Summary of medicine characteristics - ALDACTONE 50 MG FILM-COATED TABLETS
1. NAME OF THE MEDICINAL PRODUCT
Aldactone 50 mg Film-coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 50mg spironolactone BP
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
3. PHARMACEUTICAL FORMFilm-coated Tablets
White film-coated tablets with “SEARLE 916” engraved on one side.
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
Congestive cardiac failure
Hepatic cirrhosis with ascites and oedema.
Malignant ascites
Nephrotic syndrome.
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
Adults
Congestive cardiac 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.
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.
If urinary Na+/K+ ratio is greater than 1.0, 100 mg/day. If the ratio is less than 1.0, 200 mg/day to 400 mg/day. Maintenance dosage should be individually determined.
Initial dose usually 100 mg/day to 200 mg/day. In severe cases the dosage may be gradually increased up to 400 mg/day. When oedema is controlled, maintenance dosage should be individually determined.
Usual dose 100 mg/day to 200 mg/day. Spironolactone has not been shown to be antiinflammatory, nor to affect the basic pathological process. Its use is only advised if glucocorticoids by themselves are insufficiently effective.
Aldactone may be employed as an initial diagnostic measure to provide presumptive evidence of primary hyperaldosteronism while patients are on normal diets.
Long test: Aldactone is administered at a daily dosage of 400 mg for 3 to 4 weeks. Correction of hypokalaemia and hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism.
Short test: Aldactone is administered at a daily dosage of 400 mg for 4 days. If serum potassium increases during Aldactone administration but drops when Aldactone is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered.
After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures, Aldactone may be administered at doses of 100 mg to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, Aldactone may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient.
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.
Initial daily dosage should provide 1–3 mg of spironolactone per kilogram body weight given in divided doses. Dosage should be adjusted on the basis of response and tolerance (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).
Administration of Aldactone 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.
Aldactone should not be administered concurrently with other potassium conserving diuretics and potassium supplements should not be given routinely with Aldactone as hyperkalaemia may be induced.
4.4 Special warnings and precautions for useFluid and electrolyte balance
Fluid and electrolyte status should be regularly monitored particularly in the elderly, 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 Aldactone should be discontinued, and if necessary, active measures taken to reduce the serum potassium to normal (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 Aldactone 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.
Reversible increases in blood urea have been reported in association with Aldactone therapy, particularly in the presence of impaired renal function.
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).
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).
4.5 Interaction with other medicinal products and other forms of interaction
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 Aldactone is added to the treatment regime and then adjusted as necessary. Since ACE inhibitors decrease aldosterone production they should not routinely be used with Aldactone, particularly in patients with marked renal impairment.
As carbenoxolone may cause sodium retention and thus decrease the effectiveness of Aldactone concurrent use should be avoided.
Non-steroidal anti-inflammatory drugs such as aspirin, indomethacin, 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 Aldactone.
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 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.
4.6 Fertility, pregnancy and lactation
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.
Metabolites of spironolactone have been detected in breast milk. If use of Aldactone is considered essential, an alternative method of infant feeding should be instituted.
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
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:
| System Organ Class | Very Common 1 1/10 | Common 1 1/100 to < 1/10 | Uncommo n 1 1/1,000 to < 1/100 | Rare 1 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 | Agranulocytos is, Leukopenia, Thrombocyto penia | |||||
| Metabolism and nutrition disorders | Hyperkala emia | Electrolyt e imbalance | ||||
| Psychiatric disorders | Confusion al state | Libido disorder | ||||
| Nervous system disorders | Dizziness | |||||
| Gastrointesti nal disorders | Nausea | Gastrointestin al disorder |
| System Organ Class | Very Common 1 1/10 | Common 1 1/100 to < 1/10 | Uncommo n 1 1/1,000 to < 1/100 | Rare 1 1/10,000 to < 1/1,000 | Very Rare < 1/10,000 | Frequency Not Known (cannot be estimated from the available data) |
| Hepatobiliar y disorders | Hepatic function abnormal | |||||
| Skin and subcutaneou s tissue disorders | Pruritus, Rash | Urticaria | Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, Drug reaction with eosinophilia and systemic symptoms (DRESS), Alopecia, Hypertrichosis , Pemphigoid | |||
| Musculoskel etal and connective tissue disorders | Muscle spasms | |||||
| Renal and urinary disorders | Acute kidney injury | |||||
| Reproductiv e system and breast disorders | Gynaecom astia, Breast pain (male)a | Menstrual disorder, Breast pain (female)b | ||||
| General disorders and administratio n site conditions | Malaise | |||||
| Abbreviations: CDS = Core Data Sheet; | f = female; L | LT = 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 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, or hyperkalaemia may be induced , 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. Electrocardiographic 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: potassium-sparing agents, ATC code C03DA01
Mechanism of action
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.
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 (tmax), peak plasma concentration (Cmax), and elimination half-life (t1/2) for spironolactone is 2.6 hr., 80 ng/ml, and approximately 1.4 hr., respectively. For the 7-alpha-(thiomethyl) spironolactone and canrenone metabolites, tmax was 3.2 hr. and 4.3 hr., Cmax was 391 ng/ml and 181 ng/ml, and t1/2 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
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.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Calcium sulfate dihydrate
Corn starch
Polyvinyl pyrrolidone Magnesium stearate Felocofix peppermint Hypromellose Polyethylene glycol
Opaspray white (contains E171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years.
6.4 Special precautions for storage
Do not store above 30oC.
6.5 Nature and contents of container
Amber glass or plastic bottles containing 100 or 500 tablets.
HDPE containers of 50, 100 and 500 tablets.
PVC/foil blister packs containing 100 or 500 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
6.6 Special precautions for disposal and other handlingNo special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements
Pfizer Limited Ramsgate Road Sandwich
Kent, CT13 9NJ United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00057/0929
9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
Date of change of ownership:16 September 2014
Date of latest renewal: 14 February 2002