Spironolactone 100mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Spironolactone 100mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains spironolactone 100mg
3. PHARMACEUTICAL FORM
Tablet
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
1. Hepatic cirrhosis with ascites and oedema (it is not an indication in the absence of these complications)
2. Malignant ascites
3. Nephrotic syndrome
4. Diagnosis and treatment of primary hyperaldosteronism
5. Congestive heart failure
4.2 Posology and method of administration
Posology
For oral administration.
Spironolactone Tablets should always be administered with fluid and preferably with food to aid absorption.
Adults
Congestive heart failure with oedema:
Usual dose - 100mg/day.
In difficult or severe cases the dosage may be gradually increased up to 400mg/day. When oedema is controlled, the usual maintenance level is 25- 200mg/day.
Hepatic cirrhosis with ascites and oedema:
If urinary Na+/K+ ratio is greater than 1.0, 100mg/day. If the ratio is less than 1.0, 200 - 400mg/day. Maintenance dosage should be individually determined.
Malignant ascites:
Initial dose usually 100 - 200mg/day. In severe cases the dose may be increased gradually up to 400mg daily. When oedema is controlled, maintenance dosage should be individually determined. Nephrotic syndrome:
Usual dosage 100 - 200mg/day.
Spironolactone has not been shown to be anti-inflammatory, or 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 three to four 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 four 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 100mg to 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 dose determined for the individual patient.
Older People
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. The elderly in general are more likely to be at increased risk of hyperkalaemia - monitor renal function more frequently in the elderly. Paediatric Population
Initially daily dosage should provide 3mg of spironolactone per kg bodyweight given 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.
4.3 Contraindications
Spironolactone is contra-indicated in the following:
• patients with anuria (patients are at greater risk of developing hyperkalaemia)
• acute renal insufficiency, severe or rapidly progressing impairment of renal function (spironolactone may aggravate electrolyte imbalance and the risk of developing hyperkalaemia is increased)
• hyperkalaemia (spironolactone may further increase serum potassium concentrations)
• patients who are hypersensitive to spironolactone or any of the ingredients in the product
• concomitant use of eplerenone or other potassium sparing diuretics
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.^
• Diabetes mellitus, especially in patients with confirmed or suspected renal insufficiency
• Diabetic nephropathy (increased risk of hyperkalaemia. Spironolactone should be discontinued at least 3 days prior to a glucose tolerance test because of the risk of severe hyperkalaemia)
• Addison’s Disease
4.4 Special warnings and precautions for use
• Patients receiving spironolactone therapy should be carefully evaluated for possible disturbances of fluid and electrolyte balance particularly in the elderly and in those with significant renal and hepatic impairment. Fluid and electrolyte status should be regularly monitored.
• Hyperkalaemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which can be fatal. Should hyperkalaemia occur, spironolactone should be discontinued, and if necessary, active measures taken to reduce the serum potassium levels to normal (See 4.3 Contraindications). Dilutional hyponatraemia may be induced especially when spironolactone is administered concurrently with other diuretics.
• Care should be taken in patients suffering from hyponatraemia.
• Reversible increases in blood urea have been reported in association with spironolactone therapy, particularly in the presence of impaired renal function.
• 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 medicinal products known to cause hyperkalaemia with spironolactone may result in severe hyperkalaemia.
• Concomitant use of spironolactone with other potassium-sparing diuretics, ACE inhibitors, angiotensin II antagonists, aldosterone blockers, heparin, low molecular weight heparin or other drugs known to cause hyperkalaemia, potassium supplements, a diet rich in potassium, or salt substitutes containing potassium, may lead to severe hyperkalaemia.
• Caution is required in severely ill patients and those with relatively small urine volumes who are at greater risk of developing hyperkalaemia.
• Caution is required in patients with a predisposition to metabolic or respiratory acidosis. Acidosis potentiates the hyperkalaemic effects of Spironolactone and Spironolactone may potentiate acidosis.
