This information is intended for use by health professionals

1. Name of the medicinal product

Sulfadiazine 500mg Tablets

2. Qualitative and quantitative composition

Sulfadiazine 500mg

3. Pharmaceutical form

Tablet

Sulfadiazine tablets are plain white, biconvex tablets, with CP on one face.

4. Clinical particulars
4.1 Therapeutic indications

Sulfadiazine is a short-acting sulphonamide with bacteriostatic activity against a broad spectrum of organisms.

Gram-positive - particularly group A Streptococci and some strains of Streptococcus pneumoniae, Bacillus ant hracis, Nocardia (especially N.asteroides) and, to a lesser extent, Staphylococci and Clostridium perfringens.

Gram-negative - Haemophilus influenzae and H.ducreyi are often sensitive, sensitivity varies among the enterobacteriae-Escherichia coli, Klebsiella, proteus, Salmonella and Serratia and Vibrio cholerae are sometimes sensitive. Other organisms reported to be sensitive include, Actinomyces spP., Brucella, Calymmatobacterium granulomatis, Legionella, Yersinia pestis, Chlamydia, Pseudomonas pseudomallei.

4.2 Posology and method of administration

For oral administration.

Adults and elderly

The initial dose is usually 2-4 grams followed by a maintenance dose of up to 4 grams daily in divided doses for a maximum of seven days.

Dosage reduction may be necessary in renal impairment.

Children

Initially 75mg/kg, followed by a maintenance dose of 150mg/kg daily in divided doses. Maximum of 6 grams daily.

Sulphonamides should not be used for initial treatment of meningococcal meningitis although oral Sulfadiazine may be substituted for parenteral penicillin once susceptibility to sulphonamides has been established.

4.3 Contraindications

Known hypersensitivity to any sulphonamide.

Severe renal or hepatic failure.

Acute porphyria.

Jaundice or blood disorders.

Neonates

Concomitant use with clozapine.

4.4 Special warnings and precautions for use

Caution in elderly, renal or hepatic impairment and jaundice. Use with caution in patients with predisposition to folate deficiency. Sulfonamides inhibit 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). Reactions are more likely in acquired immune deficiency syndrome, lupus erythematosus, glucose-6-phosphate dehydrogenase deficiency or history of allergy or asthma Reactions are more likely in acquired immune deficiency syndrome, lupus erythematosus, glucose-6-phosphate dehydrogenase deficiency or history of allergy or asthma.

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of Sulfadiazine. 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, sulfadiazine 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 Sulfadiazine, Sulfadiazine must not be re-started in this patient at any time.

Full blood counts should be carried out during prolonged therapy with sulfadiazine in order to detect blood dyscrasias (see Section 4.8). Discontinue sulfadiazine treatment immediately if blood disorders develop. Urinalyses with microscopic examination may be required prior to and periodically during treatment to detect crystalluria and/or urinary calculi formation in patients on long-term or high dose therapy and in patients with impaired renal function. To reduce the risk of crystalluria, fluid intake should be high (5-6 pints in 24 hours), to maintain a high urine output (minimum of 1200mL daily). If necessary, the urine may be rendered alkaline to prevent crystallisation of acetyl Sulfadiazine.

4.5 Interaction with other medicinal products and other forms of interaction

Anaesthetics, general: sulphonamides may potentiate the effect of thiopentone anaesthetics.

Anti-infectives: Like other sulphonamides, Sulfadiazine demonstrated synergy with the difolate reductase release inhibitors, pyrimethamine and trimethoprim. Risk of pancytopenia and megloblastic anaemia with concurrent pyrimethamine. Increased risk of crystalluria with methenamine.

Anticoagulants: sulphonamides may potentiate the effects of coumarins, such as warfarin.

Antidiabetics: antidiabetic effect of sulphonylureas, e.g. chlorpropramide and tolbutamide, may be enhanced.

Antiepileptics: sulphonamides may potentiate the effect of phenytoin.

Antipsychotics: avoid concurrent clozapine (increased risk of agranulocytosis); see Section 4.3.

Aspirin: the toxcicty of sulphonamides may be increased by aspirin.

Ciclosporin: plasma ciclosprin concentrations may be reduced; increased risk of nephrotoxicity).

Diuretics: caution should be exercised with diuretics such as thiazide due to the importance of maintaining urinary output; increased risk of crystalluria (see Section 4.4).

Local anaesthetics: antibacterial activity of sulphonamides may be antagonised by benzocaine or tetracaine. The action of sulphonamides may be antagonised by p-aminobenzoic acid (PABA) and compounds derived from it, particularly potassium aminobenzoate and the procaine group of local anaesthetics. There is an increased risk of methaemoglobinaemia when sulphonamides administered with prilocaine

Methotrexate: sulphonamides may potentiate the effect of methotrexate

Oestrogen-containing oral contraceptives: sulphonamides may reduce the contraceptive effect of oestrogen-containing oral contraceptives- additional contraceptive precautions should be taken during treatment and for seven days after stopping.

Potassium aminobenzoate: may antagonise action of sulfadiazine.

