Spironolactone 25mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Spironolactone 25mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 25mg of Spironolactone BP
3 PHARMACEUTICAL FORM
Buff coloured biconvex film coated tablet marked “APS” or plain on one side and “25 0705” on the reverse
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Spironolactone tablets are indicated for the treatment of cirrhosis with ascites and oedema, malignant ascites, nephrotic syndrome, congestive cardiac failure, diagnosis and treatment of primary hyperaldosteronism.
4.2 Posology and method of administration
For oral administration.
Administration of spironolactone once daily with a meal is recommended. Adults
An initial dose of 100mg/day increasing if necessary to 200mg or possibly up to 400mg daily. When oedema is controlled, the maintenance dose is determined on an individual basis, usually 75 - 200mg/day.
Use of spironolactone in the treatment of nephrotic syndrome is only advised when glucocorticoids alone are insufficiently effective.
For treatment of cirrhosis with ascites and oedema the dosage is based on the urinary Na+/K+ ratio. If the ratio is greater than 1.0 a dosage of 100mg daily is recommended and if less than 1.0 a daily dosage of 200 - 400mg.
Diagnosis and treatment of primary hyperaldosteronism
Spironolactone may be used to provide presumptive evidence of primary
aldosteronism while patients are on normal diets.
Long Test: Administer 400mg of spironolactone per day for 3 - 4 weeks. If hypokalaemia and hypertension are corrected then consider a presumptive diagnosis of primary hyperaldosteronism.
Short Test: Administer 400mg of spironolactone per day for 4 days. If serum potassium increases during treatment and drops on cessation of treatment then consider a presumptive diagnosis of primary aldosteronism.
On confirmation of hyperaldosteronism, spironolactone may be administered in preparation for surgery at a dosage of 100 - 400mg daily. If surgery is unsuitable then spironolactone may be used for long term maintenance therapy at the lowest possible effective dosage.
Children
Initially 1.5 to 3.0mg/kg bodyweight in divided doses, then adjust according to the patient’s response and tolerance of the drug. If necessary the tablets may be crushed and taken with food or drink.
The Elderly
Start with a low dose and increase if necessary to achieve maximum benefit. Care should be taken in severe hepatic and renal impairment which may alter drug metabolism and excretion.
4.3 Contraindications
Spironolactone is contraindicated in patients with anuria, significant impairment of renal excretory function, acute renal insufficiency, hyperkalaemia, Addison's Disease, hypersensitivity to spironolactone or to any of the excipients and pregnancy and lactation.
4.4 Special warnings and precautions for use
Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with spironolactone therapy.
Concomitant administration of potassium-sparing diuretics and ACE inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with severe hyperkalaemia. Extreme caution should be exercised when spironolactone is given concomitantly with these drugs.
Periodic estimation of serum electrolytes is recommended especially for elderly patients and those with renal and hepatic impairment.
Long term treatment of rats with high doses of spironolactone has been shown to produce tumours. Although the clinical significance of this is uncertain, long term use of spironolactone in young patients requires careful consideration of benefits and potential hazards.
Hyperkalaemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities which may be fatal. Consequently, no potassium supplement should ordinarily be given with spironolactone. Should hyperkalaemia develop spironolactone should be discontinued, and if necessary, active measures taken to reduce the serum potassium to normal.Concomitant use of medicinal products known to cause hyperkalaemia with spironolactone may result in severe hyperkalaemia.
Reversible hyperchloraemic metabolic acidosis usually in association with hyperkalaemia has been reported in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.
Dilutional hyponatraemia may be induced, especially when spironolactone is administered in combination with other diuretics.
Spironolactone therapy may cause a transient elevation of blood urea nitrogen (BUN), especially in patients with pre-existing renal impairment. Spironolactone may cause mild acidosis.
4.5 Interaction with other medicinal products and other forms of interaction
ACE inhibitors:
Concomitant administration of ACE inhibitors with potassium-sparing diuretics has been associated with severe hyperkalaemia.
Non-steroidal anti-inflammatory drugs (NSAIDs):
The combination of NSAIDs with potassium-sparing diuretics has been associated with severe hyperkalaemia. In some patients, the administration of an NS AID can reduce the diuretic effect of spironolactone.
Drug/Laboratory test interactions:
Several reports of possible interference with digoxin radioimmunoassay by spironolactone, or its metabolites, have appeared in the literature. Neither the extent nor the potential clinical significance of its interference (which may be assay-specific) has been fully established.
Spironolactone should not be administered with other potassium conserving diuretics as hyperkalaemia may be induced. Also, except in cases of initial potassium depletion, potassium supplements should be avoided unless considered essential, when serum electrolytes should be monitored.
Spironolactone may potentiate the effects of other diuretics and antihypertensive drugs, their dosage may need to be reduced and then adjusted as necessary.
Aldosterone production is decreased by ACE inhibitors and they should not routinely be used with spironolactone, particularly in patients with marked renal impairment.
Carbenoxolone may cause sodium retention and thus decrease the effectiveness of spironolactone. Conversely, spironolactone inhibits the ulcer healing effect of carbenoxolone.
Spironolactone reduces the vascular responsiveness to noradrenaline. Caution should be exercised when patients being treated with spironolactone are subject to local or general anaesthesia.
Aspirin and indometacin antagonise the diuretic effect of spironolactone.
