Questions about Rheumatoid Arthritis? Get answers from our expert.

Sulfasalazine (Systemic)


BAN:
Sulphasalazine. {03} {45}


JAN:
Salazosulfapyridine. {03}

VA CLASSIFICATION
Primary: GA400
Secondary: MS109{26}

Commonly used brand name(s): Alti-Sulfasalazine; Alti-Sulfasalazine (Enteric-Coated); Azulfidine; Azulfidine EN-Tabs; PMS-Sulfasalazine; PMS-Sulfasalazine E.C.; S.A.S. Enteric-500; S.A.S.-500; Salazopyrin; Salazopyrin EN-Tabs.

Another commonly used name is
salicylazosulfapyridine . {03} {05} {45}
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Bowel disease (inflammatory) suppressant—

antirheumatic (disease-modifying){13}{16}{17}{18}{19}{20}{21}{22}{23}{24}{25}

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Bowel disease, inflammatory (prophylaxis and treatment)—Sulfasalazine is indicated to treat and to maintain remission of inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease affecting the colon). It is indicated in the treatment of mild to moderate ulcerative colitis and as adjunctive treatment of severe ulcerative colitis. {01} {02} {04} {06} {08} {11}{58}

Arthritis, rheumatoid (treatment)—Sulfasalazine is indicated for the treatment of rheumatoid arthritis in patients who have responded inadequately to, or who are intolerant of, analgesics or other nonsteroidal anti-inflammatory drugs (NSAIDs). {06} {08} {13} {16} {17} {18} {19} {20} {21} {22} {23} {24} {25} {56}{58}

Arthritis, juvenile rheumatoid; poly-articular course (treatment)1—Sulfasalazine delayed release tablets are indicated for the treatment of pediatric patients who have responded inadequately to salicylates or other non-steroidal anti-inflammatory drugs.
{58}
[Ankylosing spondylitis (treatment) ]1 {13} {14} {15} {22} {23} {24} {25} —Sulfasalazine is used in the treatment of ankylosing spondylitis. {06} {08} {13} {16} {17} {18} {19} {20} {21} {22} {23} {24} {25}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    398.39 {08} {45}

Mechanism of action/Effect:

Bowel disease (inflammatory) suppressant—Uncertain; may be related to sulfasalazine's immunosuppressant effects, which have been observed in animals, its affinity for connective tissue, and/or its relatively high concentrations in serous fluids, the liver, and intestinal wall. Sulfasalazine is considered a vehicle for carrying its principal metabolites to the colon. Unabsorbed sulfasalazine is cleaved in the colon by intestinal bacteria to form sulfapyridine and mesalamine (5-aminosalicylic acid; 5-ASA), both of which may act locally within the gut. Mesalamine, which is different from aminosalicylates used to treat tuberculosis, is thought to be the major active moiety. {02} {04} Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and the lipoxygenase pathways, is increased in patients with inflammatory bowel disease. {26} {28} {47} Mesalamine appears to diminish inflammation by inhibiting cyclooxygenase and lipoxygenase, thereby decreasing the production of prostaglandins, and leukotrienes and hydroxyeicosatetraenoic acids (HETEs), respectively. {06} {12} {26} {28} {47} It is also believed that mesalamine acts as a scavenger of oxygen-derived free radicals, which are produced in greater numbers in patients with inflammatory bowel disease. {06} {08} {12} {28} {47}

Antirheumatic (disease-modifying)—Uncertain; sulfapyridine moiety may suppress the activity of natural killer cells and impair lymphocyte transformation. {49} {52}

Absorption:
{02}{37}
Sulfasalazine—Poorly absorbed {11}; approximately 20% of ingested sulfasalazine dose reaches the systemic circulation. {06} {08} {12} The remaining ingested dose is split by colonic bacteria into its components, sulfapyridine and mesalamine. {04} {06} {08} {12}

Sulfapyridine—Most of the sulfapyridine metabolized from sulfasalazine (60–80%) is absorbed in the colon following oral administration.

