This information is intended for use by health professionals

1. Name of the medicinal product

Lasilactone 20 mg/50 mg Capsules

2. Qualitative and quantitative composition

Each capsule contains 20 mg Furosemide and 50 mg Spironolactone.

Excipient(s) with known effect:

Also contains 95 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Capsule.

Hard capsules with a white opaque body and a blue opaque cap

4. Clinical particulars
4.1 Therapeutic indications

Lasilactone contains a short-acting diuretic and a long-acting aldosterone antagonist. It is indicated in the treatment of resistant oedema where this is associated with secondary hyperaldosteronism; conditions include chronic congestive cardiac failure and hepatic cirrhosis.

Treatment with Lasilactone should be reserved for cases refractory to a diuretic alone at conventional doses.

This fixed ratio combination should only be used if titration with the component drugs separately indicates that this product is appropriate.

The use of Lasilactone in the management of essential hypertension should be restricted to patients with demonstrated hyperaldosteronism. It is recommended that in these patients also, this combination should only be used if titration with the component drugs separately indicates that this product is appropriate.

4.2 Posology and method of administration

Adults: 1 – 4 capsules daily.

Elderly: Furosemide and Spironolactone may both be excreted more slowly in the elderly.

Paediatric population

The product is not suitable for use in children.

Method of administration

For oral administration. The capsules should be swallowed whole. They are best taken at breakfast and/or lunch with a generous amount of liquid (approx. 1 glass). An evening dose is not recommended, especially during initial treatment, because of the increased nocturnal output of urine to be expected in such cases.

4.3 Contraindications

Lasilactone is contraindicated in:

• Patients with hypersensitivity to furosemide, spironolactone, sulphonamides or sulphonamide derivatives, or any of the excipients listed in section 6.1. Patients allergic to sulfonamides (e.g. sulfonamide antibiotics or sulfonylureas) may show cross-sensitivity to furosemide).

• Patients with hypovolaemia or dehydration (with or without accompanying hypotension).

• Patients with impaired renal function and a creatinine clearance below 30 ml/min per 1.73 m2 body surface area, anuria or renal failure with anuria not responding to furosemide.

• Patients with renal failure as a result of poisoning by nephrotoxic or hepatotoxic agents or renal failure associated with hepatic coma.

• Patients with hyperkalaemia, severe hypokalaemia (see section 4.8) or severe hyponatraemia.

• Patients with Addison's disease.

• Pregnant and breast-feeding women.

4.4 Special warnings and precautions for use

Warnings and precautions related to Lasilactone:

Urinary outflow must be secured. In patients with a partial obstruction of urinary outflow (e.g. in patients with bladder-emptying disorders, prostatic hyperplasia, prostatic hypertrophy or narrowing of the urethra), increased production of urine may provoke or aggravate complaints (such as risk of developing acute retention). Thus, these patients require careful monitoring, especially during the initial stages of treatment.

Treatment with Lasilactone necessitates regular medical supervision. Particularly careful monitoring is necessary in patients with hypotension or patients liable to electrolyte deficiency. Where indicated, steps should be taken to correct hypotension or hypovolaemia before commencing therapy.

Regular monitoring of serum sodium, potassium, creatinine and glucose is generally recommended during therapy; particularly close monitoring is required in patients at high risk of developing electrolyte imbalances or in case of significant additional fluid loss (e.g. due to vomiting, diarrhoea or intense sweating). Hypovolaemia or dehydration as well as any significant electrolyte and acid-base disturbances must be corrected. This may require temporary discontinuation of Lasilactone.

Administration of Lasilactone should be avoided in the presence of a raised serum potassium. Frequent checks of the serum potassium level are necessary in patients with impaired renal function and a creatinine clearance below 60 ml/min per 1.73 m2 body surface area as well as in cases where Lasilactone is taken in combination with certain other drugs (e.g. triamterene, amiloride, potassium supplements or non-steroidal anti-inflammatory drugs) which may lead to an increase in potassium levels.

Excipient(s) with known effect

Sodium: This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium-free'.

Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Warnings and precautions related to furosemide:

The possibility exists of exacerbation or activation of systemic lupus erythematosus.

Particularly careful monitoring is necessary in:

• Patients who are at risk from a pronounced fall in blood pressure. Symptomatic hypotension leading to dizziness, fainting or loss of consciousness can occur in patients treated with furosemide, particularly in the elderly, patients on other medications which can cause hypotension and patients with other medical conditions that are risks for hypotension.

