Sulfasalazine (Salazopyrin) is a conventional disease-modifying anti-rheumatic drug (DMARD) that is used in the treatment of rheumatoid arthritis, inflammatory bowel diseases such as ulcerative colitis and psoriatic arthritis.

Sulfasalazine (Salazopyrin) Uses:

• Juvenile rheumatoid arthritis:

  • Delayed-release tablets:
    • Treatment of pediatric patients with polyarticular-course juvenile rheumatoid arthritis who have an ineffective response to salicylates or other NSAIDs.

• Rheumatoid arthritis:

  • Delayed-release tablets:
    • Treatment of rheumatoid arthritis in patients who have an ineffective response to salicylates or other NSAIDs.
    • Note: Treatment started with a DMARD is recommended in DMARD-naive patients with either early rheumatoid arthritis (RA) (disease duration <6 months) or established RA (disease duration ≥6 months).

• Ulcerative colitis:

  • Immediate and delayed-release Tablets:
    • Treatment of mild to moderate ulcerative colitis; added therapy in severe ulcerative colitis; prolongation of the remission period between acute attacks of ulcerative colitis.

• Off Label Use of Sulfasalazine in Adults:

  • Ankylosing spondylitis;
  • Crohn disease (mild to moderately active);
  • Psoriasis;
  • Psoriatic arthritis

Sulfasalazine (Salazopyrin) Dose in Adults

Sulfasalazine (Salazopyrin) Dose in the treatment of Rheumatoid arthritis:

• Oral: Delayed-release Tablets:

  • Initial: 500 mg once daily or 1000 mg/day in 2 divided doses;
  • Increase the dose each week to the maintenance dose: 2 g/day in 2 divided doses;
  • The maximum dose is 3 g/day (if the response to 2 g/day is not adequate after 12 weeks of treatment).

Sulfasalazine (Salazopyrin) Dose in the treatment of Ulcerative colitis:

• Oral: Immediate and delayed-release tablets:

  • Initial:
    • 3 to 4 g/day in divided doses at ≤8-hour intervals;
    • May start therapy with 1 to 2 g/day to reduce GI intolerance.
    • Doses exceeding 4 g/day can increase the risk of toxicity.
    • Note: American College of Gastroenterology guideline recommendations:
      • Titrate to 4 to 6 g daily in 4 divided doses.
  • Maintenance dose:
    • 2 g/day in divided doses at ≤8-hour intervals when endoscopic exam confirms improvement
  • Dosage adjustment:
    • If GI intolerance occurs, lower the dosage by 50% and slowly increase to the target dose over several days.
    • If GI intolerance continues, stop therapy for 5 to 7 days and restart at a lower daily dose.

Sulfasalazine (Salazopyrin) Dose in the treatment of Ankylosing spondylitis (off-label):

• Oral: Initial: 500 mg once daily;
• may up titrate the dose to 2 to 3 g/day in divided doses;
• if not tolerated, decrease dose by 500 mg each week as required.

Sulfasalazine (Salazopyrin) Dose in the treatment of mild to moderately active Crohn disease (off-label):

• Oral: 3 to 6 g/day in divided doses for up to 16 weeks.

Sulfasalazine (Salazopyrin) Dose in the treatment of Psoriasis (off-label):

• Oral: Initial: 500 mg twice daily.
• Maintenance: doses may be increased to 3 to 4 g/day according to tolerability.

Sulfasalazine (Salazopyrin) Dose in the treatment of Psoriatic arthritis (off-label):

• Oral: Initial: 500 mg once daily;
• may up titrate to 2 to 3 g daily in divided doses.

• Desensitization regimen:

  • For patients who may be sensitive to treatment, it is suggested to start with a total dose of 50 to 250 mg daily and double it every 4 to 7 days until the desired therapeutic level is attained.
  • Discontinue in case symptoms of sensitivity occur.
  • Do not attempt in patients with a history of agranulocytosis or those who have had a previous anaphylactoid reaction on sulfasalazine therapy

Sulfasalazine (Salazopyrin) Dose in Childrens

Sulfasalazine (Salazopyrin) Dose in the treatment of Inflammatory bowel disease (Ulcerative colitis and Crohn disease):

• Weight-directed dosing:

  • Children and Adolescents:

    • Induction: Crohn disease, ulcerative colitis:
      • Oral: 40 to 70 mg/kg/day in 3 to 6 divided doses;
      • in some cases, higher doses up to 100 mg/kg/day may be needed;
      • maximum daily dose: 4,000 mg/day.
    • Maintenance: Ulcerative colitis:
      • Oral: 30 to 70 mg/kg/day in 3 to 6 divided doses;
      • The maximum daily dose: 4,000 mg/day;
      • effective induction dose should be continued as the initial maintenance dose;
      • may consider lowering the dose once remission sustained for several months.

