Aldactide 25.

Aldactide 50.

Each tablet contains 25mg spironolactone BP and 25mg hydroflumethiazide BP

Each tablet contains 50mg spironolactone BP and 50mg hydroflumethiazide BP

Buff, film coated tablets engraved “SEARLE 101” on one side.

Buff, film coated tablets engraved “SEARLE 180” on one side.

Congestive cardiac failure.

Administration of Aldactide once daily with a meal is recommended.

Adults

Most patients will require an initial dosage of 100mg spironolactone daily. The dosage should be adjusted as necessary and may range from 25mg to 200mg spironolactone daily.

Elderly

It is recommended that treatment is started with the lowest dose and titrated upwards as required to achieve maximum benefit. Care should be taken with severe hepatic and renal impairment which may alter drug metabolism and excretion.

Children

Although clinical trials using Aldactide have not been carried out in children, as a guide, a daily dosage providing 1.5 to 3mg of spironolactone per kilogram body weight given in divided doses, may be employed.

Aldactide is contraindicated in patients with anuria, acute renal insufficiency, rapidly deteriorating or severe impairment of renal function, hyperkalaemia, significant hypercalcaemia, Addison's disease and in patients who are hypersensitive to spironolactone, thiazide diuretics or to other sulphonamide derived drugs.

Aldactide should not be administered with other potassium conserving diuretics and potassium supplements should not be given routinely with Aldactide as hyperkalemia may be induced.

Warnings

Sulphonamide derivatives including thiazides have been reported to exacerbate or activate systemic lupus erythematosus.

Precautions

Fluid and electrolyte balance: Fluid and electrolyte status should be regularly monitored particularly in the elderly, in those with significant renal and hepatic impairment, and in patients receiving digoxin and drugs with pro-arrhythmic effects.

Hyperkalaemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities which may be fatal. Should hyperkalaemia develop Aldactide should be discontinued, and if necessary, active measures taken to reduce the serum potassium to normal. . (See 4.3 Contraindications)

Hypokalaemia may develop as a result of profound diuresis, particularly when Aldactide is used concomitantly with loop diuretics, glucocorticoids or ACTH.

Hyponatraemia may be induced especially when Aldactide is administered in combination with other diuretics.

Hepatic impairment: Caution should be observed in patients with acute or severe liver impairment as vigorous diuretic therapy may precipitate encephalopathy in susceptible patients. Regular estimation of serum electrolytes is essential in such patients.

Reversible hyperchloraemic metabolic acidosis usually in association with hyperkalaemia has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.

Urea and uric acid: Reversible increases in blood urea have been reported, particularly accompanying vigorous diuresis or in the presence of impaired renal function.

Thiazides may cause hyperuricaemia and precipitate attacks of gout in some patients.

Diabetes mellitus: Thiazides may aggravate existing diabetes and the insulin requirements may alter. Diabetes mellitus which has been latent may become manifest during thiazide administration.

Hyperlipidaemia: Caution should be observed as thiazides may raise serum lipids.

Spironolactone has been reported to increase serum digoxin concentration and to interfere with certain serum digoxin assays. In patients receiving digoxin and spironolactone the digoxin response should be monitored by means other than serum digoxin concentrations, unless the digoxin assay used has been proven not to be affected by spironolactone therapy. If it proves necessary to adjust the dose of digoxin, patients should be carefully monitored for evidence of enhanced or reduced digoxin effect. Potentiation of the effect of antihypertensive drugs occurs and their dosage may need to be reduced when Aldactide is added to the treatment regime and then adjusted as necessary. Since ACE inhibitors decrease aldosterone production they should not routinely be used with Aldactide, particularly in patients with marked renal impairment.

As carbenoxolone may cause sodium retention and thus decrease the effectiveness of Aldactide , concurrent use should be avoided.

Non-steroidal anti-inflammatory drugs may attentuate the natriuretic efficacy of diuretics due to inhibition of intrarenal synthesis of prostaglandins.

Concurrent use of lithium and thiazides may reduce lithium clearance leading to intoxication.

Spironolactone and thiazides may reduce vascular responsiveness to noradrenaline. Caution should be exercised in the management of patients subjected to regional or general anaesthesia while they are being treated with Aldactide.

Concomitant use of aldactide with other potassium-sparing diuretics, ACE inhibitors, angiotensin II antagonists, aldosterone blockers, potassium supplements, a diet rich in potassium, or salt substitutes containing potassium, may lead to severe hyperkalaemia.

In fluorimetric assays, spironolactone may interfere with the estimation of compounds with similar flourescence characteristics.

Spironolactone has been shown to increase the half-life of digoxin.

Aspirin, indometacin, and mefanamic acid have been shown to attenuate the diuretic effect of spironolactone.

Spironolactone enhances the metabolism of antipyrine.

Spironolactone can interfere with assays for plasma digoxin concentrations

The absorption of a number of drugs including thiazides is decreased when co-administered with colestyramine and colestipol.

Thiazide co-administered with calcium and/or vitamin D may increase the risk of hypercalcaemia. Thiazides may delay the elimination of quinidine.

Pregnancy

Spironolactone or its metabolites may, and hydroflumethiazide does, cross the placental barrier. With spironolactone, feminisation has been observed in male rat foetuses, thiazides may decrease placental perfusion, increase uterine inertia and inhibit labour. In the foetus or neonate thiazides may cause jaundice, thrombocytopenia, hypoglycaemia, electrolyte imbalance and death from maternal complications. The use of Aldactide in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the mother and foetus.

