Salazopyrin Suspension

1. Name Of The Medicinal Product

Salazopyrin Suspension.

2. Qualitative And Quantitative Composition

Sulfasalazine Ph.Eur., 250 mg in 5 mL.

3. Pharmaceutical Form

Oral suspension.

4. Clinical Particulars

4.1 Therapeutic Indications

Induction and maintenance of remission of ulcerative colitis and treatment of active Crohn's disease.

4.2 Posology And Method Of Administration

The dose is adjusted according to the severity of the disease and the patient's tolerance of the drug, as detailed below.

Adults and the Elderly

Severe attacks: 20 to 40 ml four times a day may be given in conjunction with steroids as part of an intensive management regime. Rapid passage of the suspension may reduce the effect of the drug.

The night time interval between doses should not exceed 8 hours.

Moderate attacks: 20 ml four times a day may be taken with or without steroids.

Maintenance therapy: With induction of remission, reduce the dose gradually to 40 ml per day. This dosage should be continued indefinitely, since discontinuance even several years after an acute attack is associated with a four-fold increase in relapse.

Children

The dose is reduced in proportion to body weight.

Acute attack or relapse: 0.8 - 1.2 ml/kg/day.

Maintenance dosage: 0.4 - 0.6 ml/kg/day.

4.3 Contraindications

• Use in infants under the age of two years.

• Use in patients where there is a significant hypersensitivity to sulfasalazine, sulfonamides, salicylates or the sodium benzoate preservative.

• Acute intermittent porphyria.

4.4 Special Warnings And Precautions For Use

Haematological and hepatic side effects may occur. Differential white cell, red cell and platelet cells should be performed initially and at least monthly for a minimum of the first three months of treatment. The patient should also be counselled to report immediately with any sore throat, fever, malaise or unexpected non-specific illness. Treatment should be stopped immediately if there is a suspicion or laboratory evidence of a potentially serious blood dyscrasia.

Liver function tests should be carried out at monthly intervals for the first three months of treatment. Patients with liver disease should be treated with caution.

Kidney function should be checked initially and at regular intervals during the treatment. Since sulfasalazine may cause haemolytic anaemia, it should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency.

Changes in blood picture (e.g. macrocytosis and pancytopenia) can be normalised by the administration of folic acid or folinic acid (leucovorin).

Sulfasalazine may colour the urine orange-yellow.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Certain types of extended wear soft contact lenses may be permanently stained during therapy.

Uptake of digoxin and folate may be reduced.

Adequate fluid intake and avoidance of acidification of the urine (such as with concomitant use of methenamine) may minimise crystalluria and stone formation.

Sulfonamides bear certain chemical similarities to some oral hypoglycemic agents. Hypoglycemia has occurred in patients receiving sulfonamides. Patients receiving sulfasalazine and hypoglycemic agents should be closely monitored.

Due to inhibition of thiopurine methyltransferase by salazopyrin, bone marrow suppression and leucopenia have been reported when the thiopurine 6-mercaptopurine or it's prodrug, azathioprine, and oral salazopyrin were used concomitantly.

4.6 Pregnancy And Lactation

Long-term clinical usage and experimental studies have failed to reveal any teratogenic or icteric hazards. The amounts of drug circulating in breast milk should not present a risk to a healthy infant.

4.7 Effects On Ability To Drive And Use Machines

No specific effects.

4.8 Undesirable Effects

Overall, about 75% of ADRs occur within three months of treatment and over 90% by six months. Some unwanted effects are dose-dependent and symptoms can often be alleviated by reduction of the dose.

General

Sulfasalazine is split by intestinal bacteria to sulfapyridine and 5-amino salicylate so ADRs to either sulfonamide or salicylate are possible. Patients with slow acetylator status are more likely to experience ADRs related to sulfapyridine. The most commonly encountered ADRs are nausea, headache, rash loss of appetite and raised temperature.

Specific

The following reactions have been recorded in patients taking sulfasalazine:

Haematological

Potentially fatal leucopenia, neutropenia, agranulocytosis, aplastic anaemia and thrombocytopenia. Leucopenia, which is normally mild and transient, may occur in up to 1.5% of patients and agranulocytosis in up to one in 700 patients during the second month of therapy.

The risk of sulfasalazine-associated blood disorders is substantially higher in patients treated for rheumatoid arthritis than it is in patients treated for inflammatory bowel disease.

Heinz body anaemia, methaemoglobinaemia, hypoprothrombinaemia, haemolytic anaemia, megaloblastic anaemia.

Hypersensitivity reactions

Generalised skin eruptions, Stevens-Johnson Syndrome, exfoliative dermatitis, epidermal necrolysis, pruritis, urticaria, photosensitisation, anaphylaxis, serum sickness, drug fever, lymphadenopathy, periorbital oedema, conjunctival and scleral injection, arthralgia, allergic myocarditis, polyarteritis nodosa, LE-phenomenon and lung complications with dyspnoea, fever, cough, eosinophilia, fibrosing alveolitis, pericarditis, vasculitis, nephritis, alopecia.

