Sulfasalazine

Generic Name

Sulfasalazine

Brand Names

Salazopyrin

Azulfidine

Salazopyrin EN-Tabs

Sazo EN

SASP

Others depending on the region and manufacturer

Drug Class

Aminosalicylate

Disease-Modifying Antirheumatic Drug (DMARD)

Anti-inflammatory agent

Sulfonamide derivative

Mechanism of Action

Sulfasalazine is a prodrug composed of sulfapyridine and 5-aminosalicylic acid (5-ASA or mesalazine) linked by an azo bond

In the colon, bacterial azoreductases cleave this bond to release the active metabolites

5-ASA exerts anti-inflammatory effects locally in the gut mucosa by inhibiting cyclooxygenase (COX) and lipoxygenase pathways, leading to reduced production of prostaglandins and leukotrienes

Sulfapyridine is systemically absorbed and believed to be responsible for many of the systemic side effects

The exact mechanism in rheumatoid arthritis and other autoimmune conditions is not fully understood but may involve suppression of pro-inflammatory cytokines such as TNF-α and IL-1 and inhibition of lymphocyte and neutrophil functions

Indications

Approved Indications

Ulcerative colitis: induction and maintenance of remission

Rheumatoid arthritis: as a DMARD for mild to moderate disease

Juvenile idiopathic arthritis

Crohn's disease (less commonly used due to proximal small bowel involvement)

Off-Label Uses

Ankylosing spondylitis

Psoriatic arthritis

Reactive arthritis

Autoimmune uveitis

Colitis associated with radiation or diversion

Dosage and Administration

Ulcerative Colitis

Induction of remission

Adults: 3 g to 4 g per day in divided doses

Children: 40–60 mg/kg/day in 3–6 divided doses

Maintenance

Adults: 2 g per day in divided doses

Children: 30–50 mg/kg/day in divided doses

Rheumatoid Arthritis

Adults: initial dose 500 mg once daily for 1 week, then increased to 500 mg twice daily, with gradual escalation to 1 g twice daily

Max dose: 3 g/day (in divided doses)

Therapeutic response is usually seen within 6 to 12 weeks

Pediatric Use

Juvenile arthritis: 30–50 mg/kg/day in two divided doses (max 2 g/day)

EC (enteric-coated) tablets are preferred to minimize gastrointestinal intolerance

Administration

Administer with food and a full glass of water

Enteric-coated formulations reduce upper GI side effects

Ensure adequate hydration to reduce risk of crystalluria and nephrotoxicity

Folic acid supplementation is often recommended concurrently

Pharmacokinetics

Absorption

About 15% of sulfasalazine is absorbed in the small intestine

The majority reaches the colon where it is cleaved into 5-ASA and sulfapyridine

Distribution

Widely distributed in body tissues and fluids

Crosses placenta and is excreted in breast milk

Metabolism

Metabolized in the colon (azo reduction) and liver (acetylation)

Sulfapyridine is further metabolized via acetylation and hydroxylation

Acetylator status (fast or slow) influences toxicity

Elimination

Excreted in urine and feces

Half-life: 5 to 10 hours (sulfapyridine), 6 hours (sulfasalazine)

Contraindications

Hypersensitivity to sulfasalazine, sulfonamides, or salicylates

Intestinal or urinary obstruction

Porphyria

Children under 2 years of age

Severe hepatic or renal impairment

Warnings and Precautions

Hematologic Effects

Bone marrow suppression may occur, including leukopenia, agranulocytosis, aplastic anemia, and thrombocytopenia

