HOW SUPPLIED

    Azulfidine En-Tabs/Sulfasalazine/Sulfazine EC Oral Tab DR: 500mg
    Azulfidine/Sulfasalazine/Sulfazine Oral Tab: 500mg

    DOSAGE & INDICATIONS

    For the treatment of mild to moderate ulcerative colitis and as adjunctive therapy for severe ulcerative colitis, and as maintenance treatment of ulcerative colitis to prolong remission.
    Oral dosage (uncoated tablets or extemporaneous suspension from noncoated tablets)
    Adults

    Initially, 1 gram PO every 6 to 8 hours. Adverse GI effects may be lessened by reducing initial dosage to 500 mg every 6 to 12 hours and titrating to response and tolerance. Usual maintenance dose: 500 mg PO every 6 hours, adjust to patient response and tolerance. Suggested Max: 4 grams/day PO. Total doses of more than 4 grams/day may increase the risk of adverse effects and toxicity. Patients should take a folic acid supplement.

    Children and Adolescents 6 years and older

    Initially, 40 to 60 mg/kg/day PO, given in 3 to 6 divided doses (not to exceed 4 grams/day PO). The recommended maintenance dose is 30 mg/kg/day PO divided every 6 hours. Patients should take a folic acid supplement. Mesalamine (5-ASA) or sulfasalazine products are preferred by guidelines given the strong evidence of efficacy of 5-ASA for induction and maintenance of remission in mild-moderate UC.

    Children 2 to 5 years

    While not specifically noted in the dosage of the label, the usual weight-based dose is 40 to 60 mg/kg/day PO, given in divided doses (not to exceed 4 grams/day PO); maintenance dosing is usually lower. In one trial, sulfasalazine was twice as effective as olsalazine for UC improvement in children. Patients should take a folic acid supplement. Mesalamine (5-ASA) or sulfasalazine products are preferred by guidelines given the strong evidence of efficacy of 5-ASA for induction and maintenance of remission in mild-moderate UC, and the availability of extemporaneous sulfasalazine oral dosage forms amenable for use in younger children.

    Oral dosage (enteric-coated tablets)
    Adults

    Initially, 3 to 4 grams/day PO in evenly divided doses (at least every 8 hours). May initiate therapy with 1 to 2 grams/day PO in divided doses to reduce GI intolerance and increase gradually over several days. If GI intolerance continues, the drug should be stopped for 5 to 7 days, then reintroduced at lower daily doses. Suggested Max: 4 grams/day PO. Total doses of more than 4 grams/day may increase the risk of adverse effects and toxicity. Usual maintenance dose: 2 grams/day PO in divided doses. Patients should take a folic acid supplement.

    Children and Adolescents 6 years and older

    Initially, 40 to 60 mg/kg/day PO in 3 to 6 divided doses (Not to exceed 4 grams/day). A maintenance dose of 30 mg/kg/day PO in 4 divided doses is recommended. Patients should take a folic acid supplement. Mesalamine (5-ASA) or sulfasalazine products are preferred by guidelines given the strong evidence of efficacy of 5-ASA for induction and maintenance of remission in mild-moderate UC.

    For the treatment of rheumatoid arthritis in patients who have responded inadequately to salicylates or other nonsteroidal anti-inflammatory drugs.
    As monotherapy.
    Oral dosage (only enteric-coated tablets FDA-approved)
    Adults

    500 mg to 1,000 mg PO per day for the first week. Increase the daily dose by 500 mg each week up to a maintenance dose of 2 grams/day, given in 2 to 3 divided doses. A therapeutic response is not observed immediately but can be seen in 4 weeks; treatment for 12 weeks may be required in some patients. Consideration can be given to increasing to 3 grams/day PO in divided doses if clinical response is inadequate after 12 weeks. Careful monitoring is recommended for doses greater than 2 grams/day. Guidelines recommend DMARD monotherapy such as sulfasalazine for patients with a disease duration less than 6 months and low disease activity regardless of poor prognostic feature presence or moderate disease activity without poor prognostic features and is an option for high disease activity without poor prognostic features. For established disease, sulfasalazine monotherapy is only recommended for patients with low disease activity without poor prognostic features. The goal is low disease activity or remission.

    In combination with methotrexate†.
    Oral dosage
    Adults

    500 to 1,000 mg PO twice daily plus methotrexate (7.5 to 17.5 mg PO once weekly) for 2 years led to an ACR20 in 49% of 55 patients with active disease and a disease duration of at least 6 months. About half of the patients had an inadequate response to previous methotrexate monotherapy, and about half of the patients were methotrexate naive. For patients with a disease duration less than 6 months, guidelines recommend use of combination DMARDs such as sulfasalazine plus methotrexate for those with moderate disease activity and poor prognostic features and is an option for those with high disease activity and poor prognostic features. For established disease, DMARD combination therapy is an option for patients with low disease activity and poor prognostic features or with moderate or high disease activity regardless of poor prognostic feature presence. If moderate or high disease activity exists after 3 months of combination DMARDs, an option is to add or switch DMARDs and reassess in another 3 months. For patients with low disease activity without poor prognostic features who have moderate or high disease activity after 3 months of DMARD monotherapy, the addition of methotrexate is an option.

    In combination with hydroxychloroquine and methotrexate†.
    Oral dosage
    Adults

    500 to 1,000 mg PO twice daily plus hydroxychloroquine (200 mg PO twice daily) and methotrexate (7.5 to 17.5 mg PO once weekly) for 2 years led to an ACR20 in 78% of 58 patients with active disease and a disease duration of at least 6 months. About half of the patients had an inadequate response to previous methotrexate monotherapy, and about half of the patients were methotrexate naive. For patients with a disease duration less than 6 months, guidelines recommend use of combination DMARDs for those with moderate disease activity and poor prognostic features and is an option for those with high disease activity and poor prognostic features. For established disease, DMARD combination therapy is an option for patients with low disease activity and poor prognostic features or with moderate or high disease activity regardless of poor prognostic feature presence. If moderate or high disease activity exists after 3 months of combination DMARDs, an option is to add or switch DMARDs and reassess in another 3 months.

