Azulfidine

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Azulfidine

Classes

Aminosalicyclic Acid and Related Intestinal Antiinflammatory Agents
Other Specific Antirheumatics

Administration
Oral Administration

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

Oral Solid Formulations

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

Extemporaneous Compounding-Oral

NOTE: Extemporaneously compounded oral sulfasalazine suspension is not FDA-approved.
Shake well before administering. Measure dosage with calibrated measuring device.
Extemporaneous preparation of 100 mg/mL sulfasalazine oral suspension†
Count out 20 film-coated sulfasalazine 500-mg tablets and place in mortar; do not use enteric-coated tablets.
Mix together 50 mL of Ora-Plus and 50 mL of Ora-Sweet vehicles.
Pour some of the measured vehicle mixture on top of tablets and let soak until tablets are softened (20 to 30 minutes).
Levigate the tablets until a smooth paste is formed. Add more vehicle mxiture to the levigated mixture until a liquid is formed.
Transfer contents to a graduated cylinder. Use additional vehicle to rinse the remaining drug from the mortar and add to the graduated cylinder.
Add enough vehicle mixture to graduated cylinder to bring the final volume to 100 mL.
Stir well. Will form thick, opaque, brownish-yellow suspension.
Transfer to amber glass, polyvinylchloride (PVC), or PET-G bottle.
Label the bottle with 'Shake well before use' and the expiration date.
Storage: The oral suspension is stable for 91 days when stored at room temperature or refrigerated.

Adverse Reactions
Severe

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

Moderate

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

Mild

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

Common Brand Names

Azulfidine, Azulfidine En-Tabs, Sulfazine, Sulfazine EC

Dea Class

Rx

Description

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

Dosage And Indications
For the treatment of mild to moderate ulcerative colitis and as an adjunct for severe ulcerative colitis. Oral dosage (uncoated tablets) Adults

1 g PO every 6 to 8 hours, initially, then 500 mg PO every 6 hours. May consider 500 mg PO every 6 to 12 hours, initially, to reduce possible gastrointestinal tolerance. Max: 4 g/day. Administer with a folic acid supplement.

Children and Adolescents 6 to 17 years

40 to 60 mg/kg/day (Max: 4 g/day) PO divided every 4 to 8 hours, initially, then 30 mg/kg/day (Max: 4 g/day) PO divided every 6 hours. Administer with a folic acid supplement. Mesalamine (5-ASA) or sulfasalazine products are preferred by guidelines given the strong evidence of efficacy of 5-ASA for induction and maintenance of remission in mild to moderate ulcerative colitis.

Oral dosage (enteric-coated tablets) Adults

1 g PO every 6 to 8 hours, initially, then 500 mg PO every 6 hours. May consider 500 mg PO every 6 to 12 hours, initially, to reduce possible gastrointestinal tolerance. Max: 4 g/day. Administer with a folic acid supplement.

Children and Adolescents 6 to 17 years

40 to 60 mg/kg/day (Max: 4 g/day) PO divided every 4 to 8 hours, initially, then 30 mg/kg/day (Max: 4 g/day) PO divided every 6 hours. Administer with a folic acid supplement. Mesalamine (5-ASA) or sulfasalazine products are preferred by guidelines given the strong evidence of efficacy of 5-ASA for induction and maintenance of remission in mild to moderate ulcerative colitis.

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

500 mg PO once or twice daily for 1 week, initially. Increase the dose by 500 mg/day every week up to 1,000 mg PO twice daily. A therapeutic response is not observed immediately but can be seen in 4 weeks; treatment for 12 weeks may be required in some patients. May consider increasing the dose to 3,000 mg/day if clinical response is inadequate after 12 weeks. Careful monitoring is recommended for doses greater than 2 grams/day. Guidelines recommend DMARD monotherapy such as sulfasalazine for patients with a disease duration less than 6 months and low disease activity regardless of poor prognostic feature presence or moderate disease activity without poor prognostic features and is an option for high disease activity without poor prognostic features. For established disease, sulfasalazine monotherapy is only recommended for patients with low disease activity without poor prognostic features. The goal is low disease activity or remission. For patients with a disease duration less than 6 months, guidelines recommend use of combination DMARDs such as sulfasalazine plus methotrexate for those with moderate disease activity and poor prognostic features and is an option for those with high disease activity and poor prognostic features. For established disease, DMARD combination therapy is an option for patients with low disease activity and poor prognostic features or with moderate or high disease activity regardless of poor prognostic feature presence. If moderate or high disease activity exists after 3 months of combination DMARDs, an option is to add or switch DMARDs and reassess in another 3 months. For patients with low disease activity without poor prognostic features who have moderate or high disease activity after 3 months of DMARD monotherapy, the addition of methotrexate and/or hydroxychloroquine is an option.

