Sulfasalazine 500mg Gastro Resistant Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
SULAZINE EC
Sulfasalazine 500 mg Gastro-resistant Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Sulfasalazine USP 500.00 mg
3 PHARMACEUTICAL FORM
Gastro-resistant Tablets
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
1. Induction and maintenance of remission of ulcerative colitis; treatment of active Crohn’s disease
2. Treatment of rheumatoid arthritis which has failed to respond to non-steroidal anti-inflammatory drugs (NSAIDs)
4.2 Posology and method of administration
Route of administration: Oral
Gastro-resistant tablets 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 to the drug, as detailed below.
1. Ulcerative colitis:
Adults and Elderly: • Severe attacks:
2-4 tablets four times a day, which 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 8 hours.
When remission occurs, maintenance therapy should be commenced.
• Moderate attacks:
2-4 tablets four times a day may be given in conjunction with steroids
• Mild attacks:
2 tablets four times a day with or without steroids
• Maintenance therapy:
With induction of remission gradually reduce dose to 4 tablets per day. The dosage should be continued indefinitely to avoid relapse.
Children over 2 years:
Adjust the dose in proportion to bodyweight
• Acute attack or relapse: 40-60 mg/kg per day
• Maintenance therapy: 20-30 mg/kg per day
Sulfasalazine suspension may provide a more flexible dosage form.
2. Crohn’s disease
In active Crohn’s disease, sulfasalazine should be administered as in attacks of ulcerative colitis (see above)
3. Rheumatoid arthritis:
Patients with rheumatoid arthritis, and those treated over a long period with NSAIDs, may have sensitive stomachs and for this reason gastro-resistant sulfasalazine tablets are recommended for this disease. NSAIDs may be taken concurrently with sulfasalazine.
Adults and Elderly:
Commence treatment with 0.5 g daily (one tablet) for one week, thereafter increasing the dose by one tablet each week to a maximum of 3 g/day (six tablets).
Should patient experience nausea, the dose should be reduced to a previously tolerated dose for one week and then increased. Alternatively, the total daily dose may be divided and taken three or four times daily. Onset of effect is slow and a marked effect may not be seen for six weeks.
Children:
Not recommended
4.3 Contraindications
Sulfasalazine is contraindicated in;
• Patients with a known hypersensitivity to sulfasalazine, it’s metabolites or any of the excipients, as well as salicylate and sulphonamide hypersensitivity;
• Children under the age of 2 years;
Patients with porphyria
4.4 Special warnings and precautions for use
Haematological and hepatic side effects may occur. Differential white cell, red cell and platelet counts, liver function tests and assessment of renal function (including urinalysis) should be performed initially and at least at monthly intervals for a minimum of the first three months of treatment. Patients should be counselled to report immediately any development of sore throat, fever, malaise, pallor, purpura, jaundice, or non-specific illness, this may indicate myelosuppression, haemolysis or hepatoxicity; a Patient Information Leaflet should also be supplied to warn patients of this requirement, and of the risks of serious blood dyscrasias. Treatment should be stopped immediately if there is suspicion of 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 severe allergy or bronchial asthma should be treated with caution.
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.
Patients with glucose-6-phosphate dehydrogenase deficiency should be closely observed for signs of haemolytic anaemia (Heinz body anaemia).
Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency 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.
The drug may colour the urine orange yellow. Extended wear soft lenses have been reported as being permanently stained during Sulfasalazine treatment. Daily wear soft contact and glass permeable lenses should respond to standard cleaning.
Oligospermia and infertility may occur in men treated with sulfasalazine. Discontinuation of the drug appears to reverse these effects within 2 to 3 months.
4.5 Interaction with other medicinal products and other forms of interaction
Digoxin and folate uptake may be reduced, resulting in non-therapeutic serum levels.
Sulfonamides bear certain chemical similarities to some oral hypoglycaemic agents. Hypoglycaemia has occurred in patients receiving sulfonamides. Patients receiving sulfasalazine and hypoglycaemic agents should be closely monitored.
Due to inhibition of thiopurine methyltransferase by sulfasalazine, bone marrow suppression and leucopenia have been reported when the thiopurine 6-mercaptopurine or its pro-drug, azathioprine, and oral sulfasalazine were used concomitantly.
Co-administration 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.
In patients with porphyria, an acute attack may be precipitated.
Concomitant antibiotic therapy may alter the patient’s response to sulfasalazine.
4.6 Pregnancy and lactation
Pregnancy:
Extensive clinical usage has not revealed any teratogenic effects. 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.
The physician should, however, decide whether or not to use the drug during pregnancy based on the clinical condition of the patient.
Lactation:
Although sulfasalazine and sulfapyridine are found in low levels in breast milk this should not present a risk to a healthy infant. Caution should be used in breastfeeding premature infants and, as sulphonamides may cause haemolytic anaemia, in glucose-6-phosphate dehydrogenase (G6PD) deficient neonates.
4.7 Effects on ability to drive and use machines
None known
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.
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 adverse effects due to sulphapyridine. The most commonly encountered ADRs are nausea, headache, rash, loss of appetite and raised temperature.
The following adverse reactions have been reported with the frequencies;
Very common (> 1/10)
Common (> 1/100 to < 1/10)
Uncommon (> 1/1000 to < 1/100)
Not known frequency cannot be estimated from the available data
Infections and infestations:
Not known: Pseudomembranous colitis
Blood and the lymphatic system disorders:
Common: Leucopenia
Uncommon: Thrombocytopenia
Not known: Agranulocytosis, aplastic anemia, haemolytic anemia, Heinz body
anaemia, hypoprothrombinaemia, lymphadenopathy, macrocytosis, megaloblastic anemia, methaemoglobinaemina, neutropenia, pancytopenia
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.
