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Document: spc-doc_PL 20416-0156 change

• spc-doc_PL 00427-0196
• spc-doc_PL 20416-0156
• spc-doc_PL 33414-0109
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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Sulfasalazine 500 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 500 mg of sulfasalazine For excipients see 6.1

3 PHARMACEUTICAL FORM

Tablet.

Yellow-brown, round, normal convex tablets engraved with RL logo on one side, with a breakline and A333 on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Recommended clinical indications

1.    Ulcerative colitis

2.    Crohn's disease

4.2 Posology and method of administration

a) Ulcerative colitis Adults:

Severe attack: 2-4 tablets four times daily 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 eight hours.

Moderate attack: 2-4 tablets four times daily may be given in conjunction with steroids.

Mild attack: 1-2 tablets four times daily, with or without steroids.

Maintenance therapy: following the induction or remission the dose is gradually reduced to 1 tablet four times daily. This dosage should be continued indefinitely, since discontinuance even several years after an acute attack is associated with a four fold increase in risk of relapse.

Children: the dose is reduced in proportion to body weight Acute attack or relapse: 40 - 60 mg / kg / day Maintenance dose: 20 - 30 mg / kg / day

b) Crohn’s Disease

In active Crohn’s disease, sulfasalazine should be administered in the same doses as given in attacks of ulcerative colitis.

4.3 Contra-indications

Hypersensitivity to sulfasalazine, its metabolites or any of the excipients as well as sulfonamides and salicylates.

Infants under 2 years.

Porphyria.

4.4 Special warnings and precautions for use

In the event of serious hypersensitivity and toxic reactions discontinue medication.

Caution should be exercised in patients with history of severe allergy or bronchial asthma and should not be given to patients with hepatic and renal dysfunction or blood dyscrasias, unless the potential benefit outweighs the risk.

Complete blood counts, including differential white cell count, 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 before starting sulfasalazine, and at least monthly for the first 3 months of treatment. Thereafter, monitoring should be performed annually during treatment (more frequently in renal impairment) or as clinically indicated.

Patients should be told to report immediately to their doctors with any unexplained bleeding, bruising, sore throat, fever, malaise, pallor, purpura, jaundice or any unexpected non-specific illness during sulfasalazine treatment, this may indicate myelosuppression, haemolysis or hepatoxicity. Treatment should be stopped immediately while awaiting the results of blood tests if there is suspicion or laboratory evidence of a blood dyscrasia.

Patients taking sulfasalazine should receive a patient information leaflet which specifically warns of the risk of serious blood dyscrasias.

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.

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

Life-threatening cutaneous reactions Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of sulfasalazine.

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, sulfasalazine 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 sulfasalazine, sulfasalazine must not be re-started in this patient at any time.

4.5 Interaction with other medicinal products and other forms of interactions

Concurrent administration of sulfasalazine with anticoagulants such as coumarin or indandione derivatives, hydantoin, phenytoin and oral hypoglycaemic agents may result in it being displaced from protein binding sites and/or their metabolism may be inhibited by sulfonamides resulting in increased or prolonged effects. Dosage adjustments may therefore be necessary when administered concomitantly with sulfasalazine. Hypoglycaemia has occurred in patients receiving sulfonamides. Patients receiving sulfasalazine and hypoglycemic agents should be closely monitored. Absorption of digitalis glycosides (e.g. digoxin) and folic acid is diminished during concomitant administration with sulfasalazine, resulting in nontherapeutic serum levels. Folic acid requirements may therefore, need to be increased. Patients taking digitalis glycosides should be monitored closely. Effects of phenylbutazone may be potentiated when administered concurrently with sulfasalazine, due to its displacement from plasma protein binding sites. Concurrent use of sulfasalazine with ciclosporin increases the risk of nephrotoxicity.

Due to inhibition of thiopurine methyltransferase by sulfasalazine, bone marrow suppression and leucopenia have been reported when the thiopurine 6-mercaptopurine or it's 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.

4.6    Fertility, pregnancy and lactation

Pregnancy

Reproduction studies in rats and rabbits have revealed no evidence of harm to the fetus. Long-term clinical use and experimental studies have failed to reveal any teratogenic or icteric hazards. Sulfonamides cross the placenta and although sulfonamides can displace bilirubin from protein binding sites in the foetal plasma, significant hyperbilirubinemia and kernicterus do not usually occur in the neonate because of maternal hepatic conjugation of bilirubin.