• Caution should be exercised in patients diagnosed with porphyria as Spironolactone is considered unsafe in these patients.
• Care should be taken in patients suffering from menstrual abnormalities or breast enlargement.
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 and so 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 one 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.
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 to other medicinal products known to cause hyperkalaemia, concomitant use of trimethoprim/sulfamethoxazole (co-trimoxazole) with spironolactone may result in clinically relevant hyperkalaemia.
• ACE inhibitors decrease aldosterone production and they should not routinely be used with spironolactone, particularly in patients with marked renal impairment. Concomitant use of Spironolactone with ACE-inhibitors may lead to severe hyperkalaemia, particularly in patients with renal failure. Spironolactone may also have an enhanced hypotensive effect when administered concomitantly with ACE-inhibitors. If concurrent use is necessary, monitor serum potassium levels.
• Angiotensin- II receptor antagonists- concurrent administration of angiotensin-II receptor antagonists with spironolactone may result in an increase in serum potassium levels and may lead to severe hyperkalaemia. If concurrent use is necessary, monitor serum potassium levels.
• Anti-hypertensives agents- potentiation of the effect of anti-hypertensive drugs occurs and their dosage may need to be reduced when spironolactone is added to the treatment regime, and then adjusted as necessary.
• Anti-diabetics- administration with chlorpropamide may increase risk of hyponatraemia.
• Aspirin may reduce the diuretic effect of Spironolactone
• Cardiac-glycosides: Spironolactone has been shown to increase the half-life of serum digoxin concentrations and interfere with certain serum digoxin assays. In patients receiving spironolactone and digoxin concomitantly, the digoxin response should be monitored by some other means other than by serum digoxin levels unless the assay used has been shown to be unaffected by spironolactone therapy. If it proves necessary to adjust the dose of digoxin, patients should be carefully monitored for enhanced or reduced effects of digoxin.
• Ciclosporin - co-administration of potassium sparing diuretics with ciclosporin may result in hyperkalaemia. Avoid concurrent use of spironolactone and ciclosporin. If concurrent therapy is necessary monitor serum potassium levels.
• Potassium salts- potassium supplements are not recommended except in cases of initial potassium depletion. If potassium supplementation is considered essential, serum electrolytes should be monitored.
• Ulcer-healing drugs- Carbenoxolone may cause sodium retention and thus decrease the effectiveness of spironolactone. Concurrent use of the two agents should be avoided.
• Non-steroidal anti-inflammatory agents (including Aspirin) may attenuate the natriuretic effects of diuretics due to inhibition of intrarenal prostaglandin synthesis. There may be an increased risk of nephrotoxicity and hyperkalaemia when NSAIDs, notably Indometacin are used with Spironolactone. Indometacin and mefenamic acid inhibit the excretion of canrenone reducing the diuretic effect.
• Sympathomimetics- Spironolactone reduces vascular responsiveness to noradrenaline (norepinephrine); Caution should be exercised in the management of patients being subjected to regional or general anaesthesia while they are being treated with Spironolactone.
• Spironolactone may interfere with certain fluorometric assays for compounds with similar fluorescence characteristics.
• Corticosteroids- co-administration of Spironolactone with fludrocortisone may result in a paradoxical dose- related increase in urinary potassium excretion. If concomitant administration is necessary, closely monitor serum potassium levels.
• Coumarins- in patients receiving oral anticoagulant therapy with warfarin, the prothrombin time ratio or INR (international normalised ratio) should be monitored with the addition and withdrawal of treatment with Spironolactone, and should be reassessed periodically during concurrent therapy. Adjustments of the warfarin dose may be necessary in order to maintain the desired level of anticoagulation.
• Diuretics- Spironolactone should not be administered concurrently with other potassiumsparing diuretics as this may induce hyperkalaemia. Potassium canrenoate, a metabolite of Spironolactone, has been shown to cause myeloid leukaemia in rats.
