Sulfasalazine

(BAN, USAN, rINN)
Sulfasalazine Chemical formula
Synonyms: Salatsosulfapyridiini; Salazosulfapyridin; Salazosulfapyridine; Salazosulfapyridinum; Salicylazosulfapyridine; SI-88; Sulfasalatsiini; Sülfasalazin; Sulfasalazin; Sulfasalazina; Sulfasalazinas; Sulfasalazinum; Sulfasalazyna; Sulphasalazine; Szulfaszalazin. 4-Hydroxy-4′-(2-pyridylsulphamoyl)azobenzene-3-carboxylic acid.
Cyrillic synonym: Сульфасалазин.

💊 Chemical information

Chemical formula: C18H14N4O5S = 398.4.
CAS — 599-79-1.
ATC — A07EC01.
ATC Vet — QA07EC01.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, and US.

Ph. Eur. 6.2

(Sulfasalazine). A bright yellow or brownish-yellow, fine powder. Practically insoluble in water and in dichloromethane; very slightly soluble in alcohol; dissolves in dilute solutions of alkali hydroxides. Protect from light.

USP 31

(Sulfasalazine). A fine odourless bright yellow or brownish-yellow powder. Practically insoluble in water, in chloroform, in ether, and in benzene; soluble 1 in 2900 of alcohol, and 1 in 1500 of methyl alcohol; soluble in aqueous solutions of alkali hydroxides. Store in airtight containers. Protect from light.

💊 Adverse Effects and Precautions

Since sulfasalazine is metabolised to sulfapyridine and 5-aminosalicylic acid (mesalazine), its adverse effects and precautions are similar to those of sulfonamides and of mesalazine. Many adverse effects have been attributed to the sulfapyridine moiety and appear to be more common if serum-sulfapyridine concentrations are greater than 50 micrograms/mL, if the daily dose of sulfasalazine is 4 g or more, or in slow acetylators of sulfapyridine. The most commonly reported adverse effects include nausea and vomiting, abdominal discomfort, headache, fever, and skin rash. Adverse effects can be broadly divided into 2 groups:
dose-related effects are dependent on acetylator phenotype, and largely predictable; this group includes nausea and vomiting, headache, haemolytic anaemia, and methaemoglobinaemia
hypersensitivity reactions are essentially unpredictable and usually occur at the start of treatment; this group includes skin rash, aplastic anaemia, hepatic and pulmonary dysfunction, and auto-immune haemolysis Oligospermia, reversible on withdrawal of sulfasalazine, has also been reported. Sulfasalazine treatment may result in yellow-orange discoloration of skin, urine, and other body fluids. Some soft contact lenses may be stained. Sulfasalazine should not be given to patients with a history of sensitivity to sulfonamides or salicylates. Use in children under 2 years of age is contra-indicated because of the risk of kernicterus. Blood counts should be performed at the start of therapy and at least once a month for a minimum of the first 3 months of treatment. If a blood dyscrasia is suspected treatment should be stopped immediately and a blood count performed. Patients or their carers should be told how to recognise signs of blood toxicity and should be advised to seek immediate medical attention if symptoms such as fever, sore throat, mouth ulcers, bruising or bleeding develop. Care is advisable in patients with G6PD deficiency because of the risk of haemolytic anaemia. Sulfasalazine should be used with caution in hepatic or renal impairment. Liver function tests should be carried out at monthly intervals for the first 3 months of treatment. Periodic monitoring of kidney function has also been recommended.
The type and incidence of adverse effects appear to be similar in both groups of patients.2 Although most reactions are minor and patients may continue therapy at the same or reduced dosage, some patients stop treatment because of adverse effects and in these cases a hyposensitisation regimen may be considered.1,4,5 Hyposensitisation should not be attempted in patients with a history of a serious adverse effect such as agranulocytosis, toxic epidermal necrolysis, erythema multiforme, frank haemolysis, or a severe hypersensitivity reaction.1,4,5 An alternative to hyposensitisation in patients with inflammatory bowel disease who cannot tolerate sulfasalazine is to try a drug that supplies the active 5-aminosalicylic acid component without sulfapyridine, as the latter is thought to be responsible for many of the adverse effects. Examples include balsalazide, mesalazine, and olsalazine; however, some patients still experience hypersensitivity, see under Mesalazine.
1. Taffet SL, Das KM. Sulfasalazine: adverse effects and desensitization. Dig Dis Sci 1983; 28: 833–42
2. Amos RS, et al. Sulphasalazine for rheumatoid arthritis: toxicity in 774 patients monitored for one to 11 years. BMJ 1986; 293: 420–3
3. Farr M, et al. Side effect profile of 200 patients with inflammatory arthritides treated with sulphasalazine. Drugs 1986; 32 (suppl 1): 49–53
4. Purdy BH, et al. Desensitization for sulfasalazine skin rash. Ann Intern Med 1984; 100: 512–14
5. Bax DE, Amos RS. Sulphasalazine in rheumatoid arthritis: desensitising the patient with a skin rash. Ann Rheum Dis 1986; 45: 139–40.