• Fixed dosing (Salazopyrin prescribing information:

  • Children ≥25 kg and Adolescents:

Note: Consider a lower dose or use of the enteric-coated tablet in patients with gastrointestinal related side effects with the uncoated tablet.

• • • Acute attacks:
      • 25 to <35 kg: Oral: 500 mg 3 times daily
      • 35 to 50 kg: Oral: 1,000 mg 2 to 3 times daily
    • Maintenance of remission:
      • 25 to <35 kg: Oral: 500 mg 2 times daily
      • 35 to 50 kg: Oral: 500 mg 2 to 3 times daily

Sulfasalazine (Salazopyrin) Dose in the treatment of Juvenile idiopathic arthritis:

• Children and Adolescents 6 to 16 years:

  • Oral: Enteric-coated tablet: 30 to 50 mg/kg/day in 2 divided doses;
  • The maximum daily dose: 2,000 mg/day.
  • Note: Although it is an FDA-labeled indication, the use of sulfasalazine for treatment of JIA is not included as a therapeutic option by experts.

Desensitization regimen:

• Children ≥6 years and Adolescents:

  • For patients who may be sensitive to treatment, it is recommended to start with a reduced total dose, for example when treating inflammatory bowel disease;
  • lower initial doses of 50 to 250 mg daily is preferred (usual is 1,500 to 3,000 mg/day) and double it every 4 to 7 days until the desired dose is attained.
  • Discontinue if symptoms of sensitivity observed.
  • Do not attempt in patients with a history of agranulocytosis or those with a prior anaphylactoid reaction on sulfasalazine therapy.

Sulfasalazine (Salazopyrin) Pregnancy Risk Category: B

• The placenta is crossed by sulfapyridine and sulfasalazine.
• According to available data, there has not been an increase in fetal malformations following maternal treatment with sulfasalazine.
• There have been reports of cases of neural tube defects (cause undetermined).
• An infant with granulocytosis was diagnosed after the maternal use of sulfasalazine during pregnancy.
• Although sulfapyridine is not able to replace bilirubin, it can cause kernicterus in newborns.
• Sulfasalazine can inhibit the absorption and metabolism folic acid, and could reduce the benefits of supplementation.
• Treatment for inflammatory bowel diseases during pregnancy may require sulfasalazine. However, it is recommended to supplement with folic acid.
• Sulfasalazine can cause oligospermia in males and reversible fertility in females.
• The use of this medication is compatible with male partners who have reproductive potential. However, stopping treatment after 3 months could increase the chances of conception.

Sulfasalazine use during breastfeeding:

• Breast milk contains sulfasalazine, sulfapyridine and other chemicals.
• The concentrations of sulfasalazine are not significant, but sulfapyridine levels are between 30% and 60% of the maternal serum.
• One case reported that sulfapyridine was found in breast milk after 4 hours of the maternal dose. It remained relatively constant throughout the duration of the dosing interval.
• Some breast milk samples also contained Acetylsulfapyridine.
• A 2-month-old exclusively breastfed infant experienced one episode of bloody diarrhea. Two weeks later, the symptoms returned with as many as six episodes per day and continued for three months. The mother was on sulfasalazine since 2005. The infant stopped having bloody stool within 72 hours after she had stopped taking the medication. The maternal plasma levels were within the therapeutic range but the mother was a slow acetylator.
• The infant was able to detect sulfapyridine in his milk, but no samples of the infant's milk were taken.
• Manufacturer notes that while sulfapyridine is not able to replace bilirubin, it can cause kernicterus in newborns.
• Manufacturer recommends caution when giving sulfasalazine breastfeeding women.
• Some guidelines recommend that sulfasalazine be used if a full-term, healthy breastfeeding mother is available. Others suggest caution or avoidance.
• If the infant is unwell, premature or has a G-6-PD deficiency, breastfeeding should be stopped.
• Diarrhea should be checked for in infants.

Dose in Kidney Disease:

There are no dosage adjustments provided in the manufacturer's labeling; however, use extreme caution.

