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Sulfasalazine

Pronunciation

Pronunciation: SULL-fuh-SAL-uh-zeen
Class: Antirheumatic agent, GI agent

Trade Names

Azulfidine
- Tablets 500 mg

Azulfidine EN-tabs
- Tablets, delayed-release 500 mg

PMS-Sulfasalazine (Canada)
PMS-Sulfasalazine EC (Canada)
Salazopyrin (Canada)
Salazopyrin En-tabs (Canada)

Pharmacology

Mode of action of sulfasalazine or its metabolites (5-aminosalicylic acid [5-ASA], sulfapyridine [SP]) is still under investigation. May be related to anti-inflammatory and/or immunomodulatory properties, to affinity for connective tissue, and/or to the relatively high concentrations reached in serous fluids, the liver, and intestinal walls.

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Pharmacokinetics

Absorption

Bioavailability of sulfasalazine is less than 15%; T max is 6 h (range, 3 to 12 h). Approximately one third of a dose of sulfasalazine is absorbed from the small intestine. The remaining two thirds passes into the colon where it is split by bacteria into 5-ASA and SP. SP is well absorbed from the colon (estimated bioavailability 60%); 5-ASA is less well absorbed (estimated bioavailability 10% to 30%).

Distribution

Sulfasalazine is highly bound to albumin (more than 99.3%); Vd is approximately 7.5 L.

Metabolism

Sulfasalazine is extensively metabolized by intestinal bacteria to 5-ASA and SP. Primary route of metabolism of SP is via acetylation. 5-ASA is primarily metabolized in the liver and intestine via a non-acetylation, phenotype-dependent route.

Elimination

Absorbed SP and 5-ASA are primarily eliminated in the urine. Majority of 5-ASA stays within the colonic lumen and is excreted as 5-ASA and acetyl-5-ASA with the feces. Sulfasalazine t ½ (IV) is approximately 7.6 h; mean plasma t ½ of SP is 10.4 h (fast acetylators) and 14.8 h (slow acetylators). Sulfasalazine Cl following IV administration is approximately 1 L/h.

Special Populations

Elderly

Elderly patients with rheumatoid arthritis showed a prolonged plasma t ½ for sulfasalazine, sulfinpyridine, and their metabolites. The clinical impact of this is unknown.

Acetylator status

SP metabolism is mediated by polymorphic enzymes such that 2 distinct populations of slow and fast metabolizer exist. Slow acetylator phenotype (approximately 60% of White patients) display a prolonged plasma t ½ and an accumulation of higher plasma levels of SP than fast aceytylators. The clinical implications of this are unclear; however, slow acetylators may experience a higher incidence of adverse reactions.

Indications and Usage

Tablets and delayed-release tablets

Treatment of mild to moderate ulcerative colitis; adjunctive therapy in severe ulcerative colitis; prolongation of the remission period between acute attacks of ulcerative colitis.

Delayed-release tablets

Treatment of rheumatoid arthritis in patients who have responded inadequately to salicylates or other NSAIDs; treatment of children with polyarticular-course juvenile rheumatoid arthritis who have responded inadequately to salicylates or other NSAIDs.

Unlabeled Uses

Ankylosing spondylitis, Crohn disease, granulomatous colitis, regional enteritis.

Contraindications

Patients with intestinal or urinary obstruction; porphyria; hypersensitivity to sulfasalazine, its metabolites, sulfonamides, or salicylates.

Dosage and Administration

Ulcerative Colitis
Adults Initial

PO 3 to 4 g/day in evenly divided doses. More than 4 g/day is associated with higher incidence of side effects. May begin with 1 to 2 g/day to lessen GI effects.

Maintenance

PO 2 g/day in 4 divided doses.

Children at least 6 yr of age

Initial PO 40 to 60 mg/kg/24 h in 3 to 6 divided doses.

Maintenance

PO 30 mg/kg/24 h in 4 divided doses.

Rheumatoid Arthritis
Adults

PO Delayed-release: 2 g/day in 2 evenly divided doses. May initiate therapy with a lower dosage (eg, 0.5 to 1 g/day) to reduce possible GI intolerance.

Children at least 6 yr of age

PO Delayed-release: 30 to 50 mg/kg/day in 2 evenly divided doses. Initiate therapy with 25% to 33% of the planned maintenance dose to lessen GI effects; increase weekly until reaching maintenance dose at 1 mo. Max, 2 g/day.

General Advice

  • Administer in evenly divided doses, preferably after meal or snack.
  • Caution patient to swallow delayed-release tablets whole and not to crush, chew, or break.
  • Administer each dose with a full glass of water.
  • Encourage fluids between meals up to 2,000 mL/day to reduce risk of crystalluria and stone formation.

Storage/Stability

Store at controlled room temperature (59° to 86°F).

Drug Interactions

Digoxin

Absorption of digoxin may be decreased.

Folic acid

Signs of folate deficiency have occurred, but specific symptoms related to deficiency have not been reported.

Methotrexate

Risk of methotrexate-induced bone marrow suppression may be enhanced.

Sulfonylureas

Increased sulfonylurea half-lives and hypoglycemia have occurred.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Ataxia, cauda equine syndrome, convulsion, depression, drowsiness, Guillain-Barré syndrome, hallucinations, headache, hearing loss, insomnia, meningitis, peripheral neuropathy, tinnitus, transient lesions of the posterior spinal column, transverse myelitis, vertigo.

