SALAZOPYRIN® SALAZOPYRIN EN-TABS®
Pharmacia & Upjohn
Action And Clinical Pharmacology: About 20% of sulfasalazine is absorbed in the small intestine after oral administration. A small percentage of the absorbed sulfasalazine is excreted in the urine and the rest via the bile into the small intestine (enterohepatic circulation). This portion together with the unabsorbed sulfasalazine enters the colon where it is split by bacteria into 2 main metabolites, sulfapyridine and 5-aminosalicylic acid. The peak serum concentration is reached after 3 to 5 hours. The mean serum half-life after a single dose is about 6 hours; after repeated doses it is about 8 hours. After intake of sulfasalazine enteric coated tablets, sulfasalazine has been detected in serum somewhat later than after intake of plain tablets, as expected, the peak serum concentration being observed between 3 and 12 hours.
Sulfapyridine is absorbed, partially acetylated and/or hydroxylated in the liver and/or conjugated with glucuronic acid. In patients who are slow acetylators the serum concentration of free sulfapyridine is higher than in fast acetylators. The major part is excreted in the urine. Nonacetylated sulfapyridine is bound to serum proteins and reaches a maximum serum concentration after 12 hours. Sulfapyridine has a tendency towards accumulation. It does not disappear completely from the serum until 3 days after withdrawal of the drug.
The total urinary recovery of sulfasalazine and its sulfapyridine metabolites in healthy subjects during 3 days after the administration of a single 2 g dose of sulfasalazine averaged about 91%.
The absorbed 5-aminosalicylic acid is partly excreted in the urine, mainly as acetyl-5-aminosalicylic acid. A larger portion of 5-aminosalicylic acid is excreted in the feces.
The mode of action of sulfasalazine is unclear, suggested as being: anti-inflammatory, immunosuppressive and bacteriostatic.
In clinical inflammatory bowel disease cases, the anti-inflammatory effects seem to relieve the acute symptoms of diarrhea, gut inflammation, mucosal edema and bleeding. The long-term protection afforded by sulfasalazine therapy may be due to immunosuppressive properties of the drug.
Anti-inflammatory Effects: Sulfasalazine inhibits superoxide production by granulocytes stimulated with immune complexes or formyl peptides. In addition 5-ASA is a powerful scavenger of oxygen free radicals. Other granulocyte functions inhibited by sulfasalazine include degranulation, chemotaxis and random migration. These inhibitory effects on inflammatory cell functions may contribute to the beneficial clinical activity of sulfasalazine.
Sulfasalazine is a relatively weak inhibitor of the cyclo-oxygenase enzyme, but a potent inhibitor of 15-prostaglandin dehydrogenase (PGDH), the main metabolic pathway for the prostaglandins.
On the lipoxygenase side of the arachidonic acid cascade, sulfasalazine has been shown to exert an inhibitory activity on several enzymes including 5-LO and LTC4 synthetase. In line with this effect sulfasalazine has been shown to inhibit the release of lipoxygenase product from inflammatory cells and tissue.
Taken together, these effects of sulfasalazine on arachidonic acid metabolizing enzymes would lead to a decrease in pro-inflammatory lipoxygenase products with a simultaneous increase in immunosuppressive, anti-inflammatory prostaglandins, which may have a bearing on the clinical activity.
Effects on Immunological Functions: Since the disorders in which sulfasalazine has clinical activity are considered to be of autoimmune nature, the effect of sulfasalazine on immune competent cells is of interest. Both natural killer cell activity and T-cell proliferation are inhibited by sulfasalazine in in vitro systems.
Antibacterial Effects: Studies in vitro have shown that both sulfasalazine and its main metabolites inhibit bacterial growth. A reduction in several bacterial species of the gut flora has also been observed after clinical treatment with sulfasalazine.