Immune system disorders:
Not known: Hypersensitivity reactions including; anaphylaxis, epidermal
necrolysis, exfoliative dermatitis, photosensitisation, polyarteritis nodosa, pruritus, rash, serum sickness, urticaria
Metabolism and nutrition:
Not known: Loss of appetite
Psychiatric disorders:
Common: Insomnia
Uncommon: Mental depression
Not known: Hallucinations
Nervous system disorders:
Common: Dizziness, headache, taste disorders
Uncommon: Convulsions
Not known: Aseptic meningitis, ataxia, encephalopathy, peripheral neuropathy,
smell disorders
Eye disorders:
Common: Conjunctival and scleral injection
Not known: Ocular complications including periorbital oedema, some soft contact
lenses may be stained
Ear and labyrinth disorders:
Common: Tinnitus
Uncommon: Vertigo
Cardiac disorders:
Not known: Allergic myocarditis, cyanosis, pericarditis
Vascular disorders:
Uncommon: Vasculitis
Respiratory, thoracic and mediastinal disorders:
Cough Dyspnoea
Common:
Uncommon:
Not known: Eosinophilia, fibrosing alveolitis, LE-phenomenon and interstitial
lung disease
Gastrointestinal disorders:
Very common: Gastric distress, nausea
Common: Abdominal pain, diarrhoea, vomiting, stomatitis
Not known: exacerbation of symptoms of colitis, acute pancreatitis, parotitis
Hepato-biliary disorders:
Not known: Hepatic failure, fulminant hepatitis, hepatitis
Skin and subcutaneous tissue disorders:
Common: Pruritis
Uncommon: Alopecia, urticaria
Not known: Lupus erythematosus-like syndrome, epidermal necrolysis (Lyell's
syndrome), Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), toxic pustuloderma, erythema, exanthema, exfoliative dermatitis, periorbital oedema, lichen planus, photosensitivity
Musculoskeletal, connective tissue and bone disorders:
Common: Arthralgia
Not known: Myalgia, systemic lupus erythematosus
Renal and urinary disorders:
Common: Proteinuria
Not known: Crystalluria, haematuria, renal dysfunction (interstitial nephritis,
nephrotic syndrome) and urine may be coloured orange
Reproductive system and breast disorders:
Not known: Oligospermia (reversible on discontinuance of drug)
General disorders and administrative site disorders:
Uncommon: Facial oedema
Not known: Drug fever, raised temperature, yellow discolouration of skin and
body fluids
Investigations:
Uncommon: Elevation of liver enzymes
Not known: Induction of autoantibodies
4.9 Overdose
Gastric lavage, correction of any electrolyte imbalance and supportive treatment. There is no specific antidote. Severe crystalluria, if occurred, should be treated accordingly.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Sulfasalazine is a chemical combination of sulfapyridine and 5-amino salicylic acid (mesalazine). Activity resides in the mesalazine moiety; sulfapyridine acts only as a carrier to the colonic site of action (in inflammatory bowel disease) where the di-azo bond linking the two moeities is broken by colonic bacteria. The exact mechanism of action of the anti-inflammatory effect of mesalazine is unknown.
Sulfasalazine was initially introduced for the treatment of rheumatoid arthritis and recent evaluation has confirmed that it has a beneficial effect in suppressing the inflammatory activity of the disease.
5.2 Pharmacokinetic properties
Sulfasalazine is partly absorbed from the small intestine and may later enter the enterohepatic circulation; the majority of the dose passes to the colon where it is broken down by bacteria to sulphapyridine and 5-aminosalicylic acid.
Most of the sulfasalazine is absorbed together with its metabolites and appears in the blood 3-6 hours after a single dose, with a mean peak serum concentration for sulfapyridine of 21 micrograms/ml at 12 hours.
Up to 10% of a dose of sulfasalazine is excreted unchanged and about 60% as sulfapyridine and its metabolites.
The majority of the 5-aminosalicylic acid is eliminated unchanged in the faeces but some appears in the blood; about 20% is excreted in urine unchanged and in the acetylated form.
Sulfasalazine has been claimed to be concentrated in connective tissue.
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 then through a direct genotoxic mechanism. In the mouse study, there was a significant increase in the incidence of heptocellular adenoma or carcinoma. The mechanism of induction of heptocellular neoplasia has been investigated and attributed to species-species 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 pertubation 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 epidemiololgy studies.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Povidone K25
Maize Starch Magnesium Stearate Stearic Acid Crospovidone Purified Water
Methacrylic Acid Copolymer Type C
Triethyl Citrate
Glycerol Monostearate 40-50
6.2 Incompatibilities
None known other than those stated in 4.4 & 4.5
6.3 Shelf life
36 months
6.4 Special precautions for storage
Store below 25°C in a dry place in well closed containers.
6.5. Nature and contents of container
High-density polyethylene containers with polythene closures fitted with desiccant capsule insert within lid and sealed with a thick paper membrane.
Polypropylene or high-density polyethylene with polythene closures and polyurethane wads or polythene inserts.
Pack sizes: 28, 56, 84, 100, 112, 224 500
PVC/aluminium foils blister packs. (250 micron PVC glass-clear/bluish rigid PVC (pharmaceutical grade). 20-micron hard-tempered aluminium foil coated on the dull side with 6-7 gsm heat seal lacquer and printed on the bright side.)
Pack sizes: 28, 56, 84, 100, 112, 224, 500
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special instructions
7 MARKETING AUTHORISATION HOLDER
Chatfield Pharmaceuticals Ltd.
T/A Chatfield Laboratories Kramer Mews London SW5 9JL
8 MARKETING AUTHORISATION NUMBER(S)
PL 02142/0009
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
01/08/1996 / 05/05/2005
10 DATE OF REVISION OF THE TEXT
12/03/2013