    In combination with hydroxychloroquine†.
    Oral dosage
    Adults

    500 mg PO twice daily plus hydroxychloroquine (200 mg PO twice daily) led to at least a 50% improvement in composite symptoms of arthritis at 9 months that was maintained over the 2-year treatment period in 14 of 35 patients. All patients had RA for at least 6 months and had a poor responses to treatment with gold, hydroxychloroquine, penicillamine, sulfasalazine, or methotrexate. For patients with a disease duration less than 6 months, guidelines recommend use of combination DMARDs such as sulfasalazine plus hydroxychloroquine for those with moderate disease activity and poor prognostic features and is an option for those with high disease activity and poor prognostic features. For established disease, DMARD combination therapy is an option for patients with low disease activity and poor prognostic features or with moderate or high disease activity regardless of poor prognostic feature presence. If moderate or high disease activity exists after 3 months of combination DMARDS, an option is to add or switch DMARDS and reassess in another 3 months. For patients with low disease activity without poor prognostic features who have moderate or high disease activity after 3 months of DMARD monotherapy, the addition of hydroxychloroquine is an option.

    For the treatment of juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA) that has responded poorly to salicylates or other nonsteroidal anti-inflammatory drugs (NSAIDs).
    Oral dosage (only enteric-coated tablets FDA-approved)
    Children and Adolescents 6 years and older

    30 to 50 mg/kg/day PO, given in 2 divided doses. To lessen GI irritation, begin treatment with one-fourth to one-third of the planned maintenance dose and increase weekly until the maintenance dose is reached (usually at week 4). In a double-blind, placebo-controlled trial, sulfasalazine 50 mg/kg/day (Max: 2 grams/day) was significantly more effective than placebo in children with oligoarticular- or polyarticular-onset JIA; however, sulfasalazine was not well tolerated in one-third of the patients.

    For the treatment of mild to moderately active Crohn's disease† with colonic involvement.
    Oral dosage
    Adults

    The usual dosage is 3 to 6 grams/day PO, given in divided doses. Based on limited data, sulfasalazine is effective for treating symptoms of mild to moderately active colonic Crohn's disease (CD) and/or ileocolonic CD, but not isolated small bowel disease. Sulfasalazine has not been demonstrated to be more effective than placebo for achieving mucosal healing in patients with CD. Sulfasalazine is not recommended for the maintenance of remission; do not use long-term. At least 2 studies have evaluated sulfasalazine in the treatment of active Crohn's disease.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    4 grams/day PO for ulcerative colitis; 3 grams/day PO for rheumatoid arthritis.

    Geriatric

    4 grams/day PO for ulcerative colitis; 3 grams/day PO for rheumatoid arthritis.

    Adolescents

    60 mg/kg/day PO (not to exceed 4 grams/day) PO for ulcerative colitis induction; 30 mg/kg/day PO for ulcerative colitis maintenance. 2 grams/day PO for juvenile rheumatoid arthritis (JRA).

    Children

    6 years and older: 60 mg/kg/day PO (not to exceed 4 grams/day) PO for ulcerative colitis induction; 30 mg/kg/day PO for ulcerative colitis maintenance. 2 grams/day PO for juvenile rheumatoid arthritis (JRA).
    2 to 5 years: 40 to 60 mg/kg/day PO (not to exceed 4 grams/day) PO has been used for ulcerative colitis.
    Less than 2 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Sulfasalazine is partially metabolized in the liver by acetylation. Due to a risk for further hepatotoxicity, only after critical appraisal of risks and benefits should sulfasalazine be given to patients with hepatic damage. No specific dosage recommendations are available. In a pharmacokinetic study, patients who were slow acetylators were noted to have an increased incidence of adverse effects.

    Renal Impairment

    Sulfasalazine and its primary metabolite, sulfapyridine are excreted by the kidney. The drug may worsen renal function in those with pre-existing impairment; no specific dosage adjustments are available. Only after critical appraisal of risks and benefits should sulfasalazine be given to patients with renal damage.

    ADMINISTRATION

    Oral Administration

    Administer sulfasalazine with a full glass of water after meals or with food to minimize indigestion or GI irritation.

    Oral Solid Formulations

    Enteric-coated tablets:
    Administer sulfasalazine enteric-coated tablets whole; do not crush or chew.

    STORAGE

    Azulfidine:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Azulfidine En-Tabs:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Sulfazine :
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Sulfazine EC:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    5-aminosalicylates hypersensitivity, asthma, salicylate hypersensitivity, serious rash, sulfonamide hypersensitivity

    Sulfasalazine is broken down to sulfapyridine (a sulfonamide) and 5-aminosalicylic acid (mesalamine). Therefore, sulfasalazine is contraindicated in patients with sulfasalazine hypersensitivity, salicylate hypersensitivity, sulfonamide hypersensitivity, and 5-aminosalicylates hypersensitivity. Patients with severe allergic conditions or bronchial asthma are at risk of developing severe and potentially fatal exacerbations of asthma after taking sulfasalazine and the drug should be avoided in asthmatics with a history of aspirin-induced bronchospasm. Serious allergic reactions, some of them fatal or life-threatening, include serious rash, drug rash with eosinophilia and systemic symptoms (DRESS), exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with the use of sulfasalazine. Patients are at highest risk for these events early in therapy, with most events occurring within the first month of treatment. Sulfasalazine should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. Severe hypersensitivity reactions may include internal organ involvement, such as hepatitis, nephritis, myocarditis, mononucleosis-like syndrome (i.e., pseudomononucleosis), hematological abnormalities (including hematophagic histiocytosis), and/or pneumonitis including eosinophilic infiltration. Sulfasalazine has also rarely caused irreversible neuromuscular and central nervous system changes, and fibrosing alveolitis. If any such signs or symptoms of potential hypersensitivity or severe reactions are present, the patient should be evaluated immediately. Sulfasalazine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

    Agranulocytosis, aplastic anemia, folate deficiency, G6PD deficiency, hematological disease, neutropenia

    Only after careful consideration should sulfasalazine be used in a patient with hematological disease since sulfonamides are associated with blood dyscrasias. Sulfasalazine decreases folate absorption and patients should be monitored for folate deficiency; in some patients, folate supplementation is recommended. Deaths related to agranulocytosis (severe neutropenia), aplastic anemia, and other blood dyscrasias have been reported following sulfasalazine treatment. Monitor for the onset of sore throat, fever, pallor, or purpura which may be signs of a serious blood disorder. Complete blood cell count (CBC) with differential should be monitored at baseline and then every other week during the first 3 months of therapy, monthly during the next 3 months, and then every 3 months or as clinically indicated after that. Discontinue treatment while awaiting the results of blood tests if serious hematologic events are suspected. Patients with glucose-6 phosphate dehydrogenase deficiency (G6PD deficiency) should be monitored carefully during sulfasalazine therapy for signs of hemolytic anemia.