Probenecid: sulphonamides are displaced by probenecid. This interaction is theoretical and unlikely to be clinically significant.

Vaccines: antibacterials should be avoided for 3 days before and after oral typhoid vaccination

Interference with diagnostic tests: sulphonamides may produce false-positive Benedict's test for urinary glucose; may interfere with test for urinary urobilinogen.

4.6 Pregnancy and lactation

Pregnancy

There is epidemiological evidence of the safety of Sulfadiazine in human pregnancy, but the clinician should assess the risk benefit factors before recommending Sulfadiazine to pregnant women. There is evidence of embryotoxicity and teratogenicity in animals at high dosage, especially during the first trimester. It is generally considered that sulphonamides are not given late in pregnancy because of the risk of haemolytic anaemia in the newborn. Fear of increased risk of kernicterus in neonates appears to be unfounded. Although kernicterus has been reported in neonates following direct administration of sulphonamides, kernicterus in the neonate following in utero exposure has not been reported.

Lactation

Sulphonamides are excreted in the breast milk in small amounts and should be used with caution in nursing mothers of healthy newborn, ill, stressed or premature infants, or infants with jaundice or hyperbilirubinaemia (risk of kernicterus) and mothers of infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency (risk of haemolytic anaemia). A decision to continue/discontinue breast-feeding or to continue/discontinue therapy with sulfadiazine should be made following careful risk benefit evaluation.

4.7 Effects on ability to drive and use machines

Not known.

4.8 Undesirable effects

These are common to all sulphonamides and more likely in slow acetylators.

Blood and lymphatic system disorders: Occasional blood disorders include, agranulocytosis, aplastic anaemia, thrombocytopenia, leucopenia, neutropenia, hypoprothrombinaemia, eosinophilia; methaemoglobinaemia with cyanosis; rarely, acute haemolytic anaemia (with glucose-6-phosphate dehydrogenase deficiency).

Immune system disorders: hypersensitivity. Hypersensitivity reactions may take the form of fever, rashes, photosensitivity, exfoliative dermatitis, toxic epidermal, necrolysis, urticaria, pruritus, erythema nodosum, erythema multiforme, erythroderma, fixed drug eruption, Stevens-Johnson syndrome, contact dermatitis, systemic lupus erythematosus, serum sickness like syndrome, liver necrosis, hepatitis, hepatomegaly, jaundice, myocarditis, pancreatitis, pulmonary eosinophilia, fibrosing alveolitis, vasculitis, including polyarteritis nodosa, nephrotoxic reactions (interstitial nephritis, tubular necrosis) may result in renal failure. Anaphylaxis is very rare.

Metabolism and nutrition disorders: hypoglycaemia, hypothyroidism.

Psychiatric disorders: depression, psychosis, hallucinations

Nervous system disorders: neurological reactions (including aseptic meningitis, ataxia, benign intracranial hypertension, convulsions, dizziness, vertigo, drowsiness, fatigue, headache, insomnia, peripheral or optic neuropathies).

Ear and labyrinth disorders: tinnitus

Respiratory, thoracic and mediastinal disorders: cough, dyspnoea

Gastrointestinal disorders: Most commonly, nausea, anorexia, vomiting, diarrhoea, stomatitis. Pseudomembranous colitis may occur with alterations in bacterial flora of the gastrointestinal tract. Salivary gland enlargement.

Hepatobiliary disorders: hepatitis, jaundice and kernicterus in premature neonates.

Skin and subcutaneous tissue disorders: purpura, severe cutaneous adverse reactions (SCARS): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4)

Renal and urinary disorders: Crystalluria may occur, with lumbar pain, haematuria, oliguria and anuria. Reduce risk by high fluid intake. Treat by alkalinisation of urine. Increased blood urea and serum creatinine concentrations.

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

Symptoms:

Nausea, diarrhoea.

Treatment.

Continuous forced fluids may be necessary and the urine should be rendered alkaline. Otherwise treatment is symptomatic.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Sulphonamides (including suiphadiazine) are structural analogues and competitive antagonists of p-aminobenzoic acid preventing bacterial utilisation of PABA in the synthesis of folic acid.

5.2 Pharmacokinetic properties

Sulfadiazine is rapidly absorbed from the gastrointestinal tract after oral dosage. Peak blood concentrations are reached within three to six hours, and about 50% is bound to plasma protein.

The serum half-life is about 17 hours, and about 80% of the dose is excreted in the urine within two to three days.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber that are additional to those included in other sections.

6. Pharmaceutical particulars
6.1 List of excipients

Maize starch

Pre-gelatinised starch

Microcrystalline cellulose

Sodium starch glycollate

Talc

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Do not store above 25°C Protected from light.

Store in the original container.

6.5 Nature and contents of container

Polypropylene or polyethylene containers of 500 and 100 tablets.

Polypropylene or polyethylene securipac in cartons of 56 tablets.

6.6 Special precautions for disposal and other handling
7. Marketing authorisation holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

UK

8. Marketing authorisation number(s)

PL 29831/0191

9. Date of first authorisation/renewal of the authorisation

01/05/2008

10. Date of revision of the text

28/09/2015