Pharmacodynamics

The mode of action of sulfasalazine (SSZ) or its metabolites, 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP), is still under investigation, but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of SSZ, SP and 5-ASA have indicated that the major therapeutic action may reside in the 5-ASA moiety. The relative contribution of the parent drug and the major metabolites in rheumatoid arthritis is unknown.

Pharmacokinetics

In vivo studies have indicated that the absolute bioavailability of orally administered SSZ is less than 15% for parent drug. In the intestine, SSZ is metabolized by intestinal bacteria to SP and 5-ASA. Of the two species, SP is relatively well absorbed from the intestine and highly metabolized, while 5-ASA is much less well absorbed.

Special Populations

General

AZULFIDINE EN-tabs Tablets should be given with caution to patients with severe allergy or bronchial asthma. Adequate fluid intake must be maintained in order to prevent crystalluria and stone formation. Patients with glucose-6-phosphate dehydrogenase deficiency should be observed closely for signs of hemolytic anemia. This reaction is frequently dose related. If toxic or hypersensitivity reactions occur, AZULFIDINE EN-tabs should be discontinued immediately.

Isolated instances have been reported when AZULFIDINE EN-tabs Tablets have passed undisintegrated. If this is observed, the administration of AZULFIDINE EN-tabs should be discontinued immediately.

Information For Patients

Patients should be informed of the possibility of adverse effects and of the need for careful medical supervision. The occurrence of sore throat, fever, pallor, purpura or jaundice may indicate a serious blood disorder. Should any of these occur, the patient should seek medical advice.

Patients should be instructed to take AZULFIDINE EN-tabs in evenly divided doses, preferably after meals, and to swallow the tablets whole. Additionally, patients should be advised that sulfasalazine may produce an orange-yellow discoloration of the urine or skin.

Ulcerative Colitis

Patients with ulcerative colitis should be made aware that ulcerative colitis rarely remits completely, and that the risk of relapse can be substantially reduced by continued administration of AZULFIDINE EN-tabs at a maintenance dosage.

Rheumatoid Arthritis

Rheumatoid arthritis rarely remits. Therefore, continued administration of AZULFIDINE EN-tabs is indicated. Patients requiring sulfasalazine should follow up with their physicians to determine the need for continued administration.

Laboratory Tests

Complete blood counts, including differential white cell count and liver function tests, should be performed before starting AZULFIDINE EN-tabs and every second week during the first three months of therapy. During the second three months, the same tests should be done once monthly and thereafter once every three months, and as clinically indicated. Urinalysis and an assessment of renal function should also be done periodically during treatment with AZULFIDINE EN-tabs.

The determination of serum sulfapyridine levels may be useful since concentrations greater than 50 µg/mL appear to be associated with an increased incidence of adverse reactions.

Drug Interactions

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

When daily doses of sulfasalazine 2 g and weekly doses of methotrexate 7.5 mg were coadministered to 15 rheumatoid arthritis patients in a drug-drug interaction study, the pharmacokinetic disposition of the drugs was not altered.

Daily doses of sulfasalazine 2 g (maximum 3 g) and weekly doses of methotrexate 7.5 mg (maximum 15 mg) were administered alone or in combination to 310 rheumatoid arthritis patients in two controlled 52-week clinical studies. The overall toxicity profile of the combination revealed an increased incidence of gastrointestinal adverse events, especially nausea, when compared to the incidence associated with either drug administered alone.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two year oral carcinogenicity studies were conducted in male and female F344/N rats and B6C3F1 mice. Sulfasalazine was tested at 84 (496 mg/m2), 168 (991 mg/m2) and 337.5 (1991 mg/m2) mg/kg/day doses in rats. A statistically significant increase in the incidence of urinary bladder transitional cell papillomas was observed in male rats. In female rats, two (4%) of the 337.5 mg/kg rats had transitional cell papilloma of the kidney. The increased incidence of neoplasms in the urinary bladder and kidney of rats was also associated with an increase in the renal calculi formation and hyperplasia of transitional cell epithelium. For the mouse study, sulfasalazine was tested at 675 (2025 mg/m2), 1350 (4050 mg/m2) and 2700 (8100 mg/m2) mg/kg/day. The incidence of hepatocellular adenoma or carcinoma in male and female mice was significantly greater than the control at all doses tested.

Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) or in the L51784 mouse lymphoma cell assay at the HGPRT gene. However, sulfasalazine showed equivocal mutagenic response in the micronucleus assay of mouse and rat bone marrow and mouse peripheral RBC and in the sister chromatid exchange, chromosomal aberration, and micronucleus assays in lymphocytes obtained from humans.

Impairment of male fertility was observed in reproductive studies performed in rats at a dose of 800 mg/kg/day (4800 mg/m2). Oligospermia and infertility have been described in men treated with sulfasalazine. Withdrawal of the drug appears to reverse these effects.

Pregnancy

Nursing Mothers

Sulfonamides, including sulfasalazine, are present in human milk (see Pregnancy, Clinical Considerations). Insignificant amounts of sulfasalazine have been found in milk, whereas levels of the active metabolite sulfapyridine in milk are about 30 to 60 percent of those in the maternal serum. Caution should be exercised when AZULFIDINE EN-tabs is administered to a nursing mother.

