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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Sulfasalazine Tablets 500mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 500mg of Sulfasalazine Ph.Eur

3    PHARMACEUTICAL FORM

Tablet

Light brown, convex tablets marked “SE”; breakline; “500” on one side and “G” on the reverse.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Sulfasalazine is indicated for the induction and maintenance of remission of ulcerative colitis and Crohn’s disease.

4.2    Posology and method of administration

Posology

The dose is adjusted according to the severity of the disease and the patient’s tolerance to the drug as described.

A) Ulcerative colitis

Adults

Severe attacks:

Sulfasalazine 2-4 tablets four times a day may be given in conjunction with steroids as part of an intensive management regime. Rapid passage of the tablets may reduce effect of the drug. Night-time interval between doses should not exceed eight hours.

Moderate Attack: 2-4 tablets four times a day may be given in conjunction with steroids.

Maintenance Therapy:

With induction of remission reduce the dose gradually to 4 tablets 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 risk of relapse.

Elderly patients

No special precautions are necessary.

Paediatric Population

The dose is reduced in proportion to body weight.

Acute Attack or Relapse    40-60 mg/kg per day

Maintenance:    20-30 mg/kg per day

B) Crohn's Disease

In active Crohn's Disease, sulfasalazine should be administered as in attacks of ulcerative colitis (see above).

Method of administration

For oral administration only.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.

Sulfasalazine is contraindicated in patients with a history of sensitivity to sulfonamides or salicylates and infants under 2 years of age and patients suffering from porphyria and jaundice.

4.4 Special warnings and precautions for use

Haematological and hepatic side effects may occur. Complete blood counts, including differential white cell, red cell and platelet counts and liver function tests, should be performed before starting sulfasalazine, and every second week during the first three months of therapy. During the second three months, the same tests should be done once monthly and thereafter once every three months, and as clinically indicated. Assessment of renal function (including urinalysis) should be performed in all patients initially and at least monthly for the first three months of treatment. Blood disorders can occur with aminosalicylates (please see recommendation below).

A patient information leaflet should be supplied to the patient which specifically warns of the risk of serious blood dyscrasias together with the need to report immediately to the doctor with any sore throat, fever, malaise, pallor, purpura, bleeding, bruising, jaundice or other unexpected non-specific illness. This may indicate myelosuppression, haemolysis or hepatoxicity. Treatment should be stopped immediately if there is suspicion or laboratory evidence of a blood dyscrasia.

Sulfasalazine should not be given to patients with impaired hepatic or renal function or with blood dyscrasias, unless the potential benefit outweighs the risk.

Patients with allergy or bronchial asthma should be treated with caution.

Patients with glucose-6-phosphate dehydrogenase deficiency should be closely observed for signs of haemolytic anaemia (heinz body anaemia).

The uptake of digoxin and folate may be reduced. An acute attack may be precipitated in patients with porphyria.

Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency (see section 4.6), potentially resulting in serious blood disorders (e.g., macrocytosis and pancytopenia), this can be normalised by administration of folic acid or folinic acid (leucovorin).

Because sulfasalazine causes crystalluria and kidney stone formation, adequate fluid intake should be ensured during treatment.

Oligospermia and infertility may occur in men treated with sulfasalazine. Discontinuation of the drug appears to reverse these effects within 2 to 3 months.

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of Sulfasalazine Tablets.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.

If symptoms or signs of SJS and TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Sulfasalazine Tablets treatment should be discontinued.

The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.

If the patient has developed SJS or TEN with the use of Sulfasalazine Tablets, Sulafsalazine Tablets must not be re-started in this patient at any time.

Paediatric population:

Use in children with the concomitant condition systemic onset juvenile rheumatoid arthritis may result in a serum sickness like reaction; therefore sulfasalazine is not recommended in these patients.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interactions with other medicinal products and other forms of interaction

Since Sulfasalazine is metabolised to sulfapyridine and 5-aminosalicyclic acid, side effects of sulfonamides or salicylates may occur. Patients with slow acetylator status are more likely to experience adverse effects due to sulfapyridine. The most commonly encountered reactions are nausea, headache rash, loss of appetite and raised temperature. The uptake of digoxin and folate may be reduced.