    Porphyria

    In patients with porphyria, sulfasalazine is contraindicated because sulfonamides can precipitate an acute attack.

    Hepatic disease, hepatotoxicity, jaundice, slow acetylation

    Only after careful consideration should sulfasalazine be used in a patient with hepatic disease since sulfonamides are metabolized in the liver and are rarely associated with severe hepatotoxicity. Deaths related to liver damage have been reported following sulfasalazine treatment. Monitor for the onset of nausea, vomiting, abdominal pain, loss of appetite, diarrhea, or jaundice which may be signs of a serious liver disorder. Liver function tests (LFTs) should be monitored at baseline and then every other week during the first 3 months of therapy, monthly during the next 3 months, and every 3 months or as clinically indicated after that. Discontinue treatment while awaiting the results of blood tests if jaundice or other indicators of hepatotoxicity are present. Slow acetylation status increases serum concentrations of sulfapyridine, and concentrations greater than 50 mcg/mL are associated with an increased risk of adverse reactions. Slow acetylation status is associated with ethnicity, with Eskimo, Oriental, and American Indian populations have the lowest prevalence of slow acetylators, while Egyptian, Israeli, Scandinavian or other White, and Black populations have the highest prevalence of slow acetylators.

    Bone marrow suppression, infection

    Caution should be exercised when considering the use of sulfasalazine in patients with a history of recurring or chronic infections or with underlying conditions or concomitant drugs which may predispose patients to infections. Serious infections, including fatal sepsis and pneumonia, have been reported during use of sulfasalazine. Some infections were associated with agranulocytosis, neutropenia, or bone marrow suppression. Discontinue sulfasalazine if a patient develops a serious infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with sulfasalazine. For a patient who develops a new infection during treatment with sulfasalazine, perform a prompt and complete diagnostic workup for infection and myelosuppression.

    Dehydration, hypovolemia, nephrolithiasis, renal failure, renal impairment, urinary tract obstruction

    Sulfasalazine is contraindicated in patients with urinary tract obstruction. Only after careful consideration should sulfasalazine be used in a patient with known renal damage, renal impairment, or renal failure because the drug is excreted in the urine, and accumulation is associated with an increased risk of toxicity. Deaths related to renal damage (nephrotoxicity) have been reported following sulfasalazine treatment. In patients with hypovolemia or dehydration, sulfasalazine may cause crystalluria and nephrolithiasis (stone formation) and contribute to urinary obstruction. Adequate fluid intake must be maintained in a treated patient in order to prevent crystalluria and stone formation. Monitor renal function, including urinalysis, periodically throughout sulfasalazine treatment.

    GI obstruction

    Sulfasalazine is contraindicated in patients with intestinal GI obstruction. Isolated cases have been reported where sulfasalazine enteric-coated tablets have passed undisintegrated. If this occurs, discontinue the administration of the enteric-coated tablets immediately.

    Sunlight (UV) exposure

    Photosensitization can occur with sulfa containing compounds, so patients taking sulfasalazine should avoid or limit sunlight (UV) exposure, including sunlamps and tanning booths. Sunscreens should be employed, but may provide limited protection for this reaction. Discontinue sulfasalazine use at the first sign of potential photosensitization.

    Pregnancy

    There are no adequate and well-controlled studies of sulfasalazine use during human pregnancy. Sulfasalazine and sulfapyridine (an active moiety) cross the placenta. There have been case reports of neural tube defects (NTDs) in infants born to mothers who were exposed to sulfasalazine during pregnancy. While the role of sulfasalazine in these defects has not been established, oral sulfasalazine does inhibit the absorption and metabolism of folic acid, which may interfere with folic acid supplementation and diminish the effect of periconceptional folic acid supplementation that has been shown to decrease the risk of NTDs. Guidelines state that sulfasalazine be continued during pregnancy for inflammatory bowel disease (IBD) or rheumatoid arthritis for maintenance of remission or treatment of a disease flare. Overall, sulfasalazine does not appear to be associated with a significant risk of teratogenicity when used during human pregnancy, with published epidemiologic literature not finding an increase in fetal malformation, morbidity or mortality. If sulfasalazine is used, then folate supplementation is especially important during treatment, with experts recommending folic acid supplementation of 2 mg/day throughout pregnancy concurrently. Although sulfapyridine has been shown to have poor bilirubin-displacing capacity, monitor the newborn for the potential for kernicterus. A case of agranulocytosis has been reported in an infant whose mother was taking both sulfasalazine and prednisone throughout pregnancy. For IBD, mesalamine products can be an alternative choice. Animal studies have revealed no evidence of impaired female fertility or harm to the fetus due to sulfasalazine at doses up to 6 times the human maintenance dose of 2 grams/day based on body surface area. The long-term effects of sulfasalazine on growth and maturation in the child are unknown.

    Breast-feeding, premature neonates

    Sulfasalazine should be used with caution in women who are breast-feeding. Unchanged sulfasalazine does not cross into breast milk in appreciable amounts. Insignificant amounts of sulfasalazine have been found in milk, whereas concentrations of the active metabolite (sulfapyridine) in milk are about 30% to 60% of those in the maternal serum. There are reports with limited data of bloody stools or diarrhea in the breast-fed infant exposed during lactation. In cases where the outcome was reported, bloody stools or diarrhea resolved in the infant after discontinuation of sulfasalazine in the mother or discontinuation of breast-feeding. Due to limited data, a causal relationship between sulfasalazine exposure and bloody stools or diarrhea cannot be confirmed or denied. Monitor the infant for signs and symptoms of diarrhea and/or bloody stools. The American Gastroenterological Association (AGA) recommends that patients preferentially be maintained on a 5-ASA agent that does not contain a sulfonamide due to the unknown side effects of sulfasalzine's sulfapyridine metabolite, which is excreted into milk at higher concentrations than the parent drug and has hemolytic and antimicrobial properties. In general, mesalamine and balsalazide may be preferred; the nursing infant should be observed for any persistent changes in bowel habits (e.g., persistent increase in stool frequency).[64164] The European League Against Rheumatism (EULAR) states that sulfasalazine is compatible with breast-feeding in the treatment of inflammatory arthritis conditions; consider continuation of sulfasalazine during lactation in women with rheumatoid arthritis as long as the nursing infant/child does not have conditions that contraindicate use. Use with caution during the breast-feeding of premature neonates, in an infant with G6PD deficiency, or in an infant with hyperbilirubinemia.[62180]

    Infertility

    Oligospermia, infertility, abnormal sperm forms, and impaired sperm motility have occurred in men during sulfasalazine therapy but are reversible upon stopping sulfasalazine.