Breast feeding.

Small amounts of sulfasalazine and its sulfapyridine metabolites are excreted in breast milk; the concentrations of sulfasalazine and total sulfapyridine may be up to 30% and 50% of maternal serum concentrations respectively.1 Bloody diarrhoea in a breast-fed infant whose mother was taking sulfasalazine 3 g daily has been reported.2 The mother was a slow acetylator with a relatively high blood concentration of sulfapyridine, which contributed to the appearance of the drug in the infant’s blood. Based on this report, the American Academy of Pediatrics3 considers that sulfasalazine should be given with caution to breast-feeding mothers. However, others consider that continued treatment with sulfasalazine can generally be recommended to breast-feeding mothers of healthy infants.4 A small study initially involving 17 mother-child pairs concluded sulfasalazine treatment could continue throughout pregnancy and lactation. The study found negligible amounts of sulfasalazine, and its main metabolite sulfapyridine, were transferred to the child via breast feeding. The authors did however warn that this conclusion could not be applied to a prematurely born child or a child with haemolytic disease.5
1. Khan AKA, Truelove SC. Placental and mammary transfer of sulphasalazine. BMJ 1979; 2: 1553
2. Branski D, et al. Bloody diarrhea—a possible complication of sulfasalazine transferred through human breast milk. J Pediatr Gastroenterol Nutr 1986; 5: 316–17
3. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 28/02/06
4. Peppercorn MA. Sulfasalazine and related new drugs. J Clin Pharmacol 1987; 27: 260–5
5. Esbjörner E, et al. Sulphasalazine and sulphapyridine serum levels in children to mothers treated with sulphasalazine during pregnancy and lactation. Acta Paediatr Scand 1987; 76: 137–42.

Effects on the blood.

Blood disorders constitute 19% of all reactions reported with sulfasalazine.1 As of June 1993 the UK CSM was aware of 191 reports of neutropenia, leucopenia, or agranulocytosis (22 fatal), 44 reports of bone marrow depression or aplastic anaemia (13 fatal) and 30 reports of thrombocytopenia (1 fatal).1 Although blood dyscrasias were initially thought to be caused by the sulfapyridine moiety, subsequent experience has shown that the aminosalicylates can also cause haematological reactions. The risk of blood dyscrasias with sulfasalazine has been estimated at 0.6 per 1000 in those given the drug for inflammatory bowel disease, but about 10 times greater in patients receiving sulfasalazine for rheumatoid arthritis.2 Sulfasalazine inhibits folic acid absorption, interferes with its metabolism, and can increase folic acid requirements through haemolysis of red blood cells.3,4 These effects are not usually significant in patients with inflammatory bowel disease unless there are additional factors causing folate deficiency, such as intercurrent illness or an exacerbation of bowel disease.3,4 However, clinical folate deficiency with macrocytosis, megaloblastic anaemia, or pancytopenia has been reported rarely.3,4 Macrocytic anaemia associated with sulfasalazine may occur more commonly in patients with rheumatoid arthritis; it was found in 7 of 50 patients within 3 to 4 months of starting treatment with sulfasalazine.5 The effects of sulfasalazine on folic acid metabolism appear to be dose-related and respond to withdrawal or dosage reduction, and folic acid supplements;3-5 intravenous folinic acid may sometimes be needed.4 Although the effects may be potentially serious, they are not a contra-indication to continuing sulfasalazine treatment.4,5 Patients with a history of leucopenia associated with gold therapy for rheumatoid arthritis should not be given sulfasalazine since a similar reaction may occur.6
1. Committee on Safety of Medicines/Medicines Control Agency. Sulphasalazine and fatal blood dyscrasias. Current Problems 1993; 19: 6. Also available at: http://www.mhra.gov.uk/home/ idcplg?IdcService=GET_FILE&dDocName=CON2024455& RevisionSelectionMethod=LatestReleased (accessed 02/07/08
2. Committee on Safety of Medicines/Medicines Control Agency. Blood dyscrasias and mesalazine. Current Problems 1995; 21: 5–6. Also available at: http://www.mhra.gov.uk/home/ idcplg?IdcService=GET_FILE&dDocName=CON2015619& RevisionSelectionMethod=LatestReleased (accessed 16/06/06
3. Swinson CM, et al. Role of sulphasalazine in the aetiology of folate deficiency in ulcerative colitis. Gut 1981; 22: 456–61
4. Logan ECM, et al. Sulphasalazine associated pancytopenia may be caused by acute folate deficiency. Gut 1986; 27: 868–72
5. Prouse PJ, et al. Macrocytic anaemia in patients treated with sulphasalazine for rheumatoid arthritis. BMJ 1986; 293: 1407
6. Bliddal H, et al. Gold-induced leucopenia may predict a similar adverse reaction to sulphasalazine. Lancet 1987; i: 390.

