Zulfidin

Approved Indications:

• Rheumatoid Arthritis (RA):
• For the treatment of active rheumatoid arthritis in adults, including those with moderate to severe disease.
• Also used in pediatric patients with polyarticular course juvenile rheumatoid arthritis (JRA).
• Ulcerative Colitis (UC):
• Treatment of mild to moderate active ulcerative colitis.
• Maintenance of remission in ulcerative colitis.

Clinically Accepted Off-label Uses:

• Crohn’s Disease (limited use):
  Occasionally used in mild to moderate colonic Crohn’s disease when mesalamine is not available or tolerated.
• Ankylosing Spondylitis:
  Used as a disease-modifying therapy in patients with peripheral joint involvement.
• Psoriatic Arthritis:
  May be used in patients with mild to moderate disease unresponsive to NSAIDs.
• Reactive Arthritis:
  Utilized in patients with persistent joint symptoms not controlled by NSAIDs alone.

Route of Administration: Oral

Ulcerative Colitis – Adults:

• Initial (active disease):
  3–4 g daily in divided doses every 6–8 hours, with food.
  Start with lower doses (e.g., 500 mg four times daily) to improve GI tolerability.
• Maintenance:
  2 g daily in divided doses to maintain remission.

Ulcerative Colitis – Pediatrics (6 years and older):

• Initial:
  40–60 mg/kg/day divided every 6 hours.
• Maintenance:
  30–50 mg/kg/day in divided doses.

Rheumatoid Arthritis – Adults:

• Start with 500 mg once or twice daily, gradually increase to 1 g twice daily.
• Maximum dose: 3 g/day (in divided doses).

Juvenile Rheumatoid Arthritis – Pediatrics (6 years and older):

• Initial: 30–50 mg/kg/day in two divided doses.
• Maintenance: Adjust based on clinical response, not to exceed adult dose.

Elderly:
Start at the lower end of the dosing range due to increased sensitivity and risk of adverse effects.

Renal Impairment:

• Use with caution.
• Avoid in severe renal dysfunction (CrCl <30 mL/min).
• Monitor renal function during therapy.

Hepatic Impairment:

• Use with caution; monitor liver enzymes regularly.
• Discontinue if significant hepatic injury occurs.

Administration Notes:

• Administer after meals and with a full glass of water.
• Tablets should not be crushed or chewed.

Sulfasalazine is a prodrug composed of sulfapyridine and 5-aminosalicylic acid (5-ASA) linked by an azo bond. In the colon, bacterial enzymes cleave this bond, releasing the active components. The 5-ASA exerts local anti-inflammatory effects on the colonic mucosa by inhibiting prostaglandin and leukotriene synthesis, reducing cytokine production, and scavenging free radicals. In rheumatoid arthritis, the mechanism is less clearly understood but is believed to involve immunomodulatory effects, including suppression of T-cell proliferation and inhibition of inflammatory mediators such as TNF-α and interleukins. Sulfapyridine may contribute to systemic anti-inflammatory activity in RA.

• Absorption:
  ~10–30% absorbed in the small intestine; remainder reaches colon for bacterial metabolism.
• Distribution:
  Highly protein-bound (>90%); distributed widely in tissues.
• Metabolism:
  In the colon, azo bond is cleaved by bacterial azoreductases into sulfapyridine and 5-ASA.
  Sulfapyridine is well absorbed and metabolized in the liver by acetylation, hydroxylation, and glucuronidation.
• Half-life:
  Sulfapyridine: 6–17 hours (acetylator status-dependent).
  5-ASA: Rapidly excreted; minimal systemic levels.
• Excretion:
  Sulfapyridine and its metabolites: Renal excretion.
  5-ASA: Mostly excreted in feces.
• Onset of Action:
  RA: 4–12 weeks
  UC: Improvement seen within 2–4 weeks

Pregnancy:

• FDA Category B
  Animal studies have not shown fetal risk, and human data are limited but reassuring.
  Supplementation with folic acid is recommended due to antifolate effects of sulfapyridine.

Lactation:

• Sulfasalazine and its metabolites are excreted in breast milk in low amounts.
• Usually considered safe; however, infants should be monitored for diarrhea or bloody stools.
• Avoid in premature or G6PD-deficient infants due to risk of hemolysis.

• Primary Class: Anti-inflammatory / Disease-Modifying Antirheumatic Drug (DMARD)
• Subclass: Aminosalicylate (5-ASA derivative)
• Prodrug: Yes

• Known hypersensitivity to sulfasalazine, sulfonamides, or salicylates
• Intestinal or urinary obstruction
• Porphyria
• Severe renal or hepatic impairment
• Infants under 2 months of age
• History of agranulocytosis or significant hematologic reactions with sulfasalazine

• Hematologic Toxicity: Risk of leukopenia, agranulocytosis, and aplastic anemia; regular CBC monitoring required.
• Hepatotoxicity: Monitor liver enzymes; discontinue if hepatic injury is suspected.
• Renal Impairment: Risk of nephrotoxicity; monitor renal function.
• Hypersensitivity Reactions: May include rash, fever, Stevens-Johnson syndrome, and exfoliative dermatitis.
• G6PD Deficiency: Increased risk of hemolysis—use cautiously or avoid.
• Male Fertility: May cause reversible oligospermia.
• Infection Risk: Immunomodulatory effects may increase susceptibility to infections.

Common Adverse Effects:

• Gastrointestinal: Nausea, vomiting, anorexia, abdominal pain, diarrhea
• Central Nervous System: Headache, dizziness
• Dermatologic: Rash, pruritus, reversible yellow-orange discoloration of urine or skin

Serious/Rare Adverse Effects:

• Hematologic: Agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia
• Hepatic: Hepatitis, liver enzyme elevations
• Renal: Interstitial nephritis, proteinuria
• Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis
• Pulmonary: Pneumonitis, fibrosis (rare)

Onset & Severity:

• Common side effects typically arise within the first few weeks.
• Serious reactions are rare but require prompt discontinuation.

• Methotrexate: May increase hematologic toxicity due to folate antagonism.
• Digoxin: May reduce digoxin bioavailability.
• Folic Acid: Sulfasalazine inhibits intestinal absorption; supplementation recommended.
• Azathioprine / Mercaptopurine: Increased risk of myelosuppression.
• Antibiotics: May reduce efficacy by inhibiting bacterial azo-reduction in the colon.

Enzyme Systems:

• Not primarily metabolized via CYP450 pathways.
• Affected more by transporter and conjugation enzymes (e.g., N-acetyltransferase).

Food/Alcohol:

• Food may improve tolerability.
• No significant alcohol interactions, but excessive alcohol use may increase hepatic risk.

• ACR & EULAR Guidelines continue to include sulfasalazine as a first-line DMARD in RA, especially in early disease or in combination regimens.
• Updated Monitoring Recommendations: More frequent blood count and LFT monitoring advised during the initial 3 months of therapy.
• No recent changes in dosing, formulation, or contraindications reported by FDA or EMA.

• Temperature: Store at 20°C to 25°C (68°F to 77°F).
• Permissible Excursion: 15°C to 30°C (59°F to 86°F).
• Humidity/Light Protection: Keep in a dry place, away from light and moisture.
• Handling Precautions: Do not crush or chew tablets.
• Reconstitution/Refrigeration: Not applicable for standard oral tablet formulation.