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  • CLASSES

    Aminosalicyclic Acid and Related Intestinal Antiinflammatory Agents
    Other Specific Antirheumatics

    DEA CLASS

    Rx

    DESCRIPTION

    Combination of sulfapyridine and 5-aminosalicylic acid (mesalamine); cleaved to these active components by bacteria in the colon; efficacy due to local actions of mesalamine.

    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; as adjunctive therapy in the treatment of severe ulcerative colitis; and to prolong the remission period between acute attacks of ulcerative colitis.
    Oral dosage (uncoated tablets)
    Adults

    Initially, 1 gram PO every 6—8 hours. Adverse GI effects may be lessened by reducing initial dosage to 500 mg every 6—12 hours. Maintenance dose is usually 500 mg PO every 6 hours, adjusted to patient response and tolerance. Total doses of more than 4 g/day may increase the risk of adverse effects and toxicity.

    Children >= 6 years and Adolescents

    Initially, 40—60 mg/kg/day PO in 3—6 divided doses. The recommended maintenance dose is 30 mg/kg/day PO divided every 6 hours, not to exceed 2 grams/day.

    Oral dosage (enteric-coated tablets)
    Adults

    Initially, 3—4 g/day PO in evenly divided doses (at least every 8 hours). It is recommended to initiate therapy with 1—2 g/day PO to reduce GI intolerance. If daily doses exceed 4 g, there is an increased risk of GI adverse effects. The recommended maintenance dose is 2 g/day PO in divided doses. If symptoms of GI intolerance occur after the first few days of therapy, they may be alleviated by halving the daily dose of sulfasalazine and subsequently increasing it gradually over several days. If gastric intolerance continues the drug should be stopped for 5—7 days, then reintroduced at lower daily doses.

    Children >= 6 years and Adolescents

    40—60 mg/kg/day PO in 3—6 divided doses initially. A maintenance dose of 30 mg/kg/day PO in 4 divided doses is recommended. Maximum maintenance dose of 2 g/day has been recommended.

    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

    0.5—1 g PO per day for the first week. Increase the daily dose by 500 mg each week up to a maintenance dose of 2 g/day, which may be given in 2—3 divided doses. As opposed to NSAIDs, a therapeutic response is not observed immediately but can be seen in 4 weeks, but treatment for 12 weeks may be required in some patients. Consideration can be given to increasing the daily dose of the enteric coated tablets to 3 g/day PO if clinical response is inadequate after 12 weeks. Careful monitoring is recommended for doses > 2 g/day. Guidelines recommend DMARD monotherapy such as sulfasalazine for patients with a disease duration < 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—1000 mg PO twice daily plus methotrexate 7.5—17.5 mg PO once/week 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 < 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—1000 mg PO twice daily plus hydroxychloroquine 200 mg PO twice daily and methotrexate 7.5—17.5 mg PO per week plus 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 < 6 months, guidelines recommend use of combination DMARDs such as sulfasalazine, methotrexate, and 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.

    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 nine 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 < 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 >= 6 years and Adolescents

    30—50 mg/kg/day PO in 2 divided doses. To lessen GI irritation, begin treatment with one-fourth to one-third of the planned maintenance dose and increase the dose 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 g/day) was significantly more effective than placebo in children with oligoarticular- or polyarticular-onset juvenile chronic arthritis; however, sulfasalazine was not well tolerated in one-third of the patients.

    For the treatment of Crohn's disease†, particularly patients with colonic involvement.
    Oral dosage
    Adults

    At least 2 studies have evaluated sulfasalazine in the treatment of Crohn's disease. Both studies found sulfasalazine to be effective, but mostly in patients with colonic involvement. In one study, a dose of 1 g of sulfasalazine per 15 kg of body weight, up to a maximum of 5 g/day was used. In the other study, a dose of 3 g/day was used.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    No defined maximum dose for ulcerative colitis, but a total dose of more than 4 g/day PO may increase the risk of adverse effects and toxicity; 3 g/day PO for rheumatoid arthritis.

    Elderly

    No defined maximum dose for ulcerative colitis, but a total dose of more than 4 g/day PO may increase the risk of adverse effects and toxicity; 3 g/day PO for rheumatoid arthritis.

    Adolescents

    2 g/day PO for juvenile rheumatoid arthritis (JRA) or for ulcerative colitis maintenance.

