SPIRONOLACTONE TABLETS BP 50mg – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

SPIRONOLACTONE TABLETS BP 50mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50mg Spironolactone.

Excipient with known effects

Each tablet contains 189.80mg lactose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablets.

Buff-coloured, circular, biconvex film-coated tablets impressed “C” on one face and the identifying letters “SM” on the reverse.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

1. 1) Congestive heart failure
2. 2) Nephrotic syndrome
3. 3) Hepatic cirrhosis with ascites and oedema
4. 4) Malignant ascites
5. 5) The diagnosis and treatment of primary aldosteronism.

Children should only be treated under guidance of a paediatric specialist. There is limited paediatric data available (see sections 5.1 and 5.2).

4.2 Posology and method of administration

Posology

Spironolactone tablets should always be administered with fluid and preferably with food to aid absorption.

Adults

Congestive heart failure with oedema:

For management of oedema an initial daily dose of 100 mg of spironolactone administered in either single or divided doses is recommended, but may range from 25 mg to 200 mg daily. Maintenance dose should be individually determined.

Severe heart failure (New York Heart Association Class III-IV) Based on the Randomized Aldactone Evaluation Study (RALES: see also section 5.1), treatment in conjunction with standard therapy should be initiated at a dose of spironolactone 25 mg once daily if serum potassium is ≤5.0 mEq/L and serum creatinine is ≤2.5 mg/dL. Patients who tolerate 25 mg once daily may have their dose increased to 50 mg once daily as clinically indicated. Patients who do not tolerate 25 mg once daily may have their dose reduced to 25 mg every other day. See section 4.4 for advice on monitoring serum potassium and serum creatinine.

Hepatic cirrhosis with ascites and oedema: If urinary Na⁺/K⁺ ratio is greater than 1.0; 100mg daily. If the ratio is less than 1.0; 200-400mg daily. Maintenance doses should be individually determined.

Malignant ascites: Initial dosage is usually 100-200mg daily. In severe cases the dosage may be gradually increased up to 400mg daily. When oedema is controlled, dosage should be individually determined.

Nephrotic syndrome: Usually 100-200mg daily. Spironolactone has not been shown to be anti-inflammatory, nor to affect the basic pathological process. Its use is only advised if glucocorticoids by themselves are insufficiently effective.

Diagnosis and treatment of primary aldosteronism: Spironolactone may be employed as an initial diagnostic measure to provide presumptive evidence of primary hyperaldosteronism while patients are on normal diets. Long test: Spironolactone is administered at a daily dosage of 400mg for 3-4 weeks. Correction of hypokalaemia and of hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism. Short test: Spironolactone is administered at a daily dosage of 400mg for 4 days. If serum potassium increases during spironolactone administration but drops when spironolactone is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered.

After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures, spironolactone may be administered in doses of 100-400mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, spironolactone may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient.

Elderly

It is recommended that treatment should commence with the lowest dose and be titrated upwards as required in order to achieve maximum benefit. Caution should be exercised in severe hepatic and renal impairment which may alter drug metabolism and excretion.

Paediatric population

Initially daily dosage should provide 1-3mg of spironolactone per kg bodyweight in divided doses. Dosage should be adjusted in accordance with response and tolerance. If necessary the tablets may be crushed and taken dispersed in food or drink (see sections 4.3 and 4.4).

Children should only be treated under guidance of a paediatric specialist. There is limited paediatric data available (see sections 5.1 and 5.2).

Method of Administration

For oral administration.

Administration of Spironolactone tablets once daily with a meal is recommended.

4.3 Contraindications

Spironolactone is contraindicated in adult and paediatric patients with the following:

• acute renal insufficiency, significant renal compromise, anuria
• Addison's disease
• hyperkalaemia
• hypersensitivity to spironolactone or to any of the excipients listed in section 6.1
• concomitant use of eplerenone or other potassium sparing diuretics.
• Spironolactone is contraindicated in paediatric patients with moderate to severe renal impairment.
• Spironolactone tablets should not be administered concurrently with other potassium conserving diuretics and potassium supplements should not be given routinely with Spironolactone tablets as hyperkalaemia may be induced.

4.4 Special warnings and precautions for use

Fluid and electrolyte balance

Fluid and electrolyte status should be regularly monitored particularly in the elderly and in those with significant renal and hepatic impairment.