Effects on the cardiovascular system.

Reports include Raynaud’s syndrome with sulfasalazine1 and myocarditis with sulfasalazine and with mesalazine.2 Myocarditis leading to fatal cardiogenic shock has been reported in a patient receiving mesalazine and it has been recommended that sulfasalazine or mesalazine should be replaced by glucocorticoids if cardiac symptoms arise.3
1. Reid J, et al. Raynaud’s phenomenon induced by sulphasalazine. Postgrad Med J 1980; 56: 106–7
2. Agnholt J, et al. Cardiac hypersensitivity to 5-aminosalicylic acid. Lancet 1989; i: 1135
3. Kristensen KS, et al. Fatal myocarditis associated with mesalazine. Lancet 1990; 335: 605.

Effects on fertility.

Although successful pregnancies have been reported in the partners of men taking sulfasalazine,1,2 male infertility is a well recognised complication of sulfasalazine treatment. Untreated inflammatory bowel disease is not associated with abnormal seminal quality or infertility, but oligospermia, reduced sperm motility, and an increase in morphological abnormalities are seen after treatment with sulfasalazine which may lead to infertility.1-4 Oligospermia has been reported in 86% of men with inflammatory bowel disease treated with sulfasalazine.1 Seminal characteristics and fertility return to normal within 2 to 3 months of withdrawing sulfasalazine and successful pregnancies have been reported after withdrawal.1-3 The mechanism involved is thought to be a direct toxic effect on immature and developing spermatozoa, possibly due to the sulfapyridine moiety.2-4 Improvement in seminal characteristics and successful pregnancies have been reported following substitution of mesalazine4,5 or balsalazide6 for sulfasalazine in patients with ulcerative colitis. However, reversible infertility, similar to that caused by sulfasalazine, has also been reported with mesalazine.7
1. Birnie GG, et al. Incidence of sulphasalazine-induced male infertility. Gut 1981; 22: 452–5
2. Riley SA, et al. Sulphasalazine induced seminal abnormalities in ulcerative colitis: results of mesalazine substitution. Gut 1987; 28: 1008–12
3. Toovey S, et al. Sulphasalazine and male infertility: reversibility and possible mechanism. Gut 1981; 22: 445–51
4. Ó’Moráin C, et al. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut 1984; 25: 1078–84
5. Cann PA, Holdsworth CD. Reversal of male infertility on changing treatment from sulphasalazine to 5-aminosalicylic acid. Lancet 1984; i: 1119
6. McIntyre PB, Lennard-Jones JE. Reversal with balsalazide of infertility caused by sulphasalazine. BMJ 1984; 288: 1652–3
7. Chermesh I, Eliakim R. Mesalazine-induced reversible infertility in a young male. Dig Liver Dis 2004; 36: 551–2.

Effects on the gastrointestinal tract.