    Children

     >= 6 years: 2 g/day PO for juvenile rheumatoid arthritis (JRA) or for ulcerative colitis maintenance.
    < 6 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Sulfasalazine is metabolized in the liver. Dosage may need to be modified depending on clinical response and degree of hepatic impairment, but no quantitative recommendations are available. Slow acetylators have been associated with an increased incidence of adverse effects, perhaps due to increased sulfapyridine concentrations.

    Renal Impairment

    Sulfasalazine and it's primary metabolite, sulfapyridine are excreted by the kidney. Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available. Slow acetylators have been associated with an increased incidence of adverse effects, perhaps due to increased sulfapyridine concentrations.

    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 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

    General Information

    Serum concentrations of sulfapyridine may be higher in patients who are slow acetylators, leading to an increased risk of adverse reactions. Serum concentrations of sulfapyridine > 50 mcg/ml are associated with more adverse reactions. Eskimo, Oriental, and American Indian populations have the lowest prevalence of slow acetylators, while Egyptian, Israeli, Scandinavian, other Caucasian, and black populations have the highest prevalence of slow acetylators.

    5-aminosalicylates hypersensitivity, carbonic anhydrase inhibitor hypersensitivity, salicylate hypersensitivity, sulfonamide hypersensitivity, sulfonylurea hypersensitivity, thiazide diuretic 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. Due to structural similarity to sulfonamides, patients with furosemide hypersensitivity, thiazide diuretic hypersensitivity, sulfonylurea hypersensitivity, or carbonic anhydrase inhibitor hypersensitivity should use sulfasalazine with caution. Deaths related to hypersensitivity reactions and irreversible neuromuscular and central nervous system changes have been reported following sulfasalazine treatment.

    Folate deficiency megaloblastic anemia, G6PD deficiency, hematological disease

    Only after careful consideration should sulfasalazine be used in a patient with hematological disease since sulfonamides are associated with blood dyscrasias. Sulfasalazine should be used with caution in patients with pre-existing folate deficiency megaloblastic anemia since it decreases folate absorption. Deaths related to agranulocytosis, 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 done at baseline and then every other week during the first three months of therapy, monthly during the next 3 months, and thereafter, every 3 months or as clinically indicated. Discontinue treatment while awaiting the results of blood tests. Patients with G6PD deficiency should be monitored carefully during sulfasalazine therapy for signs of hemolytic anemia.

    Hepatic disease, jaundice

    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 done at baseline and then every other week during the first three months of therapy, monthly during the next 3 months, and thereafter, every 3 months or as clinically indicated. Discontinue treatment while awaiting the results of blood tests.

    Porphyria

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

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

    Only after careful consideration should sulfasalazine be used in a patient with 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 have been reported following sulfasalazine treatment. Sulfasalazine is contraindicated in patients with urinary tract obstruction. In patients with hypovolemia or dehydration, sulfasalazine may cause crystalluria and contribute to urinary obstruction. In adults, adequate fluid intake should be maintained to achieve urine output of at least 1200 ml/day during sulfasalazine treatment. Alkalinization of the urine may increase the solubility of sulfasalazine in patients with low urine output or if the urinary pH is low. Monitoring of renal function including urinalysis should be done periodically throughout sulfasalazine treatment.

    Asthma

    Patients with severe allergic conditions or bronchial asthma are at risk of developing severe and potentially fatal exacerbations of asthma after taking sulfasalazine. Sulfasalazine should be avoided in asthmatics with a history of aspirin-induced bronchospasm. Deaths related to fibrosing alveolitis have been reported following sulfasalazine treatment.

    Pregnancy

    Sulfasalazine is classified as FDA pregnancy risk category B. Sulfasalazine and sulfapyridine (an active moiety) cross the placenta. There are case reports of neural tube defects (NTDs) in infants born to mothers who were exposed to sulfasalazine during pregnancy. While its' role 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. For this reason, folate supplementation is especially important during treatment, with experts recommending about 2 mg/day (i.e., 1 mg PO twice daily) if sulfasalazine is continued during pregnancy. Other evidence suggests that sulfasalazine does not appear to be associated with a significant risk of teratogenicity, with published case control series not finding an increase in congenital anomalies. Sulfonamides, such as sulfapyridine, are generally considered category D when used near term due to the potential for jaundice, hemolytic anemia, and kernicterus in the newborn; therefore, caution is warranted for use in pregnancy near term. The risk of kernicterus in the newborn if sulfasalazine is consumed in the last trimester appears to be low as sulfapyridine has poor bilirubin displacing capacity. Agranulocytosis has been reported in one infant whose mother received sulfasalazine as well as prednisone throughout pregnancy. Long-term effects of sulfasalazine on growth and maturation in the child is not known. Because there are no controlled trials of sulfasalazine use in pregnant women, the drug should be used in pregnancy only if clearly needed.