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, spironolactone should be discontinued, and if necessary, active measures taken to reduce the serum potassium to normal. Dilutional hyponatraemia may be induced especially when spironolactone is concurrently administered with other diuretics (see section 4.3).

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.

Concomitant use of Spironolactone tablets 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.

Care should be taken in patients suffering from hyponatraemia.

Urea

Reversible increases in blood urea have been reported in association with spironolactone therapy, particularly in the presence of impaired renal function.

Hyperkalaemia in Patients with Severe Heart Failure Hyperkalaemia may be fatal. It is critical to monitor and manage serum potassium in patients with severe heart failure receiving spironolactone. Avoid using other potassium-sparing diuretics. Avoid using oral potassium supplements in patients with serum potassium >3.5 mEq/L. The recommended monitoring for potassium and creatinine is 1 week after initiation or increase in dose of spironolactone, monthly for the first 3 months, then quarterly for a year, and then every 6 months. Discontinue or interrupt treatment for serum potassium >5 mEq/L or for serum creatinine >4 mg/dL (see section 4.2).

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.

Caution should be exercised in patients diagnosed with porphyria as spironolactone is considered unsafe in these patients.

Paediatric population

Potassium-sparing diuretics should be used with caution in hypertensive paediatric patients with mild renal insufficiency because of the risk of hyperkalaemia. (Spironolactone is contraindicated for use in paediatric patients with moderate or severe renal impairment; see section 4.3).

Excipients

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose – galactose malabsorption should not take this medicine.

Information on sodium content

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interactions with other medicinal products and other forms of interaction

Abiraterone – Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels in abiraterone-treated prostate cancer patients. Use with abiraterone is not recommended.

Concomitant use of drugs known to cause hyperkalaemia with spironolactone may result in severe hyperkalaemia. In addition, concomitant use of trimethoprim/sulfamethoxazole (co-trimoxazole) with spironolactone may result in clinically relevant hyperkalaemia.

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 spironolactone is added to the treatment regime and then adjusted as necessary. Since ACE inhibitors decrease aldosterone production they should not routinely be used with spironolactone, particularly in patients with marked renal impairment.

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

Non-steroidal anti-inflammatory drugs such as aspirin, indometacin, and mefenamic 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.

Spironolactone reduces 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 spironolactone.

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

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

Spironolactone enhances the metabolism of antipyrine. Spironolactone can interfere with assays for plasma digoxin concentrations.

Spironolactone may reduce mitotane plasma levels in adrenocortical carcinoma patients treated with mitotane and should not be used concomitantly with mitotane.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited data from the use of spironolactone in pregnant women. Studies in animals have shown reproductive toxicity associated with the anti-androgenic effect of spironolactone (see Section 5.3).

Diuretics can lead to reduced perfusion of the placenta and thus to impairment of intrauterine growth and are therefore not recommended for the standard therapy for hypertension and oedema during pregnancy.

Spironolactone should not be used during pregnancy, unless the potential benefit justifies the potential risk.

Breast-feeding

Canrenone, (a major and active) metabolite of spironolactone, is excreted in human milk. There is insufficient information on the effects of spironolactone in newborns/infants. Spironolactone should not be used during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from spironolactone therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Spironolactone administered to female mice reduced fertility (see Section 5.3).

4.7 Effects on ability to drive and use machines

Patients should be warned that they may experience somnolence, dizziness or drowsiness when taking this medicine. They should make sure they are not affected before driving or operating machinery.

System Organ Class

Very

Common ≥ 1/10

Common ≥ 1/100 to <

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)

General

disorders and administration site conditions

Malaise

4.8 Undesirable effects

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 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 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; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Toxic effects of overdosage are drowsiness, mental confusion, nausea, vomiting, dizziness or diarrhoea. Hyponatraemia or hyperkalaemia may be induced but these effects are unlikely to be associated with acute overdosage. Symptoms of hyperkalaemia may manifest as paraesthesia, lassitude and muscular weakness, flaccid paralysis or muscle spasm and may be difficult to distinguish clinically from hypokalaemia.

No specific antidote has been identified. Improvement may be expected on cessation of therapy. Electrocardiographic changes are the earliest specific signs of potassium disturbances. General supportive measures include 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: Potassium-sparing Agents, ATC code: C03D A01

Mechanism of action

Spironolactone is a steroid with a structure resembling that of the natural adrenocorticoid hormone, aldosterone. It acts as a competitive inhibitor of aldosterone and acts on the distal portion of the renal tubule thereby increasing sodium and water excretion and reducing potassium excretion.