• Patients where latent diabetes may become manifest, or the insulin requirements of diabetic patients may increase.

• Patients with gout.

• Patients with hepatic cirrhosis together with impaired renal function (hepatorenal syndrome).

• Patients with hypoproteinaemia, e.g. associated with nephrotic syndrome (the effect of furosemide may be weakened, and its ototoxicity potentiated). Cautious dose titration is required.

Concomitant use with risperidone

In risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3%; mean age 89 years, range 75 – 97 years) when compared to patients treated with risperidone alone (3.1%; mean age 84 years, range 70 – 96 years) or furosemide alone (4.1%; mean age 80 years, range 67 – 90 years). Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.

No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death observed. Nevertheless, caution should be exercised and the risks and benefits of this combination or co-treatment with other potent diuretics should be considered prior to the decision to use. There was no increased incidence of mortality among patients taking other diuretics as concomitant treatment with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be avoided in elderly patients with dementia (see section 4.3).

Warnings and precautions related to spironolactone:

For some patients with metastatic castration-resistant prostate cancer, tumour progression has been observed during spironolactone treatment. Spironolactone binds to the androgen receptor and can increase the prostate-specific antigen (PSA) value.

Spironolactone may cause vocal changes. In determining whether to initiate treatment with Lasilactone, special attention must be given to this possibility in patients whose voice is particularly important for their work (e.g. actors, singers, teachers).

Concomitant use of medicinal products known to cause hyperkalaemia with spironolactone may result in severe hyperkalaemia. Particularly careful monitoring is necessary in patients with reduced renal function.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions related to Lasilactone

Combinations to be taken into account:

The dosage of concurrently administered cardiac glycosides, diuretics, anti-hypertensive agents, or other drugs with blood-pressure-lowering potential may require adjustment as a more pronounced fall in blood pressure must be anticipated if given concomitantly with Lasilactone.

Non-steroidal anti-inflammatory drugs: Certain non-steroidal anti-inflammatory agents (e.g.indometacin, acetylsalicylic acid) may reduce the effect of Lasilactone. In patients with dehydration or hypovolaemia, non-steroidal anti-inflammatory drugs may cause acute renal failure. Salicylic toxicity may be increased by Lasilactone.

Lasilactone may sometimes attenuate the effects of other drugs (e.g. the effects of antidiabetics and pressor amines) and sometimes potentiate them (e.g. the effects of salicylates, theophylline and curare-type muscle relaxants).

Interactions related to Furosemide

Combinations not recommended:

Ototoxic drugs: Lasilactone may potentiate the ototoxicity of aminoglycosides and other ototoxic drugs. Since this may lead to irreversible damage, these drugs must only be used with Lasilactone if there are compelling medical reasons.

Combinations requiring precautions for use:

Cisplatin: There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of cisplatin may be enhanced if furosemide is not given in low doses (e.g. 40 mg in patients with normal renal function) and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment.

Diuretics: Patients who are receiving diuretics may suffer severe hypotension and deterioration in renal function, including cases of renal failure, especially when an angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonist is given for the first time or for the first time in an increased dose. Consideration must be given to interrupting the administration of Lasilactone temporarily or at least reducing the dose of Lasilactone for three days before starting treatment with, or increasing the dose of, an ACE inhibitor or angiotensin II receptor antagonist.

Sucralfate: Lasilactone and sucralfate must not be taken within two hours of each other because sucralfate decreases the absorption of furosemide from the intestine and so reduces its effect.

Lithium: In common with other diuretics, serum lithium levels may be increased when lithium is given concomitantly with Lasilactone, resulting in increased lithium toxicity, including increased risk of cardiotoxic and neurotoxic effects of lithium. Therefore, it is recommended that lithium levels are carefully monitored and where necessary the lithium dosage is adjusted in patients receiving this combination.

Risperidone: Caution should be exercised and the risks and benefits of the combination or co-treatment with furosemide or with other potent diuretics should be considered prior to the decision to use. See section 4.4 regarding increased mortality in elderly patients with dementia concomitantly receiving risperidone.

Levothyroxine: High doses of furosemide may inhibit binding of thyroid hormones to carrier proteins and thereby lead to an initial transient increase in free thyroid hormones, followed by an overall decrease in total thyroid hormone levels. Thyroid hormone levels should be monitored.