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

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

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

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

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

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

Renal Impairment

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

Drug Interactions

Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Concomitant use of sulfonamides and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use.
Acalabrutinib: (Moderate) Coadministration of acalabrutinib and sulfasalazine may increase sulfasalazine exposure and increase the risk of sulfasalazine toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Sulfasalazine is a BCRP subtrate.
Acarbose: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Acetaminophen; Aspirin: (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; Aspirin; Diphenhydramine: (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.
Alogliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Alpelisib: (Major) Avoid coadministration of alpelisib with sulfasalazine due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and sulfasalazine is a BCRP inhibitor.
Alpha-glucosidase Inhibitors: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Aminosalicylate sodium, Aminosalicylic acid: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Amlodipine; Celecoxib: (Moderate) Monitor patients for signs of worsening renal function during coadministration of sulfasalazine and celecoxib. Coadministration may increase the risk for drug-induced nephrotoxicity.
Amoxicillin: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Amoxicillin; Clarithromycin; Omeprazole: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Amoxicillin; Clavulanic Acid: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Ampicillin: (Minor) Sulfonamides may compete with ampicillin for renal tubular secretion, increasing ampicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Ampicillin; Sulbactam: (Minor) Sulfonamides may compete with ampicillin for renal tubular secretion, increasing ampicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Aspirin, ASA: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Butalbital; Caffeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; 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; Caffeine; Orphenadrine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Carisoprodol: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Carisoprodol; Codeine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Dipyridamole: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Omeprazole: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Aspirin, ASA; Oxycodone: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
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.
Benzalkonium Chloride; 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: (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.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking sulfasalazine. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a BCRP substrate and sulfasalazine is a BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%.
Bismuth Subsalicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like sulfasalazine; the risk of peripheral neuropathy may be additive.
Bromocriptine: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides. Bromocriptine is highly bound to serum proteins. Therefore, it may increase the unbound fraction of other highly protein-bound medications (e.g., sulfonamides), which may alter their effectiveness and risk for side effects.
Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Epinephrine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Meloxicam: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Butalbital; Aspirin; 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.
Canagliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Canagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Cardiac glycosides: (Moderate) Sulfasalazine has been reported to reduce the absorption of digoxin by 20%. It is thought that the decrease in digoxin absorption is due to alterations in the properties of the gut wall. Therefore, separating the time of administration between sulfasalazine and digoxin will probably not reduce the potential interaction. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of sulfasalazine. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
Celecoxib: (Moderate) Monitor patients for signs of worsening renal function during coadministration of sulfasalazine and celecoxib. Coadministration may increase the risk for drug-induced nephrotoxicity.
Celecoxib; Tramadol: (Moderate) Monitor patients for signs of worsening renal function during coadministration of sulfasalazine and celecoxib. Coadministration may increase the risk for drug-induced nephrotoxicity.
Chloroprocaine: (Major) Coadministration of chloroprocaine with sulfonamides may antagonize the effect of sulfonamides. Chloroprocaine is metabolized to para-aminobenzoic acid (PABA). PABA antagonized the effects of sulfonamides. Additionally, coadministration of chloroprocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Chlorpropamide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Choline Salicylate; Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Cyclosporine: (Moderate) Use caution and closely monitor cyclosporine serum concentrations when administered concurrently with sulfasalazine. Use of these drugs together may result in decreased cyclosporine serum concentrations and the potential for decreased efficacy. Cyclosporine dose adjustments may be necessary and should be guided by serum concentrations during coadministration.
Daclatasvir: (Moderate) Systemic exposure of sulfasalazine, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of sulfasalazine; monitor patients for potential adverse effects.
Dalteparin: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
Dapagliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Dapagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Dapagliflozin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Dapsone: (Moderate) Coadministration of dapsone with sulfonamides may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