Sulfasalazine-induced exacerbations of ulcerative colitis have been reported1,2 and are probably caused by the salicylate moiety rather than sulfapyridine.3 Other reported effects include intestinal villous atrophy.4
1. Schwartz AG, et al. Sulfasalazine-induced exacerbation of ulcerative colitis. N Engl J Med 1982; 306: 409–12
2. Ring FA, et al. Sulfasalazine-induced colitis complicating idiopathic ulcerative colitis. Can Med Assoc J 1984; 131: 43–5
3. Shanahan F, Targan S. Sulfasalazine and salicylate-induced exacerbation of ulcerative colitis. N Engl J Med 1987; 317: 455
4. Smith MA, et al. Angioimmunoblastic lymphadenopathy, sulphasalazine exposure and villous atrophy. Postgrad Med J 1985; 61: 337–8.

Effects on the hair.

Alopecia occurred on 2 occasions1 after starting sulfasalazine 2 or 3 g daily in a patient with ulcerative colitis. On both occasions normal hair growth returned after treatment was stopped, and the patient was later successfully desensitised. However, alopecia that developed in another patient during sulfasalazine treatment did not recur on rechallenge.2 In this case postpartum alopecia was considered to be the cause and these authors doubted whether sulfasalazine causes alopecia at all. Hair loss has been reported in 2 patients receiving mesalazine enemas.3 However, remission of alopecia universalis has been reported during sulfasalazine treatment of rheumatoid arthritis.4
1. Breen EG, Donnelly S. Alopecia associated with sulphasalazine (Salazopyrin). BMJ 1986; 292: 802
2. Fich A, Eliakim R. Does sulfasalazine induce alopecia? J Clin Gastroenterol 1988; 10: 466
3. Kutty PK, et al. Hair loss and 5-aminosalicylic acid enemas. Ann Intern Med 1982; 97: 785–6
4. Jawad ASM, Scott DGI. Remission of alopecia universalis during sulphasalazine treatment for rheumatoid arthritis. BMJ 1989; 298: 675.

Effects on the kidneys.

UK licensed product information advises that adequate fluid intake and avoidance of urinary acidifiers may reduce the incidence of crystalluria and stone formation. For reports of nephrotic syndrome and of interstitial nephritis associated with sulfasalazine treatment, see under Mesalazine.

Effects on the pancreas.

The UK CSM had received 6 reports of pancreatitis associated with sulfasalazine as of February 1994.1 There had been further reports associated with mesalazine. However, a large Danish population-based casecontrol study concluded neither sulfasalazine nor mesalazine was associated with an increased risk of pancreatitis, and that any increased risk might be associated with inflammatory bowel disease itself.2
1. Committee on Safety of Medicines/Medicines Control Agency. Drug-induced pancreatitis. Current Problems 1994; 20: 2–3. Also available at: http://www.mhra.gov.uk/home/ idcplg?IdcService=GET_FILE&dDocName=CON2024457& RevisionSelectionMethod=LatestReleased (accessed 02/07/08
2. Munk EM, et al. Inflammatory bowel diseases, 5-aminosalicylic acid and sulfasalazine treatment and risk of acute pancreatitis: a population-based case-control study. Am J Gastroenterol 2004; 99: 884–8.

Effects on the respiratory system.

Although one study reviewed 50 cases of sulfasalazine-induced pulmonary complications, pulmonary toxicity remains a rare adverse effect.1 Most reports include dyspnoea, cough, pulmonary infiltrates, fever, and eosinophilia, usually developing in the first few months of treatment although they may occur after several years.1-3 Symptoms are generally readily reversible on withdrawal of sulfasalazine, although death due to fibrosing alveolitis has been reported,2 and the need for corticosteroid therapy remains debatable.1These effects have also occurred with mesalazine; they have been reported in patients with a history of sensitivity to salicylates, sulfonamides, or with no known sensitivity to these drugs.2,3 Bronchiolitis obliterans organising pneumonia has been reported in a patient with rheumatoid arthritis receiving sulfasalazine;4 clinical improvement occurred after sulfasalazine was stopped and corticosteroid therapy started.
1. Parry SD, et al. Sulphasalazine and lung toxicity. Eur Respir J 2002; 19: 756–64
2. Wang KK, et al. Pulmonary infiltrates and eosinophilia associated with sulfasalazine. Mayo Clin Proc 1984; 59: 343–6
3. Jordan A, Cowan RE. Reversible pulmonary disease and eosinophilia associated with sulphasalazine. J R Soc Med 1988; 81: 233–5
4. Ulubaş B, et al. Bronchiolitis obliterans organizing pneumonia associated with sulfasalazine in a patient with rheumatoid arthritis. Clin Rheumatol 2004; 23: 249–51.

Effects on taste.

