sanofi-aventis

Frumil 40mg/5mg Tablets.

Each tablet contains 40mg of Furosemide and Amiloride Hydrochloride equivalent to 5 mg of anhydrous amiloride hydrochloride.

For excipients, see 6.1

Tablet

Orange, circular, uncoated tablets, 8mm in diameter, with a breakline on one face and 'FRUMIL'on the reverse.

Uses: In the management of fluid retention where potassium conservation is desirable.

The route of administration is oral.

he tablets are to be swallowed whole with sufficient amounts of liquid (approx. half a glass). They are best taken on an empty stomach.

Recommended Dosage:

Adults: The usual adult dose is 1 tablet (40mg furosemide and 5 mg amiloride) in the morning. This may be increased to 2 tablets if the initial response is unsatisfactory. It is best to divide the dosage into two daily doses, one to be taken in the morning and the other at noon.

Elderly patients: The dosage should be adjusted according to diuretic response.

Extreme care should be taken with dosage in the elderly as this patient group are more susceptible to serious side effects associated with electrolyte disturbances.

1 Use in patients with Addison's disease.

2 Use in patients hypersensitive to the active ingredients, sulfonamides or sulfonamide derivatives, or any of the excipients of Frumil. Patients allergic to sulfonamides may show cross-sensitivity to furosemide.

3 During pregnancy

4 In breast- feeding women.

5 Use in children.

6 Use in patients with impaired renal function and a creatine clearance below 30 ml/min per 1.73 m² body surface area, acute renal failure or anuria.

7 Use in patients with hyperkalemia

8 Use in patients with severe hypokalemia, however if hypokalemia developes during treatment it can usually be corrected without interrupting treatment.

9 Use in patients with hypovolemia or dehydration.

10 In patients with severe hyponatraemia

11 In patients with pre-comatose and comatose states associated with hepatic encephalopathy.

1 Patients who are being treated with this preparation require regular supervision with monitoring of fluid and electrolyte state to avoid excessive loss of fluid. Hypovolaemia or dehydration as well as any significant electrolyte and acid-base disturbances must be corrected.

2 The preparation should only be used with particular caution in elderly patients, or those with disorders rendering their electrolyte balance precarious. Urinary outflow must be secured. In patients with a partial obstruction of urinary outflow (e.g. in patients with bladder-emptying disorders, prostatic hyperplasia or narrowing of the urethra), increased production of urine may provoke or aggravate complaints. Thus, these patients require careful monitoring- especially during the initial stages of treatment.

3 Furosemide may induce hyperglycaemia, particularly in patients with latent diabetes, and may require adjustment of dose of hypoglycaemic agents in diabetes mellitus. Regular monitoring of blood glucose levels is recommended.

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

5 Hyperuricaemia and gout may be induced by furosemide.

6 Ototoxicity may occur if given concomitantly with ototoxic drugs (see Section 4.5).

7 Bone marrow depression occasionally complicates treatment necessitating withdrawal of the product. The haemopoietic state should therefore be regularly monitored during treatment.

8 Hyponatraemia, hypochloraemia and raised blood urea nitrogen may occur during vigorous diuresis, especially in seriously ill patients. Careful monitoring of serum electrolytes, creatinine and urea should therefore be undertaken in these patients.

9 Hyperkalaemia has been observed in patients receiving amiloride hydrochloride.

10 Particularly careful monitoring is necessary

Frequent checks of serum potassium levels are necessary in patients with impaired renal function and a creatine clearance below 60 ml/min per 173 m² body surface area as well as in cases where treatment is taken in combination with certain other drugs which may lead to an increase in potassium concentration.

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 when compared to patients treated with risperidone alone or furosemide alone. Caution should be exercised and the risks and benefits of this combination or co-treatment should be considered prior to the decision to use. Dehydration should be avoided. See section 4.5.

Drug Interactions:

Not recommended associations:

Furosemide may potentiate the damaging effects on hearing of aminoglycosides and other ototoxic drugs. As such hearing disorders may be irreversible, those drugs and Frumil must only be used concurrently in cases where there are compelling medical reasons.

Isolated cases have been described in which intravenous administration of furosemide within 24 hours after taking chloral hydrate has been followed by sensations of heat, sweating attacks, restlessness, nausea, rises in blood pressure and tachycardia. Such a reaction might also occur with Frumil

Precautions for use:

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 and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment.

Frumil decreases the excretion of lithium salts. This may lead to increased serum lithium levels resulting in increased risk of lithium toxicity, including cardiotoxic and neurotoxic effects of lithium. Therefore it is recommended that lithium levels be carefully monitored when patients are receiving concurrent treatment with lithium salts.

Frumil and sucralfate must not be taken simultaneously or separately within a brief time span, because sucralfate decreases the absorption of the furosemide component from the intestine

Patients who are receiving diuretics may suffer severe hypotension and deterioration in renal function, including renal failure, especially when an ACE inhibitor 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 furosemide temporarily or at least reducing the dose of furosemide for three days before starting treatment with, or increasing the dose of, an ACE inhibitor or angiotensin II receptor antagonist.

Take into account

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

Concurrent administration of nonsteroidal anti-inflammatory drugs including acetylsalicylic acid may reduce the effect of Frumil. In patients with dehydration or pre-existing hypovolaemia, non steroidal anti-inflammatory drugs may cause acute renal failure. Salicylate toxicity may be increased by furosemide.

Corticosteroids, Carbenoxolone, liquorice in larger amounts and prolonged use of laxatives may promote the development of hypokalaemia.

Amiloride may cause raised blood digoxin levels, in addition, the effects and side effects of digitalis preparations and drugs inducing QT interval prolongation syndrome may be potentiated by changes in electrolyte concentrations due to furosemide.

Phenytoin may weaken the action of Frumil

If other antihypertensives, diuretics, or drugs which can lead to a reduction in blood pressure are taken concurrently with Frumil, a more pronounced fall in blood pressure must be anticipated.

The effects of antidiabetic drugs and blood-pressure-increasing sympathomimetics may be weakened, while the effects of curare-type muscle relaxants or of theophylline may be potentiated.

The harmful effects of nephrotoxic drugs on the kidney may be potentiated by furosemide.

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

Concomitant use of cyclosporine A and furosemide is associated with increased risk of gouty arthritis secondary to furosemide-induced hyperurecemia and cyclosporine impairment or renal urate excretion.

Probenecid, methotrexate and other drugs which, like furosemide, undergo significant renal tubular secretion may reduce the effect of furosemide.

Patients who were at high risk for radiocontrast nephropathy 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

Risperidone: Caution should be exercised and the risks and benefits of the combination or co-treatment with furosemide should be considered prior to the decision to use (see section 4.4).

Frumil must not be taken during pregnancy. Breast feeding must be avoided.

During treatment the powers of concentration and reaction may be impaired, affecting the patients ability for example, to drive or to operate machinery. This applies especially at the commencement of treatment or after consumption of alcohol.

Renal & Urinary Disorders

Acute retention of urine in patients with a partial obstruction of urinary outflow may in extreme cases lead to acute retention of urine with overdistension of the bladder. Interstitial nephritis and nephrocalcinosis/nephrolithiasis in premature infants may also occur.

Metabolism and Nutrition Disorders

Frumil causes increased excretion of water and certain electrolytes (e.g. sodium, calcium, magnesium, and chloride). The serum potassium concentration may decrease, especially at the commencement of treatment, particularly as treatment is continued, the potassium concentration may increase, especially in patients with impairment of renal function.

Treatment with Frumil may lead to increases in blood creatinine and urea levels and in blood lipids (e.g. cholesterol and triglycerides). The blood concentration of uric acid may increase and may lead to attacks of gout.

Disturbances in electrolyte balance may produce various symptoms (e.g. increased thirst, headache, confusion, muscle cramps, tetany, muscle weakness and disorders of cardiac rhythm, or even gastrointestinal symptoms). In the event of an irregular pulse, tiredness or muscle weakness, the possibility of hyperkalaemia in particular must be considered.

Furosemide may contribute to the development or aggravation of metabolic alkalosis, as may amiloride to the development or aggravation of metabolic acidosis.

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

The diuretic action may lead or contribute to hypovolaemia and dehydration. To avert these it is important to compensate any undesired losses of fluid.

Glucose tolerance may decrease during treatment with furosemide. In patients with diabetes mellitus this may lead to a deterioration of metabolic control. Latent diabetes may become manifest for the first time.

Gastrointestinal Disorders

Gastrointestinal symptoms such as nausea, vomiting or diarrhoea may occur. In isolated cases, acute pancreatitis may develop.

Hepato-Billary Disorders

Intrahepatic cholestasis and an increase in liver transaminases may occur.

Ear & Labyrinth Disorders

Hearing disorders and tinnitus although usually transitory, particularly in patients with renal failure, hypoproteinaemia (e.g. in nephrotic syndrome).

Skin & Subcutaneous Tissue Disorders

Reactions (e.g. allergic) involving the skin and mucous membranes may occasionally be encountered; these may manifest themselves in various forms including itching, urticaria and other skin rashes or bullous skin lesions, erythema multiforme, bullous pemphigoid, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, purpura and photosenstivity.

Immune System Disorders

Severe anaphylactic or anaphylactoid reactions to furosemide (e.g. with shock).

Nervous System Disorders

Paraesthesiae may develop. Hepatic encephalopathy in patients with hepatocellular insufficiency may occur. Rare complications may include minor psychiatric disturbances.

General Disorders

Fever may occur.

Vascular Disorders

In conjunction with increased fluid excretion, there may be a reduction in blood pressure. This may cause some impairment of powers of concentration and reaction, sensations of pressure in the head, headache, dizziness, sleepiness, feelings of weakness, disorders of vision, dryness of the mouth as well as disorders of orthostatic circulatory regulation.

An increased tendency for thromboses and vasculitis may also occur.

Blood & The Lymphatic System Disorders

In rare cases, haemolytic anaemia, leucopenia, agranulocytosis, aplastic anaemia, eosinophilia and haemoconcentration may develop, occasionally thrombocytopenia may occur.

The clinical picture in acute or chronic overdose depends primarily on the extent and consequences of electrolyte and fluid loss. Treatment of overdosage should be aimed at reversing dehydration and correcting electrolyte imbalance, particularly hyperkalaemia. Gastric lavage may be performed. Treatment is symptomatic and supportive. If hyperkalaemia is seen, appropriate measures to reduce potassium must be instituted.

Furosemide is a loop diuretic which acts primarily to inhibit the electrolyte reabsorption in the thick ascending loop of Henle. Excretion of sodium, potassium and chloride ions is increased and water excretion enhanced.

Amiloride is a mild diuretic which moderately increases the excretion of sodium and chloride, reduces potassium excretion and does not appear to act by inhibition of aldosterone. It does not inhibit carbonic anhydrase. Amiloride adds to the natriuretic effect but diminishes the kaliuretic effect of other diuretics.

A combination of frusemide and amiloride gives a diuretic which is intended to reduce the potassium loss associated with furosemide alone and avoid the possible gastro-intestinal disturbances of potassium supplements.

Furosemide is a potent diuretic with a rapid action. Its effects are evident within 30 minutes to 1 hour after a dose by mouth, peak at 1 to 2 hours, and last for about 4 to 6 hours; after intravenous injection its effects are evident in about 5 minutes and last for about 2 hours.

Not relevant

Lactose Monohyrdate

Microcrystalline Cellulose

Sodium Starch Glycollate - Type A

Starch Maize

Anstead Sunset Yellow Dye (E110)

Talc

Colloidal Anhydrous Silica

Magnesium Stearate

Not applicable

3 years.

Do not store above 25ºC.

Store in the original package (Blisters)

Keep the container tightly closed (tablet containers)

• Grey HDPE tablet containers with white LDPE tamper evident cap or child resistant cap. Pack sizes: 50,100 or 500 tablets.

• PVC/Aluminium strips containing 28 tablets (14 tablets per blister strip) or 56 tablets (14 tablets per blister strip) and sample packs of 4, 7, 14 and 21 tablets.

Not all pack sizes may be marketed

No special requirements

sanofi-aventis Ireland Ltd.

Citywest Business Campus

Dublin 24

PA 540/101/2

May 2010.