SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Dyazide 50mg/25mg Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50mg triamterene and 25mg hydrochlorothiazide.

3. PHARMACEUTICAL FORM

Peach-coloured, half-scored, circular tablets bearing the mark E93.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Dyazide is a potassium-conserving diuretic preparation with antihypertensive activity. It is recommended for the treatment of mild to moderate hypertension, alone or in combination with other antihypertensive drugs. It is also indicated in the control of oedema in cardiac failure, cirrhosis of the liver or nephrotic syndrome, and in that associated with corticosteroid treatment.

4.2. Posology and method of administration

Adults Only: In Hypertension: Initially one tablet a day after the morning meal, thereafter adjusted to the patient’s needs. If ‘Dyazide’ is added to already established therapy with another antihypertensive drug, the dosage of the latter should be reduced, and later adjusted if necessary. If another antihypertensive drug is added to ‘Dyazide’ therapy, the dosage of the latter will not normally be reduced.

Adults Only: In Oedema: The usual starting dose is one ‘Dyazide’ tablet twice a day after meals. The optimal dosage may be 3 tablets a day, two after breakfast and one after lunch. Maintenance Dosage: Once a diuresis has been established, dosage should be reduced. Usually one tablet a day, or two tablets on alternate days, will suffice.

A dosage of 4 tablets a day should not be exceeded; at this level adverse reactions such as raised blood urea are more likely.

Elderly: Dosage as above. ‘Dyazide’ has been widely used and is usually well tolerated in patients over the age of 60 years. The normally occurring reduction in glomerular filtration with age should be borne in mind.

Children: Only limited information is available on the use of ‘Dyazide’ in children and, therefore its use in children is not recommended.

4.3 Contra-indications

Do not give ‘Dyazide’ to patients with hyperkalaemia, progressive renal failure, increasing hepatic dysfunction, hypercalcaemia, diabetic ketoacidosis, Addison’s disease or known hypersensitivity to either constituent of the product. Potassium supplements, or other potassium-conserving drugs, including ACE inhibitors, should not be given routinely with ‘Dyazide’.

4.4. Special warnings and special precautions for use

Use ‘Dyazide’ with caution in patients with hepatic or renal insufficiency, and in those predisposed to gout, since both components can elevate uric acid levels. Use with caution with hypotensive agents since an additive effect may result. Since thiazide diuretics can provoke hyperglycaemia and glycosuria; diabetic patients should be treated with care, as should patients with diabetic nephropathy due to increased risk of hyperkalaemia.

It is advisable to monitor blood urea, serum potassium levels and electrolytes periodically. This is important in the elderly, those with renal impairment and those receiving concomitant treatment with NSAIDs (see section 4.8).

Triamterene and thiazides reduce excretion of lithium and may thus precipitate intoxication.

Very rare cases of systemic lupus erythematosus (SLE) have been reported associated with ‘Dyazide’. Pancreatitis may be aggravated.

Combinations of folate antagonists and triamterene are not advisable in pregnancy or in patients with hepatic cirrhosis because of the increased theoretical risk of folate deficiency developing.

Triamterene may cause a blue fluorescence of the urine under certain light conditions.

‘Dyazide’ interferes with some laboratory tests of thyroid and parathyroid functions, and bioassay of folic acid.

4.5. Interactions with other medicinal products and other forms of interaction

Analgesics: It is advisable to monitor blood urea and serum potassium levels periodically in patients receiving concomitant treatment with NSAIDs. Renal failure, reversible on stopping treatment, has been reported very rarely which may be due to a reaction between triamterene and some NSAIDs. There have been occasional reports of decreased renal function when indometacin is given with triamterene, hence concomitant use should be avoided. NSAIDs may also antagonise the diuretic action of triamterene and hydrochlorothiazide. An increased risk of hyperkalemia also exists when NSAIDs are used concomitantly with triamterene.

Anion Exchange Resins: Colestyramine and colestipol reduce the absorption of thiazides and if administered should be taken at least two hours apart.