Mesalamine (5-ASA)—Approximately 25% of the mesalamine metabolized from sulfasalazine is absorbed in the colon following oral administration. {12}

Distribution:

Distributed to serum, connective tissue, serous fluids, liver, and intestinal wall. {02} {04} The apparent volume of distribution (Vol D) of sulfasalazine in 8 healthy volunteers was 64 L. The Vol D of sulfapyridine was found to be 0.4 to 1.2 L per kg. {37}

Protein binding:

Sulfasalazine—Very high (Approximately 99%). {37}

Sulfapyridine—Moderate (Approximately 50%). {37}

Mesalamine (5-ASA)—Moderate (Approximately 43%). {37}

Biotransformation:
{02}
Sulfasalazine (unabsorbed)—Cleaved in the colon by intestinal bacteria to form sulfapyridine and mesalamine. {04} {06} {08} {12}

Sulfapyridine (absorbed)—Acetylated and hydroxylated in the liver, followed by conjugation with glucuronic acid. {04} {06} {08} {12}

Mesalamine (5-ASA) (absorbed)—Acetylated in the intestinal mucosal wall {12} {26} and the liver. {26}

Half-life:

Sulfasalazine—5 to 10 hours. {37}

Sulfapyridine—6 to 14 hours, depending on acetylator status. {37}

Mesalamine (5-ASA)—0.6 to 1.4 hours. {37}

Time to peak serum concentration


Sulfasalazine oral suspension:

Sulfasalazine: Approximately 1.5 to 6 hours. {02}

Sulfapyridine: Approximately 9 to 24 hours. {02}



Sulfasalazine tablets:

Sulfasalazine: Approximately 1.5 to 6 hours. {04}

Sulfapyridine: Approximately 6 to 24 hours. {04}



Sulfasalazine enteric-coated tablets:

Sulfasalazine: Approximately 3 to 12 hours. {04} {06} {08}

Sulfapyridine: Approximately 12 to 24 hours. {04}


Mean peak serum concentration


Sulfasalazine oral suspension:

Sulfasalazine: Approximately 20 mcg per mL 3 hours following a single oral 2-gram dose. {02}

Sulfapyridine: Approximately 19 mcg per mL 12 hours following a single oral 2-gram dose. {02}

Mesalamine (5-ASA): Approximately 4 mcg per mL following a single oral 2-gram dose. {02}



Sulfasalazine tablets:

Sulfasalazine: Approximately 14 mcg per mL 3 hours following a single oral 2-gram dose. {04}

Sulfapyridine: Approximately 21 mcg per mL 12 hours following a single oral 2-gram dose. {04}

Mesalamine (5-ASA): Approximately 4 mcg per mL following a single oral 2-gram dose. {04}



Sulfasalazine enteric-coated tablets:

Sulfasalazine: Approximately 6 mcg per mL 6 hours following a single oral 2-gram dose. {04}

Sulfapyridine: Approximately 13 mcg per mL 12 hours following a single oral 2-gram dose. {04}

Mesalamine (5-ASA): Approximately 4 mcg per mL following a single oral 2-gram dose. {04}


Elimination:
{02}{37}    Fecal—Trace amounts of sulfasalazine, approximately 5% of sulfapyridine, and approximately 67% of mesalamine are found in feces.
    Renal—Approximately 75 to 91% of sulfasalazine and sulfapyridine metabolites excreted in urine within 3 days, depending on the dosage form used. Mesalamine is excreted in urine mostly in acetylated form. {04} {06} {08}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to one sulfonamide may be allergic to other sulfonamides also.

Patients allergic to salicylates {04} {06} {08} {11}, furosemide {06} {08}, thiazide diuretics {04} {06} {08}, sulfonylureas {04}, or carbonic anhydrase inhibitors {04} {06} {08} may be allergic to this medication also.

Carcinogenicity/Tumorigenicity

Long-term studies in humans have not been done to evaluate the carcinogenic potential of sulfasalazine.{04}{45} However, long-term administration of sulfonamides to rats has been shown to result in thyroid malignancies. In addition, rats appear to be especially susceptible to the goitrogenic effects of sulfonamides.{02}{04} {06}

Two year oral carcinogenicity studies were done in male and female rats and mice. An increase in the incidence of urinary bladder transitional cell papillomas was seen in male rats, and transitional cell papilloma of the kidney was observed in a small percentage of female rats (4%). The increased occurrence of neoplasms in the rats was also associated with an increase in renal calculi formulation and hyperplasia of the transitional cell epithelium.{58}

There was an increase in the incidence of hepatocellular adenoma or carcinoma in both male and female mice in all of the doses that were tested.{58}

Mutagenicity

Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) or in the L51784 mouse lymphoma cell assay at the HGPRT gene. Equivocal mutagenic response was seen in the micronucleus assay of mouse and rat bone marrow and mouse peripheral RBC and in the sister chromatid exchange, chromosomal aberration and the micronucleus assays in lymphocytes obtained from humans.{58}

