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Pfizer Healthcare Ireland

9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24,
Telephone: +353 1 467 6500
Fax: +353 1 467 6501
Medical Information Direct Line: 1 800 633 363


Summary of Product Characteristics last updated on medicines.ie: 25/03/2014
SPC Salazopyrin EN Tablets



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1. NAME OF THE MEDICINAL PRODUCT

Salazopyrin En-Tabs 500 mg Gastro-resistant tablets


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 500 mg of sulfasalazine

For the full list of excipients, see section 6.1


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3. PHARMACEUTICAL FORM

Gastro-resistant tablet

Orange/Yellow, oval-shaped tablets with 'KPh' imprinted on one side and '102' on the other.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

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

Treatment of rheumatoid arthritis which has failed to respond to non-steroidal and anti-inflammatory drugs (NSAIDs).


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4.2 Posology and method of administration

Salazopyrin EN-Tabs should be used where there is gastro-intestinal intolerance of plain tablets. They should not be crushed or broken.

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

(a) Ulcerative Colitis

Adults and the elderly

Severe attacks: 2 to 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 the effect of the drug.

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

Moderate attacks: 2 to 4 tablets, four times per day may be given in conjunction with steroids.

Mild attacks: 2 tablets, four times per day, may be taken with or without 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 relapse.

Paediatric population

The dose is reduced in proportion to body weight.

Acute attack or relapse: 40-60 mg/kg/per day.

Maintenance Dosage: 20-30 mg/kg per day.

Salazopyrin Suspension may provide a more flexible dosage form for children.

(b) Crohn's Disease

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

(c) Rheumatoid Arthritis

Patients with rheumatoid arthritis, and those treated over a long period with NSAIDs, may have sensitive stomachs and for this reason Salazopyrin EN-Tabs are recommended, as follows: -

The patient should start with one tablet daily, increasing the dosage by one tablet a day each week until one tablet four times a day, or two tablets three times a day, is reached, according to tolerance and response. A reduction in ESR and C-reative protein should accompany an improvement in joint mobility. NSAIDs may be taken concurrently with sulfasalazine.


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4.3 Contraindications

Use in infants under the age of two years.

Use in patients where there is a known hypersensitivity to either sulfasalazine, its metabolites or any excipients as well as sulfonamides or salicylates.

Use in patients with jaundice or porphyria.


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4.4 Special warnings and precautions for use

Serious infections associated with myelosuppression, including sepsis and pneumonia, have been reported. Patients who develop a new infection while undergoing treatment with sulfasalazine should be monitored closely. Administration of sulfasalazine should be discontinued if a patient develops a serious infection. Caution should be exercised when considering the use of sulfasalazine in patients with a history of recurring or chronic infections or with underlying conditions which may predispose patients to infections.

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. Thereafter, monitoring should be performed as clinically indicated. The patient should also be counselled to report immediately with any sore throat, fever, malaise, pallor, purpura, jaundice or unexpected non-specific illness during sulfasalazine treatment as this may indicate myelosuppression, haemolysis or hepatotoxicity. Treatment should be stopped immediately while awaiting the results of blood tests.

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

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

Severe hypersensitivity reactions may include internal organ involvement, such as hepatitis, nephritis, myocarditis, mononucleosis-like syndrome (i.e., pseudomononucleosis), hematological abnormalities (including hematophagic histiocytosis), and/or pneumonitis including eosinophilic infiltration.

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

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 the administration of folic acid or folinic acid (leucovorin).

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)

Severe, life-threatening, systemic hypersensitivity reactions such as Drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking various drugs including sulfasalazine (see section 4.8).

It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Sulfasalazine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of sulfasalazine. Patients appear to be at highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within the first month of treatment. Sulfasalazine should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

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

Because sulfasalazine causes crystalluria and kidney stone formation, adequate fluid intake must be maintained.

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

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


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4.5 Interaction with other medicinal products and other forms of interaction

Use of sulfonamides with folic-acid antagonists or hypoglycaemics may increase the effects of these agents.

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

Due to inhibition of thiopurine methyltransferase (TPMT) by sulfasalazine, bone marrow suppression and leukopenia have been reported when 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.

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.