    Children, infants

    Sulfasalazine have been administered to children with ulcerative colitis as young as 2 years of age, and patients with juvenille idiopathic arthritis age 6 years and older with selected features. Safety and effectiveness of sulfasalazine are not established in children or infants less than 2 years of age. Treatment of systemic-course JIA with sulfasalazine is not recommended due to the frequent association of sulfasalazine treatment in this subgroup with a serum sickness type reaction. This reaction is often severe and presents as fever, nausea, vomiting, headache, rash, and abnormal liver function tests.  

    Laboratory test interference

    Several reports of possible laboratory test interference with measurements, by liquid chromatography, of urinary normetanephrine causing a false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalamine/mesalazine.

    ADVERSE REACTIONS

    Severe

    hemolytic anemia / Delayed / 0-3.3
    cyanosis / Early / 0-3.3
    enterocolitis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    methemoglobinemia / Early / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    megaloblastic anemia / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known
    anuria / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    hepatic failure / Delayed / Incidence not known
    serum sickness / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    myelitis / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known
    Guillain-Barre syndrome / Delayed / Incidence not known
    seizures / Delayed / Incidence not known

    Moderate

    stomatitis / Delayed / 4.0-4.0
    elevated hepatic enzymes / Delayed / 4.0-4.0
    leukopenia / Delayed / 3.0-3.0
    thrombocytopenia / Delayed / 1.0-1.0
    hypoglycemia / Early / 0-1.0
    goiter / Delayed / 0-1.0
    colitis / Delayed / Incidence not known
    folate deficiency / Delayed / Incidence not known
    hypoprothrombinemia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    nephrolithiasis / Delayed / Incidence not known
    crystalluria / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    meningitis / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known