If sulfasalazine is used during pregnancy, the possibility of fetal 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, sulfasalazine should be used during pregnancy only if clearly needed.

Lactation

Sulfonamides are excreted in breast milk, however only approximately 1% of the maternal dose appears in the milk. Patients should avoid breastfeeding while taking this medicine. Although sulfonamides may displace bilirubin from protein-binding sites in the foetal plasma, hyperbilirubinemia does not usually occur except as a remote possibility during the first 2 weeks post partum.

Sulfonamides may cause haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD) deficient neonates. The amount of drug present in the milk should not present a risk to a healthy infant.

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

4.7    Effects on Ability to Drive and Use Machines

None reported.

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 ADRs related to sulfapyridine. The most commonly encountered ADRs are anorexia, nausea, headache, rash 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 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 (potentially fatal)
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 (see section 4.4)
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, skin

	eruptions
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

* 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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

In the event of recent overdosage the stomach should be emptied by aspiration and lavage. If kidney function is adequate, a saline purgative, such as sodium sulphate, 30g in 250 ml of water, may be given to promote peristalsis, and elimination of sulfonamide in the urine may be assisted by giving alkalis and increasing fluid intake.

Severe crystalluria may require ureteric catheterisation and irrigation with warm 2.5% sodium bicarbonate solution. The majority of sulfonamides are metabolised to acetylated derivatives which retain the toxicity of the parent compound. Therefore, active measures such as forced diuresis, haemodialysis, peritoneal dialysis and charcoal haemoperfusion may be required.

The drug has low acute per oral toxicity in the absence of hypersensitivity. There is no specific antidote and treatment should be supportive.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeuticgroup: Intestinal anti-inflammatory agents - aminosalicylic acid and similar agents.

ATC code: A07E C01

Sulfasalazine is degraded by intestinal bacteria to sulfapyridine and 5-aminosalicylic acid. Sulfapyridine does not alter gut flora. Therefore, 5-aminosalicylic acid is thought to be the active moiety and may act at the bowel wall inhibition of prostaglandin synthesis.

5.2    Pharmacokinetic properties

Sulfasalazine is partly absorbed from the small intestine following absorption, it reenters the intestine via the bile and along with the unabsorbed sulfasalazine it is cleaved by colonic bacteria to 5-aminosalicylic acid and sulfapyridine. Most of the sulfapyridine is absorbed and together with its metabolites appears in the blood within 3 to 6 hours in healthy individuals following a single dose, a mean peak serum concentration for sulfapyridine of 21 mcg/ml has been reported at 12 hours. Sulfapyridine is metabolised by acetylation, the rate being genetically determined by hydroxylation and conjugation with glucuronic acid. Sulfapyridine is excreted along with its acetylated metabolites, in the urine. Serum concentrations of sulfapyridine and its metabolites (20-40 mcg/ml) co-relates with therapeutic efficacy. Concentrations greater than 500 mcg/ml may be toxic. Slow acetylators may require a reduction in dose to avoid toxicity. Sulfapyridine and its metabolites appear in the breast milk. Approximately 10% of ingested sulfasalazine is excreted unchanged in the urine, 60% a sulfapyridine and its metabolites. About 25% of the sulfapyridine appears in the faeces of patients with ulcerative colitis. 5-aminosalicylic acid is poorly absorbed. Most of 5-aminosalicylic acid is eliminated unchanged in the faeces. But some appears in the blood mainly in the free form; about 20% excreted unchanged in the urine and in the acetylated form.

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 hepatocellular adenoma or carcinoma. The mechanism of induction of hepatocellular neoplasia has been investigated and attributed to species-specific 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

Iron oxide, yellow (E172)

Povidone

Magnesium stearate

Sodium starch glycollate (Type A)

6.2 Incompatibilities

None reported

6.3    Shelf Life

36 months in containers as packaged for sale 24 months in blister packs as packaged for sale

6.4    Special precautions for storage

Protect from heat, light and moisture

6.5    Nature and Contents of Container

1)    Opaque plastic containers composed of PP tubes and PE made tamper evident closures in pack sizes of 28, 42, 50, 56, 84, 100, 112, 250, 500 and 1000 tablets.

2)    Opaque plastic containers (HDPP or HDPE) with a tamper-evident or child-resistant tamper-evident closure (HDPE) with a packing inclusion of standard