Pharmacokinetics: Patients with Rheumatoid Arthritis: The pharmacokinetics of sulfasalazine and its metabolites after a 2 g single oral dose were compared in patients with rheumatoid arthritis and patients with ulcerative colitis. The study showed a large individual variability, which is also found in studies in healthy volunteers, but no difference between the two patient groups except for a significantly higher peak concentration of sulfapyridine in rheumatoid arthritis patients. The area under the plasma concentration curve (AUC) for sulfapyridine was also increased but the difference was not significant.
Bioavailability in Elderly Patients with Rheumatoid Arthritis: The pharmacokinetics of sulfasalazine and its metabolites were compared in young (mean age 40.5 years) and elderly (mean age 74.4 years) rheumatoid arthritis patients after a single oral (2 g) dose taken fasting and at steady state. For sulfasalazine the only difference found between the two age groups was a prolonged half-life in the elderly, but no significant difference in either the plasma concentration at steady state and the renal clearance. For sulfapyridine both Tmax and volume of distribution were significantly increased in the elderly after the single doses, but this difference with age disappeared at chronic dosing. The data indicates that there is no major age dependent difference in the pharmacokinetics of sulfasalazine but the acetylation phenotype is much more important.
Indications And Clinical Uses: Adjunctive therapy in the treatment of severe ulcerative colitis, proctitis or distal ulcerative colitis and Crohn’s disease. It is especially useful for chronic administration.
The EN-tabs are indicated for the treatment of active rheumatoid arthritis, when treatment with an adequate conventional first line therapy has failed.
Contra-Indications: Hypersensitivity to sulfonamides or salicylates.
In infants under 2 years of age.
Intestinal and urinary obstructions.
Patients with porphyria should not receive sulfonamides, as these drugs have been reported to precipitate an acute attack.
Should not be used in patients in whom acute asthmatic attacks, urticaria, rhinitis or other allergic manifestations are precipitated by ASA or other nonsteroidal anti-inflammatory agents. Fatal anaphylactic reactions have occurred in such individuals.
Manufacturers’ Warnings In Clinical States: Sulfasalazine should be used only after critical appraisal of the risk to benefit in patients with hepatic or renal damage, blood dyscrasias, severe allergy or bronchial asthma. Pancreatitis has been observed in some susceptible individuals.
Deaths associated with the administration of sulfasalazine have been reported from hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood dyscrasias, renal and liver damage, irreversible neuromuscular and CNS changes and fibrosing alveolitis. The presence of clinical signs such as sore throat, fever, pallor, purpura or jaundice may be indications of serious blood disorders. Complete blood counts as well as urinalysis with careful microscopic examination should be done frequently in patients receiving this drug.
Oligospermia with infertility have been observed in men treated with sulfasalazine. Withdrawal of the drug appears to reverse these effects.
Patients, especially those with glucose-6-phosphate dehydrogenase deficiency, should be observed closely for signs of hemolytic anemia. This reaction is frequently dose related. If toxic or hypersensitivity reactions occur, the drug should be discontinued immediately.
Precautions: Patients hypersensitive to furosemide, thiazide diuretics, carbonic anhydrase inhibitors, may also be hypersensitive to this medication.
Sulfasalazine should be administered under medical supervision. Sulfasalazine shares the toxic potentialities of other sulfonamides, especially sulfapyridine and the usual precautions of sulfonamide therapy should be observed.
Bone marrow depression (most often expressed as leukopenia) has been reported, usually within the first 3 months of starting treatment. In the majority of patients this has been reversed on stopping the drug. A full blood count, including differential white blood cell count, should be carried out before starting treatment and monitored closely during the first 3 months of treatment. Thereafter patients should be screened if their condition changes or if they present any symptoms of infection. A falling trend in the blood count is a better indicator than a single value.
Red cell and platelet counts should be carried out before and periodically during therapy.
Sulfasalazine should be used with caution in patients with reduced kidney or liver function. Liver function tests and urinalysis should be carried out before and periodically during therapy.