    Mild

    vomiting / Early / 8.0-33.0
    anorexia / Delayed / 33.0-33.0
    nausea / Early / 19.0-33.0
    oligospermia / Delayed / 33.0-33.0
    headache / Early / 9.0-33.0
    dyspepsia / Early / 13.0-13.0
    rash / Early / 0-13.0
    abdominal pain / Early / 8.0-8.0
    fever / Early / 0-5.0
    pruritus / Rapid / 0-4.0
    dizziness / Early / 4.0-4.0
    urticaria / Rapid / 0-3.3
    diuresis / Early / 0-1.0
    diarrhea / Early / Incidence not known
    purpura / Delayed / Incidence not known
    urine discoloration / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    skin discoloration / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    drowsiness / Early / Incidence not known
    insomnia / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    infection / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Concomitant use of sulfonamides and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use.
    Acalabrutinib: (Moderate) Coadministration of acalabrutinib and sulfasalazine may increase sulfasalazine exposure and increase the risk of sulfasalazine toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Sulfasalazine is a BCRP subtrate.
    Acarbose: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Acetohexamide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Albiglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Alogliptin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Alpelisib: (Major) Avoid coadministration of alpelisib with sulfasalazine due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and sulfasalazine is a BCRP inhibitor.
    Alpha-glucosidase Inhibitors: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Aminosalicylate sodium, Aminosalicylic acid: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Amlodipine; Celecoxib: (Moderate) Monitor patients for signs of worsening renal function during coadministration of sulfasalazine and celecoxib. Coadministration may increase the risk for drug-induced nephrotoxicity.
    Amoxicillin: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Amoxicillin; Clarithromycin; Lansoprazole: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Amoxicillin; Clavulanic Acid: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Ampicillin: (Minor) Sulfonamides may compete with ampicillin for renal tubular secretion, increasing ampicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Ampicillin; Sulbactam: (Minor) Sulfonamides may compete with ampicillin for renal tubular secretion, increasing ampicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Ardeparin: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
    Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Aspirin, ASA: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Carisoprodol: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Carisoprodol; Codeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Dipyridamole: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Omeprazole: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Oxycodone: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Aspirin, ASA; Pravastatin: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly. (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Azathioprine: (Moderate) 5-aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine) may interact with azathioprine and increase the risk of azathioprine-related toxicity. The inhibition of thiopurine methyltransferase activity, one of the enzymes responsible for azathioprine metabolism, by 5-aminosalicylates has been described via in vitro and in vivo study. Theoretically, this interaction could result in a higher risk of bone marrow suppression or other azathioprine dose-related side effects. If concurrent therapy cannot be avoided, closely monitor platelet and complete blood cell counts.
    Benzocaine: (Moderate) Rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine products. Examples of other drugs that can cause methemoglobinemia include the sulfonamides. Therefore, caution is warranted when combining such medications with topical or oromucosal benzocaine products. Patients using OTC benzocaine gels and liquids should be advised to seek immediate medical attention if signs or symptoms of methemoglobinemia develop. In addition, clinicians should closely monitor patients for the development of methemoglobinemia when benzocaine sprays are used during a procedure.
    Benzocaine; Butamben; Tetracaine: (Moderate) Rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine products. Examples of other drugs that can cause methemoglobinemia include the sulfonamides. Therefore, caution is warranted when combining such medications with topical or oromucosal benzocaine products. Patients using OTC benzocaine gels and liquids should be advised to seek immediate medical attention if signs or symptoms of methemoglobinemia develop. In addition, clinicians should closely monitor patients for the development of methemoglobinemia when benzocaine sprays are used during a procedure.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly. (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Bismuth Subsalicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like sulfasalazine; the risk of peripheral neuropathy may be additive.
    Bromocriptine: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. Bromocriptine is highly bound to serum proteins. Therefore, it may increase the unbound fraction of other highly protein-bound medications (e.g., sulfonamides), which may alter their effectiveness and risk for side effects.
    Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Canagliflozin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Canagliflozin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Capmatinib: (Moderate) Monitor for an increase in sulfasalazine-related adverse reactions if coadministration with capmatinib is necessary. Sulfasalazine is a BCRP substrate and capmatinib is a BCRP inhibitor.
    Cardiac glycosides: (Moderate) Sulfasalazine has been reported to reduce the absorption of digoxin by 20%. It is thought that the decrease in digoxin absorption is due to alterations in the properties of the gut wall. Therefore, separating the time of administration between sulfasalazine and digoxin will probably not reduce the potential interaction.The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of sulfasalazine. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Celecoxib: (Moderate) Monitor patients for signs of worsening renal function during coadministration of sulfasalazine and celecoxib. Coadministration may increase the risk for drug-induced nephrotoxicity.
    Chloroprocaine: (Major) Coadministration of chloroprocaine with sulfonamides may antagonize the effect of sulfonamides. Chloroprocaine is metabolized to para-aminobenzoic acid (PABA). PABA antagonized the effects of sulfonamides. Additionally, coadministration of chloroprocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Chlorpropamide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Choline Salicylate; Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Colchicine; Probenecid: (Minor) Probenecid may inhibit the renal transport of sulfonamides. Plasma concentrations of these agents may be increased.
    Cyclosporine: (Moderate) Use caution and closely monitor cyclosporine serum concentrations when administered concurrently with sulfasalazine. Use of these drugs together may result in decreased cyclosporine serum concentrations and the potential for decreased efficacy. Cyclosporine dose adjustments may be necessary and should be guided by serum concentrations during coadministration.
    Daclatasvir: (Moderate) Systemic exposure of sulfasalazine, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of sulfasalazine; monitor patients for potential adverse effects.
    Dalteparin: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
    Dapagliflozin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Dapagliflozin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Dapagliflozin; Saxagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Dapsone: (Moderate) Coadministration of dapsone with sulfonamides may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
    Darolutamide: (Moderate) Caution is advised with the coadministration of darolutamide and sulfasalazine due to the potential for increased plasma concentrations of sulfasalazine increasing the risk of adverse effects. Sulfasalazine is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
    Dicloxacillin: (Minor) Sulfonamides may compete with dicloxacillin for renal tubular secretion, increasing dicloxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Dienogest; Estradiol valerate: (Moderate) Anti-infectives that disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen-containing oral contraceptives.
    Digitoxin: (Moderate) Sulfasalazine has been reported to reduce the absorption of digoxin by 20%. It is thought that the decrease in digoxin absorption is due to alterations in the properties of the gut wall. Therefore, separating the time of administration between sulfasalazine and digoxin will probably not reduce the potential interaction.The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of sulfasalazine. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Digoxin: (Moderate) Sulfasalazine has been reported to reduce the absorption of digoxin by 20%. It is thought that the decrease in digoxin absorption is due to alterations in the properties of the gut wall. Therefore, separating the time of administration between sulfasalazine and digoxin will probably not reduce the potential interaction.The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of sulfasalazine. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
    Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Diphenhydramine; Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) L-methylfolate should be used cautiously in patients taking sulfasalazine. Sulfasalazine exhibits antifolate activity and can inhibit the absorption and lower the plasma concentrations of L-methylfolate. Patients receiving sulfasalazine should be monitored for decreased efficacy of L-methylfolate therapy.
    Dulaglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Elbasvir; Grazoprevir: (Moderate) Administering sulfasalazine with elbasvir; grazoprevir may result in elevated sulfasalazine plasma concentrations. Sulfasalazine is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
    Eltrombopag: (Moderate) Use caution and monitor for adverse reactions if eltrombopag and sulfasalazine are coadministered. Eltrombopag is an inhibitor of Breast Cancer Resistance Protein (BCRP). Drugs that are substrates for this transporter, such as sulfasalazine, may exhibit an increase in systemic exposure if coadministered with eltrombopag.
    Empagliflozin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Empagliflozin; Linagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Empagliflozin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Enoxaparin: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
    Ertugliflozin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Ertugliflozin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Ertugliflozin; Sitagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Esomeprazole; Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Anti-infectives which disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    Estradiol: (Moderate) Anti-infectives that disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen-containing oral contraceptives. (Moderate) Anti-infectives which disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen containing oral contraceptives. Alternative or additional contraception may be advisable.
    Etanercept: (Moderate) The combined use of etanercept and sulfasalazine may cause neutropenia. Carefully monitor patients who receive etanercept and sulfasalazine concurrently.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) L-methylfolate should be used cautiously in patients taking sulfasalazine. Sulfasalazine exhibits antifolate activity and can inhibit the absorption and lower the plasma concentrations of L-methylfolate. Patients receiving sulfasalazine should be monitored for decreased efficacy of L-methylfolate therapy. (Minor) Sulfasalazine exhibits antifolate activity, and can inhibit the absorption and lower the plasma concentrations of folic acid, vitamin B9. Patients receiving sulfasalazine treatment may require folic acid supplementation.
    Exenatide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Fenoprofen: (Minor) An interaction may occur between fenoprofen and sulfonamides. Fenoprofen is 99% bound to albumin. Thus, fenoprofen may displace other highly protein bound drugs from albumin or vice versa. If fenoprofen is used concurrently with sulfonamides, monitor patients for toxicity from any of the drugs.
    Fluvastatin: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as sulfonamides, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity.
    Folic Acid, Vitamin B9: (Minor) Sulfasalazine exhibits antifolate activity, and can inhibit the absorption and lower the plasma concentrations of folic acid, vitamin B9. Patients receiving sulfasalazine treatment may require folic acid supplementation.
    Fostamatinib: (Moderate) Monitor for sulfasalazine toxicities that may require sulfasalazine dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP substrate may increase the concentration of the BCRP substrate. The active metabolite of fostamatinib, R406, is a BCRP inhibitor; sulfasalazine is a substrate for BCRP. Coadministration of fostamatinib with another BCRP substrate increased the BCRP substrate AUC by 95% and Cmax by 88%.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and sulfasalazine as coadministration may increase serum concentrations of sulfasalazine and increase the risk of adverse effects. Sulfasalazine is a substrate of breast cancer resistance protein (BCRP); glecaprevir is an inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and sulfasalazine as coadministration may increase serum concentrations of sulfasalazine and increase the risk of adverse effects. Sulfasalazine is a substrate of breast cancer resistance protein (BCRP); pibrentasvir is an inhibitor of BCRP.
    Glimepiride: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Glimepiride; Pioglitazone: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Glimepiride; Rosiglitazone: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Glipizide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Glipizide; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Glyburide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Glyburide; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Heparin: (Moderate) Coadministration of 5-aminosalicylates and heparin may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of heparin. If this is not possible, it is recommended to monitor patients closely for bleeding.
    Hydrochlorothiazide, HCTZ; Losartan: (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as sulfonamides, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly. (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Incretin Mimetics: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Insulin Degludec; Liraglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Insulin Glargine; Lixisenatide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Insulins: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) A decrease in sulfasalazines therapeutic efficacy could be seen when rifampin is coadministered; monitor the patient for response to therapy. Sulfasalazine is metabolized to its active components, sulfapyridine and mesalamine, by bacteria in the colon. Concomitant use of rifampin may alter the colonic bacteria.
    Isoniazid, INH; Rifampin: (Moderate) A decrease in sulfasalazines therapeutic efficacy could be seen when rifampin is coadministered; monitor the patient for response to therapy. Sulfasalazine is metabolized to its active components, sulfapyridine and mesalamine, by bacteria in the colon. Concomitant use of rifampin may alter the colonic bacteria.
