Aldactide 25 Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Aldactide 25.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 25 mg Spironolactone BP and 25 mg hydroflumethiazide BP For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Buff, film coated tablets engraved “SEARLE 101” on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Congestive cardiac failure.
4.2 Posology and method of administration
Administration of Aldactide once daily with a meal is recommended.
Posology
Adults
Most patients will require an initial dosage of 100 mg spironolactone daily. The dosage should be adjusted as necessary and may range from 25 mg to 200 mg 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.
Paediatric population
Although clinical trials using Aldactide have not been carried out in children, as a guide, a daily dosage providing 1.5 mg to 3 mg of spironolactone per kilogram body weight given in divided doses, may be employed.
4.3 Contraindications
Hypersensitivity to the active substances or thiazide diuretics or to other sulphonamide derived drugs or to any of the excipients listed in section 6.1.
Aldactide is contraindicated in patients with anuria, acute renal insufficiency, rapidly deteriorating or severe impairment of renal function, hyperkalaemia, significant hypercalcaemia or Addison’s disease.
Aldactide should not be administered with other potassium conserving diuretics and potassium supplements should not be given routinely with Aldactide as hyperkalaemia may be induced.
4.4 Special warnings and precautions for use
Concomitant use of Aldactide with other potassium-sparing diuretics, angiotensinconverting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs, angiotensin II antagonists, aldosterone blockers, heparin, low molecular weight heparin or other drugs or conditions known to cause hyperkalaemia, potassium supplements, a diet rich in potassium, or salt substitutes containing potassium, may lead to severe hyperkalaemia.
Sulfonamide derivatives including thiazides have been reported to exacerbate or activate systemic lupus erythematosus.
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 section 4.3) Hypokalaemia may develop as a result of profound diuresis, particularly when Aldactide is used concomitantly with loop diuretics, glucocorticoids or Adrenocorticotropic Hormone.
Hyponatraemia may be induced especially when Aldactide is administered in combination with other diuretics.
Monitor serum potassium levels when using concomitantly with other drugs known to increase the risk of hypokalaemia induced by thiazide 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.
4.5 Interaction with other medicinal products and other forms of interaction
Other drugs known to cause hyperkalaemia:
Concomitant use of drugs known to cause hyperkalaemia with spironolactone may result in severe hyperkalaemia.
Other antihypertensive drugs
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.
Noradrenaline
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.
Colestyramine and colestipol
The absorption of a number of drugs including thiazides is decreased when co-administered with colestyramine and colestipol.
Lithium
Concurrent use of lithium and thiazides may reduce lithium clearance leading to intoxication. ACE Inhibitors
Since ACE inhibitors decrease aldosterone production they should not routinely be used with Aldactide, particularly in patients with marked renal impairment.
NSAIDs
Non-steroidal anti-inflammatory drugs such as aspirin, indometacin, and mefanamic acid may attentuate the natriuretic efficacy of diuretics due to inhibition of intrarenal synthesis of prostaglandins and have been shown to attenuate the diuretic effect of spironolactone.
Fluorimetric assays
In fluorimetric assays, spironolactone may interfere with the estimation of compounds with similar flourescence characteristics.
Antipyrine
Spironolactone enhances the metabolism of antipyrine.
Calcium and/or vitamin D
Thiazide co-administered with calcium and/or vitamin D may increase the risk of hypercalcaemia. Thiazides may delay the elimination of quinidine.
Digoxin:
Spironolactone has been shown to increase the half-life of digoxin.
Spironolactone can interfere with assays for plasma digoxin concentrations.
Thiazide-induced electrolyte disturbances, i.e. hypokalaemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events. (See section 4.4).
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.
Carbenoxolone
As carbenoxolone may cause sodium retention and thus decrease the effectiveness of Aldactide, concurrent use should be avoided.
Antidiabetic drugs (oral hypoglycaemic agents and insulin):
Dosage adjustments of the antidiabetic drug may be required with thiazides.
Thiazide-induced hyperglycaemia may compromise blood sugar control. Depletion of serum potassium augments glucose intolerance. Monitor glycaemic control, supplement potassium if necessary, to maintain appropriate serum potassium levels, and adjust diabetes medications as required (See section 4.4).
Corticosteroids, ACTH:
Intensified electrolyte depletion, particularly hypokalaemia with thiazides.
Gout medications (allopurinol, uricosurics, xanthine oxidase inhibitors):
Thiazide-induced hyperuricemia may compromise control of gout by allopurinol and probenecid (See section 4.4). The co-administration of hydrochlorothiazide and allopurinol may increase the incidence of hypersensitivity reactions to allopurinol.
4.6 Fertility, pregnancy and lactation
Fertility
Spironolactone
Spironolactone administered to female mice reduced fertility.
Hydroflumethiazide
A different thiazide, hydrochlorothiazide (HCTZ), when administered to mice and rats did not affect fertility.