Metallic taste has occurred in patients taking sulfasalazine for ulcerative colitis,1 although diseases causing changes in gastrointestinal absorption may lead to zinc deficiency, which has itself been associated with a metallic taste. There has also been a report of two patients developing a reversible taste dysfunction, while taking sulfasalazine for rheumatoid arthritis.2
1. Ogburn RM. Sulfamethazine-related dysgeusia. JAMA 1979; 241: 837
2. Marcus RW. Sulfasalazine induced taste disturbances. J Rheumatol 1991; 18: 634–5.

Lupus.

A study in 11 patients with sulfasalazine-induced lupus found that induction of disease was more likely in patients who were slow acetylators of sulfapyridine, and who had HLA haplotypes associated with idiopathic SLE.1 Furthermore, the risk of developing persistent SLE and lupus nephritis increased with duration of treatment and cumulative dose of sulfasalazine. Lupuslike syndrome has also occurred with mesalazine, see Lupus.
1. Gunnarsson I, et al. Predisposing factors in sulphasalazine-induced systemic lupus erythematosus. Br J Rheumatol 1997; 36: 1089–94.

Porphyria.

Sulfasalazine has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Pregnancy.

Sulfasalazine and its sulfapyridine metabolites readily cross the placenta resulting in similar concentrations in the cord serum and maternal serum at delivery.1,2 The concentration of the 5-aminosalicylic acid component of sulfasalazine in both cord serum and maternal serum is negligible.1 There have been isolated reports of congenital abnormalities associated with use of sulfasalazine during pregnancy including coarctation of the aorta with a ventricular septal defect,3,4 and genito-urinary disorders.4 There is also a theoretical risk of kernicterus in the neonate if sulfasalazine is given close to delivery. However, given the concentrations of sulfasalazine and its metabolites found in cord blood, the risk of kernicterus from maternal use is considered minimal.2 There have been many successful and uncomplicated pregnancies during sulfasalazine therapy and the general consensus favours continuing sulfasalazine throughout pregnancy when indicated.1,3-6 The minimum effective dose should be used and since sulfasalazine may precipitate folate deficiency (see Effects on the Blood, above), folic acid supplements are recommended.7
1. Khan AKA, Truelove SC. Placental and mammary transfer of sulphasalazine. BMJ 1979; 2: 1553
2. Järnerot G, et al. Placental transfer of sulphasalazine and sulphapyridine and some of its metabolites. Scand J Gastroenterol 1981; 16: 693–7
3. Hoo JJ, et al. Possible teratogenicity of sulfasalazine. N Engl J Med 1988; 318: 1128
4. Newman NM, Correy JF. Possible teratogenicity of sulphasalazine. Med J Aust 1983; 1: 528–9
5. Peppercorn MA. Sulfasalazine and related new drugs. J Clin Pharmacol 1987; 27: 260–5
6. Korelitz BI. Commentary: observations on sulfasalazine in Crohn’s disease and ulcerative colitis. J Clin Pharmacol 1987; 27: 265–6
7. Byron MA. Treatment of rheumatic diseases. BMJ 1987; 294: 236–8.

💊 Interactions

Giving sulfasalazine with antibacterial therapy may reduce conversion of sulfasalazine to its active metabolite (see below). Sulfasalazine has been reported to interfere with the absorption of digoxin or folic acid (see Effects on the Blood, above) from the gastrointestinal tract.

Antibacterials.

Since the effects of sulfasalazine depend on release of 5-aminosalicylic acid by bacterial metabolism in the gut, any drug that reduces the intestinal microflora may reduce the production of active metabolite. Evidence for this has been seen in patients also given rifampicin and ethambutol,1 or in subjects also given ampicillin.2 However, a decrease in clinical effect does not seem to have been seen.
1. Shaffer JL, Houston JB. The effect of rifampicin on sulphapyridine plasma concentrations following sulphasalazine administration. Br J Clin Pharmacol 1985; 19: 526–8
2. Houston JB, et al. Azo reduction of sulphasalazine in healthy volunteers. Br J Clin Pharmacol 1982; 14: 395–8.

Antineoplastics.

For mention of 5-aminosalicylates such as sulfasalazine inhibiting the metabolism of thiopurine antineoplastics, and increasing their toxicity, see Mercaptopurine.