Gastro-intestinal reactions

Stomatitis, parotitis, pancreatitis, hepatitis.

CNS reactions

Vertigo, tinnitus, peripheral neuropathy, aseptic meningitis, ataxia, convulsions, insomnia, mental depression and hallucinations.

Fertility

Oligospermia, reversible on discontinuance of drug.

Renal Reactions

Crystalluria, haematuria, proteinurea and nephrotic syndrome.

4.9 Overdose

The drug has low acute per oral toxicity in the absence of hypersensitivity. There is no specific antidote and treatment should be supportive.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Sulfasalazine has beneficial effects in the treatment of ulcerative colitis and maintenance of remission, and in the treatment of acute Crohn's disease. Around 90% of a dose reaches the colon where bacteria split the drug into sulpyapyridine and mesalazine. These are active, and the unsplit sulfasalazine is also active on a variety of systems. Most Sulfapyridine is absorbed, hydroxylated or glucuronidated and a mix of unchanged and metabolised sulfapyridine appears in the urine.

Some mesalazine is taken up and acetylated in the colon wall, such that renal excretion is mainly acetyl-mesalazine. Sulfasalazine is excreted unchanged in the bile and urine. Overall the drug and its metabolites exert immunomodulatory effects, antibacterial effects, effects on the arachidonic acid cascade and alteration of activity of certain enzymes. The net result clinically is a reduction in activity of the inflammatory bowel disease.

The enteric coated sulfasalazine is registered for the treatment of rheumatoid arthritis, where the effect resembles penicillamine or gold.

5.2 Pharmacokinetic Properties

With regard to the use of Salazopyrin in bowel disease there is no evidence that systemic levels are of any relevance other than with regard to ADR incidence. Here levels of sulfapyridine over about 50µg/ml are associated with a substantial risk of ADRs, especially in slow acetylators.

For sulfasalazine given as a single 3g oral dose, peak serum levels of sulfasalazine occurred in 3-5 hours, elimination half life was 5.7 ±0.7 hours, lag time 1.5 hours. During maintenance therapy renal clearance of sulfasalazine was 7.3 ±1.7ml/min, for sulfapyridine 9.9 ±1.9 and acetyl-mesalazine 100 ±20. Free sulfasalazine first appears in plasma in 4.3 hours after a single dose with an absorption half life of 2.7 hours. The elimination half life was calculated as 18 hours. For mesalazine, only acetyl-mesalazine (not free mesalazine) was demonstrable, the acetylation probably largely achieved in the colon mucosa. After 3g sulfasalazine dose lag time was 6.1 ±2.3 hours and plasma levels kept below 2µg/ml. total mesalazine. Urinary excretion half life was 6.0 ±3.1 hours and absorption half life based on these figures 3.0 ±1.5 hours. Renal clearance constant was 125 ml/min corresponding to the GFR. Studies in volunteers suggest that sulfasalazine is handled in a similar manner whether given as suspension or tablets.

5.3 Preclinical Safety Data

In two-year carcinogenicity studies in rats and mice, sulfasalazine showed some evidence of carcinogenicity. In rats, there was a small increase in the incidence of transitional cell papillomas in the urinary bladder and kidney. The tumours were judged to be induced mechanically by calculi formed in the urine rather than through a direct genotoxic mechanism. In the mouse study, there was a significant increase in the incidence of hepatocellular adenoma or carcinoma. The mechanism of induction of hepatocellular neoplasia has been investigated and attributed to species-specific effects of sulfasalazine that are not relevant to humans.

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. It did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, and in vivo mouse bone marrow chromosomal aberration tests were negative. However, sulfasalazine showed positive or equivocal mutagenic responses in rat and mouse micronucleus assays, and in human lymphocyte sister chromatid exchange, chromosomal aberration and micronucleus assays. The ability of sulfasalazine to induce chromosome damage has been attributed to perturbation of folic acid levels rather than to a direct genotoxic mechanism.

Based on information from non-clinical studies, sulfasalazine is judged to pose no carcinogenic risk to humans. Sulfasalazine use has not been associated with the development of neoplasia in human epidemiology studies.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Xanthan gum, sodium benzoate, polysorbate 80, orange/lemon flavour, microcrystalline cellulose, sucrose, purified water.

6.2 Incompatibilities

None relevant.

6.3 Shelf Life

30 months

6.4 Special Precautions For Storage

Do not store at above 25°C.

6.5 Nature And Contents Of Container

Natural HDPE bottle with a tamper evident cap or child resistant cap and containing 500 ml of suspension.

6.6 Special Precautions For Disposal And Other Handling

Take the suspension with food.

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

8. Marketing Authorisation Number(S)

PL 00032/0389

9. Date Of First Authorisation/Renewal Of The Authorisation

15 January 1994 / 25^th March 2002

10. Date Of Revision Of The Text

19^th October 2005

11. LEGAL CATEGORY

POM.

Ref: SZD 2_0 UK