Pregnancy
Spironolactone
Spironolactone or its metabolites may cross the placental barrier. With spironolactone, feminisation has been observed in male rat foetuses.
There are no studies in pregnant women.
Hydroflumethiazide
HCTZ did not cause reproductive toxicity when administered to pregnant mice or rats. Hydroflumethiazide does cross the placental barrier. Thiazides may decrease placental perfusion, increase uterine inertia and inhibit labour.
There is limited experience with hydroflumethiazide during pregnancy, especially during the first trimester. Based on the pharmacological mechanism of action of thiazides their use during the second and third trimesters may compromise placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydroflumethiazide 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.
Hydroflumethiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.
Breast-feeding
Spironolactone
Canrenone, a major (and active) metabolite of spironolactone appears in human breast milk.
Hydroflumethiazide
Hydroflumethiazide is excreted in human milk in small amounts. Hydrofluemthiazide, when given at high doses, can cause intense diuresis, which can in turn inhibit milk production. The use of Aldactide during breast feeding is not recommended. If Aldactide is used during breast feeding, doses should be kept as low as possible.
4.7 Effects on ability to drive and use machines
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.
4.8 Undesirable effects
The following adverse events have been reported in association with spironolactone/ thiazide therapy:
Neoplasms benign, malignant and unspecified (including cysts and polyps): Benign breast neoplasm
Blood and lymphatic system disorders: Leukopenia, agranulocytosis, thrombocytopenia, blood dyscrasias, aplastic anaemia
Immune system disorders: Anaphylactoid reaction
Metabolism and nutrition disorders: Electrolyte imbalance, hyperkalaemia, hypercalcaemia
Psychiatric disorders: Libido disorder, confusional state, restlessness
Nervous system disorders: Dizziness, headache, paraesthesia
Eye disorders: Xanthopsia
Ear and labyrinth disorders: Vertigo
Vascular disorders: Orthostatic hypotension, necrotising vasculitis Gastrointestinal disorders: Gastrointestinal disorder, nausea, pancreatitis Hepatobiliary disorders: Abnormal hepatic function, jaundice
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, hypertrichosis, photosensitivity reaction, pruritis, rash, urticaria, purpura
Musculoskeleta and connective tissue disorders: Muscle spasms, systemic lupus erythematosus
Renal and urinary disorders: Acute renal failure
Reproductive system and breast disorders: Menstrual disorders, gynaecomastia, breast enlargement, breast pain, erectile dysfunction
General disorders and administration site conditions: Malaise, weakness Investigations: Raised serum lipids
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.
Sulphonamide derivatives including thiazides have been reported to exacerbate or activate systemic lupus erythematosus.
Rarely hypercalcaemia has been reported in association with thiazides, usually in patients with pre-existing metabolic bone disease or parathyroid dysfunction.
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
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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: low-ceiling diuretic, ATC code: C03AA02 Pharmacotherapeutic group: potassium-sparing agents, ATC code C03DA01
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.
Mechanism of action: Spironolactone/hydroflumethiazide is a combination of two diuretic agents with different but complementary mechanisms and sites of action, thereby providing additive diuretic and antihypertensive effects. Additionally, the spironolactone component helps to minimize the potassium loss characteristically induced by the thiazide component.
The diuretic effect of spironolactone is mediated through its action as a specific pharmacologic antagonist of aldosterone, primarily by competitive binding to receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule.
5.2 Pharmacokinetic properties
No pharmacokinetic studies have been performed on spironolactone/ hydroflumethiazide. Pharmacokinetic studies have been performed on the individual component of spironolactone and hydroflumethiazide.
Absorption
Spironolactone
Following oral administration of 500 mg tritiated spironolactone in five healthy male volunteers (fasting state), the total radioactivity in plasma reached a peak between 25 and 40 minutes. Although the absolute bioavailability of spironolactone was not determined, the extent of absorption was estimated to be 75%, as 53% of the dose was excreted in the urine during 6 days and approximately 20% in the bile.
Following oral administration of 100 mg of spironolactone daily for 15 days in non-fasted healthy volunteers, time to peak plasma concentration (tmax) and peak plasma concentration (Cmax) were 2.6 hr. and 80 ng/ml, respectively. For the 7-alpha-(thiomethyl) spironolactone and canrenone metabolites, tmax values were 3.2 hr. and 4.3 hr., respectively; Cmax values were 391 ng/ml and 181 ng/ml, respectively.
Administration with food resulted in higher exposure compared to fasted conditions. Following a single oral dose of 200 mg spironolactone to four healthy volunteers, the mean (± SD) AUC (0 to 24 hours) of the parent drug increased from 288 ± 138 (empty stomach) to 493 ± 105 ng • ml-1 • hr (with food) (p <0.001).