    Itraconazole: (Moderate) Administering sulfasalazine with itraconazole may increase sulfasalazine plasma concentrations, potentially resulting in adverse events. Sulfasalazine is a substrate of the drug transporter breast cancer resistance protein (BCRP) transporter; itraconazole is a BCRP inhibitor.
    Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Concomitant use of sulfonamides and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use.
    Lansoprazole; Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
    Leflunomide: (Moderate) An additive effect may occur when leflunomide is given concomitantly with other hepatotoxic drugs. Sulfasalazine has caused elevations in liver enzymes and concomitant therapy with leflunomide may warrant caution.
    Levomefolate: (Minor) L-methylfolate should be used cautiously in patients taking sulfasalazine. Sulfasalazine exhibits antifolate activity and can inhibit the absorption and lower the plasma concentrations of L-methylfolate. Patients receiving sulfasalazine should be monitored for decreased efficacy of L-methylfolate therapy.
    Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of prilocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Linagliptin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Liraglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Lixisenatide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Losartan: (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as sulfonamides, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.
    Low Molecular Weight Heparins: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
    Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Meglitinides: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mepivacaine; Levonordefrin: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mercaptopurine, 6-MP: (Moderate) Increased bone marrow suppression may occur if mercaptopurine is coadministered with sulfasalazine. If concomitant use is necessary, use the lowest possible doses of each drug and closely monitor the patient for myelosuppression. 5-Aminosalicylates, such as sulfasalazine, have been shown to inhibit the thiopurine methyltransferase (TPMT) enzyme in vitro. Mercaptopurine is inactivated via the TPMT enzyme.
    Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Metformin; Pioglitazone: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Metformin; Repaglinide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Metformin; Rosiglitazone: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Metformin; Saxagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Metformin; Sitagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Methenamine: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.
    Methenamine; Sodium Acid Phosphate: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Sulfonamides can crystallize in an acidic urine. Because methenamine salts produce an acidic urine, these agents should not be used concomitantly.
    Methotrexate: (Moderate) Concurrent use of sulfasalazine and methotrexate may increase the incidence of methotrexate-related adverse events. Methotrexate is partially bound to albumin, and toxicity may be increased because of displacement by sulfonamides.
    Methoxsalen: (Moderate) Use methoxsalen and sulfonamides together with caution; the risk of severe burns/photosensitivity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
    Miglitol: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
    Naproxen; Pseudoephedrine: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
    Naproxen; Sumatriptan: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
    Omeprazole; Amoxicillin; Rifabutin: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Osimertinib: (Moderate) Monitor for an increase in sulfasalazine-related adverse reactions if coadministration with osimertinib is necessary. Sulfasalazine is a BCRP substrate and osimertinib is a BCRP inhibitor.
    Oxacillin: (Minor) Sulfonamides may compete with oxacillin for renal tubular secretion, increasing oxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Ozanimod: (Major) Coadministration of ozanimod with sulfasalazine is not recommended. Coadministration may increase the exposure of the active metabolites of ozanimod, which may increase the risk of adverse reactions. Ozanimod is a BCRP substrate and sulfasalazine is a BCRP inhibitor. Coadministration with another BCRP inhibitor had no effect on ozanimod exposure, but doubled the exposure of the minor active metabolites, RP101988 and RP101075 (the direct precursor of the major active metabolite CC112273). Coadministration of ozanimod with BCRP inhibitors may also increase exposure of CC112273 and CC1084037.
    Penicillin G Benzathine: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Sulfonamides may also compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects. (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Sulfonamides may also compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Penicillin G: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Penicillin V: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with sulfasalazine. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
    Photosensitizing agents (topical): (Moderate) Sulfonamides may cause photosensitization and may increase the photosensitizing effects of photosensitizing agents used during photodynamic therapy.
    Piperacillin: (Minor) Sulfonamides may compete with piperacillin for renal tubular secretion, increasing piperacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Piperacillin; Tazobactam: (Minor) Sulfonamides may compete with piperacillin for renal tubular secretion, increasing piperacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
    Ponatinib: (Moderate) Concomitant use of ponatinib, an ABCG2 (BCRP) inhibitor, and sulfasalazine, an ABCG2 (BCRP) substrate, may increase the exposure of sulfasalazine.
    Porfimer: (Major) Avoid coadministration of porfimer with sulfonamides due to the risk of increased photosensitivity. Porfimer is a light-activated drug used in photodynamic therapy; all patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like sulfonamides may increase the risk of a photosensitivity reaction.
    Pramlintide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Probenecid: (Minor) Probenecid may inhibit the renal transport of sulfonamides. Plasma concentrations of these agents may be increased.
    Pyrimethamine: (Moderate) Concomitant use of other antifolic drugs associated with myelosuppression, including sulfonamides, may increase the risk of bone marrow suppression.
    Pyrimethamine; Sulfadoxine: (Moderate) Concomitant use of other antifolic drugs associated with myelosuppression, including sulfonamides, may increase the risk of bone marrow suppression.
    Regorafenib: (Moderate) Monitor for an increase in sulfasalazine-related adverse reactions if coadministration with regorafenib is necessary. Sulfasalazine is a BCRP substrate and regorafenib is a BCRP inhibitor.
    Rifampin: (Moderate) A decrease in sulfasalazines therapeutic efficacy could be seen when rifampin is coadministered; monitor the patient for response to therapy. Sulfasalazine is metabolized to its active components, sulfapyridine and mesalamine, by bacteria in the colon. Concomitant use of rifampin may alter the colonic bacteria.
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and sulfasalazine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Rimegepant: (Major) Avoid coadministration of rimegepant with sulfasalazine; concurrent use may increase rimegepant exposure. Rimegepant is a substrate of BCRP and sulfasalazine is a BCRP inhibitor.
    Rituximab: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as sulfasalazine, may result in an increased risk of infection. Monitor patients closely for signs or symptoms of infection. For a patient who develops a new infection during treatment with sulfasalazine, perform a prompt and complete diagnostic workup for infection and myelosuppression.
    Rituximab; Hyaluronidase: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as sulfasalazine, may result in an increased risk of infection. Monitor patients closely for signs or symptoms of infection. For a patient who develops a new infection during treatment with sulfasalazine, perform a prompt and complete diagnostic workup for infection and myelosuppression.
    Rolapitant: (Moderate) Use caution if sulfasalazine and rolapitant are used concurrently, and monitor for sulfasalazine-related adverse effects. Sulfasalazine is a substrate of the Breast Cancer Resistance Protein (BCRP); rolapitant is a BCRP inhibitor. The Cmax and AUC of sulfasalazine were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration.
    Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Safinamide: (Moderate) Safinamide at the 100 mg dose and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP), which could increase plasma concentrations of BCRP substrates such as sulfasalazine. Monitor patients for increased pharmacologic or adverse effects of BCRP substrates during concurrent use of safinamide, particularly the 100 mg dose.
    Salicylates: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Salsalate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
    Semaglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    SGLT2 Inhibitors: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Simeprevir: (Moderate) Systemic exposure of sulfasalazine, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with simeprevir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of sulfasalazine; monitor patients for potential adverse effects.
    Sodium Iodide: (Moderate) Sulfonamides may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir with sulfasalazine. Taking these medications together may increase the plasma concentrations of sulfasalazine. Sulfasalazine is a substrate for the drug transporter Breast Cancer Resistance Protein (BCRP). Voxilaprevir is a BCRP inhibitor.
    Sulfonylureas: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Tafamidis: (Moderate) Caution is advised with the coadministration of tafamidis and sulfasalazine due to the potential for increased plasma concentrations of sulfasalazine increasing the risk of adverse effects. Sulfasalazine dose adjustment may be needed with coadministration. Sulfasalazine is a substrate of breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor.
    Talazoparib: (Major) Avoid coadministration of sulfasalazine with talazoparib due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a BCRP substrate and sulfasalazine is a BCRP inhibitor. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure.
    Tedizolid: (Moderate) If possible, stop use of sulfasalazine temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for sulfasalazine-associated adverse events. Sulfasalazine plasma concentrations may be increased when administered concurrently with oral tedizolid. Sulfasalazine is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
    Tetracaine: (Major) Coadministration of tetracaine with sulfonamides may antagonize the effect of sulfonamides. Tetracaine is metabolized to para-aminobenzoic acid (PABA). PABA antagonized the effects of sulfonamides. Additionally, coadministration of tetracaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Thiazolidinediones: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Thioguanine, 6-TG: (Moderate) Use these drugs together with caution; concomitant use may result in reduced metabolism of thioguanine via TPMT and an increased risk for thioguanine-induced toxicity. Monitor patients for signs and symptoms of hematologic and hepatic toxicity. There is in vitro evidence that 5-aminosalicylate derivatives inhibit thiopurine methyltransferase (TPMT), the enzyme that metabolizes thioguanine. Increased thioguanine concentrations can lead to an increased risk for severe thioguanine-induced myelosuppression. In cases of bone marrow suppression, a dose reduction of thioguanine may be necessary.
    Tinzaparin: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
    Tolazamide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Tolbutamide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
    Topotecan: (Major) Avoid coadministration of sulfasalazine with oral topotecan due to increased topotecan exposure; sulfasalazine may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and sulfasalazine is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Typhoid Vaccine: (Major) Avoid use of sulfonamides and other antibiotics during the oral typhoid vaccination series at concurrent administration may result in a reduced immune response. In order to provided immunity, the oral typhoid vaccine requires initiation of a limited infection localized within the gastrointestinal tract. Antibiotics prevent this bacterial infection from occurring, thereby, reducing the vaccines protective immune response.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with sulfasalazine. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP drug transporter; sulfasalazine is a BCRP inhibitor.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with sulfonamides is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like sulfonamides may increase the risk of a photosensitivity reaction.
    Voriconazole: (Moderate) Voriconazole is metabolized by the CYP2C9 isoenzyme, and drugs that are known to be inhibitors of CYP2C9 may theoretically lead to elevated plasma levels of voriconazole when coadministered. Drugs that are known to be inhibitors of CYP2C9 include sulfonamides.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with sulfonamides is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Warfarin doses may need to be adjusted when sulfonamide therapy is discontinued. Sulfonamides, including sulfathiazole, sulfamethoxazole, and sulfisoxazole, potentiate the anticoagulant effect of warfarin. Sulfonamides are known to inhibit the hepatic metabolism of S-warfarin and have, in some cases, doubled the hypoprothrombinemic effect of warfarin. A protein-binding interaction also may be possible, with sulfonamides displacing warfarin from protein binding sites.
    Zidovudine, ZDV: (Moderate) Concomitant use of sulfonamides and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies of sulfasalazine use during human pregnancy. Sulfasalazine and sulfapyridine (an active moiety) cross the placenta. There have been case reports of neural tube defects (NTDs) in infants born to mothers who were exposed to sulfasalazine during pregnancy. While the role of sulfasalazine in these defects has not been established, oral sulfasalazine does inhibit the absorption and metabolism of folic acid, which may interfere with folic acid supplementation and diminish the effect of periconceptional folic acid supplementation that has been shown to decrease the risk of NTDs. Guidelines state that sulfasalazine be continued during pregnancy for inflammatory bowel disease (IBD) or rheumatoid arthritis for maintenance of remission or treatment of a disease flare. Overall, sulfasalazine does not appear to be associated with a significant risk of teratogenicity when used during human pregnancy, with published epidemiologic literature not finding an increase in fetal malformation, morbidity or mortality. If sulfasalazine is used, then folate supplementation is especially important during treatment, with experts recommending folic acid supplementation of 2 mg/day throughout pregnancy concurrently. Although sulfapyridine has been shown to have poor bilirubin-displacing capacity, monitor the newborn for the potential for kernicterus. A case of agranulocytosis has been reported in an infant whose mother was taking both sulfasalazine and prednisone throughout pregnancy. For IBD, mesalamine products can be an alternative choice. Animal studies have revealed no evidence of impaired female fertility or harm to the fetus due to sulfasalazine at doses up to 6 times the human maintenance dose of 2 grams/day based on body surface area. The long-term effects of sulfasalazine on growth and maturation in the child are unknown.