Antidepressants: When co-administered with reboxetine there is an increased risk of hypokalaemia. There is an increased risk of postural hypotension with tricyclics. An enhanced hypotensive effect may also occur when given in conjunction with MAOIs.

Antidiabetics: Hypoglycaemic effect may be antagonised by thiazide diuretics. Chlorpropamide increases the risk of hyponatraemia associated with thiazides in combination with potassium sparing diuretics. When used in conjunction with sulphonylureas, the dosage of the hypoglycaemic agent may require upward adjustment.

Antifungals: There is an increased risk of hypokalaemia if thiazides are given with amphotericin. Hydrochlorothiazide increases the plasma concentration of fluconazole.

Antihypertensives: ‘Dyazide’ may enhance the effect of other antihypertensive drugs. There is an enhanced hypotensive effect and an increased risk of first-dose hypotensive effect of post-synaptic alpha-blockers such as prazosin. ‘Dyazide’ should be used with caution in conjunction with ACE inhibitors or Angiotensin II receptor antagonists due to an increased risk of hyperkalaemia with potassium sparing diuretics.

Antipsychotics: Hypokalemia increases risk of ventricular arrhythmias with pimozide or thioridazine (avoid concomitant use) and with amisulpride and sertindole.

Calcium Salts: Concurrent administration with thiazides increases the risk of hypercalcaemia.

Cardiac Glycosides and Antiarrhythmic Drugs: Increased toxicity if hypokalaemia occurs with thiazide.

Ciclosporin: An increased risk of hyperkalemia exists when used with triamterene.

Corticosteroids: Use with caution in conjunction with corticosteroids, since an additive effect may result in excess potassium loss and an increased risk of hypokalaemia. Corticosteroids are also reported to antagonise the diuretic effect.

Cytotoxics: Increased risk of nephrotoxicity and ototoxicity has been reported with platinum compounds like cisplatin.

Other Diuretics: An increased risk of hypokalaemia if acetazolamide, loop diuretics or thiazides are given together.

Lithium: Triamterene and thiazides reduce excretion of lithium and may thus precipitate intoxication.

Muscle Relaxants: Enhanced hypotensive effect with baclofen and tizanidine.

Oestrogens andProgestogens: Oestrogens and combined oral contraceptives antagonise diuretic effect. Possible hyperkalemia may occur with potassium sparing diuretics.

Potassium Supplements: An increased risk of hyperkalaemia exists with concomitant triamterene use.

Sympathomimetics: There is an increased risk of hypokalaemia if thiazides are taken with high doses of bambuterol, fenoterol, eformoterol, ritodrine, salbutamol, salmeterol and terbutaline.

Tacrolimus: Increased risk of hyperkalemia with potassium sparing diuretics.

Theophylline: If taken with thiazides, there is an increased risk of hypokalaemia.

Ulcer Healing Drugs: Such as carbenoxolone antagonises the diuretic effect concurrent administration with thiazides inceases the risk of hypokalaemia.

Vitamin D: The risk of hypercalcaemia is increased if thiazides are taken with Vitamin D.

4.6 Fertility, pregnancy and lactation

Pregnancy

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.-

Triamterene

There is no clinical evidence to suggest any associated hazards to the foetus, However triamterene has been found to cross the placenta in humans. Nevertheless, drugs should be avoided in pregnancy unless essential, especially during the first trimester.

Breast feeding

Hydrochlorothiazide

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Dyazide during breast feeding is not recommended. However due to the triamterene component Dyazide should not be used during breast feeding.

Triamterene

Triamterene may appear in the breast milk, and if the drug is essential, the patient should stop breastfeeding.

4.7. Effects on ability to drive and use machines

There are no known effects of ‘Dyazide’ on the ability to drive and operate machinery.

4.8 Undesirable effects

Nausea, vomiting, diarrhoea, muscle cramps, weakness, dizziness, headache, dry mouth, thirst, undesirable decrease in blood pressure, and rash have been reported. Photosensitivity and systemic lupus erythemayosus (SLE) have also been rarely reported. Anaphylaxis is a remote possibility.