Pregnancy/Reproduction
Fertility—
Studies in rats and rabbits given doses of up to 6 times the human dose have not shown that sulfasalazine impairs female fertility. However, these studies have shown that sulfasalazine does impair male fertility. {02} {04} {06} {08} {45} In addition, oligospermia and infertility, reported to be reversible upon discontinuation of sulfasalazine, have been reported in men. {02} {04} {06} {08} {11} {12}

Pregnancy—
Sulfasalazine and sulfapyridine cross the placenta. {04} {06} {08} Adequate and well-controlled studies in humans have not been done. However, a national survey of 186 women with inflammatory bowel disease (IBD) who took sulfasalazine, alone or concurrently with corticosteroids, showed an incidence of adverse effects in the fetus comparable to that in 245 untreated IBD pregnancies. Another study of 1445 pregnancies in which sulfonamides, including sulfasalazine, were taken did not show that sulfasalazine causes fetal malformations. {02} {04}

Appropriate studies have not been performed on the effect of sulfasalazine on growth, development, and functional maturation of children whose mothers received sulfasalazine during pregnancy. {02} {04}

Studies in rats and rabbits given doses of up to 6 times the human dose have not shown that sulfasalazine causes adverse effects in the fetus. {04} {06} {08}

FDA Pregnancy Category B. {04} {56}

Breast-feeding

Uncleaved sulfasalazine is distributed into breast milk in small amounts. Sulfapyridine is distributed into breast milk in concentrations that are 30 to 60% of those in the maternal serum. {04} {06} {08} Although sulfonamides may displace bilirubin from protein-binding sites in the fetal plasma, hyperbilirubinemia has occurred rarely. {06}

Sulfonamides may cause hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD)–deficient neonates. {06} {44}

Pediatrics

Use is contraindicated in infants and children up to 2 years of age {04} {06} {08} because sulfonamides may cause kernicterus. {04}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of sulfasalazine in the elderly. {06} {08} {45}


Pharmacogenetics

Mean serum concentrations of sulfapyridine and its metabolites may be significantly increased in patients who are slow acetylators. {02} {04} {06} {08} {12} {37} Eskimo, Oriental, and American Indian populations have the lowest prevalence of slow acetylators, while Egyptian, Israeli, Scandinavian, other Caucasian, and black populations have the highest prevalence of slow acetylators. {48}


Dental

The leukopenic and thrombocytopenic effects of sulfasalazine may result in an increased incidence of certain microbial infections, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Anticoagulants, coumarin- or indandione-derivative{06}{08}{57} or
» Anticonvulsants, hydantoin{06}{08}{57} or
» Antidiabetic agents, oral{06}{08}{57}    (may be displaced from protein binding sites and/or metabolism may be inhibited by sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy {39})


Bone marrow depressants (see Appendix II )    (concurrent use of sulfasalazine with bone marrow depressants may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered)


Digitalis glycosides{11}{56}{57} or
Folic acid{56}{57}    (sulfasalazine may inhibit absorption and lower the serum concentrations of these medications {04} {06} {08}; folic acid requirements may be increased in patients receiving sulfasalazine {06} {08} {11} {35} {38}; patients taking digitalis glycosides should be monitored closely for evidence of altered digitalis effect {06} {08} {35} {38})


» Hemolytics, other (see Appendix II )    (concurrent use with sulfasalazine may increase the potential for toxic side effects)


» Hepatotoxic medications, other (see Appendix II )    (concurrent use with sulfonamides may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with a history of liver disease, should be carefully monitored)


» Methotrexate{06}{08}{57} or
Phenylbutazone{06}{08}{57} or
Sulfinpyrazone{06}{08}{57}    (the effects of these medications may be potentiated during concurrent use with sulfonamides because of displacement from plasma protein binding sites; phenylbutazone and sulfinpyrazone have also been reported to potentiate the effects of sulfonamides)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Bentiromide{09}{10}    (administration of sulfonamides during a bentiromide test period will invalidate test results because sulfonamides are also metabolized to arylamines and will thus increase the percent of p-aminobenzoic acid (PABA) recovered; discontinuation of sulfonamides at least 3 days prior to the administration of bentiromide is recommended)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Intestinal obstruction{56}{57} or
» Urinary obstruction{56}{57}
» Previous allergic reaction to sulfasalazine{04} , sulfonamides{04}{06}{08}{11} , salicylates{04}{06}{08}{11} , furosemide{06}{08} , thiazide diuretics{04}{06}{08} , sulfonylureas{04} , or carbonic anhydrase inhibitors{04}{06}{08}
Risk-benefit should be considered when the following medical problems exist
» Allergy, severe{56}{57} or
» Asthma, bronchial{56}{57}    (risk of hypersensitivity reaction to sulfasalazine may be increased with use of sulfasalazine)