Dicloxacillin: (Minor) Sulfonamides may compete with dicloxacillin for renal tubular secretion, increasing dicloxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Dienogest; Estradiol valerate: (Moderate) Anti-infectives that disrupt the normal GI flora, including sulfonamides, may potentially decrease the effectiveness of estrogen-containing oral contraceptives.
Digoxin: (Moderate) Sulfasalazine has been reported to reduce the absorption of digoxin by 20%. It is thought that the decrease in digoxin absorption is due to alterations in the properties of the gut wall. Therefore, separating the time of administration between sulfasalazine and digoxin will probably not reduce the potential interaction. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of sulfasalazine. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary.
Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
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) Monitor blood glucose during concomitant incretin mimetic and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
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) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Linagliptin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Enoxaparin: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
Ertugliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Ertugliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Ertugliflozin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
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.
Exenatide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Fenoprofen: (Minor) An interaction may occur between fenoprofen and sulfonamides. Fenoprofen is 99% bound to albumin. Thus, fenoprofen may displace other highly protein bound drugs from albumin or vice versa. If fenoprofen is used concurrently with sulfonamides, monitor patients for toxicity from any of the drugs.
Fluvastatin: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as sulfonamides, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity.
Folic Acid, Vitamin B9: (Minor) Sulfasalazine exhibits antifolate activity, and can inhibit the absorption and lower the plasma concentrations of folic acid, vitamin B9. Patients receiving sulfasalazine treatment may require folic acid supplementation.
Fostamatinib: (Moderate) Monitor for sulfasalazine toxicities that may require sulfasalazine dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP substrate may increase the concentration of the BCRP substrate. The active metabolite of fostamatinib, R406, is a BCRP inhibitor; sulfasalazine is a substrate for BCRP. Coadministration of fostamatinib with another BCRP substrate increased the BCRP substrate AUC by 95% and Cmax by 88%.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and sulfasalazine as coadministration may increase serum concentrations of sulfasalazine and increase the risk of adverse effects. Sulfasalazine is a substrate of breast cancer resistance protein (BCRP); glecaprevir is an inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and sulfasalazine as coadministration may increase serum concentrations of sulfasalazine and increase the risk of adverse effects. Sulfasalazine is a substrate of breast cancer resistance protein (BCRP); pibrentasvir is an inhibitor of BCRP.
Glimepiride: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Glipizide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Glipizide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Glyburide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Glyburide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Heparin: (Moderate) Coadministration of 5-aminosalicylates and heparin may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of heparin. If this is not possible, it is recommended to monitor patients closely for bleeding.
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) Monitor blood glucose during concomitant incretin mimetic and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Degludec; Liraglutide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Glargine; Lixisenatide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulins: (Moderate) Monitor blood glucose during concomitant insulin and sulfonamide use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) A decrease in sulfasalazines therapeutic efficacy could be seen when rifampin is coadministered; monitor the patient for response to therapy. Sulfasalazine is metabolized to its active components, sulfapyridine and mesalamine, by bacteria in the colon. Concomitant use of rifampin may alter the colonic bacteria.
Isoniazid, INH; Rifampin: (Moderate) A decrease in sulfasalazines therapeutic efficacy could be seen when rifampin is coadministered; monitor the patient for response to therapy. Sulfasalazine is metabolized to its active components, sulfapyridine and mesalamine, by bacteria in the colon. Concomitant use of rifampin may alter the colonic bacteria.
Itraconazole: (Moderate) Administering sulfasalazine with itraconazole may increase sulfasalazine plasma concentrations, potentially resulting in adverse events. Sulfasalazine is a substrate of the drug transporter breast cancer resistance protein (BCRP) transporter; itraconazole is a BCRP inhibitor.
Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Concomitant use of sulfonamides and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use.
Lansoprazole; Amoxicillin; Clarithromycin: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Leflunomide: (Moderate) An additive effect may occur when leflunomide is given concomitantly with other hepatotoxic drugs. Sulfasalazine has caused elevations in liver enzymes and concomitant therapy with leflunomide may warrant caution.
Levomefolate: (Minor) L-methylfolate should be used cautiously in patients taking sulfasalazine. Sulfasalazine exhibits antifolate activity and can inhibit the absorption and lower the plasma concentrations of L-methylfolate. Patients receiving sulfasalazine should be monitored for decreased efficacy of L-methylfolate therapy.
Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Epinephrine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of prilocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Liraglutide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Lixisenatide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
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.
Losartan; Hydrochlorothiazide, HCTZ: (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as sulfonamides, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.