4.6 Fertility, pregnancy and lactation

Pregnancy

Reproduction studies in rats and arabbits revealed no evidence of harm to the foetus. Published data regarding use of sulfasalazine in pregnant women have revealed no evidence of teratogenic hazards. If sulfasalazine is used during pregnancy, the possibility of foetal harm appears remote. Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency. Because the possibility of harm cannot be completely ruled out, sulfasalazine should be used during pregnancy only if clearly needed.

Breastfeeding

Sulfasalazine and sulfapyridine are found in low levels in breast milk. Patients should avoid breastfeeding while taking this medicine.

There have been reports of bloody stools or diarrhoea in infants who were breastfeeding from mothers on sulfasalazine. In cases where the outcome was reported, bloody stools or diarrhoea resolved in the infant after discontinuation of sulfasalazine in the mother.

4.7    Effects on ability to drive and use machines

Sulfasalazine has no influence on the ability to drive and use machines..

4.8    Undesirable effects

Overall, about 75% of ADRs occur within 3 months of starting therapy, and over 90% by 6 months. Some undesirable 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 sulphonamide or salicylate are possible. Patient 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 adverse reactions observed during clinical studies conducted with Sulfasalazine have been provided in a single list below by class and frequency (very common (>1/10); common (> 1/100 to <1/10); uncommon (> 1/1000 to < 1/100). Where an adverse reaction was seen at different frequencies in clinical studies, it was assigned to the highest frequency reported.

Additional reactions from post-marketing experience are included as frequency Not known (cannot be estimated from the available data) in the list below.

System Organ Class    Adverse drug reactions

Infections and infestations

Not known    Pseudomembranous colitis

Blood and Lymphatic System disorders Common

Uncommon

Not known

Immune system disorders

Not known    Anaphylaxis, polyarteritis nodosa,

serum sickness

Eye disorders

Common

Conjuctivial and scleral injection

Cardiac disorders Not known	Allergic myocarditis, cyanosis, pericarditis
Vascular disorders Uncommon	Vasculitis
Respiratory, Thoracic and Mediastinal disorders Common Uncommon Not known	Cough Dyspnoea Fibrosing alveolitis, eosinophilic infiltration, interstitial lung disease, bronchospasm
Gastrointestinal disorders Very common Common	Gastric distress, nausea Abdominal pain, diarrhoea, vomiting, stomatitis
Not known	Aggravation of ulcerative colitis, pancreatitis, parotitis
Hepatobiliary disorders Not known	Hepatic failure, fulminant hepatitis, hepatitis*
Skin and Subcutaneous tissue disorders Common Uncommon Very rare	Pruritus Alopecia, urticaria Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)
Not known	Drug rash with eosinophilia and systemic symptoms (DRESS), toxic pustuloderma, erythema, exanthema, exfoliative dermatitis, periorbital oedema, lichen planus, photosensitivity, purpura, erythema nodosum, erythema multiforme
Musculoskeletal and Connective tissue disorders Common Not known	Arthralgia Systemic lupus erythematosus
Renal and Urinary disorders Common Not known	Proteinuria Nephrotic syndrome, interstitial nephritis, crystalluria*, haematuria, renal failure
Reproductive system and breast disorders Not known	Oligospermia * and abnormal spermatogenesis, impotence reversible on discontinuation of the medicinal product

Common Uncommon Not known

Investigations Uncommon Not known

*See section 4.4 for further information.

Fever

Facial oedema

Yellow discoloration of skin and body fluids, malaise, fatigue

Elevation of liver enzymes Induction of antibodies

Potentially fatal leucopenia, neutropenia, pancytopenia, agranulocytosis, aplastic anaemia and thrombocytopenia. Leucopenia 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 for patients treated for inflammatory bowel disease.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

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

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Sulfonamides, ATC code: A07AB

Mechanism of action:

The mechanism of action is thought to be due to the local anti-inflammatory effect of 5-amino salicylic acid.