» Blood dyscrasias{02}{04}{06}{08}    (sulfasalazine may cause agranulocytosis, aplastic anemia, or other blood dyscrasias)


» Glucose-6-phosphate dehydrogenase (G6PD) deficiency{02}{04}{06}{08}{11}    (sulfasalazine may cause hemolytic anemia in G6PD-deficient patients)


» Hepatic function impairment{02}{04}{06}{08}    (sulfonamides are metabolized in the liver and may cause hepatitis)


» Porphyria{02}{04}{06}{08}    (sulfonamides may precipitate an acute attack of porphyria)


» Renal function impairment{04}{06}{08}{45}    (the metabolite, sulfapyridine, is excreted primarily through the kidneys)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Complete blood counts (CBCs){04}{06}{08}{11}    (recommended prior to, and every 2 to 3 weeks for the first 2 to 3 months of treatment {49}, then every 3 to 6 months during treatment to detect blood dyscrasias in patients on prolonged therapy; therapy should be discontinued if a significant decrease in the count of any formed blood elements occurs)


» Liver function tests{56}{57}    (recommended prior to, and every 2 weeks for the first 3 months of treatment {56}, then monthly during the second 3 months of treatment, and thereafter once every 3 months and as clinically indicated during treatment to detect hepatotoxicity)


Proctoscopy{06}{08} and
Sigmoidoscopy{04}{06}{08}    (may be required periodically during treatment to determine patient response and dosage adjustments)


Sulfapyridine concentrations, serum{56}{57}    (determinations may be useful since concentrations greater than 50 mcg/mL appear to be associated with an increased incidence of adverse reactions)


Urinalyses{04}{06}{08}    (may be required prior to and periodically during treatment)




Side/Adverse Effects

Note: Deaths have been reported from hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood dyscrasias, renal and hepatic damage, irreversible neuromuscular and central nervous system (CNS) changes, and fibrosing alveolitis in patients taking sulfasalazine. If toxic or hypersensitivity reactions occur, sulfasalazine should be discontinued immediately. {02} {04} {06} {08}
Oligospermia and infertility, reported to be reversible upon discontinuation of sulfasalazine, have been reported in males taking this medication. {02} {04} {06} {08} {11} {12}
Daily doses of 4 grams or more and total sulfapyridine serum concentrations > 50 mcg per mL may be associated with an increased incidence of side/adverse effects. {02} {04} {06} {08}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Headache, continuing {04} {08} {11} {12}
    
hypersensitivity reaction {04} {06} {08} {11} (aching of joints; fever; itching; skin rash)
    
photosensitivity (increased sensitivity of skin to sunlight)
    
serum sickness-like syndrome (fever; headache; nausea; rash; vomiting)—seen in pediatric patients being treated for juvenile rheumatoid arthritis{58}

Incidence less frequent or rare
    
Blood dyscrasias, including agranulocytosis or neutropenia {04} {06} {08} {35} {36} (fever and sore throat), aplastic anemia {56} (fever, chills, or sore throat; unusual bleeding or bruising; unusual tiredness or weakness ), Heinz body or hemolytic anemia {04} {06} {08} {35} {36} (back, leg, or stomach pains; loss of appetite; pale skin; unusual tiredness or weakness; fever), leukopenia {56} (fever, chills, or sore throat), or thrombocytopenia {04} {06} {08} {11} {12} (unusual bleeding or bruising)
    
cyanosis {04} {06} {08} (bluish fingernails, lips, or skin)
    
exacerbation of ulcerative colitis {04} {06} {08} {35} {36} (bloody diarrhea; fever; rash)
    
hepatitis {04} {06} {08} {35} {36} (yellow eyes or skin)
    
interstitial pneumonitis {04} {06} {08} {35} {36} (cough; difficult breathing ; fever)
    