Combinations to be taken into account:

Probenecid, methotrexate and other drugs which, like furosemide, undergo significant renal tubular secretion may reduce the effect of Lasilactone. Conversely, furosemide may decrease renal elimination of these drugs. In case of high-dose treatment (in particular, of both furosemide and the other drugs), this may lead to increased serum levels and an increased risk of adverse effects due to furosemide or the concomitant medication.

The effects of antidiabetic drugs and blood pressure increasing sympathomimetics may be reduced.

The effects of curare-type muscle relaxants or of theophylline may be increased.

The toxic effects of nephrotoxic drugs may be increased by concomitant administration of potent diuretics such as furosemide.

Radiocontrast agents: Patients who were at a high risk for radiocontrast neuropathy treated with furosemide experienced a higher incidence of deterioration in renal function after receiving radiocontrast compared to high-risk patients who received only intravenous hydration prior to receiving radiocontrast. As such, in patients who are at high risk for radiocontrast nephropathy, furosemide is not recommended to be used for diuresis as part of the preventative measures against radiocontrast-induced nephropathy.

Phenytoin: Attenuation of the effect of Lasilactone may occur following concurrent administration of phenytoin.

Drugs increasing the risk of electrolyte imbalance: Corticosteroids, carbenoxolone, liquorice, B2 sympathomimetics in large amounts, and prolonged use of laxatives, reboxetine and amphotericin may increase the risk of developing hypokalaemia.

Concomitant administration of carbamazepine, corticosteroids or aminoglutethimide may increase the risk of hyponatraemia.

Some electrolyte disturbances (e.g. hypokalaemia, hypomagnesaemia) may increase the toxicity of certain other drugs (e.g. digitalis preparations and drugs inducing QT interval prolongation syndrome).

Cephalosporins: Impairment of renal function may develop in patients receiving concurrent treatment with furosemide and high doses of certain cephalosporins.

Ciclosporin: Concomitant use of ciclosporin and furosemide is associated with increased risk of gouty arthritis secondary to furosemide-induced hyperuricaemia and cyclosporin impairment of renal urate excretion.

Interactions related to Spironolactone

Combinations not recommended:

When Lasilactone is taken in combination with potassium salts, with drugs which reduce potassium excretion, with non-steroidal anti-inflammatory drugs or with ACE inhibitors, an increase in serum potassium concentration and hyperkalaemia may occur.

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.

Combinations to be taken into account:

Cholestyramine: Hyperkalaemia could occur in the context of hyperchloraemic metabolic acidosis in patients given Lasilactone concurrently with cholestyramine.

Carbenoloxone: Both spironolactone and carbenoloxone may impair the action of the other substance. In this regard, liquorice in large amounts acts in a similar manner to carbenoxolone.

Digoxin: Spironolactone may cause raised digoxin levels.

Food effect

Furosemide: It is recommended that oral formulations of furosemide be taken on an empty stomach. Whether and to what extent the absorption of furosemide is affected by taking it with food seems to be dependent on the pharmaceutical formulation.

Spironolactone: Absorption of spironolactone is increased if Lasilactone is taken together with food. The clinical relevance of this interaction is unknown.

4.6 Fertility, pregnancy and lactation

Pregnancy

Lasilactone must not be given during pregnancy (see section 4.3).

Results of animal work, in general, show no hazardous effect of furosemide in pregnancy. There is clinical evidence of safety of the drug in the third trimester of human pregnancy; however, furosemide crosses the placental barrier.

Spironolactone or its metabolites may cross the placental barrier. Animal studies have shown feminisation of the genitalia in male offspring. Anti-androgenic effects have been reported in humans with the risk of ambiguous external genitalia in male newborns (see section 4.3).

Breast-feeding

Furosemide passes into breast milk and may inhibit lactation. Canerone, a metabolite of spironolactone, appears in breast milk and Lasilactone must therefore not be used in breast-feeding mothers (see section 4.3).

4.7 Effects on ability to drive and use machines

Some adverse effects (e.g. an undesirably pronounced fall in blood pressure, reduced mental alertness) may impair the patient's ability to concentrate and react and therefore, drive or operate dangerous machinery. This applies especially at the commencement of treatment.

4.8 Undesirable effects

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); not known (cannot be estimated from the available data).

Furosemide is generally well tolerated.