Pharmacodynamic effects

Additionally there is an immunosuppressive effect shown in inhibition of lymphocyte and granulocyte metabolism as well as inhibition of different enzyme systems by the parent and metabolites (Sulfasalazine, sulfapyridine and 5-amino salicylic acid). It is also possible that the bacteriostatic activity of sulfapyridine locally in the colon has some clinical effect. Both aerobic and anaerobic bacteria are affected.

Around 90% of a dose reaches the colon where bacteria split the drug into sulfapyridine (SP) and mesalazine (ME). These are active, and the unsplit sulfasalazine (SASP) is also active on a variety of symptoms. Most SP is absorbed, hydroxylated or glucuronidated and a mix of unchanged and metabolised SP appears in the urine. Some ME is taken up and acetylated in the colon wall, such that renal excretion is mainly ac-me. SASP 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 SASP is registered for the treatment of rheumatoid arthritis, where the effect resembles penicillamine or gold.

5.2 Pharmacokinetic properties

Absorption

Sulfasalazine is partly absorbed from the small intestine and may later enter the enterohepatic circulation but the majority of a dose passes on to the colon where it is broken down to a sulfapyridine and 5-aminosalicyclic acid (mesalazine) by bacteria.

Distribution

Most of the sulfapyridine is absorbed and together with its metabolites, appear in the blood 3 to 6 hours after a single 2g dose of Sulfasalazine is given to healthy subjects; a mean peak serum concentration for sulfapyridine of 21 pg per ml has been reported at 12 hours.

Biotransformation

Sulfapyridine is metabolised by acetylation, the rate being genetically determined by hydroxylation and by conjugation with glucuronic acid.

Elimination

Up to 10% of a dose of Sulfasalazine is excreted unchanged in the urine and about 60% as sulfapyridine and its metabolites. A small proportion of the sulfapyridine appears in the faeces and unchanged Sulfasalazine may be excreted in the faeces of patients with ulcerative colitis.

The majority of 5-aminosalicyclic acid is eliminated unchanged in the faeces but some appears in the blood; about 20% is excreted in the urine unchanged and in the acetylated form.

Sulfasalazine has been claimed to be concentrated in connective tissue.

With regard to the use of salazopyrin in the bowel disease there is no evidence that systemic levels are of any relevance other than with regard to ADR incidence. Here levels of SP over about 50 pg/ml are associated with a substantial risk of ADRs, especially in slow acetylators. For SASP given as a single 3 g oral dose, peak serum levels of SASP 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 SASP was 7.3 ± 1.7 ml/min, for SP 9.9 ±1.9 and AC-ME 100±20. Free SP 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. Turning to mesalazine, in urine only AC-ME (not free ME) was demonstrable, the acetylation probably largely achieved the colon mucosa. After a 3 g SASP dose lag time was 6.1±2.3 hours and plasma levels kept below 2 pg/ml total ME. 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.

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 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 L5178Y 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

Tablet core:

Lactose

Cellulose, microcrystalline Povidone K30 Lake Brown CL9301 Maize Starch Magnesium Stearate Sodium Starch Glycolate

6.2    Incompatibilities

None stated.

6.3    Shelf life

36 months.

6.4    Special precautions for storage

Store below 25°C.

6.5    Nature and contents of container

Amber glass bottles with wadless plastic caps in packs of 100 and 500 tablets.

Polypropylene pots with white polyethylene caps and optional polyethylene ullage filler in packs of 50, 100, 112, 224, 250 and 500 tablets.

6.6    Instruction for use and handling

None Known.

7 MARKETING AUTHORISATION HOLDER

Generics [UK] Ltd t/a Mylan

Station Close

Potters Bar

Herts

EN6 1TL

8.    MARKETING AUTHORISATION NUMBER

PL 04569/0062

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

06/02/2009

DATE OF REVISION OF THE TEXT

23/06/2014