    Sulfasalazine should be used with caution in women who are breast-feeding. Unchanged sulfasalazine does not cross into breast milk in appreciable amounts. Insignificant amounts of sulfasalazine have been found in milk, whereas concentrations of the active metabolite (sulfapyridine) in milk are about 30% to 60% of those in the maternal serum. There are reports with limited data of bloody stools or diarrhea in the breast-fed infant exposed during lactation. In cases where the outcome was reported, bloody stools or diarrhea resolved in the infant after discontinuation of sulfasalazine in the mother or discontinuation of breast-feeding. Due to limited data, a causal relationship between sulfasalazine exposure and bloody stools or diarrhea cannot be confirmed or denied. Monitor the infant for signs and symptoms of diarrhea and/or bloody stools. The American Gastroenterological Association (AGA) recommends that patients preferentially be maintained on a 5-ASA agent that does not contain a sulfonamide due to the unknown side effects of sulfasalzine's sulfapyridine metabolite, which is excreted into milk at higher concentrations than the parent drug and has hemolytic and antimicrobial properties. In general, mesalamine and balsalazide may be preferred; the nursing infant should be observed for any persistent changes in bowel habits (e.g., persistent increase in stool frequency).[64164] The European League Against Rheumatism (EULAR) states that sulfasalazine is compatible with breast-feeding in the treatment of inflammatory arthritis conditions; consider continuation of sulfasalazine during lactation in women with rheumatoid arthritis as long as the nursing infant/child does not have conditions that contraindicate use. Use with caution during the breast-feeding of premature neonates, in an infant with G6PD deficiency, or in an infant with hyperbilirubinemia.[62180]

