Sulphasalazine Tablets 500mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Sulfasalazine Tablets 500mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Sulfasalazine 500mg For excipients see 6.1
3. PHARMACEUTICAL FORM
Tablet
Flat, orange-brown bevelled tablets scored on one side and marked MP42 on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
1. Induction and maintenance of remission of ulcerative colitis,
2. Treatment of active Crohn’s disease, (including distal proctocolitis)
3. Rheumatoid Arthritis
4.2 Posology and method of administration
Route of administration: Oral
The dose should be 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, this 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.
When remission occurs maintenance therapy should be commenced.
• Moderate attacks:
2-4 tablets four times a day may be given in conjunction with steroids.
• Maintenance Therapy:
Gradually reduce dose to 4 tablets per day. The dosage should be continued indefinitely to avoid relapse.
Children over 2years:
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:
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 a patient experience nausea, the dose should be reduced to previously tolerated dose for one week and then increased. Alternatively, the total daily dose may be divided and taken three or four times daily.
Children:
Not recommended
4.3 Contraindications
Sulfasalazine is contraindicated in;
• Patients with a know hypersensitivity to sulfasalazine, its metabolites, (as well as salicylates or sulphonamides), or any of the excipients;
• Those with glucose-6-phosphate dehydrogenase deficiency;
• Patients with porphyria;
• Children under the age of 2 years
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.
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. Because the possibility of harm cannot be completely ruled out 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, particularly if breastfeeding premature infants, and, due to the risk of neonatal haemolysis, those deficient in G-6-PD.
4.7. Effects on Ability to Drive and Use Machines
Not Applicable
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 sulfapyridine. 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.
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Immune system disorders: | ||
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Not known: |
Hypersensitivity reactions including; anaphylaxis, necrolysis, exfoliative dermatitis, photosensitisation, nodosa, pruritus, rash, serum sickness, urticaria |
epidermal polyarteritis |
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Metabolism and nutrition: | ||
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Not known: |
Loss of appetite | |
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Psychiatric disorders: | ||
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Common: |
Insomnia | |
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Uncommon: |
Mental depression | |
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Not known: |
Hallucinations | |
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Nervous system |
disorders: | |
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Common: |
Dizziness, headache, taste disorders | |
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Uncommon: |
Convulsions | |
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Not known: |
Aseptic meningitis, ataxia, encephalopathy, peripheral neuropathy, smell disorders | |
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Eye disorders: | ||
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Common: |
Conjunctival and scleral injection | |
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Not known: |
Ocular complications including periorbital oedema, some lenses may be stained |
soft contact |
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Ear and labyrinth disorders: | ||
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Common: |
Tinnitus | |
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Uncommon: |
Vertigo | |
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Cardiac disorders: | ||
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Not known: |
Allergic myocarditis, cyanosis, pericarditis | |
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Vascular disorders: | ||
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Uncommon: |
Vasculitis | |
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Respiratory, thoracic and mediastinal disorders: | ||
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Common: |
Cough | |
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Uncommon: |
Dyspnoea | |
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Not known: |
Eosinophilia, fibrosing alveolitis, LE-phenomenon and interstitial lung disease | |
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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.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic Properties
The sulpha moiety of Sulfasalazine is the analogue of para-aminobenzoic acid, best known for its anti-bacterial activity.
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 sulphapyridine of 21 micrograms/ml at 12 hours. Up to 10% of a dose of Sulfasalazine is excreted unchanged in the urine and about 60% as sulphapyridine and its metabolites.
The majority of the 5-aminosalicylic acid is eliminated unchanged in the faeces but some appears in the urine; 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 epidemiology studies.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Povidone K25 Maize starch Stearic acid Magnesium stearate Crospovidone
6.2. Incompatibilities
Not applicable
6.3. Shelf Life
36 months
6.4. Special Precautions for Storage
a) Container: Do not store above 25°C. Keep the container tightly closed.
b) Blister: Do not store above 25°C. Store in the original package.
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.
PVC / Aluminium foil 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.
Container and Blister packs of 28, 30, 50, 56, 60, 84, 100, 112, 250, 500 & 1000 tablets
6.6. Instruction for Use/Handling
Not Applicable
7 MARKETING AUTHORISATION HOLDER
Metwest Pharmaceuticals Limited 15 Runnelfield Harrow on the Hill Middlesex HA1 3NY United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 17521/0042
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/02/2009
10 DATE OF REVISION OF THE TEXT
13/11/2012