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1. Diuresal (Furosemide) Injection 10mg/Ml
2. Diuresal (Furosemide) Injection 10mg/Ml

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Diuresal* (Furosemide) Injection 10mg/ml.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1ml contains furosemide BP 10mg.

3 PHARMACEUTICAL FORM

Liquid for injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Diuretic. Oedema of cardiac, hepatic or renal origin, pulmonary oedema, toxaemia of pregnancy, and mild or moderate hypertension, toxaemia of pregnancy

4.2 Posology and method of administration

Diuresal* Injection may be used when oral application of furosemide is precluded or in cases of emergency.

Adults:

Intravenous injections of Diuresal* must be given slowly. In cases of emergency or when oral therapy is precluded, an initial dose of 2ml to 4ml (20 to 40mg) intramuscularly or intravenously is recommended. Further adjustment may then be necessary according to the observed clinical response.

Children:

Parenteral doses for children range from 0.5mg to 1.5mg per kilogram body weight daily.

Elderly:

In the elderly furosemide is generally eliminated more slowly. Dosage should be adjusted according to the observed clinical response.

Method of administration: by intravenous infusion or intramuscular injection.

4.3 Contraindications

Diuresal * is contraindicated in electrolyte deficiency or digitalis intoxication, and should be used with great caution in advanced renal failure.

Hypersensitivity to furosemide or any of the excipients of this product.

Hypersensitivity to sulphonamides or sulphonamide derivatives (because of crosssensitivity between sulphonamides and furosemide).

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

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.

Pre-comatose and comatose states associated with hepatic encephalopathy or liver cirrhosis.

Severe hypokalaemia, severe hyponatraemia.

Addison's disease Porphyria

Breast feeding women

4.4 Special warnings and precautions for use

Diuresal * should not be mixed with any other preparation. Opened ampoules should be used immediately, and any material remaining should be discarded.

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.

Particular caution and/or dose reduction required

Symptomatic hypotension leading to dizziness, fainting or loss of consciousness cana 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 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 hepatorenal syndrome

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

•    premature infants (possible development nephrocalcinosis/nephrolithiasis; renal function must be monitored and renal ultrasonography performed).

Caution should be observed in patients liable to electrolyte deficiency. Regular monitoring of serum sodium, potassium and creatinine is generally recommended during furosemide 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 furosemide. 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.

Intravenous administration rate should not usually exceed 4 mg/minute, however single doses of up to 80 mg may be administered more rapidly; a lower infusion rate may be considered in those with renal impairment.

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).

4.5 Interaction with other medicinal products and other forms of interaction

The dosage of concurrently administered cardiac glycosides, diuretics, antihypertensive 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 Furosemide.

Furosemide may also precipitate diabetes, or necessitate increased dosage of insulin.

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 Furosemide 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.

Enhanced hypotensive effect when diuretics are given with adrenergic neurone blockers, diazoxide, sodium nitroprusside, aldesleukin, alprostadil, general anaesthetics, anxiolytics and hypnotics, baclofen, clonidine, hydralazine, levodopa, MAOIs, methyldopa, minoxidil, moxisylyte, moxonidine, phenothiazines, tizanidine, prazosin, beta blockers and calcium channel blockers.

There is increased risk of postural hypotension when diuretics given with tricyclics

The toxic effects of nephrotoxic drugs like cephaloridine, amphotericine and the aminoglycoside antibiotics may be increased by concomitant administration with potent diuretics such as furosemide.

Oral furosemide 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.

Furosemide may reduce the elimination of lithium, 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.

Certain non-steroidal anti-inflammatory agents (e.g. indometacin, acetylsalicylic acid) may attenuate the action of furosemide and may cause acute renal failure in cases of pre-existing hypovolaemia or dehydration. Diuretics increase risk of nephrotoxicity of NSAIDs , also antagonism of diuretic effect.

Salicylic toxicity may be increased by furosemide. Furosemide decreases the effects of some drugs (e.g. antidiabetics and pressor amines) and may potentiate the effects of others (e.g. salicylates, and curare type muscle relaxants).

Furosemide may potentiate the ototoxicity of aminoglycoside and other ototoxic drugs. Since this may lead to irreversible damage, these drugs must only be used with furosemide 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.

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).

Concomitant administration of carbamazepine may increase the risk of hyponatraemia.

Concurrent administration of corticosteroids may cause sodium retention.

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

Increased risk of hypokalaemia when loop diuretics are given with acetazolamide, theophylline

Potassium depletion that can result from furosemide administration may potentiate digitalis toxicity. Hypokalaemia caused by loop diuretics increases cardiac toxicity with amiodarone, disopyramide, flecainide. Hypokalaemia caused by loop diuretics antagonises action of lidocaine (lignocaine).

Attenuation of the effect of Furosemide may occur following concurrent administration of phenytoin.

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

Probenecid may reduce the renal clearance of Furosemide. 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.

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.

4.6    Fertility, pregnancy and lactation

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.

Furosemide passes into breast milk and may inhibit lactation. Women must not breast-feed if they are treated with furosemide. Furosemide should not be used to treat gestational hypertension.

4.7    Effects on ability to drive and use machines

Nausea has been reported to occur with Furosemide.

In patients receiving diuretics, some reduction in mental alertness may impair ability to drive or to operate machinery.