• Lithium- concurrent use of lithium and Spironolactone may result in increased lithium concentrations and lithium toxicity (weakness, tremor, excessive thirst and confusion) due to decreased lithium excretion. If concomitant therapy is necessary monitor serum lithium levels within the first 5-7 days of adding or discontinuing Spironolactone and periodically thereafter. Lower lithium doses may be required with concomitant Spironolactone therapy
• Tacrolimus- Spironolactone should not be used in patients undergoing therapy with tacrolimus as concomitant use has resulted in mild to severe hyperkalaemia.
• Liver function tests- Spironolactone may enhance the metabolism of antipyrine used in liver functions tests.
• Cancer medication - avoidance of Spironolactone recommended if receiving Mitotane treatment
• Colestyramine- reports of hyperchloraemic metabolic acidosis
• Oestrogen- diuretic effect of Spironolactone antagonised by oestrogen
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 to other medicinal products known to cause hyperkalaemia, concomitant use of trimethoprim/sulfamethoxazole (co-trimoxazole) with spironolactone may result in clinically relevant hyperkalaemia.
• ACE inhibitors decrease aldosterone production and they should not routinely be used with spironolactone, particularly in patients with marked renal impairment. Concomitant use of Spironolactone with ACE-inhibitors may lead to severe hyperkalaemia, particularly in patients with renal failure. Spironolactone may also have an enhanced hypotensive effect when administered concomitantly with ACE-inhibitors. If concurrent use is necessary, monitor serum potassium levels.
• Angiotensin- II receptor antagonists- concurrent administration of angiotensin-II receptor antagonists with spironolactone may result in an increase in serum potassium levels and may lead to severe hyperkalaemia. If concurrent use is necessary, monitor serum potassium levels.
• Anti-hypertensives agents- potentiation of the effect of anti-hypertensive drugs occurs and their dosage may need to be reduced when spironolactone is added to the treatment regime, and then adjusted as necessary.
• Anti-diabetics- administration with chlorpropamide may increase risk of hyponatraemia.
• Aspirin may reduce the diuretic effect of Spironolactone
• Cardiac-glycosides: Spironolactone has been shown to increase the half-life of serum digoxin concentrations and interfere with certain serum digoxin assays. In patients receiving spironolactone and digoxin concomitantly, the digoxin response should be monitored by some other means other than by serum digoxin levels unless the assay used has been shown to be unaffected by spironolactone therapy. If it proves necessary to adjust the dose of digoxin, patients should be carefully monitored for enhanced or reduced effects of digoxin.
• Ciclosporin - co-administration of potassium sparing diuretics with ciclosporin may result in hyperkalaemia. Avoid concurrent use of spironolactone and ciclosporin. If concurrent therapy is necessary monitor serum potassium levels.
• Potassium salts- potassium supplements are not recommended except in cases of initial potassium depletion. If potassium supplementation is considered essential, serum electrolytes should be monitored.
• Ulcer-healing drugs- Carbenoxolone may cause sodium retention and thus decrease the effectiveness of spironolactone. Concurrent use of the two agents should be avoided.
• Non-steroidal anti-inflammatory agents (including Aspirin) may attenuate the natriuretic effects of diuretics due to inhibition of intrarenal prostaglandin synthesis. There may be an increased risk of nephrotoxicity and hyperkalaemia when NSAIDs, notably Indometacin are used with Spironolactone. Indometacin and mefenamic acid inhibit the excretion of canrenone reducing the diuretic effect.
• Sympathomimetics- Spironolactone reduces vascular responsiveness to noradrenaline (norepinephrine); Caution should be exercised in the management of patients being subjected to regional or general anaesthesia while they are being treated with Spironolactone.
• Spironolactone may interfere with certain fluorometric assays for compounds with similar fluorescence characteristics.
• Corticosteroids- co-administration of Spironolactone with fludrocortisone may result in a paradoxical dose- related increase in urinary potassium excretion. If concomitant administration is necessary, closely monitor serum potassium levels.