Low Molecular Weight Heparins: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Meglitinides: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Mercaptopurine, 6-MP: (Moderate) Increased bone marrow suppression may occur if mercaptopurine is coadministered with sulfasalazine. If concomitant use is necessary, use the lowest possible doses of each drug and closely monitor the patient for myelosuppression. 5-Aminosalicylates, such as sulfasalazine, have been shown to inhibit the thiopurine methyltransferase (TPMT) enzyme in vitro. Mercaptopurine is inactivated via the TPMT enzyme.
Metformin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Repaglinide: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Rosiglitazone: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
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.
Methenamine; Sodium 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.
Methotrexate: (Moderate) Concurrent use of sulfasalazine and methotrexate may increase the incidence of methotrexate-related adverse events. Methotrexate is partially bound to albumin, and toxicity may be increased because of displacement by sulfonamides.
Methoxsalen: (Moderate) Use methoxsalen and sulfonamides together with caution; the risk of severe burns/photosensitivity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
Miglitol: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with sulfonamides, monitor patients for toxicity from either drug.
Naproxen; Esomeprazole: (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.
Omeprazole; Amoxicillin; Rifabutin: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Osimertinib: (Moderate) Monitor for an increase in sulfasalazine-related adverse reactions if coadministration with osimertinib is necessary. Sulfasalazine is a BCRP substrate and osimertinib is a BCRP inhibitor.
Oxacillin: (Minor) Sulfonamides may compete with oxacillin for renal tubular secretion, increasing oxacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Penicillin G Benzathine: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Sulfonamides may also compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects. (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Sulfonamides may also compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Penicillin G: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Penicillin V: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with sulfasalazine. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
Photosensitizing agents (topical): (Moderate) Sulfonamides may cause photosensitization and may increase the photosensitizing effects of photosensitizing agents used during photodynamic therapy.
Pioglitazone; Glimepiride: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Pioglitazone; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Piperacillin; Tazobactam: (Minor) Sulfonamides may compete with piperacillin for renal tubular secretion, increasing piperacillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Porfimer: (Major) Avoid coadministration of porfimer with sulfonamides due to the risk of increased photosensitivity. Porfimer is a light-activated drug used in photodynamic therapy; all patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like sulfonamides may increase the risk of a photosensitivity reaction.
Pramlintide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Pretomanid: (Major) Avoid coadministration of pretomanid with sulfasalazine, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications.
Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Probenecid: (Minor) Probenecid may inhibit the renal transport of sulfonamides. Plasma concentrations of these agents may be increased.
Probenecid; Colchicine: (Minor) Probenecid may inhibit the renal transport of sulfonamides. Plasma concentrations of these agents may be increased.
Pyrimethamine: (Moderate) Concomitant use of other antifolic drugs associated with myelosuppression, including sulfonamides, may increase the risk of bone marrow suppression.
Regorafenib: (Moderate) Monitor for an increase in sulfasalazine-related adverse reactions if coadministration with regorafenib is necessary. Sulfasalazine is a BCRP substrate and regorafenib is a BCRP inhibitor.
Rifampin: (Moderate) A decrease in sulfasalazines therapeutic efficacy could be seen when rifampin is coadministered; monitor the patient for response to therapy. Sulfasalazine is metabolized to its active components, sulfapyridine and mesalamine, by bacteria in the colon. Concomitant use of rifampin may alter the colonic bacteria.
Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and sulfasalazine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
Rituximab: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as sulfasalazine, may result in an increased risk of infection. Monitor patients closely for signs or symptoms of infection. For a patient who develops a new infection during treatment with sulfasalazine, perform a prompt and complete diagnostic workup for infection and myelosuppression.
Rituximab; Hyaluronidase: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as sulfasalazine, may result in an increased risk of infection. Monitor patients closely for signs or symptoms of infection. For a patient who develops a new infection during treatment with sulfasalazine, perform a prompt and complete diagnostic workup for infection and myelosuppression.
Rolapitant: (Moderate) Use caution if sulfasalazine and rolapitant are used concurrently, and monitor for sulfasalazine-related adverse effects. Sulfasalazine is a substrate of the Breast Cancer Resistance Protein (BCRP); rolapitant is a BCRP inhibitor. The Cmax and AUC of sulfasalazine were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration.
Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Safinamide: (Moderate) Safinamide at the 100 mg dose and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP), which could increase plasma concentrations of BCRP substrates such as sulfasalazine. Monitor patients for increased pharmacologic or adverse effects of BCRP substrates during concurrent use of safinamide, particularly the 100 mg dose.
Salicylates: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Salsalate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Semaglutide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
SGLT2 Inhibitors: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
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.
Sotagliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sulfonylureas: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic age

