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

NOTE

Urospir 50 mg/5 ml Oral Solution is only suitable for administration of single doses up to 100 mg (10 ml) and up to 200 mg/day in two equally divided doses (10 ml twice a day). When doses more than 200 mg/day are required, other suitable spironolactone formulations should be used.

Urospir is not bioequivalent to the innovator tablet. Switching between spironolactone tablets or other spironolactone products and this formulation should be avoided if possible. If a switch is necessary, caution and increased clinical supervision are required. Refer to Section 5.2.

Posology

Adults

Congestive cardiac failure with oedema

For management of oedema an initial daily dose of 100 mg (10 ml) of spironolactone administered in either single or divided doses is recommended, but may range from 25 mg (2.5 ml) to 200 mg daily (10 ml twice a day). 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 (2.5 ml) 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 (5 ml) 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, 100 mg (10 ml)/day. If the ratio is less than 1.0, 200 mg/day (10 ml twice a day) to 400 mg/day (use a suitable spironolactone formulation; see NOTE above). Maintenance dosage should be individually determined.

Malignant ascites

Initial dose usually 100 mg (10 ml)/day to 200 mg/day (10 ml twice a day). In severe cases the dosage may be gradually increased up to 400 mg/day (use a suitable spironolactone formulation; see NOTE above). When oedema is controlled, maintenance dosage should be individually determined.

Nephrotic syndrome

Usual dose 100 mg (10 ml)/day to 200 mg/day (10 ml twice a day). 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. As the tests require daily doses higher than 200 mg, other suitable spironolactone formulations should be used; see NOTE above.

Long test: Spironolactone 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: Spironolactone is administered at a daily dosage of 400 mg 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 at doses of 100 mg (10 ml) to 400 mg daily (see NOTE above) 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 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

Initial daily dosage should provide 1-3 mg of spironolactone per kilogram (kg) body weight (0.1 ml/kg-0.3 ml/kg) given in divided doses. Dosage should be adjusted on the basis of response and tolerance (see sections 4.3 and 4.4).

Due to the level of medium chain triglycerides in Spironolactone Oral Solution, it is recommended that doses of 3mg/kg be administered using the 50 mg/5ml Oral Solution.

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 with a meal is recommended.

For instructions on how to use the device refer to section 6.6.

This product is incompatible with polystyrene or PVC and therefore, other devices may react with the product.

Dosage equivalence for the syringe

Each 1 ml = 10 mg

Measure Amount (ml)

Amount of spironolactone (mg)

0.5 ml

5 mg

1 ml

10 mg

2.5 ml

25 mg

5 ml

50 mg

7.5 ml

75 mg

10 ml

100 mg

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 should not be administered concurrently with other potassium conserving diuretics and potassium supplements should not be given routinely with spironolactone 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, 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 (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 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.

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).

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).

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 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, 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 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 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

Pregnancy

There are limited data from the use of spironolactone in pregnant women.

Studies in animals have shown reproductive toxicity associated with the antiandrogenic 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

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:

Adverse effects have been ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100; <1/10); uncommon (≥1/1,000; <1/100); rare (≥1/10,000; <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

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

Metabolism and nutrition disorders

Hyperkalaemia

Electrolyte imbalance

Psychiatric disorders

Confusional state

Libido disorder

Nervous system disorders

Dizziness

Gastrointestinal disorders

Nausea

Gastrointestinal disorder

Hepatobiliary disorders

Hepatic function abnormal

Skin and subcutaneous tissue disorders

Pruritus, Rash

Urticaria

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

Musculoskeletal and connective tissue disorders

Muscle spasms

Renal and urinary disorders

Acute kidney injury

Reproductive system and breast disorders

Gynaecomastia, Breast pain (male)a

Menstrual disorder, Breast pain (female)b

General disorders and administration site conditions

Malaise

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 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.