AZULFIDINE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AZULFIDINE (AZULFIDINE).
Sulfasalazine is a prodrug that is cleaved by gut bacteria to form 5-aminosalicylic acid (5-ASA) and sulfapyridine. 5-ASA acts locally in the colon to reduce inflammation by inhibiting prostaglandin synthesis and leukotriene formation, antioxidant effects, and inhibition of cytokine production. Sulfapyridine provides additional immunosuppressive effects.
| Metabolism | Metabolized by gut bacteria to sulfapyridine (acetylated and hydroxylated in liver) and 5-ASA (acetylated in liver and colon). |
| Excretion | Renal: 75% (sulfapyridine metabolites), 15% (5-aminosalicylic acid). Biliary/fecal: 10%. |
| Half-life | Sulfapyridine: 10-14 hours; 5-ASA: 0.6-1.4 hours (rapid acetylation). Clinical context: Twice-daily dosing maintains therapeutic sulfapyridine levels. |
| Protein binding | Sulfapyridine: 30-50% (albumin); 5-ASA: 43%. |
| Volume of Distribution | Sulfapyridine: 0.2 L/kg (distributes into joint fluid, intestinal tissue). |
| Bioavailability | Oral (enteric-coated): 10-20% (5-ASA), 85-90% (sulfapyridine). |
| Onset of Action | Oral: 3-5 days (ulcerative colitis). |
| Duration of Action | Oral: 12-24 hours (sulfapyridine). Clinical note: Steady-state achieved in 3-5 days. |
Oral, 500 mg to 1 g twice daily, initially 500 mg twice daily, increase to 1 g twice daily after 1 week if tolerated; maximum 3 g/day.
| Dosage form | TABLET |
| Renal impairment | CrCl 30-60 mL/min: 50% of usual dose; CrCl 15-30 mL/min: 25% of usual dose; CrCl <15 mL/min: contraindicated (risk of sulfonamide accumulation). |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: use with caution, reduce dose by 50%; Child-Pugh C: contraindicated (risk of hepatotoxicity and accumulation). |
| Pediatric use | Children ≥6 years: initially 30-50 mg/kg/day in 2 divided doses, maintenance up to 50 mg/kg/day; maximum 2 g/day. |
| Geriatric use | Start at lower end of dosing range (e.g., 500 mg twice daily), monitor renal function and blood counts closely due to age-related decline in renal function and increased sensitivity to sulfonamides. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AZULFIDINE (AZULFIDINE).
| Breastfeeding | Sulfasalazine and its metabolites are excreted in breast milk. The M/P ratio for sulfapyridine is approximately 0.6. Concentrations in milk are low and considered compatible with breastfeeding. However, caution is advised in premature infants or those with hyperbilirubinemia or G6PD deficiency due to potential risk of hemolysis or kernicterus. |
| Teratogenic Risk | Sulfasalazine (Azulfidine) is classified as FDA Pregnancy Category B. There is no evidence of teratogenicity in humans. First trimester: Risk of neural tube defects due to folate antagonism; folate supplementation is recommended. Second and third trimesters: No known increased risk of congenital anomalies; however, sulfapyridine crosses the placenta and may displace bilirubin, increasing risk of neonatal hyperbilirubinemia and kernicterus near term. |
■ FDA Black Box Warning
None specifically for Azulfidine; however, sulfonamide component carries risk of severe hypersensitivity reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, and hepatotoxicity.
| Serious Effects |
Hypersensitivity to sulfonamides or salicylates, porphyria, urinary tract obstruction, intestinal obstruction, severe hepatic/renal impairment.
| Precautions | Risk of agranulocytosis, severe hypersensitivity reactions (SJS/TEN), hepatotoxicity, renal toxicity, pulmonary fibrosis, oligospermia, folate deficiency, and sulfonamide allergies. Monitor CBC, LFTs, renal function periodically. |
| Food/Dietary | No specific food restrictions, but take with meals to minimize GI distress. Maintain adequate fluid intake. Avoid alcohol due to potential disulfiram-like reaction with sulfapyridine. |
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| Fetal Monitoring | Monitor maternal complete blood count (CBC) for hemolysis or agranulocytosis, and bilirubin levels in neonates. Assess for signs of folate deficiency. Ultrasonography may be considered to assess fetal growth if concerns arise. Monitor neonatal bilirubin levels if drug used near term. |
| Fertility Effects | Sulfasalazine may cause reversible oligospermia and infertility in men. This effect is related to the sulfapyridine moiety and resolves within months of discontinuation. No significant effects on female fertility have been reported. |
| Clinical Pearls | Initiate at low doses (500 mg BID) and titrate weekly to reduce GI intolerance; sulfapyridine metabolite causes orange-yellow urine and skin discoloration; monitor CBC and LFTs regularly due to risk of agranulocytosis and hepatotoxicity; use with caution in G6PD deficiency; avoid in patients with sulfonamide or salicylate allergy. |
| Patient Advice | Take with food or milk to reduce stomach upset. · Drink plenty of fluids to prevent kidney stones. · Urine, tears, or contact lenses may turn orange-yellow. · Report immediately: fever, sore throat, rash, jaundice, dark urine, or unusual bleeding. · Avoid prolonged sun exposure; use sunscreen. · Notify doctor if pregnant or breastfeeding. |