Dose in Liver disease:

There are no dosage adjustments provided in the manufacturer's labeling; however, use extreme caution.

Common Side Effects of Sulfasalazine (Salazopyrin):

• Central Nervous System:

  • Headache

• Dermatologic:

  • Skin Rash

• Gastrointestinal:

  • Nausea
  • Dyspepsia
  • Anorexia
  • Gastric Distress
  • Vomiting

• Genitourinary:

  • Oligospermia

Less Common Side Effects of Sulfasalazine (Salazopyrin):

• Central Nervous System:

  • Dizziness

• Dermatologic:

  • Pruritus
  • Urticaria

• Gastrointestinal:

  • Abdominal Pain
  • Stomatitis

• Hematologic & Oncologic:

  • Leukopenia
  • Thrombocytopenia
  • Heinz Body Anemia
  • Hemolytic Anemia

• Hepatic:

  • Abnormal Hepatic Function Tests

• Respiratory:

  • Cyanosis

• Miscellaneous:

  • Fever

Contraindications to Sulfasalazine (Salazopyrin):

• Hypersensitivity to sulfasalazine, its metabolism, sulfonamides and salicylates or any component of formulation
• Intestinal or urinary obstruction
• porphyria

Notification:

• Although the FDA-approved product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged. 
• See "Warnings/Precautions" for more detail.

Canadian labeling: Additional contraindications not in US labeling

• Grave renal impairment (GFR 30mL/minute/1.73m2)
• Grave hepatic impairment
• Use in children under 2 years old;
• patients in whom acute asthmatic attacks, urticaria, rhinitis, or other allergic manifestations are precipitated by acetylsalicylic acid (ASA) or other NSAIDs

Warnings and precautions

• Blood dyscrasias:

  • There have been fatalities linked to severe reactions such as agranulocytosis and aplastic anemia. Stop using the medication at the first sign of rash, or signs of serious adverse effects.
  • A serious blood disorder may be indicated by the presence of symptoms such as fever, sore throat, pallor, or purpura.
  • Patients with blood disorders should be treated with extreme caution. Keep an eye on the CBC and take note of any changes.

• CNS effects

  • There have been reports of deaths from irreversible neuromuscular or CNS changes.

• Dermatologic reactions

  • Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis and exfoliative dermatitis (TEN) have all been reported with sulfonamides. These reactions are most common during the first month. Stop using sulfasalazine if you notice skin rash, mucosal lesion or any other signs of dermatologic toxicity.

• Fibrosing Alveolitis

  • Reports of fibrosing veinlitis have led to fatalities.

• Folate deficiency:

  • Might decrease folic acid absorption.

• GI effects

  • Nausea, vomiting and abdominal discomfort are common. Adjusting the dose or using an enteric-coated formulation can help reduce GI adverse reactions.

• Hepatic necrosis

  • There have been deaths due to hepatic injury. Stop using the medication immediately if you notice jaundice or hepatotoxicity.

• Hypersensitivity reactions

  • There have been reports of severe and life-threatening reactions to drugs, including drug rash with Eosinophilia (DRESS) syndrome and drug rash with systemic symptoms.
  • Before rash development, fever or lymphadenopathy could be present.
  • Other serious hypersensitivity reactions include myocarditis and nephritis.
  • If you have severe reactions, discontinue treatment and consult a physician immediately.

• Infections

  • Sepsis, pneumonia and other serious infections have been reported (some of which can be fatal).
  • Agranulocytosis and neutropenia may also be causes of infection.
  • Monitor for signs/symptoms and discontinue sulfasalazine treatment for serious infections.
  • Patients with a history or concomitant treatment for recurring or chronic infections, or patients with underlying conditions that could predispose to infection should be cautious.

• Oligospermia:

  • Males have reported oligospermia (rare) as well as infertility. These conditions are usually reversible upon discontinuation.

• Allergy to sulfonamide ("sulfa")

  • Cross-reactivity concerns have been a concern for all compounds with the sulfonamide structural.
  • A better understanding of allergy mechanisms suggests that cross-reactivity between nonantibiotic and antibiotic sulfonamides is unlikely.
  • Mechanisms of anaphylaxis (cross-reaction) due to antibody production are unlikely to occur with antibiotic sulfonamides or nonantibiotic sulfuramides.
  • Sulfasalazine is an antibiotic sulfonamide that has the arylamine structure. It may cross-react to antibiotic sulfonamides.
  • T-cell-mediated (type IV), reactions (eg maculopapular skin rash) are less well understood. It is difficult to exclude this possibility based on current knowledge.
  • Some clinicians opt to avoid these classes in cases of severe reactions (Stevens Johnson syndrome/TEN).