💊 Pharmacokinetics

About 15% of an oral dose of sulfasalazine is absorbed from the small intestine, although some of this is subsequently returned to the intestine in bile via enterohepatic circulation. The great majority of the dose reaches the colon where the azo bond is cleaved by the action of the intestinal flora, producing sulfapyridine and 5-aminosalicylic acid (mesalazine). Results in patients who have undergone colectomy suggest that be tween 60 and 90% of the total dose is metabolised in this way, but the degree of metabolism depends both on the activity of the intestinal flora and the speed of intestinal transit; colonic metabolism is reduced in patients with diarrhoea (for example, in active inflammatory bowel disease). The small amount of intact sulfasalazine that is absorbed is extensively protein bound and subsequently excreted unchanged in urine. It crosses the placenta and is found in breast milk. After cleavage of the sulfasalazine molecule about 60 to 80% of available sulfapyridine is absorbed, and undergoes extensive metabolism by acetylation, hydroxylation, and glucuronidation. Peak steady-state concentrations of sulfapyridine are higher in slow acetylators than fast acetylators after similar doses and the former are 2 to 3 times more likely to have adverse effects. Some 60% of the original dose of sulfasalazine is excreted in urine as sulfapyridine and its metabolites. As with sulfasalazine, absorbed sulfapyridine crosses the placenta and is found in breast milk. The 5-aminosalicylic acid (5-ASA) moiety is much less well absorbed. About one-third of liberated 5-ASA is absorbed and almost all of this is acetylated and excreted in urine. For further details of the pharmacokinetics of 5-aminosalicylic acid see under Mesalazine.
1. Klotz U. Clinical pharmacokinetics of sulphasalazine, its metabolites and other prodrugs of 5-aminosalicylic acid. Clin Pharmacokinet 1985; 10: 285–302.

💊 Uses and Administration

Sulfasalazine is a compound of a sulfonamide, sulfapyridine, with 5-aminosalicylic acid (mesalazine). Its activity is generally considered to lie in the 5-aminosalicylic acid moiety, which is released in the colon by bacterial metabolism, although intact sulfasalazine has some anti-inflammatory properties in its own right. In inflammatory bowel disease it is used alone or as an adjunct to corticosteroids in the treatment of active ulcerative colitis and is effective in maintaining remission. Sulfasalazine may also be effective in the treatment of active Crohn’s disease, particularly of the colon, but it does not appear to be of value in maintaining remissions. Sulfasalazine is also used as a disease modifying drug in the treatment of severe or progressive rheumatoid arthritis (below). In inflammatory bowel disease the usual initial adult dose of sulfasalazine is 1 to 2 g orally 4 times daily in the UK. However, doses over 4 g daily are associated with an increased risk of toxicity, and in the USA, therefore, the usual dose is 1 g given 3 or 4 times daily, and an initial dose of 500 mg every 6 to 12 hours may be recommended to lessen gastrointestinal adverse effects. Enteric-coated tablets are also claimed to reduce the incidence of adverse gastrointestinal effects. The overnight interval between doses should not exceed 8 hours. On remission the dose in patients with ulcerative colitis is gradually reduced to 2 g daily and then generally continued indefinitely. For children 2 years of age or older doses should be proportional to body-weight; initially 40 to 60 mg/kg may be given daily in divided doses reduced to 20 to 30 mg/kg daily for the maintenance of remission. Sulfasalazine is also given rectally, as suppositories, initially at a dose of 1 g at night and in the morning. After three weeks the dosage is gradually reduced according to response. Rectal sulfasalazine can be given as 0.5 to l g night and morning as an adjunct to treatment by mouth. Sulfasalazine may also be given by enema in a dose of 3 g at bedtime. The BNFC suggests the following daily dosage may be given in divided doses to children as suppositories according to age: 5 to 8 years old: 1 g; 8 to 12 years old: 1.5 g; 12 to 18 years old: 2 g. Enemas, to be retained for at least 1 hour, may be given at night in doses of 1 to 1.5 g for children aged 2 to 7 years, 1.5 to 2.25 g for children aged 7 to 12 years, and 3 g for children 12 to 18 years. In adult rheumatoid arthritis treatment is usually started with an oral dose of 500 mg daily, as entericcoated tablets, for the first week; dosage is then increased by 500 mg daily each week to a maximum of 3 g daily given in 2 to 4 divided doses according to tolerance and response. In the USA, sulfasalazine can also be used for polyarticular juvenile rheumatoid arthritis in children aged 6 years and older who have not responded adequately to salicylates or other NSAIDs. A dose of 30 to 50 mg/kg daily is given in two divided doses, to a maximum dose of 2 g daily. To reduce adverse gastrointestinal effects, an enteric-coated tablet is used and the initial dose should be a quarter to a third of the planned maintenance; it is then increased weekly to reach the maintenance dose after one month. Although sulfasalazine is not licensed for juvenile rheumatoid arthritis in the UK, the BNFC suggests that children aged 2 to 18 years are given an initial oral dose of 5 mg/kg twice daily for 1 week. The dose is then increased to 10 mg/kg twice daily for 1 week, then 20 mg/kg twice daily for 1 week, and maintained on a dose of 20 to 25 mg/kg twice daily. For children aged 2 to 12 years the maximum dose suggested is 2 g daily, and for children aged 12 to 18 years 3 g daily.