Lactation

Metabolites of spironolactone and hydroflumethiazide, have been detected in breast milk. If use of Aldactide is considered essential, an alternative method of infant feeding should be instituted.

Somnolence and dizziness have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.

Gynaecomastia may develop in association with the use of spironolactone. Development appears to be related to both dosage level and duration of therapy and is normally reversible when the drug is discontinued. In rare instances some breast enlargement may persist.

The following adverse events have been reported in association with spironolactone therapy:

Body as a Whole: malaise

Endocrine Disorders: benign breast neoplasm, breast pain

Gastrointestinal Disorders: gastrointestinal disturbances, nausea

Hematologic Disorders: leukopenia (including agranulocytosis), thrombocytopenia

Liver Disorders: hepatic function abnormal

Metabolic and Nutritional Disorders: electrolyte disturbances, hyperkalemia

Musculoskeletal Disorders: leg cramps

Nervous System Disorders: dizziness

Psychiatric Disorders: changes in libido, confusion

Reproductive Disorders: menstrual disorders

Skin and Appendages: alopecia, hypertrichosis, pruritus, rash, urticaria,

Urinary System Disorders: acute renal failure

The following isolated adverse event has been reported in association with spironolactone therapy:

Skin and Appendages: Stevens Johnson Syndrome

Adverse reactions reported in association with thiazides include: gastrointestinal upsets, skin rashes, photosensitivity, blood dyscrasias, raised serum lipids, aplastic anaemia, purpura muscle cramps, weakness, restlessness, headache, dizziness, vertigo, jaundice, orthostatic hypotension, impotence, paraesthesia, and rarely pancreatitis, necrotising vasculitis and xanthopsia. Rarely hypercalcaemia has been reported in association with thiazides, usually in patients with pre-existing metabolic bone disease or parathyroid dysfunction.

Acute overdosage may be manifested by drowsiness, mental confusion, nausea, vomiting, dizziness or diarrhoea. Hyponatraemia, Hypokalaemia or hyperkalaemia may be induced or hepatic coma may be precipitated in patients with severe liver disease, but these effects are unlikely to be associated with acute overdosage. Symptoms of hyperkalaemia may manifest as paraesthesia, weakness, flaccid paralysis or muscle spasm and may be difficult to distinguish clinically from hypokalaemia. Electro-cardiographic changes are the earliest specific signs of potassium disturbances. No specific antidote has been identified. Improvement may be expected after withdrawal of the drug. General supportive measures including replacement of fluids and electrolytes may be indicated. . For hyperkalaemia, reduce potassium intake, administer potassium-excreting diuretics, intravenous glucose with regular insulin or oral ion-exchange resins.

Spironolactone, as a competitive aldosterone antagonist, increases sodium excretion whilst reducing potassium loss at the distal renal tubule. It has a gradual and prolonged action.

Hydroflumethiazide is a thiazide diuretic. Diuresis is initiated usually within 2 hours and lasts for about 12-18 hours.

Spironolactone is well absorbed orally and is principally metabolised to active metabolites: sulphur containing metabolites (80%) and partly canrenone (20%). Although the plasma half life of spironolactone itself is short (1.3 hours) the half lives of the active metabolites are longer (ranging from 2.8 to 11.2 hours). Elimination of metabolites occurs primarily in the urine and secondarily through biliary excretion in the faeces.

Following the administration of 100 mg of spironolactone daily for 15 days in non-fasted healthy volunteers, time to peak plasma concentration (t_max), peak plasma concentration (C_max), and elimination half-life (t_1/2) for spironolactone is 2.6 hr., 80 ng/ml, and approximately 1.4 hr., respectively. For the 7-alpha-(thiomethyl) spironolactone and canrenone metabolites, t_max was 3.2 hr. and 4.3 hr., C_max was 391 ng/ml and 181 ng/ml, and t_1/2 was 13.8 hr. and 16.5 hr., respectively.

The renal action of a single dose of spironolactone reaches its peak after 7 hours, and activity persists for at least 24 hours

Hydroflumethiazide is incompletely but fairly rapidly absorbed from the gastro-intestinal tract. It appears to have a biphasic biological half-life with an estimated alpha-phase of about 2 hours and an estimated beta-phase of about 17 hours; it has a metabolite with a longer half-life, which is extensively bound to the red blood cells. Hydroflumethiazide is excreted in the urine; its metabolite has also been detected in the urine.

Carcinogenicity: Spironolactone has been shown to produce tumours in rats when administered at high doses over a long period of time. The significance of these findings with respect to clinical use is not certain. However, the long term use of spironolactone in young patients requires careful consideration of the benefits and the potential hazard involved. Spironolactone or its metabolites may cross the placental barrier. With spironolactone, feminisation has been observed in male rat foetuses. The use of Aldactone in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the mother and foetus.

Aldactide 25 and 50 contains: Calcium sulphate dihydrate, corn starch, polyvinyl pyrrolidone, magnesium stearate, felocofix peppermint, hypromellose, polyethylene glycol and opaspray yellow (contains E172 and E171).

None stated.

The shelf life of Aldactide tablets is 5 years.

Store in a dry place below 30°C.

Aldactide 25mg and 50mg tablets may be packaged in the following containers: Amber glass bottles, HDPE containers or PVC/foil blister packs containing 100 and 500 tablets.

There are no special instructions for handling.

Pfizer Limited

Ramsgate Road

Sandwich CT13 9NJ

United Kingdom

Aldactide 25 - PL 00057/0925

Aldactide 50 - PL 00057/0926

Aldactide 25 - 6 July 2002

Aldactide 50 – 23 May 2002

January 2012

POM

Ref: AD 4_0