Blood and lymphatic system disorders

Not known: Bone marrow depression has been reported as a rare complication and necessitates withdrawal of treatment.

Occasionally, thrombocytopenia may occur. In rare cases, eosinophilia, leucopenia and, in isolated cases, agranulocytosis, aplastic anaemia or haemolytic anaemia may develop.

Nervous system disorders

Not known: Paraesthesia may occur.

Hepatic encephalopathy in patients with hepatocellular insufficiency may occur (see section 4.3).

Dizziness, fainting and loss of consciousness (caused by symptomatic hypotension), headache.

Renal and urinary disorders

Not known: Serum calcium levels may be reduced; in very rare cases tetany has been observed. Nephrocalcinosis / Nephrolithiasis has been reported in premature infants.

Increased production of urine may provoke or aggravate complaints in patients with an obstruction of urinary outflow. Thus, acute retention of urine with possible secondary complications may occur for example, in patients with bladder-emptying disorders, prostatic hyperplasia or narrowing of the urethra.

Ear and labyrinth disorders

Uncommon: Cases of deafness, sometimes irreversible have been reported after oral or IV administration of furosemide.

Not known: Hearing disorders and tinnitus, although usually transitory, may occur in rare cases, particularly in patients with renal failure, hypoproteinaemia (e.g. in nephrotic syndrome) and/or when intravenous furosemide has been given too rapidly.

Vascular disorders

Not known: Furosemide may cause a reduction in blood pressure which, if pronounced may cause signs and symptoms such as impairment of concentration and reactions, light-headedness, sensations of pressure in the head, headache, dizziness, drowsiness, weakness, disorders of vision, dry mouth, orthostatic intolerance.

Hepatobiliary disorders

Not known: In isolated cases, intrahepatic cholestasis, an increase in liver transaminases or acute pancreatitis may develop.

Skin and subcutaneous tissue disorders

Not known: The incidence of allergic reactions, such as skin rashes, photosensitivity, vasculitis, fever or interstitial nephritis, is very low, but when these occur treatment should be withdrawn. Skin and mucous membrane reactions may occasionally occur, e.g. itching, urticaria, other rashes or bullous lesions, erythema multiforme, bullous pemphigoid, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, purpura, AGEP (acute generalized exanthematous pustulosis) and DRESS (Drug rash with eosinophilia and systemic symptoms), lichenoid reactions.

Metabolism and nutrition disorders

Not known: As with other diuretics, electrolytes and water balance may be disturbed as a result of diuresis after prolonged therapy.

Furosemide leads to increased excretion of sodium and chloride and consequently water. In addition, excretion of other electrolytes (in particular, calcium and magnesium) is increased. The two active ingredients exert opposing influences on potassium excretion. The serum potassium concentration may decrease, especially at the commencement of treatment (owing to the earlier onset of action of furosemide), although particularly as treatment is continued, the potassium concentration may increase (owing to the later onset of action of spironolactone), especially in patients with renal failure.

Symptomatic electrolyte disturbances and metabolic alkalosis may develop in the form of a gradually increasing electrolyte deficit or, e.g. where higher furosemide doses are administered to patients with normal renal function, acute severe electrolyte losses. Warning signs of electrolyte disturbances include increased thirst, headache, hypotension, confusion, muscle cramps, tetany, muscle weakness, disorders of cardiac rhythm and gastrointestinal symptoms. In the event of an irregular pulse, tiredness or muscle weakness (e.g., in the legs), particular consideration must be given to the possibility of hyperkalaemia. Pre-existing metabolic alkalosis (e.g. in decompensated cirrhosis of the liver) may be aggravated by furosemide treatment. Pseudo-Bartter syndrome may occur in the context of misuse and/or long-term use of furosemide.

Disturbances in electrolyte balance, particularly if pronounced, must be corrected.

The diuretic action may lead to hypovolaemia and dehydration, and contribute to the development or worsening of a hyperchloraemic metabolic acidosis, especially in elderly patients. Hypovolaemia may occur as a result of excessive diuresis. This may manifest as anorexia, dry mouth and thirst, vomiting, headache or feelings of pressure in the head, drowsiness, visual disturbances, apathy, confusional states or circulatory disturbances. Dizziness or leg cramps in the context of hypovolaemia, dehydration or hyperkalaemia may also occur.