Psoriasis.

In a double-blind placebo-controlled study involving 50 patients with moderate to severe plaque-type psoriasis, sulfasalazine 3 to 4 g daily produced a significantly greater clinical improvement than placebo after 4 weeks of treatment with a further improvement at 8 weeks.1 See also Psoriatic Arthritis, below.
1. Gupta AK, et al. Sulfasalazine improves psoriasis: a doubleblind analysis. Arch Dermatol 1990; 126: 487–93.

Pyoderma gangrenosum.

Sulfasalazine is licensed in some countries for the treatment of pyoderma gangrenosum, a condition that may be associated with inflammatory bowel disease, although published evidence of benefit is scanty.
1. Shenefelt PD. Pyoderma gangrenosum associated with cystic acne and hidradenitis suppurativa controlled by adding minocycline and sulfasalazine to the treatment regimen. Cutis 1996; 57: 315–9.

Rheumatoid arthritis.

Sulfasalazine is considered to be a useful disease-modifying antirheumatic drug (DMARD) in the treatment of rheumatoid arthritis. Studies have found a beneficial clinical effect of sulfasalazine, compared with placebo, on tender and swollen joints, pain, and erythrocyte sedimentation rate.1,2 Meta-analyses3,4 of generally short-term comparative studies suggest that sulfasalazine is roughly comparable in efficacy to methotrexate, intramuscular gold (sodium aurothiomalate), and penicillamine. Other reviews2,5 have also suggested that it may have similar efficacy to hydroxychloroquine and leflunomide. Although there are regional differences in the prescription of DMARDs, sulfasalazine has been widely used for initial therapy, especially of less severe disease.5 In an open study6 of 200 patients with rheumatoid arthritis who were randomly allocated to treatment with sulfasalazine or auranofin, 31% of the sulfasalazine recipients were still taking the drug after 5 years compared with 15% of auranofin recipients. Improvement over baseline was still significant at 5 years for those patients receiving sulfasalazine but not in those treated with auranofin. Although one study7 failed to find convincing evidence that using sulfasalazine with methotrexate was more effective than either drug alone, other studies have shown that combination treatment with sulfasalazine plus methotrexate and hydroxychloroquine was more effective than methotrexate alone or with sulfasalazine or hydroxychloroquine or the combination of sulfasalazine with hydroxychloroquine.8,9 A review of sulfasalazine use in the management of rheumatoid arthritis concluded that combination therapy may be of benefit in patients with early or advanced rheumatoid arthritis but that there is still a need for studies to determine the efficacy and tolerability of various combinations.5
1. Suarez-Almazor ME, et al. Sulfasalazine for treating rheumatoid arthritis. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 1998 (accessed 28/02/06)
2. Weinblatt ME, et al. Sulfasalazine treatment for rheumatoid arthritis: a metaanalysis of 15 randomized trials. J Rheumatol 1999; 26: 2123–30
3. Felson DT, et al. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Arthritis Rheum 1990; 33: 1449–61
4. Capell HA, et al. Second line (disease modifying) treatment in rheumatoid arthritis: which drug for which patient? Ann Rheum Dis 1993; 52: 423–8
5. Plosker GL, Croom KF. Sulfasalazine: a review of its use in the management of rheumatoid arthritis. Drugs 2005; 65: 1825–49
6. McEntegart A, et al. Sulfasalazine has a better efficacy/toxicity profile than auranofin—evidence from a 5 year prospective, randomized trial. J Rheumatol 1996; 23: 1887–90
7. Dougados M, et al. Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis 1999; 58: 220–5
8. O’Dell JR, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 1996; 334: 1287–91
9. O’Dell JR, et al. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a twoyear, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46: 1164–70.
JUVENILE IDIOPATHIC ARTHRITIS. Juvenile idiopathic arthritis is generally managed similarly to rheumatoid arthritis, but there is limited experience with the use of some antirheumatic drugs in children. Sulfasalazine has produced significant improvement in studies of patients with juvenile chronic arthritis; a literature review found that it was consistently reported to be of benefit.1 Adverse effects were reported to be similar to those in adults, with the exception of a serum-sickness-like reaction which was mostly seen in systemic onset patients and may be unique to juvenile rheumatoid arthritis.1
1. Brooks CD. Sulfasalazine for the management of juvenile rheumatoid arthritis. J Rheumatol 2001; 28: 845–53.