When concurrent therapy with other drugs is administered, as in rheumatoid arthritis, the recommended frequency of monitoring is as follows: initially, every second week during first 3 months after onset of treatment, every 6 months thereafter.
Sulfasalazine may produce an orange-yellow color of the urine. Similar discoloration of the skin and yellow staining of soft contact lenses have occasionally been reported.
Isolated instances have been reported when the EN-tabs have passed undisintegrated. This may be due, in part, to a lack of intestinal esterase in these patients. If this is observed, the administration of EN-tabs should be discontinued.
Adequate fluid intake must be maintained in order to prevent crystalluria and stone formation.
Pregnancy and Reproduction: Teratogenic Effects: Reproduction studies have been performed in rats and rabbits at doses up to 6 times the human dose and have revealed no evidence of impaired female fertility or harm to the fetus due to sulfasalazine.
The outcome of pregnancy in a group of pregnant women with intestinal bowel disease (IBD) treated with sulfasalazine alone or sulfasalazine and concomitant steroid therapy was compared with untreated IBD pregnancies. The incidence of fetal morbidity and mortality was comparable between the groups and to the expected outcome in the general population.
Sulfasalazine should be used during pregnancy only if clearly needed.
Nonteratogenic Effects: Sulfasalazine and sulfapyridine pass the placental barrier. Although sulfapyridine has been shown to have a poor bilirubin displacing capacity, the potential for kernicterus in newborns should be kept in mind.
A case of agranulocytosis has been reported in an infant whose mother was taking both Salazopyrin and prednisone throughout pregnancy.
Lactation: Caution should be exercised when sulfasalazine is administered to a nursing woman, since it is excreted in the milk. The concentration of sulfapyridine in milk is about 30 to 60% of that in serum. However, since sulfapyridine has a poor bilirubin displacing capacity, the risk for kernicterus in healthy suckling children may be low with therapeutic doses.
Drug Interactions: 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):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
- Anticoagulants, coumarin or indandione derivatives.
- Anticonvulsants, hydantoin.
- Antidiabetic agents, oral.
- Digitalis glycosides or folic acid (sulfasalazine may inhibit absorption and lower the serum concentrations of these medications; folic acid requirements may be increased in patients receiving sulfasalazine); (patients taking digitalis glycosides should be monitored closely for evidence of altered digitalis effect).
- Methenamine (in acid urine methenamine breaks down into formaldehyde which may form an insoluble precipitate with certain sulfonamides and may also increase the danger of crystalluria; concurrent use is not recommended).
- Methotrexate (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).
- Oxyphenbutazone or phenylbutazone (effects may be potentiated when used concurrently with sulfonamides because of displacement from plasma protein binding sites).Photosensitizing medications, other (caution in concurrent use of sulfasalazine with these medications is recommended because of possible additive photosensitizing effects).
- Probenecid (decreases renal tubular secretion of sulfonamides when used concurrently, resulting in increased and more prolonged sulfonamide concentrations and/or toxicity; sulfonamide dosage adjustments may be necessary during and after probenecid therapy and sulfonamide serum determinations may be useful in prolonged probenecid therapy).
- Sulfinpyrazone (concurrent use may displace sulfonamides from protein binding sites and may decrease renal excretion, resulting in increased sulfonamide concentrations and/or toxicity; sulfonamide dosage adjustments may be necessary during and after sulfinpyrazone therapy).
- Medical Problems: Use of this medication should be carefully considered when the following medical problems exist: blood dyscrasias, glucose-6-phosphate dehydrogenase (G6PD) deficiency, hepatic function impairment, intestinal and urinary tract obstruction, porphyria or renal function impairment.
- Laboratory Tests: The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on their condition): Complete blood count, including differential white blood cell count and platelets, should be carried out before starting treatment and monitored closely during the first 3 months of treatment. Thereafter, patients should be screened if their condition changes or if they present with any symptoms of infection. A falling trend in the blood count is a better indicator than a single value.