    MECHANISM OF ACTION

    Sulfasalazine is metabolized to its active components, sulfapyridine and mesalamine (5-ASA), by bacteria in the colon. When given as sulfasalazine, a larger quantity of sulfapyridine and mesalamine reach the colon than when these agents are administered as single agents. Once sulfapyridine and mesalamine reach the colon, the beneficial effects result primarily from the antiinflammatory properties of mesalamine. The antiinflammatory mechanism of mesalamine is believed to occur, at least in part, through the inhibition of arachidonic acid metabolism in the bowel mucosa by inhibition of cyclooxygenase. This effectively diminishes the production of prostaglandins, thereby reducing colonic inflammation. Production of arachidonic metabolites appears to be increased in patients with inflammatory bowel disease. Mesalamine also inhibits leukotriene synthesis, possibly through the inhibition of lipoxygenase. This action has been suggested as a major component of the drug's antiinflammatory effects. Inhibition of colonic mucosal sulfidopeptide leukotriene synthesis and chemotactic stimuli for polymorphonuclear leukocytes may also occur.

    PHARMACOKINETICS

    Sulfasalazine is administered orally. The absorbed sulfapyridine is acetylated and hydroxylated in the liver followed by glucuronide formation. Absorbed 5-aminosalicylic acid is acetylated in the intestinal mucosa or liver. The majority of a systemically-absorbed sulfasalazine is excreted in the urine, consisting of 15% unchanged drug, 60% sulfapyridine and its metabolites, and 20% to 33% 5-ASA and its metabolites. Approximately 67% of 5-ASA is excreted in the feces. The half-life of sulfasalazine is 5.7 hours following oral administration of a single dose and 7.6 hours after the administration of multiple doses. The half-life of sulfapyridine is 6 to 14 hours, depending upon the acetylator status. Slow acetylators have an increased incidence of adverse effects, perhaps due to increased sulfapyridine concentrations.
     
    Affected cytochrome P450 isoenzymes and drug transporters: None

    Oral Route

    Approximately 20% of an oral dose is absorbed as unchanged sulfasalazine from the small intestine. A portion of the absorbed sulfasalazine is believed to be excreted into the intestine via the bile. The remainder of the oral dose passes to the colon where the azo-linkage is cleaved by intestinal bacteria, generating sulfapyridine and 5-aminosalicylic acid (mesalamine). The majority of sulfapyridine (60% to 80%) is then absorbed, while only about 25% of 5-aminosalicylic acid is absorbed systemically. Peak serum concentrations of sulfasalazine occur within 1.5 to 6 hours of oral administration of the uncoated-tablets and within 3 to 12 hours following administration of the enteric-coated tablets. Peak serum concentrations of sulfapyridine occur within 6 to 24 hours after oral administration of the uncoated-tablets and 12 to 24 hours after the enteric-coated tablets. Mean peak serum concentrations of sulfapyridine 12 hours after a single 2 g dose are 21 mcg/mL and 13 mcg/mL for uncoated and enteric-coated tablets, respectively. Serum concentrations of 5-aminosalicylic acid range from 0 to 4 mcg/mL in patients with ulcerative colitis.