Spondyloarthropathies.

ANKYLOSING SPONDYLITIS. Sulfasalazine has been found to be effective1 in the treatment of active ankylosing spondylitis, but there is evidence that it is more useful in the treatment of active disease and peripheral articular manifestations than in the management of chronic long-standing disease.2-4 The active moiety appears to be sulfapyridine rather than mesalazine.5 Sulfasalazine was no better than placebo for the treatment of inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis, but it was more effective than placebo in a subgroup of patients with no peripheral arthritis.6
1. Ferraz MB, et al. Meta-analysis of sulfasalazine in ankylosing spondylitis. J Rheumatol 1990; 17: 1482–6
2. Clegg DO, et al. Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis: a Department of Veterans Affairs Cooperative study. Arthritis Rheum 1996; 39: 2004–12
3. Clegg DO, et al. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondyloarthropathies: a Department of Veterans Affairs cooperative study. Arthritis Rheum 1999; 42: 2325–9
4. Chen J, Liu C. Sulfasalazine for ankylosing spondylitis. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 2005 (accessed 28/02/06)
5. Taggart A, et al. Which is the active moiety of sulfasalazine in ankylosing spondylitis? A randomized, controlled study. Arthritis Rheum 1996; 39: 1400–5
6. Braun J, et al. Efficacy of sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis: a multicentre randomised controlled trial. Ann Rheum Dis 2006; 65: 1147–53.
PSORIATIC ARTHRITIS. A systematic review1 of interventions for psoriatic arthritis concluded that sulfasalazine was one of only two drugs with published evidence of well proven efficacy in psoriatic arthritis (the other being highdose parenteral methotrexate). See also under Psoriasis, above.
1. Jones G, et al. Interventions for treating psoriatic arthritis. Available in The Cochrane Database of Systematic Reviews, Issu
3. Chichester: John Wiley; 2000 (accessed 29/04/05).

💊 Preparations

BP 2008: Sulfasalazine Tablets; USP 31: Sulfasalazine Delayed-release Tablets; Sulfasalazine Tablets.

Proprietary Preparations

Arg.: Azulfidine; Flogostop; Austral.: Pyralin; Salazopyrin; Austria: ColoPleon; Salazopyrin; Belg.: Salazopyrine; Braz.: Azulfin; Salazoprin; Canad.: Salazopyrin; SAS†; Chile: Azulfidine; Cz.: Salazopyrin; Denm.: Salazopyrin; Fin.: Salazopyrin; Fr.: Salazopyrine; Ger.: Azulfidine; Colo-Pleon; Pleon RA; Gr.: Salopyrine; Hong Kong: Salazopyrin; Hung.: Salazopyrin; India: Saaz; Salazar; Sazo; Indon.: Lazafin; Sulcolon; Irl.: Salazopyrin; Israel: Salazopyrin; Ital.: Salazopyrin; Jpn: Azulfidine; Malaysia: Salazopyrin; Mex.: Azulfidina; Neth.: Salazopyrine; Norw.: Salazopyrin; NZ: Salazopyrin; Pol.: Salazopyrin; Port.: Salazopirina; S.Afr.: Salazopyrin; Singapore: Salazopyrin; Spain: Salazopyrina; Swed.: Salazopyrin; Switz.: Salazopyrin; Thai.: Salazopyrin; Saridine; Turk.: Salazopryn; UK: Salazopyrin; Sulazine; USA: Azulfidine; Venez.: Azulfidine.
Published April 10, 2019.