Stevens-Johnson syndrome {04} {06} {08} {11} (aching of joints and muscles; redness, blistering, peeling, or loosening of skin; unusual tiredness or weakness)
    
systemic lupus erythematosus (SLE)–like syndrome {41} {42} {43} (blisters on skin; chest pain; general feeling of discomfort or illness; skin rash, hives, and/or itching)
    
toxic epidermal necrolysis {04} {06} {08} (difficulty in swallowing; redness, blistering, peeling, or loosening of skin)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Gastrointestinal disturbances {04} {06} {08} {11} {12} (abdominal or stomach pain or upset; diarrhea; loss of appetite; nausea or vomiting)



Those not indicating need for medical attention
Incidence more frequent
    
Orange-yellow discoloration of urine or skin {02} {04} {06} {08}





Overdose
For specific information on the agents used in the management of sulfasalazine overdose, see Ipecac (Oral-Local) monograph.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

The severity of sulfasalazine toxicity is directly related to the total serum sulfapyridine concentration. {04} Daily doses of 4 grams or more and total sulfapyridine serum concentrations > 50 mcg per mL may be associated with an increased incidence of side/adverse effects. {02} {04} {06} {56}

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Anuria, crystalluria, or hematuria (blood in urine; lack of urination; lower back pain; pain or burning while urinating)
    
drowsiness
    
gastrointestinal disturbances (abdominal or stomach pain or upset; diarrhea; loss of appetite; nausea or vomiting)
    
seizures


Treatment of overdose
To decrease absorption—the stomach may be emptied by inducing emesis with ipecac syrup (taking care to guard against aspiration) or by gastric lavage. {04} {06} {08} {45}

To enhance elimination—The urine may be alkalinized and, if kidney function is normal, fluids forced. If anuria is present, fluids and salt should be restricted. Catheterization of the ureters may be indicated when there is complete renal blockage by crystals. {04} {06} {08} {45} The low molecular weight of sulfasalazine and its metabolites may facilitate removal by dialysis. {04} {08}

Monitoring—Serum sulfapyridine concentrations may be monitored so that the progress of recovery can be followed. {04}

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Sulfasalazine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergies to sulfasalazine, sulfonamides, salicylates, furosemide, thiazide diuretics, sulfonylureas, carbonic anhydrase inhibitors

Pregnancy—Sulfasalazine and sulfapyridine cross the placenta





Breast-feeding—Sulfasalazine and sulfapyridine are distributed into breast milk





Use in children—Use is contraindicated in infants and children up to 2 years of age because sulfonamides may cause kernicterus

Other medications, especially coumarin- or indandione-derivative anticoagulants, hemolytics, hepatotoxic medications, hydantoin anticonvulsants, methotrexate, and oral antidiabetic agents
Other medical problems, especially intestinal obstruction, urinary obstruction, severe allergies, bronchial asthma, blood dyscrasias, G6PD deficiency, hepatic function impairment, porphyria, and renal function impairment

Proper use of this medication
» Not giving to infants up to 2 years of age; sulfasalazine may cause kernicterus

Taking after meals or with food to lessen gastrointestinal irritation

» Maintaining adequate fluid intake

Proper administration technique for enteric-coated tablets

» Compliance with full course of therapy

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check blood counts in patients on long-term therapy

Checking with physician if no improvement within 1 or 2 months

Using caution in use of regular toothbrushes, dental floss, and toothpicks; deferring dental work until blood counts have returned to normal; checking with physician or dentist concerning proper oral hygiene

» Possible photosensitivity reactions

» Caution if dizziness occurs

Possible interference with bentiromide diagnostic test for pancreatic function


Side/adverse effects
Signs of potential side effects, especially headache (continuing), hypersensitivity reaction, photosensitivity, blood dyscrasias, cyanosis, exacerbation of ulcerative colitis, hepatitis, interstitial pneumonitis, Stevens-Johnson syndrome, systemic lupus erythematosus (SLE)–like syndrome, and toxic epidermal necrolysis

Orange-yellow discoloration of alkaline urine or skin may be alarming to patient although medically insignificant


General Dosing Information
Fluid intake should be sufficient to maintain urine output of at least 1200 to 1500 mL per day in adults.

Sulfasalazine should preferably be taken immediately after meals or with food. {04} {06} {08} Also, when sulfasalazine is being taken for inflammatory bowel disease, the total daily dose may be spread evenly over a 24-hour period. {04} {06} {08} In some patients it may be necessary to initiate therapy with smaller doses (e.g., 1 to 2 grams daily) to lessen gastrointestinal irritation.

When endoscopic examination confirms satisfactory improvement, dosage may be reduced to maintenance level. If diarrhea recurs, dosage should be increased to previously effective level.