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4.6 Pregnancy and lactation

Pregnancy

Reproduction studies in rats and rabbits have revealed no evidence of harm to the foetus. Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency (see section 4.4 ). There have been reports of babies with neural tube defects born to mothers who were exposed to sulfasalazine during pregnancy, although the role of sulfasalazine in these defects has not been established.Because the possibility of harm cannot be completely ruled out, sulfasalazine should be used during pregnancy only if clearly needed.

Breast-feeding

Sulfasalazine and sulfapyridine are found in low levels in breast milk. Caution should be used, particularly if breastfeeding premature infants or those deficient in glucose 6 phosphate dehydrogenase. 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.


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4.7 Effects on ability to drive and use machines

The effect of sulfasalazine on the ability to drive and use machinery has not been systematically evaluated.


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4.8 Undesirable effects

The following events have been reported in patients receiving sulfasalazine:

MedDRA System Organ Class

Frequency

Adverse Drug Reaction

Infections and infestations

Not known

aseptic meningitis, pseudomembranous colitis, parotitis

Blood and lymphatic system disorders

Common

leukopenia

Uncommon

thrombocytopenia

Not known

pancytopenia, agranulocytosis, aplastic anaemia, pseudomononucleosis*, haemolytic anaemia, macrocytosis, megaloblastic anaemia, Heinz body anaemia, hypoprothrombinaemia, lymphadenopathy, methaemoglobinaemina, neutropenia, pancytopenia

Immune system disorders

Not known

anaphylaxis*, serum sickness, polyarteritis nodosa

Metabolism and nutrition system disorders

Common

loss of appetite

Not known

folate deficiency*

Psychiatric disorders

Uncommon

depression, hallucinations, insomnia

Nervous system disorders

Common

dizziness, headache, taste disorders

Not known

encephalopathy, peripheral neuropathy, smell disorders, ataxia, convulsions

Ear and labyrinth disorders

Common

tinnitus

Not known

vertigo

Eye disorders

Not known

conjuctivial and scleral infection

Cardiac disorders

Not known

allergic myocarditis*, pericarditis, cyanosis

Vascular disorders

Not known

pallor*, vasculitis

Congenital, familial and genetic disorders

Not known

Acute attack may be precipitated in patients with porphyria

Respiratory, thoracic and mediastinal disorders

Common

cough

Uncommon

dyspnoea

Not known

interstitial lung disease* , eosinophilic infiltration, fibrosing alveolitis, oropharyngeal pain*

Gastrointestinal disorders

Very common

gastric distress, nausea

Common

abdominal pain, diarrhoea*, vomiting*

Not known

aggravation of ulcerative colitis* , pancreatitis, stomatitis

Hepatobiliary disorders

Uncommon

jaundice*

Not known

hepatic failure*, hepatitis fulminant*, hepatitis, hepatitis cholestatic*, cholestasis*

Skin and subcutaneous tissue disorders

Common

purpura*, pruritus

Uncommon

alopecia, urticaria

Very rare

toxic epidermal necrolysis

Not known

drug rash with eosinophilia and systemic symptoms (DRESS)*, epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, exanthema, exfoliative dermatitis, angioedema*, toxic pustuloderma, lichen planus, photosensitvity, erythema, periorbital oedema

Musculoskeletal and connective tissue disorders

Common

arthralgia

Not known

system lupus erythematosus, Sjogren's syndrome

Renal and urinary disorders

Common

proteinuria

Not known

nephrotic syndrome, interstitial nephritis, nephrolithiasis*, haematuria, crystalluria

Reproductive system and breast disorders

Not known

reversible oligospermia

General disorders and administration site conditions

Common

fever

Uncommon

facial oedema

Not known

yellow discoloration of skin and body fluids*, drug fever, generalised skin eruptions

Investigations

Uncommon

elevation of liver enzymes

Not known

induction of autoantibodies

Frequency categories: Very common ≥1/10; Common ≥1/100 to <1/10; Uncommon ≥1/1000 to <1/100; Rare ≥1/10000 to <1/1000; Very rare <1/10000; Not known (cannot be estimated from available data)

* ADR identified post-marketing

see section 4.4 Special warnings and precautions for use

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. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine. Reports may be made by following the links to the online reporting option accessible from the IMB homepage, or by completing the downloadable report form also accessible from the IMB website, which may be completed manually and submitted to the IMB via freepost, to the following address:

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O'Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6767836

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie


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4.9 Overdose

The most common symptoms of overdose, similar to other sulfonamides, are nausea and vomiting. Patients with impaired renal function are at increased risk of serious toxicity. Treatment is symptomatic and should be supportive, including alkalinisation of urine. Patients should be observed for development of methemoglobinemia or sulfahemoglobinemia. If these occur treat appropriately.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Aminosalicylic acid and similar agents

ATC Code: A07EC01

Sulfasalazine is split by bacteria in the colon into sulphapyridine and mesalazine. All three compounds have pharmacological effects, principally immunomodulatory, antibacterial and alteration of the arachidonic acid cascade and the activity of certain enzymes. The net result is a reduction of the activity of certain inflammatory diseases namely ulcerative colitis, Crohn's Disease and rheumatoid arthritis. In rheumatoid arthritis the effect is disease modifying, taking one to three months to develop. Mesalazine is not believed to cause this effect. Improvement in ESR and CRP, and progression (Larsen or Sharp Index) have been shown to be markedly reduced in early patients compared with placebo or hydroxychloroquine treatment over two years. The benefit appears to be maintained when the drug is stopped.


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5.2 Pharmacokinetic properties

Around 90% of a sulfasalazine (SU) dose reaches the colon where bacteria split the drug into sulphapyridine (SP) and mesalazine (ME). Most SP is absorbed, either hydroxlylated or glucoronidated, 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 acetylated ME (Ac-ME). SU is excreted in the bile and urine.

Studies with Salazopyrin EN-Tabs show no statistically significant differences in the main parameters compared with an equivalent dose of SU powder, and the data below relate to ordinary tablets. In respect of the use of Salazopyrin in bowel disease, there is no evidence that systemic levels are of any special clinical relevance other than with regard to ADR incidence. Here, levels of SP over about 50 µg/mL are associated with a substantial risk of ADRs, especially in slow acetylators. For SU given as a single 3g oral dose: peak plasma levels of SU occurred in 3-5 hours, elimination half-life was 5.7 + 0.7 hours and lap time was 1.5 hours.

During maintenance therapy, renal clearance was: 7.2 + 1.7 mL/min. for SU, 9.9 + 1.9 mL/min. for SP and 100 + 20 mL/min. for Ac-ME. Free SP first appears in plasma 4.3 hours after a single oral dose with an absorption half-life of 2.7 hours. The elimination half-life was calculated as 18 hours. As regards mesalazine, in urine only Mc-ME (not free ME) was demonstrable, the acetylation probably largely achieved in the colon mucosa.

After a 3g dose of SU the dose lag-time was 6.1 + 2.3 hours and plasma levels were below 2µg/ml total ME. Urinary excretion half-life was 6.0 + 3.1 hours and absorption half-life, based on these figures was 3.0 + 1.5 hours. The renal clearance constant was 125 mL/min. corresponding to the GFR.

As regards rheumatoid arthritis, there are no data that suggest any differences to the above.


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5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to those already included in other sections of the SPC.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Povidone

maize starch

magnesium stearate

silica, colloidal anhydrous

cellulose acetate phthalate

macrogol

bees wax (trace)

carnauba wax

glyceryl monostearate

talc

propylene glycol


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6.2 Incompatibilities

Not Applicable


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6.3 Shelf life

5 years.


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6.4 Special precautions for storage

Do not store above 25°C. Keep the container tightly closed


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6.5 Nature and contents of container

Polylefin square HDPE pot with orange knurled cap, designed for easy opening, and containing 112 tablets.


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6.6 Special precautions for disposal and other handling

Take the tablet(s) whole with water. Do not break or crush.

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


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7. MARKETING AUTHORISATION HOLDER

Pfizer Limited,

Ramsgate Road,

Sandwich,

Kent,

CT13 9NJ,

United Kingdom


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8. MARKETING AUTHORISATION NUMBER(S)

PA 19/84/1


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

1st April 2007


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10. DATE OF REVISION OF THE TEXT

03/2014


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11. LEGAL STATUS

POM

SZ 11_2



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Active Ingredients

 
   Sulfasalazine