To avert these, it is important to compensate any undesired losses of fluid (e.g. due to vomiting or diarrhoea, or to intense sweating). Severe fluid depletion may lead to haemoconcentration with a tendency for thromboses to develop.

Serum cholesterol and triglyceride levels may rise during furosemide treatment. During long-term therapy they will usually return to normal within six months.

Glucose tolerance may decrease with furosemide. In patients with diabetes mellitus this may lead to a deterioration of metabolic control; latent diabetes mellitus may become manifest.

As with other diuretics, treatment with furosemide may lead to transitory increases in blood creatinine and urea levels. Serum levels of uric acid may increase, and attacks of gout may occur.

Immune system disorders

Not known: Severe anaphylactic or anaphylactoid reactions (e.g. with shock) occur rarely. Exacerbation or activation of systemic lupus erythematosus.

Gastrointestinal disorders

Not known: Side-effects of a minor nature such as nausea, malaise or gastric upset (vomiting or diarrhoea) may occur but are not usually severe enough to necessitate withdrawal of treatment.

Spironolactone has been reported to induce gastrointestinal intolerance. Stomach ulcers (sometimes with bleeding) have been reported rarely. Spironolactone may also cause drowsiness, headache, ataxia and mental confusion.

Reproductive system and breast disorders

Not known: Because of its chemical similarity to the sex hormones, spironolactone may make the nipples more sensitive to touch. Dose dependent mastodynia and reversible gynaecomastia may occur in both sexes. Maculopapular or erythematous cutaneous eruptions have been reported rarely, as have mild androgenic manifestation such as hirsutism and menstrual irregularities.

In men, potency may be impaired. Progression of castration-resistant prostate cancer.

If furosemide is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus.

Respiration, thoracic and mediastinal disorders

Not known: Rarely, spironolactone may cause vocal changes in the form of hoarseness and (in women), deepening of the voice or (in men) increase in pitch. In some patients these vocal changes persist even after Lasilactone has been discontinued.

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

The clinical picture in acute or chronic overdose depends primarily on the extent and consequences of electrolyte and fluid loss, e.g. hypovolaemia, dehydration, haemoconcentration, cardiac arrhythmias due to excessive diuresis. Symptoms of these disturbances include severe hypotension (progressing to shock), acute renal failure, thrombosis, delirious states, flaccid paralysis, apathy and confusion.

Treatment should therefore be aimed at fluid replacement and correction of the electrolyte imbalance. Together with the prevention and treatment of serious complications resulting from such disturbances and of other effects on the body (e.g. hyperkalaemia), this corrective action may necessitate general and specific intensive medical monitoring and therapeutic measures (e.g. to promote potassium elimination).

No specific antidote to furosemide is known. If ingestion has only just taken place, attempts may be made to limit further systemic absorption of the active ingredient by measures such as gastric lavage or those designated to reduce absorption (e.g. activated charcoal).

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diuretics; High-ceiling diuretics and potassium-sparing agents, ATC code: C03EB01

Furosemide: Furosemide is a diuretic acting on the Loop of Henle.

Spironolactone: Spironolactone is a competitive inhibitor of aldosterone.

5.2 Pharmacokinetic properties

Furosemide: Furosemide is a short-acting diuretic; diuresis usually commences within one hour and lasts for four to six hours.

Spironolactone: Spironolactone, a competitive inhibitor of aldosterone, increases sodium excretion whilst reducing potassium loss at the distal renal tubule. It has a slow and prolonged action; maximum response being usually attained after 2 – 3 days' treatment.

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.

6. Pharmaceutical particulars
6.1 List of excipients

Capsule contents:

Microcrystalline cellulose

Lactose monohydrate

Talc

Magnesium stearate

Sodium starch glycolate type C

Capsule shell:

Indigotin (E132, FD&C Blue 2)

Titanium dioxide (E171)

Gelatin

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store below 25°C. Keep the blister strip in the outer carton in order to protect from light.

6.5 Nature and contents of container

PVC/Aluminium blister packs containing 28 or 50 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Aventis Pharma Limited

410 Thames Valley Park Drive

Reading

Berkshire

RG6 1PT

UK

Trading as:

Sanofi

410 Thames Valley Park Drive

Reading

Berkshire

RG6 1PT

UK

8. Marketing authorisation number(s)

PL 04425/0372

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 17 March 1977

Date of latest renewal: 8 February 2005

10. Date of revision of the text

15/12/2021

LEGAL STATUS

POM