Patients with impaired renal function may require a reduction in dose.

Adverse reactions tend to increase with total daily doses of 4 grams or more or with serum concentrations greater than the equivalent of 50 mcg of sulfapyridine per mL. {02} {04} {06} {08}

Patients experiencing mild hypersensitivity reactions may be ``desensitized'' to allow continued treatment with sulfasalazine. {08} {12} {45} {46} Desensitization involves withdrawal of the medication followed by reinstitution, beginning with a lower dose {12} and increasing it slowly over at least 23 days. {08} {45} Desensitization should not be attempted in patients with a history of agranulocytosis. {08} {12} {45} Some medical experts believe that with the availability of mesalamine preparations, desensitization may no longer be indicated. {53} {54} {55}

Diet/Nutrition
Folic acid requirements may be increased in patients on sulfasalazine therapy, because sulfasalazine inhibits the absorption of folic acid {04} {06} {08} {11} {35} {38} {56}.

For treatment of adverse effects
Recommended treatment consists of the following:

   • Discontinuing the drug immediately if agranulocytosis or hypersensitivity reactions occur. {08} {45}
   • Controlling hypersensitivity reactions with antihistamines and/or corticosteroids. {08} {45}


Oral Dosage Forms

SULFASALAZINE TABLETS USP

Usual adult and adolescent dose
Bowel disease (inflammatory) suppressant {33}
Initial: Oral, 1 gram every six to eight hours. {04} {06} An initial dose of 500 mg every six to twelve hours may be recommended to lessen gastrointestinal side effects. {04}

Maintenance: Oral, 500 mg every six hours, adjusted according to patient response and tolerance. {02} {04} {06} {08} {11}

Antirheumatic (disease-modifying)
Oral, 500 mg to 1 gram daily for the first week, with the daily dose being increased by 500 mg each week, up to a maintenance dose of 2 grams daily. The dose may be administered two times a day. {36} {45} If no response is seen after two months, the dose may be increased to 3 grams daily. {06} {08} {45} {57}


Usual adult prescribing limits
Total daily doses of greater than 4 grams may increase the risk of side effects and toxicity. {04} {06} {08} {40} {45}

Usual pediatric dose
Bowel disease (inflammatory) suppressant


Infants and children up to 2 years of age:
Use is contraindicated because sulfonamides may cause kernicterus. {04}



Children 2 years of age and older {04} {33}:
Initial—Oral, 6.7 to 10 mg per kg of body weight every four hours; 10 to 15 mg per kg of body weight every six hours; or 13.3 to 20 mg per kg of body weight every eight hours.

Maintenance—Oral, 7.5 mg per kg of body weight every six hours.


Antirheumatic (disease-modifying)
Safety and efficacy have not been established. {06} {08} {45}


Usual geriatric dose
See Usual adult and adolescent dose. {06} {08}

Strength(s) usually available
U.S.—


500 mg (Rx) [Azulfidine][Generic]{27}{29}

Canada—


500 mg (Rx) [Alti-Sulfasalazine (scored)] [PMS-Sulfasalazine (scored)] [Salazopyrin (scored)] [S.A.S.-500 ( scored)][Generic]{05}{07}{30}{31}{32}{45}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • Take with a full glass of water.
   • Avoid use of sunlamp and unprotected exposure to sun.
   • Continue medicine for full time of treatment.
   • May discolor urine.


SULFASALAZINE DELAYED-RELEASE TABLETS USP

Usual adult and adolescent dose
See Sulfasalazine Tablets USP.

Usual adult prescribing limits
See Sulfasalazine Tablets USP.

Usual pediatric dose
Bowel disease (inflammatory) suppressant


Infants and children up to 2 years of age:
Safety and efficacy have not been established.{58}



Children 6 years of age and older:
See Sulfasalazine Tablets USP


Antirheumatoid (treatment) 1


Infants and children up to 2 years of age:
Safety and efficacy have not been established.{58}



Children 6 years of age and older:
Oral, 30 to 50 mg per kg of body weight a day divided into two equal doses. To lessen gastrointestinal side effects, lower doses (a quarter to a third of the planned maintenance dose) may be recommended and increased every week until reaching the maintenance dose at one month.
{58}


Note: Desensitization-like regimens may be used in some patients who may be sensitive to treatment with sulfasalazine. If the symptoms of sensitivity recur, sulfasalazine should be discontinued. Desensitization should not be attempted in patients with a history of agranulocytosis or an anaphylactoid reaction while receiving sulfasalazine previously.{58}


Usual pediatric prescribing limits
Maximum dose is typically 2 grams per day.
{58}
Usual geriatric dose
See Sulfasalazine Tablets USP.