4.8 Undesirable Effects

Adverse reactions reported for furosemide are given below according to organ systems. The frequencies of the adverse reactions are classified as follows: very common( >1/10); common (>1/100 to < 1/10); uncommon (>1/100 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):

System Organ Class		Adverse Drug Reactions- Frequency Category
	Uncommon	Rare	Very Rare	Not known
	(> 1/100 to <1/10)	(i 1/10,000 to <1/1,000)	(<1/10,000)	(cannot be estimated from the available data)
Blood and lymphatic system disorders		Eosinophilia Leucopenia Bone marrow depression (may necessitate withdrawal of treatment)		*Thrombocytopenia *Agranulocytosis Aplastic anaemia *Haemolytic anaemia
Immune system disorders		Severe anaphylactic or anaphylactoid reactions (e.g. with shock)		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.
Metabolism and nutrition disorders				Electrolyte and water imbalance1 *Hyponatraemia Hypokalaemia *Hypochloraemia *Hypomagnesaemia
				*Metabolic alkalosis
				*Hypovolaemia2 *Dehydration

			cholesterol and triglyceride levels3 *Decrease in glucose tolerance4 *Hyperuricaemia Gout
Nervous system disorders	Paraesthesia		Impairment of concentration and reactions Light-headedness Sensations of pressure in the head *Headache Drowsiness Weakness *Confusion Dizziness, fainting or loss of consciousness (caused by symptomatic hypotension)
Eye disorders			Disorders of vision
Ear and Deafness labyrinth (sometimes disorders irreversible)	Hearing disorders Tinnitus
Cardiac disorders			*Disorders of cardiac rhythm *Persistence of patent ductus arteriosus (in premature infants)
Vascular disorders			*Hypotension

			*Orthostatic intolerance
Gastrointestinal disorders			*Nausea *Vomiting *Diarrhoea *Dry mouth *Thirst
Hepatobiliary disorders			*Intrahepatic cholestasis Increase in liver transaminases Acute pancreatitis Hepatic encephalopathy
Skin and subcutaneous tissue disorders			*Itching Urticaria Skin rashes Bullous lesions Erythema multiforme Bullous pemphigoid Stevens-Johnson Syndrome *Toxic epidermal necrolysis Exfoliative dermatitis, Purpura

			*AGEP (acute generalised exanthematous pustulosis) and DRESS (Drug rash with eosinophilia and systemic symptoms)
Musculoskeletal and connective tissue disorders		Tetany	*Muscle cramps *Muscle weakness Hypocalcaemia
Renal and urinary disorders			Increase in blood creatinine and urea levels Increased production of urine *Nephrocalcinosis / Nephrolithiasis (in premature infants)
General disorders and administration site conditions			*Malaise *Fever Pain at injection site (intramuscular injection)

*These ADRs have been observed in different frequency categories with oral formulations of Furosemide

Additional information

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. 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.

Severe fluid depletion may lead to haemoconcentration with a tendency for thromboses to develop.

3

During long term therapy they will usually return to normal within six months.

⁴In patients with diabetes mellitus this may lead to a deterioration of metabolic control; latent diabetes mellitus may become manifest.

Paediatric population

Nephrocalcinosis / Nephrolithiasis has been reported in premature infants.

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

Other special populations

Elderly patients

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

Patients with hepatic impairment

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

Pre-existing metabolic alkalosis (e.g. in decompensated cirrhosis of the liver) may be aggravated by furosemide treatment.

Patients with renal impairment

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.

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.

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

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, this corrective action may necessitate general and specific intensive medical monitoring and therapeutic measures.

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

Furosemide is a potent diuretic.

It is an anthranilic acid derivative and chemically it is 4-chloro-N-furfuryl-5-sulphamoylanthranilic acid. Furosemide inhibits the reabsorption of sodium and chloride in the loop of Henle as well as in the proximal and distal tubules; its action is independent of any inhibitory effect on carbonic anhydrase. The urinary excretion of potassium, calcium and magnesium is increased by furosemide. Hyperuricaemia may occur and is presumed to result from a competitive inhibition of urate secretion in the proximal tubules.

Furosemide has a steep dose-response curve and is designated a high-ceiling diuretic. Following intravenous administration, the onset of diuresis is within 5 minutes and the duration of diuretic effect is approximately two hours.

Pharmacokinetic properties

In a study when Diuresal *injection containing 40mg of furosemide was given intravenously to volunteers, the serum concentrations ranged from 1.3pg/ml to 8.3pg/ml (mean 3.9pg/ml) half an hour after the injection and 0 to 0.9pg/ml (mean 0.4pg/ml) 6 hours thereafter.

Furosemide is extensively bound to plasma proteins and is mainly excreted in the urine, largely unchanged. Furosemide glucuronide is the main biotransformation product.

Furosemide has a biphasic half-life in patients with a terminal elimination phase of approximately 1.5 hours. Although mainly excreted in the urine, variable amounts are also excreted in bile and non-renal elimination may be considerably increased in renal failure.

Furosemide is a weak carboxylic acid which exists mainly in the dissociated form in the gastrointestinal tract. Furosemide is rapidly but incompletely absorbed (60-70%) on oral administration and its effect is largely over within 4 hours. The optimal absorption site is the upper duodenum at pH 5.0. Regardless of route of administration 69-97% of activity from a radio-labelled dose is excreted in the first 4 hours after the drug is given. Furosemide is bound to plasma albumin and little biotransformation takes place. Furosemide is mainly eliminated via the kidneys (8090%); a small fraction of the dose undergoes biliary elimination and 10-15% of the activity can be recovered from the faeces.

In renal/ hepatic impairment

Where liver disease is present, biliary elimination is reduced up to 50%. Renal impairment has little effect on the elimination rate of Furosemide Injection, but less than 20% residual renal function increases the elimination time.

The elderly

The elimination of furosemide is delayed in the elderly where a certain degree of renal impairment is present.

New born

A sustained diuretic effect is seen in the newborn, possibly due to immature tubular function.

5.3 Preclinical safety data

Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride, sodium hydroxide and water for injections.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/08/2012

DATE OF REVISION OF THE TEXT

13/04/2016