    Breast-feeding, infants, neonates

    According to the manufacturer, sulfasalazine should be used with caution in women who are breast-feeding. Sulfasalazine is a combination of sulfapyridine and 5-aminosalicylic acid (mesalamine). Unchanged sulfasalazine does not cross into breast milk in appreciable amounts; however, the active moieties (i.e., sulfapyridine, a sulfonamide and mesalamine) do enter the milk in small quantities. In addition, the mesalamine metabolite N-acetyl-5-ASA also appears in breast milk. Neonatal concentrations of sulfapyridine may be as high as 30—60% of maternal serum concentrations; however, in many infants kernicterus is not thought to be a significant concern, due to the poor bilirubin displacing capacity of sulfapyridine. In breast-feeding infants and neonates less than 2 months of age, sulfonamides may increase the risk of kernicterus by displacing bilirubin from plasma proteins. The American Academy of Pediatrics (AAP) reports that sulfapyridine is usually compatible with breast-feeding, but suggests to use with caution in stressed or ill infants, those with G-6PD deficiency, or premature infants. Furthermore, the AAP classifies 5-ASA as a drug that should be given to nursing mothers with caution; diarrhea has been reported with maternal use of 5-ASA agents, including sulfasalazine, during breast-feeding. Bloody diarrhea has occurred in an infant whose mother was taking sulfasalazine. In general, other agents that do not contain a sulfonamide, such as 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). Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Infertility

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

    Children

    The safety and effectiveness of either the delayed-release or immediate-release sulfasalazine tablets in children or infants less than 2 years of age with ulcerative colitis have not been determined. Both formulations are only indicated for use in children at least 6 years of age (see Dosage).

    GI obstruction

    Sulfasalazine is contraindicated in patients with 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

    Photosensitivity can occur with sulfa containing compounds, so patients 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 erythema.

    Immunosuppression, infection

    Carefully consider the risks of using sulfasalazine in patients with chronic infections, recurring infections, or pre-existing immunosuppression due to underlying medical conditions or concomitant drugs, as serious infections have been reported with use. Fatal sepsis and pneumonia have occurred. If a patient develops a serious infection, discontinue sulfasalazine. Monitor patients for signs or symptoms of infection during and following use, and promptly conduct diagnostic evaluations for patients who develop new infections.

    ADVERSE REACTIONS

    Severe

    cyanosis / Early / 0-3.3
    hemolytic anemia / Delayed / 0-3.3
    pancreatitis / Delayed / Incidence not known
    enterocolitis / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    megaloblastic anemia / Delayed / Incidence not known
    methemoglobinemia / Early / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    anuria / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    serum sickness / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    myelitis / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    Guillain-Barre syndrome / 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
    hypoprothrombinemia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    nephrolithiasis / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    crystalluria / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    meningitis / Delayed / Incidence not known
    hallucinations / Early / Incidence not known