Dermatologic

Orange-yellow discoloration of skin.

GI

Abdominal pain, anorexia, bloody diarrhea, diarrhea, impaired folic acid absorption, gastric distress, nausea, pancreatitis, pseudomembranous enterocolitis, stomatitis, vomiting.

Genitourinary

Crystalluria, elevated creatinine, hematuria, hemolytic-uremic syndrome, nephritis, nephrotic syndrome, orange-yellow urine, proteinuria, toxic nephrosis with oliguria and anuria, UTI.

Hematologic

Agranulocytosis, aplastic anemia, congenital neutropenia, Heinz body anemia, hemolytic anemia, hypoprothrombinemia, leukopenia, megaloblastic (macrocytic) anemia, methemoglobinemia, myelodysplastic syndrome, purpura, thrombocytopenia.

Hepatic

Hepatocellular necrosis; cholestatic jaundice, cirrhosis, elevated LFTs, jaundice, Kawasaki-like syndrome, possible hepatocellular damage including liver necrosis and failure (postmarketing).

Hypersensitivity

Allergic myocarditis, alopecia, anaphylactoid reactions, arthralgia, epidermal necrolysis with or without corneal damage, erythema multiforme of Stevens-Johnson type, exfoliative dermatitis, fibrosing alveolitis, fulminant hepatitis, hepatic necrosis, hepatitis, generalized skin eruptions, lupus erythematosus phenomenon, parapsoriasis varioliformis acuta, pericarditis with or without tamponade, periorbital edema, photosensitization, pleuritis, polyarteritis nodosa, pruritus, rhabdomyolysis, serum sickness, transient pulmonary changes with eosinophilia and decreased pulmonary function, urticaria.

Respiratory

Cyanosis, pulmonary infiltrates.

Miscellaneous

Arthralgia, chills, drug fever, myalgia, periarteritis nodosum, pyrexia.

Precautions

Monitor

Obtain CBC with differential and LFTs before starting therapy and every 2 wk during first 3 mo of therapy, then every month during the next 3 mo, then every 3 mo thereafter, and as clinically indicated. Urinalysis with microscopic examination and assessment of renal function should be done periodically. Serum SP levels may be useful because concentrations above 50 mcg/mL appear to be associated with an increased incidence of adverse reactions.


Pregnancy

Category B .

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established for children younger than 2 yr of age with ulcerative colitis. Safety and efficacy of delayed-release tablets not established for children younger than 6 yr of age with rheumatoid arthritis.

Renal Function

Use with caution.

Hepatic Function

Use with caution.

Fertility

Oligospermia and infertility have been observed in men treated with sulfasalazine; effects appear to be reversible when drug is withdrawn.

Allergy or asthma

Use with caution.

Contact lenses

May permanently stain soft contact lenses yellow.

Delayed-release tablets

Isolated instances of delayed-release tablets being passed undisintegrated. Immediately discontinue use of this doseform if noted.

Fluid intake

Maintain adequate fluid intake to prevent crystalluria and stone formation.

Glucose-6-phosphate dehydrogenase deficiency

Can produce clinically significant hemolysis in patients with G-6-PD deficiency.

Porphyria

May precipitate acute attacks of porphyria.

Severe reactions

Reactions, including death, have been associated with hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood dyscrasias, and renal and hepatic damage. Irreversible neuromuscular and CNS changes and fibrosing alveolitis may occur.

Sulfonamides

There are chemical similarities to some goitrogens, diuretics (acetazolamide and thiazides), and oral hypoglycemic agents. Goiter production, diuresis, and hypoglycemia have occurred rarely in patients receiving sulfonamides. Cross-sensitivity may exist.

Overdosage

Symptoms

Abdominal pain, anuria, drowsiness, gastric distress, nausea, seizures, vomiting.

Patient Information

  • Instruct patient to take exactly as prescribed and not to change the dose or discontinue therapy unless advised by health care provider.
  • Advise patient to take in equally divided doses, with a full glass of water, preferably after meal or snack.
  • Caution patient using delayed-release tablets to swallow tablets whole and not to crush, chew, break, or cut tablets.
  • Advise patient that medication may cause an orange-yellow discoloration of the skin and urine but it is of no concern. Caution patient that soft contact lenses may be permanently stained yellow by this same effect.
  • Advise patient that drug may cause dizziness and to use caution driving or performing other hazardous tasks until tolerance is determined.
  • Instruct patient to notify health care provider if symptoms of condition being treated (ulcerative colitis or arthritis) do not appear to improve or worsen.
  • Advise patient to discontinue therapy and immediately notify health care provider if any of the following occur: fever, paleness, red or purple spots under the skin, skin rash or other signs of allergic reaction, sore throat, yellowing of the skin or eyes.
  • Advise patient to avoid unnecessary exposure to direct and indirect sunlight or tanning lamps, and to use sunscreen and wear protective clothing to avoid photosensitivity reactions during therapy. Advise patient to discontinue therapy and notify health care provider if any of the following occur following exposure to sunlight or artificial ultraviolet light (eg, sunlamp): blistering, rash or itching, redness, sensation of skin burning, swelling.
  • Advise patient to report any other bothersome side effects to health care provider.

Copyright © 2009 Wolters Kluwer Health.

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