- Liver function tests and urinalysis with careful microscopic examination should be carried out before and periodically during therapy.
- Proctoscopy and sigmoidoscopy (may be required periodically during treatment to determine patient response and dosage adjustments).
Adverse reactions with sulfasalazine may be more frequent and more severe in patients who are slow acetylators.
Most side effects are dose dependent, and the symptoms can be alleviated by reducing the dosage. Increased incidences of adverse reactions are seen with the daily dosage of 4 g or more, or total serum sulfapyridine levels above 50 g/mL. Hypersensitivity reactions have been noted, in which a dose reduction is irrelevant.
It has been shown that the frequency and severity of the rather common dyspeptic manifestations experienced by patients with gastric intolerance to uncoated tablets are markedly reduced when using enteric coated tablets.
The most commonly reported adverse reactions are: nausea, vomiting, gastric distress, methemoglobinemia, anorexia, headache and apparently reversible oligospermia. These occur in about one-third of patients. Less frequent adverse reactions are skin rash, erythema, pruritus, urticaria, fever, Heinz-body anemia, hemolytic anemia, leukopenia, megaloblastic (macrocytic) anemia, and cyanosis, which may occur in a frequency of 1 in every 30 patients or less.
Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the sulfonamides require that each of these reactions be considered when sulfasalazine is administered.
Other adverse reactions which occur rarely, in approximately 1 in 1 000 patients or less are:
- Blood Dyscrasias: aplastic anemia, agranulocytosis, purpura, thrombocytopenia and hypoprothrombinemia.
- Hypersensitivity: erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, epidermal necrolysis (Lyell’s syndrome) with corneal damage, anaphylaxis, serum sickness syndrome, pneumonitis with or without eosinophilia, vasculitis, fibrosing alveolitis, pleuritis, pericarditis with or without tamponade, allergic myocarditis, polyarteritis nodosa, L.E. syndrome, hepatitis and hepatic necrosis with or without immune complexes, parapsoriasis varioliformis acuta (Mucha Habermann syndrome), photosensitization, arthralgia, periorbital edema, conjunctival and scleral injection and alopecia.
- Gastrointestinal: hepatitis, pancreatitis, bloody diarrhea, impaired folic acid absorption, impaired digoxin absorption, stomatitis, diarrhea and abdominal pains.
- CNS: transverse myelitis, convulsions, transient lesions of the posterior spinal column, peripheral neuropathy, mental depression, vertigo, hearing loss, insomnia, ataxia, hallucinations, tinnitus and drowsiness. Three cases of aseptic meningitis have been reported during the use of enteric coated sulfasalazine in the treatment of rheumatic disease.
- Renal: toxic nephrosis with oliguria and anuria, nephrotic syndrome, hematuria, crystalluria and proteinuria.
- Other: urine discoloration and skin discoloration. The sulfonamides bear certain chemical similarities to some goitrogens, diuretics, acetazolamide and the thiazides, and oral hypoglycemic agents. Goiter production, diuresis, and hypoglycemia have occurred rarely in patients receiving sulfonamides. Cross-sensitivity may exist with these agents. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides and long-term administration has produced thyroid malignancies in this species.
Symptoms And Treatment Of Overdose: Symptoms: Similar to those of any sulfonamide, the most likely symptoms would be gastrointestinal disturbances, drowsiness, convulsions, hematuria, crystalluria or anuria. Serum sulfapyridine concentrations may be used to monitor progress of recovery from overdosage. tag_Treatment
Treatment: Gastric lavage or emesis plus catharsis as indicated. Alkalinize urine. If kidney function is normal, force fluids. If anuria is present, restrict fluids and salt, and treat appropriately. Catheterization of the ureters may be indicated for complete renal blockage by crystals. The low molecular weight of sulfasalazine and its metabolites may facilitate their removal by dialysis. For agranulocytosis, discontinue the drug immediately, hospitalize the patient and institute appropriate therapy.