    Mild

    nausea / Early / 19.0-33.0
    anorexia / Delayed / 33.0-33.0
    vomiting / Early / 8.0-33.0
    oligospermia / Delayed / 33.0-33.0
    headache / Early / 9.0-33.0
    dyspepsia / Early / 13.0-13.0
    rash (unspecified) / 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
    skin discoloration / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    tinnitus / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    insomnia / Early / Incidence not known
    drowsiness / Early / 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.
    Acarbose: (Moderate) Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and 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 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. Also, taking these drugs together may increase risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas
    Albiglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of incretin mimetics and other antidiabetic agents. 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. Patients should be closely monitored for this potential pharmacodynamic interaction while receiving any of these drugs in combination with incretin mimetics.
    Alogliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Alogliptin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Alogliptin; Pioglitazone: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Alpha-glucosidase Inhibitors: (Moderate) Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and sulfonamides.
    Aminobenzoate Potassium: (Moderate) Aminobenzoate potassium should not be administered to patients taking sulfonamides or aminosalicylate sodium, aminosalicylic acid. Bacteria preferentially absorb aminobenzoate potassium instead of the antibacterial agents, decreasing their efficacy.
    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.
    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; 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; 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.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (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.
    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) 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.
    Canagliflozin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Canagliflozin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    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.
    Chloroprocaine: (Major) Ester-type local anesthetics are metabolized to PABA. Para-aminobenzoic acid, PABA, in turn, antagonizes the effects of sulfonamides. Thus, ester-type local anesthetics should not be used in patients receiving sulfonamides.
    Chlorpropamide: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. Also, taking these drugs together may increase risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas
    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.
    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.
    Dapagliflozin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Dapagliflozin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Dapagliflozin; Saxagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    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.
    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 incretin mimetics and other antidiabetic agents. 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. Patients should be closely monitored for this potential pharmacodynamic interaction while receiving any of these drugs in combination with incretin mimetics.
    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. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Empagliflozin; Linagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents, such as linagliptin. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Empagliflozin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    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.
    Ester local anesthetics: (Major) Ester-type local anesthetics are metabolized to PABA. Para-aminobenzoic acid, PABA, in turn, antagonizes the effects of sulfonamides. Thus, ester-type local anesthetics should not be used in patients receiving sulfonamides.
    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 incretin mimetics and other antidiabetic agents. 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. Patients should be closely monitored for this potential pharmacodynamic interaction while receiving any of these drugs in combination with incretin mimetics.
    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) 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.
    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 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. Also, taking these drugs together may increase risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas
    Glimepiride; Pioglitazone: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. Also, taking these drugs together may increase risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas
    Glimepiride; Rosiglitazone: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. Also, taking these drugs together may increase risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas
    Glipizide: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. Also, taking these drugs together may increase risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas
    Glipizide; Metformin: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. Also, taking these drugs together may increase risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas
    Glyburide: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. Also, taking these drugs together may increase risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas
    Glyburide; Metformin: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. Also, taking these drugs together may increase risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas
    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 incretin mimetics and other antidiabetic agents. 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. Patients should be closely monitored for this potential pharmacodynamic interaction while receiving any of these drugs in combination with incretin mimetics.
    Insulin Degludec; Liraglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of incretin mimetics and other antidiabetic agents. 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. Patients should be closely monitored for this potential pharmacodynamic interaction while receiving any of these drugs in combination with incretin mimetics.
    Insulin Glargine; Lixisenatide: (Moderate) Sulfonamides may enhance the hypoglycemic action of incretin mimetics and other antidiabetic agents. 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. Patients should be closely monitored for this potential pharmacodynamic interaction while receiving any of these drugs in combination with incretin mimetics.
    Insulins: (Moderate) Monitor patients receiving sulfonamides concomitantly with insulin for changes in glycemic control. Sulfonamides may enhance the hypoglycemic action of insulin. 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.
    Iron Salts: (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.
    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.
    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.
    Levomefolate; Mecobalamin; Pyridoxal-5-phosphate: (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.
    Linagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents, such as linagliptin.
    Linagliptin; Metformin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents, such as linagliptin. (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Liraglutide: (Moderate) Sulfonamides may enhance the hypoglycemic action of incretin mimetics and other antidiabetic agents. 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. Patients should be closely monitored for this potential pharmacodynamic interaction while receiving any of these drugs in combination with incretin mimetics.
    Lixisenatide: (Moderate) Sulfonamides may enhance the hypoglycemic action of incretin mimetics and other antidiabetic agents. 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. Patients should be closely monitored for this potential pharmacodynamic interaction while receiving any of these drugs in combination with incretin mimetics.
