SULFASALAZINE 500 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Sulfasalazine 500 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 500 mg of sulfasalazine

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

4.   CLINICAL PARTICULARS

4.1 Therapeutic Indications

Recommended clinical indications

1. Ulcerative colitis

2. 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 to the medicine, as detailed below.

Elderly Patients

No special precautions are necessary.

a) Ulcerative colitis

Adults:

Severe attack: 2–4 tablets four times daily 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 daily may be given in conjunction with steroids.

Mild attack: 1–2 tablets four times daily, with or without steroids.

Maintenance therapy: following the induction or remission the dose is gradually reduced to 1 tablet four times daily. This dosage should be continued indefinitely since discontinuation even several years after an acute attack is associated with a four fold increase in risk of relapse.

Children over 2 years: the dose is reduced in proportion to body weight Acute attack or relapse: 40 – 60 mg / kg / day

Maintenance dose: 20 – 30 mg / kg / day

Sulfasalazine suspension may provide a more flexible dosage form.

b) Crohn’s Disease

In active Crohn’s disease, sulfasalazine should be administered in the same doses as given in attacks of ulcerative colitis (see above).

Method of administration: For oral use

4.3 Contraindications

Sulfasalazine is contraindicated in:

Patients with a known hypersensitivity to sulfasalazine, its metabolites or any of the excipients as well as sulfonamides and salicylates.

Infants under the age of 2 years.

Patients with porphyria.

4.4 Special warnings and precautions for use

In the event of serious hypersensitivity and toxic reactions discontinue medication.

Caution should be exercised in patients with history of severe allergy or bronchial asthma and should not be given to patients with hepatic and renal dysfunction or blood dyscrasias, unless the potential benefit outweighs the risk. Complete blood counts, including differential white cell count, 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 3 months of treatment. Thereafter, monitoring should be performed annually during treatment (more frequently in renal impairment) or as clinically indicated.

Patients should be counselled to report immediately any sore throat, fever, malaise, pallor, purpura, jaundice or any unexpected non-specific illness during sulfasalazine treatment, this may indicate myelosuppression, haemolysis or hepatoxicity Treatment should be stopped immediately while awaiting the results of blood tests. Please see section 4.4 „Interference with laboratory testing“.

Sulfasalazine should be given with caution to patients with severe allergy or bronchial asthma.

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.

Since sulfasalazine may cause haemolytic anaemia, it should be used with caution in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

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.

This medicine contains less than 1mmol sodium (23mg) per tablet. It is essentially ‚sodium-free‘.

Interference with laboratory testing

Several reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine causing a false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalamine/ mesalazine.

Sulfasalazine or its metabolites may interfere with ultraviolet absorbance, particularly at 340 nm, and may cause interference with some laboratory assays that use NAD(H) or NADP(H) to measure ultraviolet absorbance around that wavelength. Examples of such assays may include urea, ammonia, LDH, a-HBDH and glucose. It is possible that alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase-muscle/brain (CK-MB), glutamate dehydrogenase (GLDH), or thyroxine may also show interference when sulfasalazine treatment is given at high doses. Consult with the testing laboratory regarding the methodology used. Caution should be exercised in the interpretation of these laboratory results in patients who are receiving sulfasalazine. Results should be interpreted in conjunction with clinical findings.

4.5 Interaction with other medicinal products and other forms of interaction

Reduced absorption of digoxin, resulting in non-therapeutic serum levels, has been reported when used concomitantly with oral sulfasalazine.

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

Due to inhibition of thiopurine methyltransferase by sulfasalazine, bone marrow suppression and leukopenia have been reported when the thiopurine 6-mercaptopurine or its prodrug, azathioprine, and oral sulfasalazine were used concomitantly.

Coadministration of oral sulfasalazine and methotrexate to rheumatoid arthritis patients did not alter the pharmacokinetic disposition of the drugs. However, an increased incidence of gastrointestinal adverse events, especially nausea, was reported.

4.6 Fertility, pregnancy and lactation

Pregnancy

Reproduction studies in rats and rabbits have revealed no evidence of harm to the foetus. Published data regarding the 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.

Lactation

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 by 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

None reported.

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

* See Section 4.4 for further information

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 the Yellow Card Scheme at:

www.mhra.gov.uk/y­ellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

Pharmacotherapeutic group: Intestinal anti-inflammatory agents – aminosalicylic acid and similar agents.

ATC code: A07E C01

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 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 sulfasalazine 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 50gg/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 acetylmesalazine 100±20. Free sulfapyridine 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.

Up to 10% of a dose of Sulfasalazine is excreted unchanged and about 60% as Sulfapyridine and its metabolites.

In urine only acetyl-mesalazine (not free mesalazine) was demonstrable, the acetylation probably largely achieved in the colon mucosa. After a 3g sulfasalazine dose lag time was 6.1±2.3 hours and plasma levels kept below 2gg/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 125ml/min corresponding to the GFR.

5.3 Preclinical safety data

6.  PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

Iron oxide, yellow (E172)

Povidone

Magnesium stearate

Sodium starch glycollate (Type A)

6.2 Incompatibilities

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

6.3 Shelf life

3 years in containers as packaged for sale.

2 years in blister packs as packaged for sale.

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package in order to protect from light and moisture.

6.5 Nature and Contents of Container

1) Opaque plastic containers composed of PP tubes and PE made tamper evident closures in pack sizes of 28, 42, 50, 56, 84, 100, 112, 250, 500 and 1000 tablets.

2) Opaque plastic containers (HDPP or HDPE) with a tamper-evident or childresistant tamper-evident closure (HDPE) with a packing inclusion of standard polyether foam or PE or PP made filler in pack sizes 28, 42, 50, 56, 84, 100, 112, 250, 500 and 1000 tablets.

3) Aluminium / opaque PVC blister packs in pack sizes of 28, 42, 56, 84 and 112 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

8.   MARKETING AUTHORISATION NUMBER(S)

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

09/03/2009