This information is intended for use by health professionals

1. Name of the medicinal product

Aldactide 25 mg/25 mg film-coated tablets

2. Qualitative and quantitative composition

Each tablet contains 25 mg spironolactone and 25 mg hydroflumethiazide

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

Buff, biconvex tablets, approximately 9.5 mm in diameter and engraved “SEARLE 101” on one side.

4. Clinical particulars
4.1 Therapeutic indications

Congestive cardiac failure.

4.2 Posology and method of administration

Posology

Adults

Most patients will require an initial dosage of 100mg 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.

Method of administration

Administration of Aldactide once daily with a meal is recommended.

4.3 Contraindications

Hypersensitivity to the active substances or thiazide diuretics or to other sulfonamide 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, angiotensin-converting 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 hyperuricemia 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.

Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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.

Cholestyramine and colestipol

The absorption of a number of drugs including thiazides is decreased when co-administered with cholestyramine 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 attenuate 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 fluorescence 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 trimester 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. Hydroflumethiazide, 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:

System Organ Class

Very Common

≥ 1/10

Common

≥ 1/100 to < 1/10

Uncommon

≥ 1/1,000 to < 1/100

Rare

≥ 1/10,000 to < 1/1,000

Very Rare

< 1/10,000

Frequency not known (cannot be estimated from the available data)

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Benign breast neoplasm (male)

Blood and lymphatic system disorders

Agranulocytosis, Leukopenia, Thrombocytopenia, Blood dyscrasias, Aplastic anaemia

Immune system disorders

Anaphylactoid reaction

Metabolism and nutrition disorders

Hyperkalaemia

Electrolyte imbalance

Hypercalcaemia

Psychiatric disorders

Confusional state

Libido disorder, Restlessness

Nervous system disorders

Dizziness, Headache

Paraesthesia

Eye disorders

Angle closure glaucoma, Acute myopia, Xanthopsia

Gastrointestinal disorders

Diarrhoea, Vomiting, Nausea, Abdominal pain

Pancreatitis

Gastrointestinal disorder

Hepatobiliary disorders

Jaundice cholestatic, Hepatic function abnormal

Skin and subcutaneous tissue disorders

Pruritus, Rash

Photosensitivity reaction, Dermatitis, Urticaria

Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), Drug reaction with eosinophilia and systemic symptoms (DRESS), Alopecia, Hypertrichosis, Purpura

Musculoskeletal and connective tissue disorders

Muscle spasms

Systemic lupus erythematosus

Renal and urinary disorders

Acute kidney injury

Reproductive system and breast disorders

Gynaecomastia, Breast pain (male)a

Menstrual disorder, Breast pain (female)b

Breast enlargement, Erectile dysfunction

General disorders and administration site conditions

Pyrexia, Asthenia, Malaise

Ear and labyrinth disorders

Vertigo

Vascular disorders

Orthostatic hypotension, Necrotising vasculitis

Investigations

Raised serum lipids

Abbreviations: CDS = Core Data Sheet; F= female; LLT = lower level term; M = male; PT = preferred term; WHO-ART = World Health Organization-Adverse Drug Reaction Terminology

aThe term Breast pain is mapped from CDS and the frequency is derived from the WHO-ART term Breast pain (M); however, Breast pain male is the LLT.

bBreast pain is the PT from CDS and the frequency is derived from the WHO-ART term Breast pain (F).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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-α-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% to 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 (t1/2) value for spironolactone was 1.4 hr. For the 7-alpha-(thiomethyl) spironolactone and canrenone metabolites, t1/2 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 tumours 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 leukaemia was observed for a period of 1 year. In 2 year studies in rats, oral administration of potassium canrenoate was associated with myelocytic leukaemia and hepatic, thyroid, testicular and mammary tumours.

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 doses of 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 anti-androgenic 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

Opaspray yellow (contains iron oxides/hydroxides (E172) and titanium dioxide (E171))

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

Store below 30°C.

6.5 Nature and contents of container

Aldactide 25 mg/25 mg 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 and other handling

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: 06 July 2002

10. Date of revision of the text

05/2019

Ref: AD 10_2