Frumil, Frumil LS

1. Name Of The Medicinal Product

Frumil 40 mg/5 mg Tablets

Frumil LS 20 mg/2.5 mg Tablets

2. Qualitative And Quantitative Composition

The active ingredient is Furosemide 40.0mg and amiloride hydrochloride equivalent to 5.0mg anhydrous amiloride hydrochloride.

The active ingredient is Furosemide 20.0mg and amiloride hydrochloride equivalent to 2.5mg anhydrous amiloride hydrochloride.

For excipients, see section 6.1

3. Pharmaceutical Form

Tablets for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

Frumil 40 mg/5 mg Tablets/ Frumil LS 20 mg/2.5 mg Tablets is a potassium sparing diuretic which is 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 and for ascites associated with cirrhosis.

4.2 Posology And Method Of 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 the diuretic response; serum electrolytes and urea should be carefully monitored.

4.3 Contraindications

Patients with hypovolaemia or dehydration (with or without accompanying hypotension). Patients with an impaired renal function and a creatinine clearance below 30ml/min per 1.73 m² 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.

Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets contraindicated in children and adolescents under 18 years of age as safety in this age group has not yet been established.

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

4.4 Special Warnings And Precautions For Use

Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets should be discontinued before a glucose tolerance test.

Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets should be used with particular 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 outflow, for example patients with prostatic hypertrophy or impairment of micturition have an increased risk of developing acute retention and require careful monitoring.

Where indicated, steps should be taken to correct hypotension or hypovolaemia before commencing therapy.

Particularly careful monitoring is necessary in:

• patients with hypotension.

• patients who are 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.

• patients with gout.

• patients with hepatic cirrhosis together with impaired renal function.

• 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.

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 Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets

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 Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets 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.

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).

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

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 Frumil 40 mg/5 mg Tablets/ Frumil LS 20 mg/2.5 mg Tablets. 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 Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets 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 nonsteroidal 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.

Oral Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets and sucralfate must not be taken within 2 hours of each other because sucralfate decreases the absorption of furosemide from the intestine and so reduces its effect.

In common with other diuretics, serum lithium levels may be increased when lithium is given concomitantly with Frumil 40 mg/5 mg Tablets/ Frumil LS 20 mg/2.5 mg Tablets, 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 Special warnings and precautions for use regarding increased mortality in elderly patients with dementia concomitantly receiving risperidone.

Certain non-steroidal anti-inflammatory agents (e.g. indometacin, acetylsalicylic acid) may attenuate the action of Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets and may cause acute renal failure in cases of pre-existing hypovolaemia or dehydration. Salicylic toxicity may be increased by furosemide. Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets may sometimes attenuate the effects of other drugs (e.g. the effects of anti-diabetics and of pressor amines) and sometimes potentiate them (e.g. the effects of salicylates, theophylline and curare-type muscle relaxants).

Furosemide may potentiate the ototoxicity of aminoglycosides and other ototoxic drugs. Since this may lead to irreversible damage, these drugs must only be used with Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets if there are compelling medical reasons.

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.

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 interval prolongation syndrome).

Attenuation of the effect of Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets may occur following concurrent administration of phenytoin.

Concomitant administration of carbamazepine or aminoglutethimide 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 furosemide, undergo significant renal tubular secretion may reduce the effect of Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets. 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.

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 Pregnancy And Lactation

Pregnancy:

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. 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. Breastfeeding must be avoided during treatment with Frumil 40 mg/5 mg Tablets / Lasoride 40 mg/5 mg Tablets/ Frumil LS 20 mg/2.5 mg Tablets.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Frumil/Frumil LS Tablets are generally well tolerated.

Eosinophilia is rare.

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.

Rarely, paraesthesiae or hepatic encephalopathy in patients with hepatocellular insufficiency may occur.

Serum calcium levels may be reduced; in very rare cases tetany has been observed. Nephrocalcinosis / Nephrolithiasis has been reported in premature infants.

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.

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

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.

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

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 bullous lesions, erythema multiforme, bullous pemphigoid, Stevens-Johnson Syndrome, toxic epidermal necrolysis exfoliative dermatitis, purpura.

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 potassium, calcium and magnesium) is increased. 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. 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, 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.

Rare complications may include minor psychiatric disturbances.

The diuretic action of furosemide may lead to or contribute to hypovolaemia and dehydration, especially in elderly patients. Severe fluid depletion may lead to haemoconcentration with a tendency for thromboses to develop.

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.

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

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

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.

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.

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.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: CO3C A01

FUROSEMIDE:

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

AMILORIDE:

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

A combination of Furosemide and Amiloride is a diuretic which reduces the potassium loss of furosemide alone while avoiding the possible gastro-intestinal disturbances of potassium supplements.

5.2 Pharmacokinetic Properties

FUROSEMIDE:

Approximately 65% of the dose is absorbed after oral administration. The plasma half-life is biphasic with a terminal elimination phase of about 1½ hours. Furosemide is up to 99% bound to plasma proteins and is mainly excreted in the urine, largely unchanged, but also excreted in the bile, non-renal elimination being considerably increased in renal failure. Furosemide crosses the placental barrier and is excreted in the milk.

AMILORIDE:

Approximately 50% of the dose is absorbed after oral administration and peak serum concentrations are achieved by about 3 - 4 hours. The serum half-life is estimated to be about 6 hours. Amiloride is not bound to plasma proteins. Amiloride is not metabolised and is excreted unchanged in the urine.

Pharmacokinetic studies have been completed on Frumil Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets.

FUROSEMIDE:

Cp MAX = 1/14 µg/ml SD = 0.67

Tmax = 3.0 hours

AUC = 3.17µg/ml hr SD = ± 1.25

AMILORIDE:

Cp MAX = 13.42 ng/ml SD = 5.74

Tmax = 4.0 hours

AUC = 154 ng/ml hr SD = ± 65.2

5.3 Preclinical Safety Data

No further information available

6. Pharmaceutical Particulars

6.1 List Of Excipients

Frumil tablets contain the following excipients:

Lactose

Starch Maize

Microcrystalline Cellulose

Sodium Starch Glycollate

Sunset Yellow Dye (E110)

French Chalk Powdered

Colloidal Anhydrous Silica

Magnesium Stearate

Frumil LS 20 mg/2.5 mg Tablets contain the following excipients:

Lactose

Starch Maize

Microcrystalline Cellulose

Sodium Starch Glycollate

Sunset Yellow Dye (E110)

French Chalk Powdered

Colloidal Anhydrous Silica

Magnesium Stearate

6.2 Incompatibilities

None stated

6.3 Shelf Life

The shelf-life of Frumil 40 mg/5 mg Tablets / Frumil LS 20 mg/2.5 mg Tablets is 3 years.

6.4 Special Precautions For Storage

Store below 25°C in a dry place. Protect from light.

6.5 Nature And Contents Of Container

PVC/Aluminium foil blisters (14's) in cartons with 28 or 56 tablets

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

Frumil PL 04425/0573

Frumil LS PL 04425/0574

9. Date Of First Authorisation/Renewal Of The Authorisation

20^th June 2006

10. Date Of Revision Of The Text

20^th September 2010

11. LEGAL CLASSIFICATION

POM