Digoxin:
Spironolactone has been shown to increase the half-life of digoxin. Serum levels of digoxin may be increased by concomitant administration of spironolactone. Spironolactone may interfere with certain serum digoxin assays.
Spironolactone may interfere with fluorometric assay estimation of compounds with similar fluorescence characteristics.
Trimethoprim/Sulfamethoxazole (co-trimoxazole):
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.
4.6 Fertility, pregnancy and lactation
Pregnancy: The anticipated benefit in the use of spironolactone should be weighed against the possible hazards to the mother and foetus. Spironolactone or its metabolites may cross the placental barrier. Animal studies have shown feminization of the genitalia of male offspring, as well as evidence of endocrine disruption in female and male offspring.
Breast-feeding: Canrenone, a major (and active) metabolite of spironolactone, appears in human breast milk. If spironolactone treatment becomes necessary during lactation, then lactation should be discontinued and the infant should be fed in an alternative way.
4.7 Effects on ability to drive and use machines
Patients should be advised not to drive or use dangerous machines if affected by drowsiness, dizziness or mental confusion.
4.8 Undesirable effects
List of adverse reactions
The frequencies of adverse events are ranked according to the following: 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), not known (cannot be estimated from the available data).
Blood and lymphatic system disorders
Not known: leukopenia (including agranulocytosis), thrombocytopenia
Metabolism and nutrition disorders
Common: hyperkalaemia
Not known: electrolyte disturbances,
Psychiatric disorders Common: mental confusion Not known: changes in libido
Nervous system disorders
Common: headache, drowsiness, lethargy, ataxia
Not known: dizziness
Gastrointestinal disorders
Common: nausea, vomiting, abdominal pain, diarrhoea or constipation Not known: gastrointestinal disturbances
Hepatobiliary disorders
Common: hepatotoxicity
Not known: hepatic function abnormal
Skin and subcutaneous tissue disorders Common: skin rashes
Not known: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, hypertrichosis, pruritus, urticaria, pemphigoid
Renal and urinary disorders Common: hyperkalaemia Not known: acute renal failure
Reproductive system and breast disorders
Common: menstrual irregularities, breast soreness, impotence, mild androgenic effects Rare: breast enlargement Not known: gynaecomastia
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.
4.9 Overdose
Acute overdosage symptoms may include drowsiness, mental confusion, nausea, vomiting, dizziness or diarrhoea.
Symptoms of hyperkalaemia may occur and these include cardiac irregularities, paraesthesia, weakness, flaccid paralysis or muscle spasm. Electrocardiographic changes are the earliest specific signs of potassium disturbance.
There is no specific antidote.
Overdose should be treated by withdrawal of spironolactone and instigation of general supportive measures which should include maintaining the fluid balance together with an adequate supply of electrolytes (not potassium).
Emergency treatment of hyperkalaemia is by the administration of glucose and insulin together, possibly as continuous infusions to acutely lower plasma potassium. Thiazide diuretics to enhance renal losses of body potassium or oral ion exchange resins to retain potassium in the gastro-intestinal tract may be used as adjunctive treatment or used alone when urgent reduction of plasma potassium is not required.
5.1 Pharmacodynamic properties
Spironolactone is a competitive antagonist of aldosterone, it binds to the aldosterone receptor preventing it from assuming its active conformation. It increases sodium excretion whilst reducing potassium loss at the distal renal tubule.
Spironolactone is often used in conjunction with other, more proximally acting diuretics thus preventing excessive potassium loss.
5.2 Pharmacokinetic properties
Spironolactone is absorbed fairly rapidly from the gastro-intestinal tract. The extent of absorption is particle size and formulation dependent. Spironolactone is metabolised to a significant extent during its first passage through the liver, and there is considerable enterohepatic circulation. It is extensively bound to plasma proteins, virtually no unmetabolised drug is excreted in the urine.
Spironolactone or its metabolites may cross the placental barrier. Canrenone, a metabolite of spironolactone, is excreted in breast milk.
ATC Code: C03D A01 (potassium-sparing agents, aldosterone antagonists).
5.3 Preclinical safety data
Preclinical information has not been included because the safety profile of spironolactone has been established after many years of clinical use. Please refer to section 4.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
The tablet contains:
Colloidal anhydrous silica Sodium laurilsulfate Lactose monohydrate
Microcrystalline cellulose (E460)
Sodium starch glycolate Rice starch Povidone (E1201)
Peppermint oil Menthol
Magnesium stearate
The coating contains:
Hypromellose (E464)
Polyethylene glycol Titanium dioxide (E171) Iron oxide (E172)
Talc (E553b)
6.2 Incompatibilities
None known
6.3 Shelf life
48 months
6.4 Special precautions for storage
Store below 25°C. Protect from light.
6.5 Nature and contents of container
HDPE containers with LDPE lids or polypropylene containers with polyethylene caps (or child resistant caps) or amber glass bottles in packs of 500 tablets.
PVdC coated PVC film with hard temper aluminium foil blister strips in packs of 7, 10, 14, 21, 28, 30, 56, 60, 84, 90, 100, 110, 112, 120, 150, 160 or 168 tablets.
6.6 Special precautions for disposal
Not applicable
7 MARKETING AUTHORISATION HOLDER
TEVA UK Limited
Brampton Road, Hampden Park
Eastbourne, East Sussex, BN22 9AG
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/0071
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
07/05/1985
10 DATE OF REVISION OF THE TEXT
08/04/2016