Strength(s) usually available
U.S.—


500 mg (Rx) [Azulfidine EN-Tabs (cellulose acetate phthalate)][Generic]{27}

Canada—


500 mg (Rx) [Alti-Sulfasalazine (Enteric-Coated)] [PMS-Sulfasalazine E.C.] [Salazopyrin EN-Tabs] [S.A.S. Enteric-500][Generic]{05}{07}{30}{31}{32}{45}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • Take with a full glass of water.
   • Take after meals.{58}
   • Avoid use of sunlamp and unprotected exposure to sun.
   • Continue medicine for full time of treatment.
   • May discolor urine.
   • Swallow tablets whole.

Note: Dissolution of enteric-coated tablets is much more variable and unreliable than that of nonenteric-coated tablets.




Rectal Dosage Forms

SULFASALAZINE RECTAL SUSPENSION

Usual adult and adolescent dose
Bowel disease (inflammatory) suppressant
Rectal, 3 grams each night at bedtime. {06} {45}


Usual pediatric dose
Bowel disease (inflammatory) suppression
Infants and children up to 2 years of age: Use is contraindicated because sulfonamides cause kernicterus.

Children 2 years of age and older: Dosage has not been established.


Usual geriatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


3 grams per 100-mL unit (Rx) [Salazopyrin]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • For rectal use.
   • Shake well.
   • Continue medicine for full time of treatment.