There are reports with limited data of bloody stools or diarrhea in human milk fed infants of mothers taking sulfasalazine. 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 breastfeeding. Due to limited data, a causal relationship between sulfasalazine exposure and bloody stools or diarrhea cannot be confirmed or denied. Monitor human milk fed infants of mothers taking sulfasalazine for signs and symptoms of diarrhea and/or bloody stools.

Pediatric Use

The safety and effectiveness of AZULFIDINE EN-tabs in pediatric patients below the age of 2 years with ulcerative colitis have not been established.

The safety and effectiveness of AZULFIDINE EN-tabs for the treatment of the signs and symptoms of polyarticular-course juvenile rheumatoid arthritis in pediatric patients aged 6–16 years is supported by evidence from adequate and well-controlled studies in adult rheumatoid arthritis patients. The extrapolation from adults with rheumatoid arthritis to children with polyarticular-course juvenile rheumatoid arthritis is based on similarities in disease and response to therapy between these two patient populations. Published studies support the extrapolation of safety and effectiveness for sulfasalazine to polyarticular-course juvenile rheumatoid arthritis1,5 (see ADVERSE REACTIONS).

It has been reported that the frequency of adverse events in patients with systemic-course of juvenile arthritis is high.6 Use in children with systemic-course juvenile rheumatoid arthritis has frequently resulted in a serum sickness-like reaction.5 This reaction is often severe and presents as fever, nausea, vomiting, headache, rash, and abnormal liver function tests. Treatment of systemic-course juvenile rheumatoid arthritis with sulfasalazine is not recommended.

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

Instructions for Overdosage

Gastric lavage or emesis plus catharsis as indicated. Alkalinize urine. If kidney function is normal, force fluids. If anuria is present, restrict fluids and salt, and treat appropriately. Catheterization of the ureters may be indicated for complete renal blockage by crystals. The low molecular weight of sulfasalazine and its metabolites may facilitate their removal by dialysis.

Initial Therapy

Adults: 3 to 4 g daily in evenly divided doses with dosage intervals not exceeding eight hours. It may be advisable to initiate therapy with a lower dosage, e.g., 1 to 2 g daily, to reduce possible gastrointestinal intolerance. If daily doses exceeding 4 g are required to achieve the desired therapeutic effect, the increased risk of toxicity should be kept in mind.

Children, six years of age and older: 40 to 60 mg/kg of body weight in each 24-hour period, divided into 3 to 6 doses.

Maintenance Therapy

Adults: 2 g daily.

Children, six years of age and older: 30 mg/kg of body weight in each 24-hour period, divided into 4 doses. The response of acute ulcerative colitis to AZULFIDINE EN-tabs can be evaluated by clinical criteria, including the presence of fever, weight changes, and degree and frequency of diarrhea and bleeding, as well as by sigmoidoscopy and the evaluation of biopsy samples. It is often necessary to continue medication even when clinical symptoms, including diarrhea, have been controlled. When endoscopic examination confirms satisfactory improvement, dosage of AZULFIDINE EN-tabs should be reduced to a maintenance level. If diarrhea recurs, dosage should be increased to previously effective levels.

AZULFIDINE EN-tabs is particularly indicated in patients who cannot take uncoated sulfasalazine tablets because of gastrointestinal intolerance (e.g., anorexia, nausea). If symptoms of gastric intolerance (anorexia, nausea, vomiting, etc.) occur after the first few doses of AZULFIDINE EN-tabs, they are probably due to increased serum levels of total sulfapyridine, and may be alleviated by halving the daily dose of AZULFIDINE EN-tabs and subsequently increasing it gradually over several days. If gastric intolerance continues, the drug should be stopped for 5 to 7 days, then reintroduced at a lower daily dose.

Adult Rheumatoid Arthritis

2 g daily in two evenly divided doses. It is advisable to initiate therapy with a lower dosage of AZULFIDINE EN-tabs, e.g., 0.5 to 1.0 g daily, to reduce possible gastrointestinal intolerance. A suggested dosing schedule is given below.

In rheumatoid arthritis, the effect of AZULFIDINE EN-tabs can be assessed by the degree of improvement in the number and extent of actively inflamed joints. A therapeutic response has been observed as early as 4 weeks after starting treatment with AZULFIDINE EN-tabs, but treatment for 12 weeks may be required in some patients before clinical benefit is noted. Consideration can be given to increasing the daily dose of AZULFIDINE EN-tabs to 3 g if the clinical response after 12 weeks is inadequate. Careful monitoring is recommended for doses over 2 g per day.

Suggested Dosing Schedule for Adult Rheumatoid Arthritis:

Juvenile Rheumatoid Arthritis - polyarticular course

Children, six years of age and older: 30 to 50 mg/kg of body weight daily in two evenly divided doses. Typically, the maximum dose is 2 g per day. To reduce possible gastrointestinal intolerance, begin with a quarter to a third of the planned maintenance dose and increase weekly until reaching the maintenance dose at one month.

Some patients may be sensitive to treatment with sulfasalazine. Various desensitization-like regimens have been reported to be effective in 34 of 53 patients,8 7 of 8 patients,9 and 19 of 20 patients.10 These regimens suggest starting with a total daily dose of 50 to 250 mg sulfasalazine initially, and doubling it every 4 to 7 days until the desired therapeutic level is achieved. If the symptoms of sensitivity recur, AZULFIDINE EN-tabs should be discontinued. Desensitization should not be attempted in patients who have a history of agranulocytosis, or who have experienced an anaphylactoid reaction while previously receiving sulfasalazine.

Storage

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].