The drug has low acute per oral toxicity in the absence of hypersensitivity. There is no specific antidote and treatment should be supportive.
Azulfidine EN-tabse is contraindicated in:
- Infants under the age of two years.
- Patients with a known hypersensitivity to Azulfidine EN-tabse, its metabolites or any of the excipients as well as sulfonamides, salicylates or the sodium benzoate preservative.
- Patients with porphyria.
None relevant
Overall, about 75% of ADRs occur within three months of treatment and over 90% by six months. Some unwanted effects are dose-dependent and symptoms can often be alleviated by reduction of the dose.
General
Azulfidine EN-tabse 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 Azulfidine EN-tabse 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); rare (>1/10,000 to <1/1000); very rare (<1/10,000)). 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.
Body System | Adverse drug reactions |
Infections and infestations | |
Not known | Pseudomembranous colitis |
Blood and Lymphatic System Disorders | |
Common | Leukopenia |
Uncommon | Thrombocytopenia* |
Not known | Agranulocytosis, aplastic anemia, haemolytic anemia, Heinz body anaemia, hypoprothrombinaemia, lymphadenopathy, macrocytosis, megaloblastic anemia, methaemoglobinaemina, neutropenia, pancytopenia |
Immune System Disorders: | |
Not known | Anaphylaxis, polyarteritis nodosa, serum sickness |
Metabolism and Nutrition Disorders: | |
Not known | Loss of appetite |
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 |
Eye Disorders: | |
Common | Conjuctivial and scleral injection |
Cardiac Disorders: | |
Not known | Allergic myocarditis, cyanosis, pericarditis |
vascular Disorders: | |
Uncommon | Vasculitis |
Respiratory, Thoracic and Mediastinal Disorders: | |
Common | Cough |
Uncommon | Dyspnoea |
Not known | Fibrosing alveolitis, eosinophilic infiltration, interstitial lung disease |
Gastrointestinal Disorders: | |
Very Common | Gastric distress, nausea |
Common | Abdominal pain, diarrhoea, vomiting, stomatitis |
Not known | Aggravation of ulcerative colitis, pancreatitis, parotitis |
Hepato-biliary Disorders: | |
Not known | Hepatic failure, fulminant hepatitis, hepatitis* |
Skin and Subcutaneous Tissue Disorders: | |
Common | Pruritus |
Uncommon | Alopecia, urticaria |
Very rare | Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported |
Not known | Epidermal necrolysis (Lyell's syndrome), Drug rash with eosinophilia and systemic symptoms (DRESS), toxic pustuloderma, erythema, exanthema, exfoliative dermatitis, periorbital oedema, lichen planus, photosensitivity |
Musculoskeletal and Connective Tissue Disorders: | |
Common | Arthralgia |
Not known | Systemic lupus erythematosus |
Renal and Urinary Disorders: | |
Common | Proteinuria |
Not known | Nephrotic syndrome, interstitial nephritis, crystalluria*, haematuria |
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 |
Investigations: | |
Uncommon | Elevation of liver enzymes |
Not known | Induction of autoantibodies 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. |
In two-year carcinogenicity studies in rats and mice, Azulfidine EN-tabse 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 hepatocellular adenoma or carcinoma. The mechanism of induction of hepatocellular neoplasia has been investigated and attributed to species-specific effects of Azulfidine EN-tabse that are not relevant to humans.
Azulfidine EN-tabse 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, Azulfidine EN-tabse 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 Azulfidine EN-tabse 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, Azulfidine EN-tabse is judged to pose no carcinogenic risk to humans. Azulfidine EN-tabse use has not been associated with the development of neoplasia in human epidemiology studies.
Induction and maintenance of remission of ulcerative colitis and treatment of active Crohn's disease.
Azulfidine EN-tabse has beneficial effects in the treatment of ulcerative colitis and maintenance of remission, and in the treatment of acute Crohn's disease. Around 90% of a dose reaches the colon where bacteria split the drug into sulpyapyridine and mesalazine. These are active, and the unsplit Azulfidine EN-tabse is also active on a variety of systems. Most sulfapyridine is absorbed, hydroxylated or glucuronidated and a mix of unchanged and metabolised sulfapyridine appears in the urine.
Some mesalazine is taken up and acetylated in the colon wall, such that renal excretion is mainly acetyl-mesalazine. Azulfidine EN-tabse 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 Azulfidine EN-tabse is registered for the treatment of rheumatoid arthritis, where the effect resembles penicillamine or gold.
With regard to the use of Azulfidine EN-tabse 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 50µg/ml are associated with a substantial risk of ADRs, especially in slow acetylators.
For Azulfidine EN-tabse given as a single 3g oral dose, peak serum levels of Azulfidine EN-tabse 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 Azulfidine EN-tabse was 7.3 ±1.7ml/min, for sulfapyridine 9.9 ±1.9 and acetyl-mesalazine 100 ±20. Free Azulfidine EN-tabse 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. For mesalazine, only acetyl-mesalazine (not free mesalazine) was demonstrable, the acetylation probably largely achieved in the colon mucosa. After 3g Azulfidine EN-tabse dose lag time was 6.1 ±2.3 hours and plasma levels kept below 2µg/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 125 ml/min corresponding to the GFR. Studies in volunteers suggest that Azulfidine EN-tabse is handled in a similar manner whether given as suspension or tablets.
Complete blood counts, including differential white cell count and liver function tests, should be performed before starting Azulfidine EN-tabse, 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 Azulfidine EN-tabse treatment, this may indicate myelosuppression, haemolysis or hepatoxicity. Treatment should be stopped immediately while awaiting the results of blood tests.
Azulfidine EN-tabse should not be given to patients with impaired hepatic or renal function or with blood dyscrasias, unless the potential benefit outweighs the risk.
Azulfidine EN-tabse 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 Azulfidine EN-tabse is not recommended in these patients.
Since Azulfidine EN-tabse may cause haemolytic anaemia, it should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency.
Oral Azulfidine EN-tabse 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 Azulfidine EN-tabse causes crystalluria and kidney stone formation, adequate fluid intake should be ensured during treatment.
Oligospermia and infertility may occur in men treated with Azulfidine EN-tabse. Discontinuation of the drug appears to reverse these effects within 2 to 3 months.
Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of Azulfidine EN-tabse. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment. If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Azulfidine EN-tabse treatment should be discontinued. The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis. If the patient has developed SJS or TEN with the use of Azulfidine EN-tabse, Azulfidine EN-tabse must not be re-started in this patient at any time.
Azulfidine EN-tabse may colour the urine orange-yellow.
Excipient warnings
This product contains small amounts of ethanol (alcohol), less than 100mg per 5ml.
No specific effects.
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: 20 to 40 ml four times a day may be given in conjunction with steroids as part of an intensive management regime. Rapid passage of the suspension may reduce the effect of the drug.
The night time interval between doses should not exceed 8 hours.
Moderate attacks: 20 ml four times a day may be taken with or without steroids.
Maintenance therapy: With induction of remission, reduce the dose gradually to 40 ml 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.
Children
The dose is reduced in proportion to body weight.
Acute attack or relapse: 0.8 - 1.2 ml/kg/day.
Maintenance dosage: 0.4 - 0.6 ml/kg/day.
B) Crohn's Disease
In active Crohn's Disease, Azulfidine EN-tabse should be administered as in attacks of ulcerative colitis (see above).
Take the suspension with food.
