Sulfasalazine - Drug Monograph

Introduction

Sulfasalazine is a disease-modifying anti-rheumatic drug (DMARD) and anti-inflammatory agent that combines 5-aminosalicylic acid (5-ASA) with sulfapyridine through an azo bond. Originally developed in the 1930s for rheumatoid arthritis, it has become a cornerstone therapy for inflammatory bowel diseases and rheumatic conditions. This sulfonamide-class medication requires careful clinical management due to its unique pharmacokinetic profile and potential adverse effects.

Mechanism of Action

Sulfasalazine's mechanism involves both local and systemic effects. After oral administration, the azo bond remains largely intact until reaching the colon, where gut flora cleave it into two active components: sulfapyridine and 5-aminosalicylic acid (mesalamine).

The anti-inflammatory effects are multifactorial:

• 5-ASA component: Acts locally in the colon to inhibit cyclooxygenase and lipoxygenase pathways, reducing prostaglandin and leukotriene production
• Sulfapyridine component: Provides systemic antibacterial and immunomodulatory effects
• Overall immunomodulation: Inhibits lymphocyte proliferation, neutrophil chemotaxis, and cytokine production (particularly TNF-α and IL-1)
• Folate antagonism: Interferes with folate metabolism, which may contribute to both therapeutic and adverse effects

Indications

• Ulcerative colitis (mild to moderate, for induction and maintenance of remission)
• Rheumatoid arthritis (as a DMARD, typically in combination therapy)

• Crohn's disease (particularly colonic involvement)
• Ankylosing spondylitis
• Psoriatic arthritis
• Juvenile idiopathic arthritis

Dosage and Administration

• Initial: 500 mg twice daily, increasing gradually to 3-4 g/day in divided doses
• Maintenance: 2 g/day in divided doses

• Start: 500 mg daily or 1 g daily in divided doses
• Titrate: Increase by 500 mg weekly to target dose of 2-3 g/day in divided doses

• Administer with food to reduce gastrointestinal upset
• Tablets should be swallowed whole, not crushed or chewed
• Ensure adequate fluid intake (8-10 glasses daily) to prevent crystalluria

• Renal impairment: Use with caution; consider dose reduction
• Hepatic impairment: Contraindicated in severe hepatic disease
• Elderly: Increased risk of adverse effects; initiate at lower doses
• Pediatrics: 40-60 mg/kg/day divided into 3-6 doses

Pharmacokinetics

Contraindications

• Hypersensitivity to sulfonamides, salicylates, or any component
• Intestinal or urinary obstruction
• Porphyria
• Severe hepatic or renal impairment
• Children under 2 years of age
• Pregnancy at term and during lactation

Warnings and Precautions

• Serious, sometimes fatal, hematologic reactions including agranulocytosis, aplastic anemia, thrombocytopenia, and leukopenia
• Hepatic toxicity including fulminant hepatic necrosis

• Oligospermia: Reversible infertility reported in males
• Photosensitivity: Increased risk of sunburn; recommend sun protection
• Exacerbation of porphyria: Avoid in patients with porphyria
• Folate deficiency: May require folic acid supplementation (1 mg daily)
• Cross-sensitivity: Patients allergic to sulfonamides may react to sulfasalazine
• Lupus-like syndrome: Discontinue if symptoms develop

Drug Interactions

• Digoxin: Reduced absorption and efficacy
• Folate antagonists (methotrexate, trimethoprim): Increased risk of hematologic toxicity
• Warfarin: Potential increased anticoagulant effect
• Oral iron supplements: Decreased sulfasalazine absorption; separate administration by 2 hours
• Antibiotics: May reduce bacterial cleavage of sulfasalazine, decreasing efficacy
• Hepatotoxic drugs: Increased risk of liver injury

Adverse Effects

• Gastrointestinal: Nausea, vomiting, anorexia, abdominal pain
• Central nervous system: Headache, dizziness
• Dermatological: Rash, photosensitivity
• Other: Orange-yellow discoloration of skin, urine, and other body fluids

• Hematologic: Agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia
• Hepatic: Hepatitis, hepatic necrosis
• Pulmonary: Pulmonary fibrosis, eosinophilic pneumonia
• Renal: Crystalluria, nephrotic syndrome
• Hypersensitivity: Stevens-Johnson syndrome, toxic epidermal necrolysis
• Neurologic: Peripheral neuropathy, seizures

Monitoring Parameters

• Complete blood count with differential
• Liver function tests
• Renal function tests
• G6PD deficiency screening (in at-risk populations)
• Pregnancy test if applicable

• CBC every 2-4 weeks for first 3 months, then every 3 months
• LFTs every 3-6 months
• Renal function every 6-12 months
• Monitor for signs of infection, bruising, or bleeding
• Symptom assessment for gastrointestinal and neurological effects

Patient Education

• Take with food to minimize stomach upset
• Maintain adequate fluid intake (8-10 glasses daily)
• Urine, sweat, and tears may turn orange-yellow; this is harmless
• Use sun protection (SPF 30+, protective clothing)
• Report immediately: fever, sore throat, mouth ulcers, unusual bleeding/bruising, rash, yellowing of skin/eyes, or persistent nausea
• Do not crush or chew tablets
• Inform all healthcare providers about sulfasalazine use
• Notify physician if planning pregnancy or becoming pregnant
• Male patients should discuss potential fertility effects with their physician

References

1. American College of Gastroenterology Guidelines for Ulcerative Colitis. Am J Gastroenterol. 2019;114(3):384-413. 2. Singh JA, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res. 2016;68(1):1-25. 3. Sulfasalazine prescribing information. FDA.gov. 4. Taggart AJ, et al. Sulfasalazine in rheumatoid arthritis: a meta-analysis of 10 randomized controlled trials. J Rheumatol. 1999;26(10):2121-2124. 5. Peppercorn MA. Sulfasalazine: Pharmacology, clinical use, toxicity, and related new drug development. Ann Intern Med. 1984;101(3):377-386. 6. UpToDate Drug Information: Sulfasalazine. Wolters Kluwer. 7. Micromedex Solutions: Sulfasalazine. IBM Watson Health. 8. Clinical Pharmacology [database online]. Tampa, FL: Elsevier; 2022.