Side Effects of Azulfidine (sulfasalazine)

Azulfidine (sulfasalazine) is an anti-inflammatory and immunomodulatory drug used to treat mild to severe ulcerative colitis and rheumatoid arthritis. It has also been used “off label” (not approved by the FDA) for Crohn's disease and ankylosing spondylitis. 

Common side effects of Azulfidine include:

• gastrointestinal disturbances (nausea, vomiting, gastric distress, and loss of appetite),
• headache,
• allergic reactions, and
• photosensitivity (development of a rash when exposed to sunlight), and
• changes in skin or urine color (orange-yellow discoloration of the urine is no cause for concern).

Serious side effects of Azulfidine include:

• a drop in white blood cell count or a type of anemia in which red blood cells are disrupted (hemolyzed).
  • These effects are characterized by fever, pale skin, sore throat, fatigue, and unusual bleeding and bruising, and require discontinuation of the drug.
• Liver failure, pancreatitis, and kidney failure also have been associated with sulfasalazine.

Drug interactions of Azulfidine include folic acid and digoxin, because Azulfidine may cause reduced absorption. 

Sulfonamides increase blood levels of methotrexate, resulting in increased methotrexate toxicity. 

Conversely, methotrexate can increase the occurrence of the anemia caused by sulfonamides because methotrexate also causes folic acid deficiency. 

Sulfonamides can increase the risk of kidney damage from cyclosporine. They also may increase the blood glucose lowering effect of oral anti-diabetic drugs and potentially cause excessive reductions in blood sugar (hypoglycemia) by decreasing elimination of anti-diabetic drugs by the liver and elevating the levels of the anti-diabetic drugs in the blood. 

Combining Azulfidine with drugs that affect kidney function such as nonsteroidal anti-inflammatory drugs may increase the likelihood of kidney dysfunction. 

Concurrent use of Azulfidine and 6-mercaptopurine or azathioprine may increase the likelihood of blood disorders. Azulfidine may increase the blood thinning effect of warfarin. 

In hundreds of pregnant women with ulcerative colitis or Crohn's disease treated with Azulfidine, there has been no increase in the risk of fetal malformations relative to other women with these illnesses who have not been treated with Azulfidine. Azulfidine may be used during pregnancy if the physician feels the benefit outweighs the possible risks. 

Azulfidine and its constituents are secreted into breast milk. There is a small risk that sulfapyridine (a byproduct of sulfasalazine) may displace bilirubin from albumin in the blood of infants and cause jaundice. Caution should be exercised by breastfeeding women.

Gastrointestinal disturbances frequently occur in patients taking sulfasalazine that may include:

• nausea,
• vomiting,
• gastric distress, and
• loss of appetite.

Headache, allergic reactions, and photosensitivity (development of a rash when exposed to sunlight) may develop during sulfasalazine therapy and require medical attention. Some of the allergic reactions may progress from a rash to difficulty in swallowing, blistering, peeling, or loosening of the skin, aching joints and muscles, and unusual tiredness or weakness. It may be accompanied by fever. The more severe allergic reactions are rare.

Sulfasalazine may cause the skin or the urine to change color.

Development of an orange-yellow discoloration of the urine is no cause for concern.

Several potentially dangerous side effects have been reported rarely with sulfasalazine. A drop in white blood cell count or a type of anemia in which red blood cells are disrupted (hemolyzed) may occur. These effects are characterized by fever, pale skin, sore throat, fatigue, and unusual bleeding and bruising, and require discontinuation of the drug. Liver failure, pancreatitis, and kidney failure also have been associated with sulfasalazine.

The most common adverse reactions associated with sulfasalazine are anorexia, headache, nausea, vomiting, gastric distress, and apparently reversible oligospermia. These occur in about one-third of the patients. Less frequent adverse reactions are skin rash, pruritus, urticaria, fever, Heinz body anemia, hemolytic anemia, and cyanosis, which may occur at a frequency of one in every thirty patients or less. Experience suggests that with a daily dosage of 4 g or more, or total serum sulfapyridine levels above 50 μg/mL, the incidence of adverse reactions tends to increase.

Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the sulfonamides require that each of these reactions be considered when Azulfidine Tablets are administered. Less common or rare adverse reactions include:

Blood dyscrasias: aplastic anemia, agranulocytosis, leukopenia, megaloblastic (macrocytic) anemia, purpura, thrombocytopenia, hypoprothrombinemia, methemoglobinemia, congenital neutropenia, and myelodysplastic syndrome.

Hypersensitivity reactions: erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, epidermal necrolysis (Lyell's syndrome) with corneal damage, drug rash with eosinophilia and systemic symptoms (DRESS), anaphylaxis, serum sickness syndrome, interstitial lung disease, pneumonitis with or without eosinophilia, vasculitis, fibrosing alveolitis, pleuritis, pericarditis with or without tamponade, allergic myocarditis, polyarteritis nodosa, lupus erythematosus-like syndrome, hepatitis and hepatic necrosis with or without immune complexes, fulminant hepatitis, sometimes leading to liver transplantation, parapsoriasis varioliformis acuta (Mucha-Haberman syndrome), rhabdomyolysis, photosensitization, arthralgia, periorbital edema, conjunctival and scleral injection, and alopecia.

Gastrointestinal reactions: hepatitis, hepatic failure, pancreatitis, bloody diarrhea, impaired folic acid absorption, impaired digoxin absorption, stomatitis, diarrhea, abdominal pains, and neutropenic enterocolitis.

Central nervous system reactions: transverse myelitis, convulsions, meningitis, transient lesions of the posterior spinal column, cauda equina syndrome, Guillian-Barre syndrome, peripheral neuropathy, mental depression, vertigo, hearing loss, insomnia, ataxia, hallucinations, tinnitus, and drowsiness.

Renal reactions: toxic nephrosis with oliguria and anuria, nephritis, nephrotic syndrome, urinary tract infections, hematuria, crystalluria, proteinuria, and hemolytic-uremic syndrome.

Other reactions: urine discoloration and skin discoloration.

The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides), and oral hypoglycemic agents. Goiter production, diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides. Cross-sensitivity may exist with these agents. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides and long-term administration has produced thyroid malignancies in this species.

Postmarketing Reports

The following events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine:

Blood dyscrasias: pseudomononucleosis

Cardiac disorders: myocarditis

Hepatobiliary disorders: reports of hepatotoxicity, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, hepatitis cholestatic, cholestasis and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome, which included hepatic function changes, was also reported.

Immune system disorders: anaphylaxis

Metabolism and nutrition system disorders: folate deficiency

Renal and urinary disorders: nephrolithiasis

Respiratory, thoracic and mediastinal disorders: oropharyngeal pain

Skin and subcutaneous tissue disorders: angioedema, purpura

Vascular disorders: pallor

Drug Abuse And Dependence

None reported.

Reduced absorption of folic acid and digoxin have been reported when those agents were administered concomitantly with sulfasalazine.

Drug/Laboratory Test Interactions

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