Revised: 06/01/2001



References
  1. Indications index review 1986.
  1. Azulfidine (Pharmacia). In: PDR Physicians" desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company, 1988: 1626-8.
  1. Fleeger CA, editor. USAN 1995. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: 639.
  1. Azulfidine (Kabi Pharmacia). In: PDR Physicians" desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data, 1994: 1110-1.
  1. PMS-Sulfasalazine (Pharmascience). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 1036.
  1. Salazopyrin (Pharmacia). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 1177-9, B47.
  1. S.A.S (ICN). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 1187.
  1. Sulfasalazine package insert (Kenral—Canada), Rev 9/20/91, Rec 11/4/93.
  1. Bentiromide package insert (Chymex, Adria—US), Rev 6/88, Rec 8/92.
  1. Toskes P. The bentiromide test for pancreatic exocrine insufficiency. Pharmacotherapy 1984; 4: 74-80.
  1. Diarrhoeal diseases in adults. WHO Drug Information 1994; 8: 36-41.
  1. Allgayer H. Sulfasalazine and 5-ASA compounds. Gastrointest Pharmacol 1992; 21: 643-57.
  1. Reviewers" consensus on monograph revision.
  1. Med World News 1986 Jul 28: 15.
  1. Dougados M, Boumeir P, Amor B. Sulphasalazine in ankylosing spondylitis: a double blind controlled study in 60 patients. Br Med J 1986; 293: 911-4.
  1. Farr M, Scott DGI, Bacon PA. Side effect profile of 200 patients with inflammatory arthritis treated with sulphasalazine. Drugs 1986; 32(Suppl 1): 49-53.
  1. Pullar T, Hunter JA, Capell HA. Which component of sulphasalazine is active in rheumatoid arthritis? Br Med J 1985; 290: 1535-8.
  1. McConkey B, Amos RS, Durham S, et al. Sulphasalazine in rheumatoid arthritis. Br Med J 1980: 442-4.
  1. Neumann VC, Grindulis KA, Hubball S, et al. Comparison between penicillamine and sulphasalazine in rheumatoid arthritis: Leeds-Birmingham trial. Br Med J 1983; 287: 1099-102.
  1. Pullar T, Hunter JA, Capell HA. Sulphasalazine in rheumatoid arthritis: a double blind comparison of sulphasalazine with placebo and sodium aurothiomalate. Br Med J 1983; 287: 1102-4.
  1. Situnayake RD, McConkey B. Long term outcome of treatment with sulphasalazine in rheumatoid arthritis. Drugs 1986; 32(Suppl 1): 71-2.
  1. Semin Arthritis Rheum 1988; 17: 246-59.
  1. Br J Rheumatol 1984; 23: 26-34.
  1. J Rheumatol 1987; 14: 633-4.
  1. Arthritis Rheum 1986; 29: 1427-34.
  1. Mesalamine delayed-release tablets package insert (Asacol, Norwich Eaton—US), Rev 1/92, Rec 5/18/92.
  1. Azulfidine (Pharmacia). In: Garrett HM, editor. Red book. 93rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 167.
  1. Gaginella TS, Walsh RE. Sulfasalazine. Multiplicity of action. Dig Dis Sci 1992; 37: 801-12.
  1. Sulfasalazine (General). In: Garrett HM, editor. Red book. 93rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 656.
  1. PMS-Sulfasalazine (Pharmascience). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 23rd ed. Ottawa: Canadian Pharmaceutical Association, 1988: 726.
  1. Salazopyrin (Pharmacia). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 23rd ed. Ottawa: Canadian Pharmaceutical Association, 1988: 825.
  1. S.A.S. (ICN). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 23rd ed. Ottawa: Canadian Pharmaceutical Association, 1988: 831.
  1. Azulfidine package insert (Pharmacia—US), Rev 8/87, Rec 10/88.
  1. Caspi D, Fuchs D, Yaron M. Sulphasalazine induced hepatitis in juvenile rheumatoid arthritis. Ann Rheum Dis 1992; 51: 275-6.
  1. Peppercorn MA. Sulfasalazine. Pharmacology, clinical use, toxicity, and related drug development. Ann Intern Med 1984; 3: 377-86.
  1. Pinals RS. Sulfasalazine in the rheumatic disease. Semin Arthritis Rheum 1988; 17: 246-59.
  1. Klotz U. Clinical pharmacokinetics of sulphasalazine, its metabolites and other prodrugs of 5-aminosalicylic acid. Clin Pharmacokinet 1985; 10: 285-302.
  1. Watkinson G. Sulphasalazine: a review of 40 years" experience. Drugs 1986; 32(Suppl 1): 1-11.
  1. Young LY, Koda-Kimble MA, editors. Applied therapeutics. The clinical use of drugs. 4th ed. Vancouver, WA: Applied Therapeutics, Inc., 1988: 910.
  1. Azulfidine (Pharmacia). In: PDR Physicians" desk reference. 45th ed. 1991. Oradell, NJ: Medical Economics Data, 1991: 1720.
  1. Walker EM, Carty JE. Sulphasalazine-induced systemic lupus erythematosus in a patient with erosive arthritis. Br J Rheumatol 1994; 33: 175-6.
  1. Caulier M. Sulfasalazine induced lupus in rheumatoid arthritis. J Rheumatol 1994; 21: 750-1.
  1. Siam ARM, Hammoudeh M. Sulphasalazine induced systemic lupus erythematosus in a patient with rheumatoid arthritis [letter]. J Rheumatol 1993; 20: 207.
  1. Bactrim (Roche). In: PDR Physicians" desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company, 1988: 1713-4.
  1. Salazopyrin package insert (Pharmacia—Canada), Rec 12/13/94.
  1. Tolia V. Sulfasalazine desensitization in children and adolescents with chronic inflammatory bowel disease. Am J Gastroenterol 1992; 87: 1029-32.
  1. Small RE, Schraa CC. Chemistry, pharmacology, pharmacokinetics, and clinical applications of mesalamine for the treatment of inflammatory bowel disease. Pharmacotherapy 1994; 14: 385-98.
  1. Nydrazid injection package insert (Squibb—US), Rev 11/87, Rec 3/89.
  1. Panel comment, 2/95.
  1. Reviewers" consensus on monograph revision of 2/95.
  1. McKenna KE, Burrows D. Leucopenia, thrombocytopenia and lymphadenopathy associated with sulphasalazine. Clin Exp Dermatol 1994; 19: 419-20.
  1. Gilman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman"s the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990: 1273.
  1. Panel comment, 2/95.
  1. Panel comment, 2/95.
  1. Panel comment, 2/95.
  1. Azulfidine EN-tabs package insert (Pharmacia & Upjohn—U.S.), Rev 1/97, Rec 10/30/97.
  1. Alti-Sulfasalazine product monograph (AltiMed—Canada), Rev 10/3/96, Rec 5/7/97.
  1. Product Information: Azulfidine EN-tabs®, sulfasalazine. Pharmacia & Upjohn, Kalamazoo, MI, (PI revised 10/2000) PI reviewed (12/2000).

Got questions about Rheumatoid Arthritis? Get answers from our expert Dr. Carteron. Click Here

Close
Hide
(web3)