Regular complete blood counts are required during therapy

Hepatic Effects

Hepatitis and liver failure have been reported

Monitor liver function tests regularly

Renal Effects

Crystalluria and interstitial nephritis may occur

Ensure adequate hydration and monitor renal function

Skin Reactions

Exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported

Discontinue immediately if rash or hypersensitivity occurs

G6PD Deficiency

Increased risk of hemolysis

Use with caution and monitor blood counts closely

Fertility

Reversible oligospermia in men is a well-known effect

Typically resolves within 2–3 months of discontinuation

Folic Acid Deficiency

Sulfasalazine impairs folate absorption and metabolism

Routine supplementation with folic acid (1 mg/day) is recommended

Infections

Risk of infection is increased due to immunomodulatory effects

Use caution in patients with recurrent infections

Adverse Effects

Very Common

Headache

Anorexia

Nausea

Vomiting

Abdominal discomfort

Common

Fever

Rash

Arthralgia

Reversible oligospermia

Leukopenia

Orange-yellow discoloration of urine

Uncommon

Hepatitis

Elevated liver enzymes

Nephrotoxicity

Hypersensitivity pneumonitis

Photosensitivity

Rare and Serious

Agranulocytosis

Aplastic anemia

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Pancreatitis

Peripheral neuropathy

Myocarditis and pericarditis

Overdose

Symptoms include nausea, vomiting, drowsiness, seizures, and hematuria

Treatment is supportive

Alkalinization of urine may enhance excretion of sulfonamide components

Dialysis is generally not effective

Drug Interactions

Methotrexate

Additive bone marrow suppression risk

Monitor CBC and folate status

Azathioprine and Mercaptopurine

Increased risk of myelosuppression

Monitor CBC closely

Digoxin

Sulfasalazine reduces digoxin absorption

Monitor digoxin levels

Warfarin

Potentiation of anticoagulant effect possible

Monitor INR closely

Folic Acid

Sulfasalazine reduces absorption

Supplementation recommended

Iron

Iron may reduce absorption of sulfasalazine

Separate doses by at least 2 hours

Antibiotics (broad spectrum)

May interfere with colonic bacterial azo reduction and efficacy

Use in Special Populations

Pregnancy

Generally considered safe for use in pregnancy

Category B (US classification before removal of categories)

Folic acid supplementation is mandatory due to risk of neural tube defects

Monitor fetal growth and maternal hemoglobin

Lactation

Excreted in breast milk

Use with caution

May cause diarrhea or blood in stool in breastfed infants

Pediatrics

Used for juvenile idiopathic arthritis and inflammatory bowel disease

Monitor for growth, nutritional status, and laboratory abnormalities

Geriatrics

Increased susceptibility to adverse effects, particularly hematologic

Start at lower dose and monitor more frequently

Renal Impairment

Use cautiously

Monitor serum creatinine and urinalysis periodically

Hepatic Impairment

Avoid in severe liver disease

Monitor liver function regularly in all patients

Monitoring Parameters

CBC with differential: baseline, every 2 weeks for first 3 months, then monthly for 3 months, then every 3 months

Liver function tests: same schedule as CBC

Renal function: baseline and periodically

Urinalysis: periodically

Folate levels if signs of deficiency

Signs of rash, hypersensitivity, respiratory symptoms

Male fertility if oligospermia suspected

Comparative Pharmacology

Sulfasalazine vs Mesalazine (5-ASA)

Mesalazine is the active component with fewer systemic side effects

Sulfasalazine is less expensive but more likely to cause rash and hematologic issues

Sulfasalazine vs Methotrexate

Both are first-line DMARDs

Sulfasalazine is often better tolerated initially but may be less potent

Methotrexate has more hepatic toxicity and teratogenicity

Sulfasalazine vs Biologics (e.g., adalimumab)

Biologics are more potent and used in severe or refractory cases

Sulfasalazine is preferred in mild to moderate disease and as step-up therapy

Formulations Available

Oral tablets: 500 mg (immediate-release and enteric-coated)

Suspension formulation not widely available

Combination therapy: sometimes used with other DMARDs such as hydroxychloroquine and methotrexate in triple therapy for RA

Regulatory and Legal Status

Prescription-only medication

Approved globally for ulcerative colitis and rheumatoid arthritis

Listed in the WHO Model List of Essential Medicines for inflammatory bowel disease and rheumatic conditions