It has a gradual and prolonged action.

It is classed as a potassium sparing diuretic or aldosterone antagonist.

Clinical efficacy and safety

Severe Heart Failure

RALES was a multinational, double-blind study in 1663 patients with an ejection fraction of ≤35%, a history of NYHA Class IV heart failure within 6 months, and Class III-IV heart failure at the time of randomization. All patients were taking a loop diuretic, 97% were taking an ACE inhibitor and 78% were on digoxin (at the time this trial was conducted, b-blockers were not widely used to treat heart failure and only 15% were treated with a b-blocker). Patients with a baseline serum creatinine of >2.5 mg/dL or a recent increase of 25% or with a baseline serum potassium of >5.0 mEq/L were excluded. Patients were randomized 1:1 to spironolactone 25 mg orally once daily or matching placebo. Patients who tolerated 25 mg once daily had their dose increased to 50 mg once daily as clinically indicated. Patients who did not tolerate 25 mg once daily had their dosage reduced to 25 mg every other day. The primary endpoint for RALES was time to all-cause mortality. RALES was terminated early, after a mean follow-up of 24 months, because of significant mortality benefit detected on a planned interim analysis. Spironolactone reduced the risk of death by 30% compared to placebo (p<0.001; 95% confidence interval 18% - 40%). Spironolactone also significantly reduced the risk of cardiac death, primarily sudden death and death from progressive heart failure as well as the risk of hospitalization for cardiac causes. Changes in NYHA class were more favourable with spironolactone. Gynaecomastia or breast pain was reported in 10% of men who were treated with spironolactone, as compared with 1% of men in the placebo group (p<0.001). The incidence of serious hyperkalaemia was low in both groups of patients.

Paediatric population

There is a lack of substantive information from clinical studies on spironolactone in children. This is a result of several factors: the few trials that have been performed in the paediatric population, the use of spironolactone in combination with other agents, the small numbers of patients evaluated in each trial and the different indications studied. The dosage recommendations for paediatrics are based upon clinical experience and case studies documented in the scientific literature.

5.2 Pharmacokinetic properties

Spironolactone is well absorbed orally and is principally metabolised to active metabolites: sulfur 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.

Paediatric population

There are no pharmacokinetic data available in respect of use in paediatric population. The dosage recommendations for paediatrics are based upon clinical experience and case studies documented in the scientific literature.

5.3 Preclinical safety data

Spironolactone has been shown to be tumourigenic 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 known.

Nonclinical data reveal no evidence of teratogenicity, but embryo-foetal toxicity has been seen in rabbits, and an anti-androgenic effect in rat offspring has raised concern about possible adverse effects on male genital development. Endocrine disrupting effects have also been observed in female rodents at clinically relevant exposures. In adult rats, spironolactone was found to increase the length of the estrous cycle, and in female offspring exposed late in pregnancy, endocrine dysfunction persisting to adulthood was observed. In mice spironolactone inhibited ovulation and implantation, thereby decreasing fertility. The clinical relevance of these findings is unknown.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The tablets also contain: lactose, magnesium stearate, maize starch, microcrystalline cellulose, peppermint flavour, polyvidone, sodium starch glycollate and purified water.

The film coating contains: iron oxide red (E172), iron oxide yellow (E172), methylhydroxypropylcellulose (E5) (E464), propylene glycol, purified water and titanium dioxide (E171).

6.2. Incompatibilities

None known.

6.3. Shelf life

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

6.4. Special precautions for storage

Blister packs

Do not store above 25ºC

Store in the original package

Keep container in the outer carton

Polypropylene containers, polyethylene containers and amber glass bottles

Do not store above 25°C

Store in the original container

Keep the container tightly closed

6.5 Nature and contents of container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps.

The product may also be supplied in blister packs in cartons:

1. a) Carton: Printed carton manufactured from white folding box board.
2. b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil.

Pack sizes: 14s, 20s, 28s, 30s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s, 500s

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Accord-UK Ltd

(Trading style: Accord)

Whiddon Valley

Barnstaple

Devon

EX32 8NS

8 MARKETING AUTHORISATION NUMBER(S)

PL 0142/0369

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorization: 15 December 1993

Date of latest renewal: 21 December 2004

10 DATE OF REVISION OF THE TEXT

05/02/2026