• Allergies and asthma

  • Patients with severe allergies or bronchial asthma should be cautious.

• G6PD deficiency:

  • Patients with G6PD deficiency should be cautious; hemolytic anemia can occur (dose-related).

• Hepatic impairment

  • Patients with impaired liver function should be used with caution.

• Renal impairment

  • Patients with impaired renal function should be used with caution. To prevent crystalluria or stone formation, ensure adequate hydration.

Sulfasalazine: Drug Interaction

Monitoring parameters:

Manufacturer's labeling:

• CBC with differential and liver function tests (before starting therapy, then every alternate week for the first 3 months of therapy, followed by every month for the next 3 months, then once every 3 months thereafter or as clinically required);
• periodic urinalysis and renal and liver function tests;
• stool frequency;
• signs of infection,
• dermatologic toxicity, or
• hypersensitivity reactions.

Alternate recommendations:

• Rheumatoid arthritis:
  • Complete blood count, serum creatinine, and LFTs:
    • Baseline and every 2 to 4 weeks for 3 months after initiation or following dose increases, then every 8 to 12 weeks during 3 to 6 months of treatment, followed by every 12 weeks beyond 6 months of treatment;
    • monitor more frequently if clinically indicated.

How to administer Sulfasalazine (Salazopyrin)?

Administer tablets in evenly divided doses, preferably after meals. Swallow delayed-release whole.

Mechanism of action of Sulfasalazine (Salazopyrin):

• 5-aminosalicylic Acid (5-ASA), the active component in sulfasalazine, is not yet known.
• However, it is believed that 5-ASA modulates local chemical mediators of inflammatory response, particularly leukotrienes.
• It is also thought to be a free radial scavenger and tumor necrosis factor inhibitor. The action seems more topical than systemic.

The onset of action:

• Rheumatoid arthritis: >4 weeks;
• Ulcerative colitis: >3 to 4 weeks

Absorption: Oral:

• Sulfasalazine: <15% as parent drug

Protein binding:

• Sulfasalazine: >99% to albumin;
• Sulfapyridine: ~70% to albumin;
• Acetylsulfapyridine (AcSP): ~90% to plasma proteins

Metabolism:

• Via colonic intestinal flora to sulfapyridine and 5-aminosalicylic acid (5-ASA).
• After absorption, sulfapyridine undergoes acetylation to form AcSP and ring hydroxylation while 5-ASA undergoes N-acetylation (non-acetylation phenotype dependent process);
• The rate of metabolism via acetylation depends on acetylation phenotype

Bioavailability:

• Sulfasalazine: <15%;
• Sulfapyridine: ~60%;
• 5-aminosalicylic acid: ~10% to 30%

Half-life elimination:

• Sulfasalazine: 7.6 ± 3.4 hours (prolonged in elderly patients);
• Sulfapyridine: 14.8 hours (slow acetylators) and 10.4 hours (fast acetylators)

Time to peak:

• Sulfasalazine: 3 to 12 hours (mean: 6 hours);
• Sulfapyridine and 5-aminosalicylic acid (5-ASA): ~10 hours

Excretion:

• Primarily urine (as unchanged drug, conjugates, and acetylated metabolites);
• feces (small amounts)

International Brand Names of Sulfasalazine:

• Azulfidine
• Azulfidine EN-tabs
• APO-Sulfasalazine
• PMS-Sulfasalazine
• Salazopyrin
• Azulfidina
• Azulfidine
• Azulfidine EN-tabs
• Azulfidine-EN
• Azulfin
• Bomecon
• Colo-Pleon
• Disalazin
• Falazine
• Gastropyrin
• Lazafin
• Lazo
• Pyralin EN
• Rosulfant
• SAAZ
• Salazex
• Salazine
• Salazo
• Salazodin
• Salazopirina
• Salazopyrin
• Salazopyrin EN
• Salazopyrin Entabs
• Salazopyrin-EN
• Salazopyrina
• Salazopyrine
• Salazopyrine EC
• Salazosin
• Salivon
• Salopyr
• Salopyrine
• Saridine-E
• Sazo
• Sulcolon
• Sulfasalazin
• Sulfitis
• Sulsa 500
• Sulzin
• Zopyrin

Sulfasalazine Brand Names in Pakistan: