4.1. Therapeutic indications

Co-amilofruse tablets are indicated where a prompt diuresis is required. It is of particular value in conditions where potassium conservation is important; congestive cardiac failure, nephrosis, corticosteroid therapy, oestrogen therapy. Ascites associated with cirrhosis.

4.2. Posology and method of administration

For oral administration

Adults: One or two tablets to be taken in the morning.

Children: Not recommended for children under 18 years of age as safety and efficacy have not been established.

Elderly: The dosage should be adjusted according to diuretic response; serum electrolytes and urea should be carefully monitored.

4.3. Contraindications

Hypersensitivity to furosemide, amiloride, sulphonamides or sulphonamide derivatives, or to any of the excipients of the product.

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

Patients with impaired renal function and a creatinine clearance below 30ml/min 1.73m2 body surface area, anuria or renal failure with anuria not responding to furosemide, renal failure as a result of poisoning by nephrotoxic or hepatotoxic agents or renal failure associated with hepatic coma, hyperkalaemia, severe hypokalaemia, severe hyponatraemia, concomitant potassium supplements or potassium sparing diuretics, precomatose states associated with cirrhosis, Addison's disease, and breast feeding women.

Co-amilofruse is contraindicated in children and adolescents under 18 years of age as safety in this age group has not yet been established.

4.4. Special warnings and precautions for use

Co-amilofruse should be discontinued before a glucose tolerance test.

Co-amilofruse should be used in caution in elderly patients or those with potential obstruction of the urinary tract or disorders rendering electrolyte balance precarious.

Urinary output must be secured. Patients with partial obstruction of urinary flow, (e.g. in prostatic hypertrophy, impairment of micturition), are at increased risk of developing acute urinary retention and require careful monitoring.

Where indicated, steps should be taken to correct hypotension or hypovolaemia before commencing therapy with co-amilofruse (see section 4.3).

Particularly careful monitoring is necessary in elderly or seriously ill patients and those with:

• Hypotension

• those at risk from a pronounced fall in blood pressure.

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

• Gout

• Patients with hepatic cirrhosis together with impaired renal function

• Patients with hypoproteinaemia e.g. associated with nephrotic syndrome (the therapeutic effect of furosemide may be reduced and its ototoxicity potentiated (see also section 4.8). Cautious dose titration is required.

• 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.

Caution should be observed in patients liable to electrolyte deficiency. 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. Hypovolaemia or dehydration as well as any significant electrolyte and acid-base disturbances must be corrected. This may require temporary discontinuation of Co-amilofruse.

Frequent checks of the serum potassium level are necessary in patients with impaired renal

function and a creatinine clearance below 60ml/min per 1.73m2 body surface area as well as in cases where Co-amilofruse is taken in combination with certain other drugs which may lead to an increase in potassium levels.

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.

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

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 Contraindications).

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

Co-amilofruse contains Sunset yellow aluminium lake (E110) which may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

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 Co- amilofruse. A marked fall in blood pressure and deterioration in renal function may be seen when ACE inhibitors or angiotensin II receptor antagonists are added to furosemide therapy, or their dose level increased. The dose of Co-amilofruse should be reduced for at least three days, or the drug stopped, before initiating the ACE inhibitor or angiotensin II receptor antagonist or increasing their dose.

When amiloride 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.

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

Sucralfate decreases the intestinal absorption of furosemide, and should not be taken within two hours of co-amilofruse.

As with other diuretics, serum levels of lithium may be increased with concomitant use of furosemide, resulting in increased lithium toxicity, including increased risk of cardiotoxic and neurotoxic effects of lithium. Patients should be carefully monitored, and the lithium dosage adjusted if necessary.

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 Special warnings are precautions for use regarding increased mortality in elderly patients with dementia concomitantly receiving risperidone.

Certain NSAIDs (e.g. indomethacin, acetylsalicyclic acid) may attenuate the action of co-amilofruse and may cause acute renal failure in cases of pre-existing hypovolaemia or dehydration. Salicylic toxicity may be increased by furosemide. Co-amilofruse may sometimes attenuate the effects of other drugs (e.g. anti-diabetics and pressor amines) and sometimes potentiate them (e.g. the effects of salicylates, theophylline and curare-type muscle relaxants).

Furosemide may potentiate the ototoxicity of aminoglycoside antibacterials and other ototoxic drugs. Since damage may be irreversible, co-administration of co-amilofruse should be avoided if possible.

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

Amiloride may cause raised blood digoxin levels. Some electrolyte disturbances (e.g. hypokalaemia, hypomagnesaemia) may increase the toxicity of certain other drugs (e.g. digitalis preparations and drugs inducing QT prolongation syndrome).

Attenuation of the effect of Co-amilofruse may occur following concurrent administration of phenytoin.

Concomitant administration of carbamazepine or aminogluthethimide may increase the risk of hyponatraemia.

Corticosteroids administered concurrently may cause sodium retention.

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

Probenecid, methotrexate and other drugs which, like Co-amilofruse undergo significant renal tubular secretion may reduce the diuretic effect of co-amilofruse. In turn furosemide may decrease the renal elimination of such 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 events due to furosemide, and the concurrent medication.

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

Concomitant use of ciclosporin and furosemide is associated with increased risk of gouty arthritis.

4.6. Fertility, pregnancy and lactation

Pregnancy

Results of animal work, in general show no hazardous effects 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. It must not be given during pregnancy unless there are compelling medical reasons. Treatment during pregnancy requires monitoring of foetal growth.

The safety of amiloride hydrochloride has not been established and is therefore not recommended for use during pregnancy.

Lactation

Furosemide passes into breast milk and may inhibit lactation. It is not known whether amiloride hydrochloride is excreted in breast milk. Breast-feeding must be avoided during treatment with Co- amilofruse.

4.7. Effects on ability to drive and use machines

Co-amilofruse tablets may cause dizziness, fainting and loss of consciousness. Thus, may influence on the ability to drive and use machines.

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

Co-amilofruse Tablets 5/40 mg are generally well tolerated.

Blood and lymphatic system disorders

Frequency not known:

Eosinophilia, haemoconcentration.

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

Bone marrow depression has been reported as a rare complication and necessitates withdrawal of treatment.

Nervous system disorders

Frequency 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) and headache.

Metabolism and nutrition disorders

Frequency not known:

Serum calcium levels may be reduced; in very rare cases tetany has been observed.

Blood cholesterol and blood triglyceride levels may increase during furosemide treatment. During long term therapy they will usually return to normal within six months.

Glucose tolerance may be impaired 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, electrolytes and water balance may be disturbed as a result of diuresis after prolonged therapy. However, as treatment is continued, the serum potassium

concentration may increase due to the later onset of action of amiloride, especially in patients with impaired renal function. 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, although amiloride may contribute to the development or aggravation of metabolic acidosis. Warning signs of electrolyte disturbances include increased thirst, headache, hypotension, confusion, muscle cramps, tetany, muscle weakness, disorders of cardiac rhythm and gastrointestinal symptoms. Disturbances of electrolyte balance, particularly if pronounced, must be corrected. 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.

The diuretic action of furosemide may lead to or contribute to hypovolaemia and dehydration, especially in elderly patients.

As with other diuretics, treatment with furosemide may lead to increases in blood creatinine and blood uric acid, hyponatremia, hypochloremia, hypokalaemia, attacks of gout, hypocalcemia, hypomagnesemia and increased blood urea.

Ear and labyrinth disorders

Frequency not known:

- Hearing disorders and tinnitus, although usually transitory, may occur in rare cases, particularly in patients with renal failure, hypoproteinaemia (e.g. nephrotic syndrome) and/or when intravenous furosemide has been given too rapidly.

- Tinnitus

Frequency uncommon:

Cases of deafness, sometimes irreversible, have been reported after administration of furosemide.

Vascular disorders

Frequency 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/tiredness, disorders of vision, dry mouth, orthostatic intolerance.

- Thrombosis

- Vasculitis

Hepatobiliary disorders

Frequency not known:

In isolated cases, intrahepatic cholestasis, an increase in liver transaminases or acute pancreatitis may develop.

Skin and subcutaneous tissue disorders

Frequency not known:

The incidence of allergic reactions, such as skin rashes, photosensitivity, vasculitis, fever, interstitial nephritis, or shock 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 dermatitis bullous lesions, erythema multiforme, bullous pemphigoid, exfoliative dermatitis, purpura, photosensitivity, Stevens- Johnson syndrome, toxic epidermal necrolysis, AGEP (acute generalized exanthematous pustulosis) and DRESS (Drug rash with eosinophilia and systemic symptoms), lichenoid reactions.

Psychiatric disorders

Frequency not known:

Rare complications may include minor psychiatric disturbances.

Renal and urinary disorders

Frequency not known:

Increased production of urine may provoke or aggravate complaints in patients with an obstruction of urinary outflow. Thus, acute retention of urine, associated with increased levels of sodium and chloride in urine with possible secondary complications may occur. For example, in patients with bladder emptying disorders, prostatic hyperplasia or narrowing of the urethra.

Nephrocalcinosis/nephrolithisasis has been reported in premature infants.

Tubulointerstitial nephritis

Renal failure

Reproductive system and breast disorders

Frequency not known:

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

Immune system disorders

Frequency not known:

Severe anaphylactic or anaphylactoid reactions (e.g. with shock) occur rarely.

Exacerbation or activation of systemic lupus erythematosus.

Gastrointestinal disorders

Frequency not known:

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

Pancreatitis acute

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 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

Treatment of overdosage should be aimed at reversing dehydration and correcting electrolyte imbalance, particularly hyperkalaemia. Emesis should be induced, or gastric lavage performed. Treatment should be symptomatic and supportive.

If hyperkalaemia is seen, appropriate measures to reduce serum potassium must be instituted.