Hydroflumethiazide
Hydroflumethiazide is incompletely but fairly rapidly absorbed from the gastro-intestinal tract.
Distribution
Spironolactone
Approximately 90% of spironolactone was protein bound based on equilibrium dialysis.
Hydroflumethiazide
No pharmacokinetic studies have been performed with hydroflumethiazide in protein binding.
Biotransformation
Spironolactone
Spironolactone is metabolized by both the kidneys and liver. Following deacetylation and S-methylation, spironolactone is converted to 7-a-thiomethylspironolactone, a sulfur-containing active metabolite that is considered the major metabolite of spironolactone in serum. Approximately 30% of spironolactone is also converted to canrenone by dethioacetylation (non-sulfur containing active metabolite).
Hydroflumethiazide
No pharmacokinetic studies have been performed with hydroflumethiazide in biotransformation.
Elimination
Spironolactone
Elimination of metabolites occurs primarily in the urine and secondarily through biliary excretion in the faeces.
In one pharmacokinetic study in five healthy male volunteers receiving 500 mg of spironolactone, 53% (range 47%-57%) of the dose was excreted in the urine within 6 days and the remaining amount could be detected in the faeces (total recovery 90%). In another study of five healthy men, a single dose of spironolactone 200 mg (with radioactive tracer) was administered and in 5 days, 31.6% ± 5.87% of the radioactivity was excreted in the urine mainly as metabolites and 22.7% ± 14.1% in the faeces.
Following oral administration of 100 mg of spironolactone daily for 15 days in non-fasted healthy volunteers, elimination half-life (tJ/2) value for spironolactone was 1.4 hr. For the 7-alpha-(thiomethyl) spironolactone and canrenone metabolites, tJ/2 values were 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
After oral absorption, hydroflumethiazide 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.
Special Populations
No pharmacokinetic studies have been performed with spironolactone/hydroflumethiazide in the elderly or paediatric population or in patients with hepatic or renal insufficiency.
5.3 Preclinical safety data
Spironolactone
Orally administered spironolactone has been shown to be a tumorigen in dietary administration studies performed in Sprague Dawley rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150 and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study using doses of about 10, 30, and 100 mg/kg/day, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females.
In a 12-month study dietary study in rats with potassium canrenoate (a compound chemically similar to spironolactone and whose primary metabolite, canrenone, is also a major product of spironolactone in man) a dose-related (above 30 mg/kg/day) incidence of myelocytic leukemia was observed for a period of 1 year. In 2 year studies in the rats, oral administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular and mammary tumors.
Neither spironolactone nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither spironolactone nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro. In the presence of metabolic activation, spironolactone and canrenoate have been found to be mutagenic, inconclusive or negative in mammalian tests in vitro. In vivo, neither spironolactone nor potassium canrenoate were found to be genotoxic.
Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects. In a continuous breeding study there was a small increase in incidence of stillborn pups but no effects on mating and fertility at 500 mg spironolactone /kg/day. In female rats treatment with spironolactone for 7 days (100 mg/kg i.p), was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a 2-week post-treatment observation period due to retarded ovarian follicle development and a reduction in circulating oestrogen levels. In female mice spironolactone dosed i.p, caused a decrease in the number of mated mice that conceived and a decreased in the number of implanted embryos in those that became pregnant at dosesof 100 mg/kg/day and also increased the latency period to mating at 200 mg/kg. These effects are associated with an inhibition of ovulation and implantation.
No teratogenic or other embryo-toxic effects were observed in mice at doses up to 20 mg/kg however, this dose caused an increased rate of resorption and a lower number of live foetuses in rabbits. On a body surface area basis, 20 mg/kg is either substantially below or approximate to the maximum recommended human dose in mice and rabbits respectively. Because of its antiandrogenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. Following administration of 200 mg/kg/day in rats on gestation Days 13 to 21, feminization of male foetuses was observed. Dose dependent changes to the reproductive tract which persisted into adulthood including decreases in weights of the ventral prostate and seminal vesicle in males, increased ovary and uterus weights in females, and other indications of endocrine dysfunction were seen in offspring exposed to Spironolactone during late pregnancy at 50 and 100 mg/kg/day.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Calcium sulfate dihydrate, corn starch, polyvinyl pyrrolidone, magnesium stearate, felocofix peppermint, hypromellose, polyethylene glycol and opaspray yellow (contains E172 and E171).
6.2 Incompatibilities
None stated.
6.3 Shelf life 5 years.
6.4 Special precautions for storage
Store in a dry place below 30oC.
6.5 Nature and contents of container
Aldactide 25mg tablets may be packaged in the following containers: Amber glass bottles, HDPE containers or PVC/foil blister packs containing 100 and 500 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Pfizer Limited Ramsgate Road Sandwich Kent
CT13 9NJ United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00057/0925
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation:23 May 2002
10 DATE OF REVISION OF THE TEXT
18/05/2015