    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.
    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 induce hypoglycemia by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and sulfonamides.
    Mercaptopurine, 6-MP: (Moderate) 5-aminosalicylates (e.g., balsalazide, olsalazine, mesalamine, or sulfasalazine) may inhibit the thiopurine methyltransferase (TPMT) enzyme, leading to increased sensitivity to the myelosuppressive effects of mercaptopurine and rapid development of bone marrow suppression following initiation of treatment. These agents should be administered with caution to patients receiving concurrent mercaptopurine, 6-MP therapy.
    Metformin: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Metformin; Pioglitazone: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Metformin; Repaglinide: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Metformin; Rosiglitazone: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Metformin; Saxagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Metformin; Sitagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    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: (Major) Methotrexate is partially bound to plasma proteins, and drugs that can displace methotrexate from these proteins, such as sulfonamides could cause methotrexate-induced toxicity. Due to the potential toxicity of methotrexate, interactions with sulfonamides can be very serious even if methotrexate is administered in low doses.
    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 induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and 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.
    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.
    Penicillins: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Photosensitizing agents: (Moderate) Use photosensitizing agents 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.
    Ponatinib: (Moderate) Concomitant use of ponatinib, an ABCG2 (BCRP) inhibitor, and sulfasalazine, an ABCG2 (BCRP) substrate, may increase the exposure of sulfasalazine.
    Porfimer: (Moderate) Use photosensitizing agents 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.
    Pramlintide: (Moderate) Sulfonamides may induce hypoglycemia by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and sulfonamides.
    Prilocaine: (Minor) Patients treated with prilocaine who are receiving other drugs that can cause methemoglobin formation, such as sulfonamides, are at greater risk for developing methemoglobinemia.
    Prilocaine; Epinephrine: (Minor) Patients treated with prilocaine who are receiving other drugs that can cause methemoglobin formation, such as sulfonamides, are at greater risk for developing methemoglobinemia.
    Probenecid: (Minor) Probenecid may inhibit the renal transport of sulfonamides. Plasma concentrations of these agents may be increased.
    Procaine: (Major) Ester-type local anesthetics are metabolized to PABA. Para-aminobenzoic acid, PABA, in turn, antagonizes the effects of sulfonamides. Thus, ester-type local anesthetics should not be used in patients receiving sulfonamides.
    Pyrimethamine: (Major) The combination of pyrimethamine with sulfonamides can be synergistic against susceptible organisms, however, bone marrow suppression may be more likely to occur with combination therapy. CBCs should be monitored routinely in patients receiving both drugs simultaneously. Some references suggest routinely administering leucovorin during therapy with pyrimethamine even when used without any of the above drugs.
    Pyrimethamine; Sulfadoxine: (Major) The combination of pyrimethamine with sulfonamides can be synergistic against susceptible organisms, however, bone marrow suppression may be more likely to occur with combination therapy. CBCs should be monitored routinely in patients receiving both drugs simultaneously. Some references suggest routinely administering leucovorin during therapy with pyrimethamine even when used without any of the above drugs.
    Regorafenib: (Moderate) Use caution if coadministration of regorafenib with sulfasalazine is necessary, and monitor for an increase in sulfasalazine-related adverse reactions. Sulfasalazine is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to sulfasalazine.
    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: (Major) Riluzole can cause hepatic injury. The safety profile of concomitant use of potentially hepatotoxic drugs, such as sulfasalazine, and riluzole has not been established. Caution is recommended if sulfasalazine is to be used concomitantly with riluzole.
    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.
    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.
    Saxagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    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.
    Simvastatin; Sitagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    Sitagliptin: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents.
    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 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. Also, taking these drugs together may increase risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas
    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) Ester-type local anesthetics are metabolized to PABA. Para-aminobenzoic acid, PABA, in turn, antagonizes the effects of sulfonamides. Thus, ester-type local anesthetics should not be used in patients receiving sulfonamides.
    Thiazolidinediones: (Moderate) Sulfonamides may induce hypoglycemia by increasing the secretion of insulin from the pancreas. Therefore, a pharmacodynamic interaction leading to an increased risk of hypoglycemia may occur in patients taking antidiabetic agents and sulfonamides.
    Thioguanine, 6-TG: (Moderate) There is in vitro evidence that 5-aminosalicylate derivatives (e.g., balsalazide, olsalazine, mesalazine, or sulphasalazine) inhibit thiopurine methyltransferase (TPMT), the enzyme that metabolizes thioguanine. 5-Aminosalicylates should be administered with caution to patients receiving concurrent thioguanine therapy. Increased thioguanine concentrations can lead to an increased risk for severe thioguanine-induced myelosuppression. Monitor patients for signs and symptoms of hematologic toxicity and monitor liver function, another indicator of thioguanine toxiciy. In cases of bone marrow suppression, a dose reduction of thioguanine may be necessary.
    Tolazamide: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. Also, taking these drugs together may increase risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas
    Tolbutamide: (Moderate) 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. Patients should be closely monitored while receiving any of these drugs in combination with antidiabetic agents. Also, taking these drugs together may increase risk for phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas
    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.
    Verteporfin: (Moderate) Use photosensitizing agents 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.
    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: (Major) Sulfonamides, including sulfamethizole, sulfamethoxazole, and sulfisoxazole, may potentiate the anticoagulant effect of warfarin. Sulfonamides are known to inhibit the hepatic metabolism of the 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. Most of the reported cases of an interaction between warfarin and a sulfonamide drug involved the combination of sulfamethoxazole and trimethoprim, which may be due to the additive effects of trimethoprim mediated CYP2C8 inhibition of warfarin metabolism. Among older patients receiving long-term warfarin therapy, recent sulfamethoxazole; trimethoprim use (i.e., within 14 days) was associated with an increased risk of hospitalization for upper GI bleed (adjusted OR 3.84; 95% CI 2.33-6.33) compared to other antibiotics commonly used for the treatment of UTI (amoxicillin, ampicillin, nitrofurantoin, and norfloxacin). Due to the potential severity of excessive anticoagulation, sulfonamides should be administered cautiously to a patient already stabilized on warfarin. Warfarin doses may need to be adjusted when sulfonamide therapy is discontinued.
    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