For hypersensitivity reactions, discontinue treatment immediately. Such reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids.
Dosage And Administration:
- The dosage should be adjusted according to the response to the treatment and the patient’s tolerance to the drug. The tablets/enteric coated tablets should be taken at regular and even intervals over the 24-hour period. The uncoated tablets should preferably be taken with a meal. For intestinal inflammatory diseases the nighttime dose interval should not exceed 8 hours.
Patients not previously treated with sulfasalazine should increase the dose gradually during the first few weeks. The incidence of adverse reactions tends to increase with daily dosages of 4 g or more; patients receiving these doses should be advised of this possibility and should be carefully observed for the appearance of adverse reactions.
- Geriatrics: Based on pharmacokinetic studies, no special dosage instructions are required for elderly patients.
- Renal Deficiency: Sulfasalazine should be used with caution in patients with renal deficiency.
- Inflammatory Bowel Disease, Ulcerative Colitis, Crohn’s Disease: Acute attacks: Adults: Severe attacks: 2 to 4 tablets, 3 to 4 times daily. Moderate and mild attacks: 2 tablets 3 to 4 times daily.
- Children: 25 to 35 kg: 1 tablet 3 times daily; 35 to 50 kg: 2 tablets 2 to 3 times daily.
- Prophylaxis: Adults: In the state of remission in ulcerative colitis the maintenance dose recommended for keeping the patient free from symptoms is 2 tablets 2 to 3 times a day. Treatment with this dosage should continue indefinitely, unless adverse effects are observed. In case of deterioration, raise the dosage to 2 to 4 tablets, 3 to 4 times a day.
- Children: 25 to 35 kg: 1 tablet twice daily; 35 to 50 kg: 1 tablet 2 to 3 times daily.
- Patients experiencing gastrointestinal side effects with the uncoated tablet should use the enteric coated tablets or a lower dose.
- Rheumatoid Arthritis: Adults: 2 enteric coated tablets, 2 times daily.
- When starting therapy, it is suggested to increase the daily dose as follows: 1st week: 1 enteric coated tablet in the evening. 2nd week: 1 enteric coated tablet in the morning and 1 enteric coated tablet in the evening. 3rd week: 1 enteric coated tablet in the morning and 2 enteric coated tablets in the evening. 4th week and after: 2 enteric coated tablets in the morning and 2 enteric coated tablets in the evening.
- If no response has been seen after 2 months’ treatment, the dose may be increased to 3 g/day. Some patients may do well with 1.5 g/day.
- A clinical effect generally appears 1 to 2 months after initiation of treatment. Concurrent therapy with analgesics and/or anti-inflammatory agents is recommended until the therapeutic effect of the EN-tabs is apparent. The EN-tabs are effective and well tolerated in long-term treatment.
- Children: The use of sulfasalazine in Juvenile Rheumatoid Arthritis is not recommended since its efficacy/safety has not been established.
- Information for the Patient: See Blue Section – Information for the Patient “Salazopyrin, Salazopyrin EN-tabs”.
Availability And Storage: EN-tabs: Each orange, elliptical, biconvex, enteric coated tablet, engraved with “KPh” on one side and “102” on the other side, contains: sulfasalazine USP 500 mg. Nonmedicinal ingredients: beeswax, carnauba wax, cellulose acetate phthalate, glyceryl monostearate, polyethylene glycol, propylene glycol and talc. Tartrazine-free. Bottles of 100 and 300.
Tablets: Each yellow-orange, round, biconvex tablet, engraved with “KPh” on one side and “101” and a score on the other side, contains: sulfasalazine USP 500 mg. Nonmedicinal ingredients: silicon dioxide, starch and magnesium stearate. Tartrazine-free. Bottles of 100, 300 and 500.
SALAZOPYRIN® SALAZOPYRIN EN-TABS® Pharmacia & Upjohn Sulfasalazine Anti-inflammatory