• Coumarins- in patients receiving oral anticoagulant therapy with warfarin, the prothrombin time ratio or INR (international normalised ratio) should be monitored with the addition and withdrawal of treatment with Spironolactone, and should be reassessed periodically during concurrent therapy. Adjustments of the warfarin dose may be necessary in order to maintain the desired level of anticoagulation.
• Diuretics- Spironolactone should not be administered concurrently with other potassiumsparing diuretics as this may induce hyperkalaemia. Potassium canrenoate, a metabolite of Spironolactone, has been shown to cause myeloid leukaemia in rats.
• Lithium- concurrent use of lithium and Spironolactone may result in increased lithium concentrations and lithium toxicity (weakness, tremor, excessive thirst and confusion) due to decreased lithium excretion. If concomitant therapy is necessary monitor serum lithium levels within the first 5-7 days of adding or discontinuing Spironolactone and periodically thereafter. Lower lithium doses may be required with concomitant Spironolactone therapy
• Tacrolimus- Spironolactone should not be used in patients undergoing therapy with tacrolimus as concomitant use has resulted in mild to severe hyperkalaemia.
• Liver function tests- Spironolactone may enhance the metabolism of antipyrine used in liver functions tests.
• Cancer medication - avoidance of Spironolactone recommended if receiving Mitotane treatment
• Colestyramine- reports of hyperchloraemic metabolic acidosis
• Oestrogen- diuretic effect of Spironolactone antagonised by oestrogen
4.6 Pregnancy and lactation
Pregnancy
Spironolactone or its metabolites may cross the placental barrier. With spironolactone, feminisation has been observed in male rat foetuses. The use of spironolactone in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the mother and foetus.
Lactation
Metabolites of spironolactone have been detected in breast milk. If use of spironolactone is considered essential, an alternative method of infant feeding should be instituted.
4.7 Effects on ability to drive and use machines
Drowsiness and dizziness may occur, therefore, care should be taken when driving or operating machinery. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.
4.8 Undesirable effects
Reproductive system and breast disorders: 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. Alteration in voice pitch may also occur on rare occasions, which may not be reversible. Impotence and decreased sexual ability has been reported. This is usually reversible on discontinuation of Spironolactone. Breast tenderness and increased hair growth in females, irregular menstrual periods and sweating have been reported.
The following adverse events have been reported in association with spironolactone therapy:
Neoplasms benign, malignant and unspecified (including cysts and polyps): benign breast neoplasm
Blood and lymphatic system disorders: leukopenia (including agranulocytosis), eosinophilia and thrombocytopenia have been reported rarely. Spironolactone may cause transient elevations in blood urea nitrogen (BUN) especially in patients with renal impairment.
Hypersensitivity: these occur rarely and are usually mild but very occasionally may be severe causing swelling, shock and collapse. Shortness of breath, skin rash or itching has been reported rarely.
Metabolic and nutritional disorders: electrolyte disturbances, hyponatraemia and hyperkalaemia have been reported rarely.
Nervous system disorders: ataxia, drowsiness, dizziness, headache and clumsiness have been reported although these are less common.
General disorders and administration site conditions: malaise
Cardiac disorders: severe hyperkalaemia may result in paralysis, flaccid paraplegia and cardiac arrhythmias with subsequent cardiovascular collapse. This can be fatal in patients with impaired renal function.
Hepatobiliary disorders: hepatic function abnormal, hepatotoxicity has been reported
Gastrointestinal disorders: gastrointestinal disturbances, nausea, gastritis, gastric bleeding, stomach cramps, diarrhoea, vomiting and ulceration are more frequent events
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, hypertrichosis, pruritus, rash, urticaria and pemphigoid.
Musculoskeletal disorders: osteomalacia, leg cramps
Psychiatric disorders: lethargy, changes in libido, confusion
Renal and urinary system disorders: acute renal failure, particularly in those with pre-existing renal impairment.