    Sulfasalazine is classified as FDA pregnancy risk category B. Sulfasalazine and sulfapyridine (an active moiety) cross the placenta. There are case reports of neural tube defects (NTDs) in infants born to mothers who were exposed to sulfasalazine during pregnancy. While its' role 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. For this reason, folate supplementation is especially important during treatment, with experts recommending about 2 mg/day (i.e., 1 mg PO twice daily) if sulfasalazine is continued during pregnancy. Other evidence suggests that sulfasalazine does not appear to be associated with a significant risk of teratogenicity, with published case control series not finding an increase in congenital anomalies. Sulfonamides, such as sulfapyridine, are generally considered category D when used near term due to the potential for jaundice, hemolytic anemia, and kernicterus in the newborn; therefore, caution is warranted for use in pregnancy near term. The risk of kernicterus in the newborn if sulfasalazine is consumed in the last trimester appears to be low as sulfapyridine has poor bilirubin displacing capacity. Agranulocytosis has been reported in one infant whose mother received sulfasalazine as well as prednisone throughout pregnancy. Long-term effects of sulfasalazine on growth and maturation in the child is not known. Because there are no controlled trials of sulfasalazine use in pregnant women, the drug should be used in pregnancy only if clearly needed.

    According to the manufacturer, sulfasalazine should be used with caution in women who are breast-feeding. Sulfasalazine is a combination of sulfapyridine and 5-aminosalicylic acid (mesalamine). Unchanged sulfasalazine does not cross into breast milk in appreciable amounts; however, the active moieties (i.e., sulfapyridine, a sulfonamide and mesalamine) do enter the milk in small quantities. In addition, the mesalamine metabolite N-acetyl-5-ASA also appears in breast milk. Neonatal concentrations of sulfapyridine may be as high as 30—60% of maternal serum concentrations; however, in many infants kernicterus is not thought to be a significant concern, due to the poor bilirubin displacing capacity of sulfapyridine. In breast-feeding infants and neonates less than 2 months of age, sulfonamides may increase the risk of kernicterus by displacing bilirubin from plasma proteins. The American Academy of Pediatrics (AAP) reports that sulfapyridine is usually compatible with breast-feeding, but suggests to use with caution in stressed or ill infants, those with G-6PD deficiency, or premature infants. Furthermore, the AAP classifies 5-ASA as a drug that should be given to nursing mothers with caution; diarrhea has been reported with maternal use of 5-ASA agents, including sulfasalazine, during breast-feeding. Bloody diarrhea has occurred in an infant whose mother was taking sulfasalazine. In general, other agents that do not contain a sulfonamide, such as 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). Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Sulfasalazine is metabolized to its active components, sulfapyridine and mesalamine, 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 dose of sulfasalazine is excreted in the urine, consisting of 15% unchanged drug, 60% sulfapyridine and its metabolites, and 20—33% 5-aminosalicylic acid and its metabolites. Approximately 67% of 5-aminosalicylic acid 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—14 hours, depending upon the acetylator status. Slow acetylators have been associated with an increased incidence of adverse effects, perhaps due to increased sulfapyridine concentrations.

    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—80%) is then absorbed, while only about 25% of 5-aminosalicylic acid is absorbed systemically. Peak serum concentrations of sulfasalazine occur within 1.5—6 hours of oral administration of the uncoated-tablets and within 3—12 hours following administration of the enteric-coated tablets. Peak serum concentrations of sulfapyridine occur within 6—24 hours after oral administration of the uncoated-tablets and 12—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—4 mcg/mL in patients with ulcerative colitis.