Summary of Product Characteristics (SmPC) - Sulphasalazine tablets 500 mg
1 NAME OF THE MEDICINAL PRODUCT
Sulfasalazine Tablets 500mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 500 mg Sulfasalazine
For the full list of excipients, see section 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
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:
With induction of remission gradually reduce dose to 4 tablets per day. The dosage should be continued indefinitely to avoid relapse, since discontinuance even several years after an acute attack is associated with a four-fold increase in risk of relapse.
Paediatric population (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:
Adults and Elderly:
Commence treatment with 0.5 g daily (one tablet) for one week, thereafter increasing the dose by one tablet each week until one tablet four times a day, or two three times a day are reached, according to tolerance and response, 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. Onset of effect is slow and a marked effect may not be seen for six weeks. A reduction in ESR and C-reactive protein should accompany an improvement in joint mobility.
Children: Not recommended
Route of administration: Oral
4.3 Contraindications
Sulfasalazine is contraindicated in;
- Patients with a known hypersensitivity to sulfasalazine, its metabolites, (as well as salicylates or sulfonamides), or any of the excipients listed in section 6.1;
- Patients with porphyria;
- Children under the age of 2 years
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 at monthly intervals for a minimum of the first three months of treatment. For patients with baseline renal impairment, treatment with sulfasalazine should only be initiated if the benefits are considered to outweigh risk. Thereafter, periodic renal function monitoring should be performed as clinically indicated, especially in the early months of treatment. Treatment should be discontinued if renal function deteriorates. Patients should be counselled to report immediately any development of sore throat, fever, malaise, pallor, purpura, jaundice, or unexpected non-specific illness during sulfasalazine treatment, 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 while awaiting the results of blood tests. Please see Section 4.4 for Interference with laboratory testing.
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.
Severe hypersensitivity reactions may include internal organ involvement, such as hepatitis, nephritis, myocarditis, mononucleosis-like syndrome (i.e., pseudo-mononucleosis), haematological abnormalities (including haematophagic histiocytosis), and/or pneumonitis including eosinophilic infiltration.
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. 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.
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.
Sulfasalazine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
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 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.
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.
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, α-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 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.
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.
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 use of sulfasalazine in pregnant women have revealed no evidence of teratogenic hazards. If sulfasalazine is used during pregnacy, the possibility of foetal harm appears remote. 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 breastfed 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
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 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.
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 know (cannot be estimated from the available data) in the list below.
Body System Adverse drug reactions
Infections and infestations:
Not known: Aseptic meningitis and Pseudomembranous colitis
Blood and the lymphatic system
disorders:
Common: Leukopenia
Uncommon: Thrombocytopenia**
Not known: Agranulocytosis, aplastic anaemia, haemolytic anaemia, Heinz body anaemia, hypoprothrombinaemia, lymphadenopathy, macrocytosis, megaloblastic anaemia, methaemoglobinaemina, neutropenia, pancytopenia, pseudomononucleosis**
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: Anaphylaxis*, polyarteritis nodosa, serum sickness
Metabolism and nutrition:
Common: Loss of appetite
Not known: Folate deficiency**
Psychiatric disorders:
Common: Insomnia
Uncommon: Depression
Not known Hallucinations
Nervous system disorders:
Common: Dizziness, headache, taste disorders Uncommon: Convulsions
Not known: Aseptic meningitis, ataxia, encephalopathy, peripheral neuropathy, smell disorders
Ear and labyrinth disorders:
Common: Tinnitus Uncommon: Vertigo
Cardiac disorders:
Not known: Allergic myocarditis**, cyanosis, pericarditis
Vascular disorders:
Uncommon: Vasculitis
Not known: Pallor**
Respiratory, thoracic and mediastinal disorders:
Common: Cough
Uncommon: Dyspnoea
Not known: Fibrosing alveolitis, eosinophilic infiltration, interstitial lung disease*, oropharyngeal pain**
Gastrointestinal disorders:
Very common: Gastric distress, nausea
Common: Abdominal pain, diarrhoea*, vomiting*, stomatitis Not known: Aggravation of ulcerative colitis*, pancreatitis, parotitis
Hepato-biliary disorders:
Uncommon: Jaundice**
Not known: Hepatic failure*, fulminant hepatitis*, hepatitis**, hepatitis cholestatic*, cholestasis**
Skin and subcutaneous tissue disorders:
Common: Pruritis, purpura**
Uncommon: Alopecia, urticaria
Not known: Epidermal necrolysis (Lyell's syndrome)**, Stevens-Johnson syndrome**, drug rash with eosinophilia and systemic symptoms (DRESS)**, toxic pustuloderma, erythema, exanthema, exfoliative dermatitis**, angioedema*, periorbital oedema, lichen planus, photosensitivity
Musculoskeletal, connective tissue and bone disorders:
Common: Arthralgia
Not known: Systemic lupus erythematosus, Sjogren’s syndrome
Renal and urinary disorders:
Common: Proteinuria
Not known: Nephrolithiasis*, Crystalluria**, haematuria, renal dysfunction (interstitial nephritis, nephrotic syndrome)
Reproductive system and breast disorders:
Not known: Reversible Oligospermia**
General disorders and administrative site disorders:
Common: Fever
Uncommon: Facial oedema
Not known: Yellow discolouration of skin and body fluids*
Investigations:
Uncommon: Elevation of liver enzymes
Not known: Induction of autoantibodies
* ADR identified post-marketing
**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 website 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. Gastric lavage, correction of any electrolyte imbalance and supportive treatment. There is no specific antidote.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC code: A07EC01
Pharmacotherapeutic group: Aminosalicylic acid and similar agents
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 acetyl-mesalazine. SASP is excreted unchanged in the bile and urine. Overall the drug and its metabolites exert immunomodulatory effects, anti-bacterial activity, 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
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 SP over about 50μg/ml are associated with a substantial risk of ADRs, especially in slow acetylators.
For SASP given as a single 3g 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 ±1.7ml/min, for SP 9.9 ±1.9 and acetyl- mesalazine (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 acetyl-mesalazine (AC-ME) (not free mesalazine (ME)) was demonstrable, the acetylation probably largely achieved in the colon mucosa. After a 3g SASP dose lag time was 6.1 ±2.3 hours and plasma levels kept below 2μg/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 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 L51784 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
Povidone K25
Maize starch
Stearic acid
Magnesium stearate
Crospovidone
6.2 Incompatibilities
Not applicable
6.3 Shelf life
For Blister pack:36 months
For Container: 48 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 polyolefin (a combination of polyethylene and polypropylene) lids and PET/Al/PE foil laminated closure liner.
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 Special precautions for disposal and other handling
Not Applicable
7 MARKETING AUTHORISATION HOLDER
Genethics Europe Limited
41 - 43 Klimentos
Klimentos Tower
Nicosia 1061
Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 42976/0026
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
04/02/2009
10 DATE OF REVISION OF THE TEXT
09/12/2024