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/vellowcard 4.9. Overdose
Acute overdose 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 overdose. Symptoms of hyperkalaemia may manifest as paraesthesia, weakness, flaccid paralysis or muscle spasm and may be difficult to distinguish 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 include replacement of fluids and electrolytes. For hyperkalaemia, reduce potassium intake, administer potassium-excreting diuretics, intravenous glucose with regular insulin or oral ion-exchange resins.
5.1 Pharmacodynamic properties
ATC Code: C03D A01
Spironolactone, a steroid with a structure resembling that of the natural adrenocortical hormone aldosterone, acts as a competitive inhibitor of aldosterone. It thus increases sodium excretion and reduces potassium excretion in the distal renal tubule. It has a gradual and prolonged action. Provided that production of aldosterone is sufficiently high, spironolactone is active when given to patients on a low salt diet but is ineffective if aldosterone output is low.
Severe heart failure: The Randomized Aldactone Evaluation Study (RALES) was a multinational, double-blind study in 1663 patients with an ejection fraction of < 35%, a history of New York Heart Association (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% to 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.
5.2 Pharmacokinetic properties
Absorption: Spironolactone is incompletely but fairly rapidly absorbed from the gastrointestinal tract and the extent of absorption will depend on the particle size and formulation and is improved after food. Bioavailability is estimated from 60 to 90%. Time to peak plasma concentration is approximately one hour.
Distribution: although the plasma half life of Spironolactone itself is short (1.3 hours) the half lives of the active metabolites a re longer (ranging from 2.8 to 11.2 hours). Spironolactone is estimated to be 90% protein bound. Volume of distribution, extent of tissue accumulation and ability to cross the blood brain barrier are not known. Spironolactone or its metabolites may cross the placental barrier and canrenone is secreted in breast milk, Spironolactone is know to have a slow onset of action (two to three days), and a slow diminishment of action.
Metabolism- The main sight of biotransformation is the liver where it is metabolised, to 80% sulphur containing metabolites such as 7 alpha-thiomethylspironolactone and canrenone (20%). Many of these metabolites also have a diuretic- activity. Canrenone, which is an active metabolite, has a biphasic plasma half-life of about 4-17 hours.
Elimination- Spironolactone is excreted in the urine and faeces in the form of metabolites.
The renal action of a single dose of Spironolactone reaches its peak after 7 hours, and activity persists for at least 24-hours.
5.3 Preclinical safety data
Carcinogenicity: Spironolactone has been shown to produce tumours in rats when administered in high doses over a long period of time. The significance of these 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 potential hazards involved. Spironolactone or its metabolites may cross the placental barrier. With spironolactone, feminisation has been observed in male rat foetuses. The use of spironolactone 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
Maize starch
Calcium sulphate dihydrate
Snowflake starch (pregelatinised maize starch)
Kollidon CL (crospovidone)
Povidone K25
Quinoline yellow aluminium lake (E104)
Sodium starch glycollate
Peppermint flavour Magnesium stearate Water Ethanol
6.2. Incompatibilities
None reported
6.3.
Shelf life
36 months
6.4. Special precautions for storage
Store below 25oC in a dry place. Protect from light
6.5 Nature and contents of container
Polypropylene pot and polyethylene cap with appropriate bellows or polyurethane foam wads. Pack sizes: 28, 30, 56, 60, 84, 90, 100, 112 and 500 Tablets.
Not all pack sizes may be marketed.
Blister packs composed of 250 micron white opaque PVC film and 20 micron hard tempered aluminium foil.
Pack size: 28 tablets.
6.6. Instructions for Use/Handling
No special instructions
7. MARKETING AUTHORISATION HOLDER
Athlone Laboratories Limited,
Ballymurray,
Co. Roscommon,
Ireland.
8. MARKETING AUTHORISATION NUMBER
PL 6453/0042
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
26/10/2005
10 DATE OF REVISION OF THE TEXT
12/03/2016