nts; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Sumatriptan; 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.
Tafamidis: (Moderate) Caution is advised with the coadministration of tafamidis and sulfasalazine due to the potential for increased plasma concentrations of sulfasalazine increasing the risk of adverse effects. Sulfasalazine dose adjustment may be needed with coadministration. Sulfasalazine is a substrate of breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of sulfasalazine is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a BCRP substrate and sulfasalazine is a BCRP inhibitor.
Tedizolid: (Moderate) If possible, stop use of sulfasalazine temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for sulfasalazine-associated adverse events. Sulfasalazine plasma concentrations may be increased when administered concurrently with oral tedizolid. Sulfasalazine is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
Tetracaine: (Major) Coadministration of tetracaine with sulfonamides may antagonize the effect of sulfonamides. Tetracaine is metabolized to para-aminobenzoic acid (PABA). PABA antagonized the effects of sulfonamides. Additionally, coadministration of tetracaine with oxidizing agents, such as sulfonamides, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Thiazolidinediones: (Moderate) Monitor blood glucose during concomitant thiazolidinedione and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Thioguanine, 6-TG: (Moderate) Use these drugs together with caution; concomitant use may result in reduced metabolism of thioguanine via TPMT and an increased risk for thioguanine-induced toxicity. Monitor patients for signs and symptoms of hematologic and hepatic toxicity. There is in vitro evidence that 5-aminosalicylate derivatives inhibit thiopurine methyltransferase (TPMT), the enzyme that metabolizes thioguanine. Increased thioguanine concentrations can lead to an increased risk for severe thioguanine-induced myelosuppression. In cases of bone marrow suppression, a dose reduction of thioguanine may be necessary.
Tirzepatide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and sulfonamide use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Tolazamide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Tolbutamide: (Moderate) Sulfonamides may enhance the hypoglycemic action of antidiabetic agents; patients with diabetes mellitus should be closely monitored during sulfonamide treatment. Taking these drugs together may also increase risk for phototoxicity. Patients should limit sunlight and UV exposure, and follow proper precautions for sunscreens and protective clothing. Sulfonamides may induce hypoglycemia in some patients by increasing the secretion of insulin from the pancreas. Patients at risk for hypoglycemia due to sulfonamides include those with compromised renal function, those fasting for prolonged periods, those that are malnourished, and those receiving high or excessive doses of sulfonamides.
Topotecan: (Major) Avoid coadministration of sulfasalazine with oral topotecan due to increased topotecan exposure; sulfasalazine may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and sulfasalazine is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
Typhoid Vaccine: (Major) Avoid use of sulfonamides and other antibiotics during the oral typhoid vaccination series at concurrent administration may result in a reduced immune response. In order to provided immunity, the oral typhoid vaccine requires initiation of a limited infection localized within the gastrointestinal tract. Antibiotics prevent this bacterial infection from occurring, thereby, reducing the vaccines protective immune response.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with sulfasalazine. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP drug transporter; sulfasalazine is a BCRP inhibitor.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with sulfonamides is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like sulfonamides may increase the risk of a photosensitivity reaction.
Vonoprazan; Amoxicillin: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Vonoprazan; Amoxicillin; Clarithromycin: (Minor) Sulfonamides may compete with amoxicillin for renal tubular secretion, increasing amoxicillin serum concentrations. Use this combination with caution, and monitor patients for increased side effects.
Voriconazole: (Moderate) Voriconazole is metabolized by the CYP2C9 isoenzyme, and drugs that are known to be inhibitors of CYP2C9 may theoretically lead to elevated plasma levels of voriconazole when coadministered. Drugs that are known to be inhibitors of CYP2C9 include sulfonamides.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with sulfonamides is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Warfarin doses may need to be adjusted when sulfonamide therapy is discontinued. Sulfonamides, including sulfathiazole, sulfamethoxazole, and sulfisoxazole, potentiate the anticoagulant effect of warfarin. Sulfonamides are known to inhibit the hepatic metabolism of S-warfarin and have, in some cases, doubled the hypoprothrombinemic effect of warfarin. A protein-binding interaction also may be possible, with sulfonamides displacing warfarin from protein binding sites.
Zidovudine, ZDV: (Moderate) Concomitant use of sulfonamides and zidovudine may result in additive hematological abnormalities. Use caution and monitor for hematologic toxicity during concurrent use.

How Supplied

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

Maximum Dosage
Adults

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

Geriatric

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

Adolescents

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

Children

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

Infants

Safety and efficacy have not been established.

Mechanism Of Action

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

Pharmacokinetics

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

Oral Route

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

Pregnancy And Lactation
Pregnancy

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

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