Minor serum electrolyte changes have been observed infrequently, and marked fluctuations in serum potassium levels are uncommon. Long-term use has confinned that little change occurs in serum potassium and sodium levels in most patients. Metabolic acidosis occasionally occurs. Electrolyte imbalance may also indicate excessive dosage or be secondary to the condition under treatment. Hyperglycaemia, increased uric acid levels which sometimes lead to gout, and hypercalcaemia that does not lead to tertiary hyperparathyroidism may also occur

In common with most other diuretics, ‘Dyazide’ may reduce glomerular filtration rate and cause a temporary increase in blood urea and creatinine levels; again this may also indicate excessive dosage or be secondary to the condition under treatment: it can also cause increases in plasma lipid levels.

Renal failure, reversible on stopping treatment, has been reported very rarely and has been due to acute interstitial nephritis or an interaction between triamterene and some NSAIDs.

Triamterene has been found in renal stones both alone and in association with other usual calculus components. There is no evidence that stone formation is increased in patients taking triamterene containing drugs.

Rare cases of thrombocytopenic purpura and megaloblastic anaemia have been reported with triamterene; thiazides alone have caused jaundice, acute pancreatitis and, rarely, blood dyscrasias including agranulocytosis, thrombocytopenia and leucopenia.

Acute interstitial pneumonitis and pulmonary oedema of non-cardiac origin have been reported very rarely.

Reporting of side effects

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 of electrolyte imbalance, especially hyperkalaemia, are likely. Symptoms include nausea, vomiting, weakness, lassitude, muscular weakness, hypotension and cardiac arrhythmias. Treatment consists of gastric lavage with careful monitoring of electrolytes and fluid balance. Cardiac rhythm should be monitored and appropriate measures taken to correct hyperkalaemia as necessary. There is no specific antidote. Renal dialysis may be of some benefit in cases of severe overdosage.

PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

The product contains triamterene and hydrochlorothiazide.

Triamterene is a potassium conserving diuretic thought to act by directly inhibiting the exchange of sodium for potassium and hydrogen in the distal renal tubule.

Hydrochlorothiazide is a thiazide diuretic which reduces the reabsorption of electrolytes from the renal tubules, thereby increasing the excretion of sodium and chloride ions, and consequently of water. Potassium ions are excreted to a lesser extent.

5.2. Pharmacokinetic properties

Onset of diuresis takes place within one hour, peaks at two to three hours and tapers off during the subsequent seven to nine hours.

Triamterene is incompletely but fairly rapidly absorbed from the gastrointestinal tract. It has been estimated to have a plasma half-life of about two hours. It is extensively metabolised and is mainly excreted in the form of metabolites with some unchanged triamterene; variable amounts are also excreted in the bile.

Hydrochlorothiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract. It is excreted unchanged in the urine.

5.3. Pre-clinical safety data

Long term carcinogenicity studies have not been conducted with Dyazide, the hydrochlorothiazide /triamterene combination. In two year feeding studies with triamterene in rodents there was some evidence of an increase in the incidence of liver tumours, including carcinoma, in both sexes of mice and in male rats. The relevance of this finding to humans is unknown.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Core:

Maize Starch Povidone 30 Sodium Lauryl Sulphate FD & C Yellow No.6 (E110)

Purified water

Coating:

Maize Starch

Sodium Starch Glycollate

Magnesium Stearate

6.2.    Incompatibilities

Not applicable.

6.3.    Shelf life

‘Dyazide’ tablets have a shelf-life of five years.

6.4.    Special precautions for storage

There are no special storage requirements.

6.5.    Nature and content of container

Opaque blister packs containing either 15, 30 or 60 tablets.

Securitainers, polythene vials or amber glass bottles containing either 20, 100, 500 or 1000 tablets.

6.6.    Instructions for use, handling and disposal

None.

7    MARKETING AUTHORISATION HOLDER

Mercury Pharmaceuticals Ltd No. 1 Croydon,

12-16 Addiscombe Road,

Croydon CR0 0XT, UK

MARKETING AUTHORISATION NUMBER

PL 12762/0042

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

8 May 2000

10 DATE OF REVISION OF THE TEXT

07/01/2014