Summary of medicine characteristics - DIURESAL (FUROSEMIDE) INJECTION 10 MG / ML
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
Hypersensitivity to the active substance or any of the excipients listed in
section 6.1
Hypersensitivity to amiloride, sulphonamides or sulphonamide derivatives
Hypovolaemia and dehydration (with or without accompanying hypotension) (see section 4.4)
Severe hypokalaemia, severe hyponatraemia (see section 4.4).
Comatose or pre-comatose states associated with hepatic cirrhosis (see section 4.4)
Anuria or renal failure with anuria not responding to furosemide, renal failure as a result of poisoning by nephrotoxic or hepatotoxic agents, renal failure associated with hepatic coma
Impaired renal function with a creatinine clearance below 30ml/min per 1.73 m2 body surface area (see section 4.4)
Addison's disease (see section 4.4)
Digitalis intoxication (see section 4.5)
Porphyria
Breast-feeding women (see section 4.6)
4.4 Special warnings and precautions for use
Conditions requiring correction before furosemide is started (see also section 4.3)
Hypotension.
Hypovolaemia.
Severe electrolyte disturbances – particularly hypokalaemia, hyponatraemia and acid-base disturbances.
In patients at high risk for radiocontrast nephropathy – it should not be used for diuresis as part of the preventative measures against radiocontrast-induced nephropathy.
In patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.
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.
Older people (lower initial dose as particularly susceptible to side-effects -see section 4.2)
Difficulty with micturition including prostatic hypertrophy (increased risk of urinary retention: consider lower dose). Closely monitor patients with partial occlusion of the urinary tract
Diabetes mellitus (latent diabetes may become overt: insulin requirements in established diabetes may increase: stop furosemide before a glucose tolerance test)
Pregnancy (see section 4.6)
Gout (furosemide may raise uric acid levels/precipitate gout)
Patients with hepatorenal syndrome
Impaired hepatic function (see section 4.3 and below – monitoring required)
Impaired renal function (see section 4.3 and below – monitoring required)
Adrenal disease (see section 4.3 – contraindication in Addison's disease)
Hypoproteinaemia e.g. nephritic syndrome (effect of furosemide may be impaired and its ototoxicity potentiated – cautious dose titration required).
Acute hypercalcaemia (dehydration results from vomiting and diuresis -correct before giving furosemide). Treatment of hypercalcaemia with a high dose of furosemide results in fluid and electrolyte depletion – meticulous fluid replacement and correction of electrolyte required.
Patients who are at risk from a pronounced fall in blood pressure
Premature infants (possible development nephrocalcinosis/nephrolithiasis; renal function must be monitored and renal ultrasonography performed).
concurrent NSAIDs should be avoided – if not possible diuretic effect of furosemide may be attenuated
ACE-inhibitors & Angiotensin II receptor antagonists – severe hypotension may occur – dose of furosemide should be reduced/stopped (3 days) before starting or increasing the dose of these
Serum sodium
Particularly in the older people or in patients liable to electrolyte deficiency
Serum potassium
The possibility of hypokalaemia should be taken into account, in particular in patients with cirrhosis of the liver, those receiving concomitant treatment with corticosteroids, those with an unbalanced diet and those who abuse laxatives. Regular monitoring of the potassium, and if necessary treatment with a potassium supplement, is recommended in all cases, but is essential at higher doses and in patients with impaired renal function. It is especially important in the event of concomitant treatment with digoxin, as potassium deficiency can trigger or exacerbate the symptoms of digitalis intoxication (see section 4.5).
A potassium-rich diet is recommended during long-term use.
Frequent checks of the serum potassium are necessary in patients with impaired renal function and creatinine clearance below 60ml/min per 1.73m2 body surface area as well as in cases where furosemide is taken in combination with certain other drugs which may lead to an increase in potassium levels (see section 4.5 & refer to section 4.8 for details of electrolyte and metabolic abnormalities)
Renal function
Frequent BUN in first few months of treatment, periodically thereafter. Long term/high-dose BUN should regularly be measured. Marked diuresis can cause reversible impairment of kidney function in patients with renal dysfunction. Adequate fluid intake is necessary in such patients. Serum creatinine and urea levels tend to rise during treatment
Glucose
Adverse effect on carbohydrate metabolism – exacerbation of existing carbohydrate intolerance or diabetes mellitus. Regular monitoring of blood glucose levels is desirable.
Other electrolytes
Patients with hepatic failure/alcoholic cirrhosis are particularly at risk of hypomagnesia (as well as hypokalaemia). During long-term therapy (especially at high doses) magnesium, calcium, chloride, bicarbonate and uric acid should be regularly measured.
Regular monitoring for
blood dyscrasias. If these occur, stop furosemide immediately
liver damage
idiosyncratic reactions
Serum cholesterol and triglycerides may rise but usually return to normal within 6 months of starting furosemide
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
General: The dosage of concurrently administered cardiac glycosides, diuretics, antihypertensive agents, or other drugs with blood-pressurelowering potential may require adjustment as a more pronounced fall in blood pressure must be anticipated if given concomitantly with Furosemide.
The toxic effects of nephrotoxic drugs may be increased by concomitant administration with potent diuretics such as furosemide.
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).
Antihypertensives: Enhanced hypotensive effect possible with all types. Concurrent use with ACE inhibitors or Angiotensin II receptor antagonists can result in marked falls in blood pressure, furosemide should be stopped or the dose reduced before starting an ACE-inhibitor or Angiotensin II receptor antagonists (see section 4.4)
Antipsychotics: furosemide-induced hypokalaemia increases the risk of cardiac toxicity. Avoid concurrent use with pimozide. Increased risk of ventricular arrhythmias with amisulpride or sertindole.
Enhanced hypotensive effect with phenothiazines.
When administering 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.
Anti-arrhythmics (including amiodarone, disopyramide, flecanaide and sotalol): risk of cardiac toxicity (because of furosemide-induced hypokalaemia). The effects of lidocaine, tocainide or mexiletine may be antagonised by furosemide.
Cardiac glycosides: hypokalaemia and electrolyte disturbances (including hypomagnesia) increase the risk of cardiac toxicity.
Drugs that prolong Q-T interval: increased risk of toxicity with furosemide-induced electrolyte disturbances
Vasodilators: enhanced hypotensive effect with moxisylyte (thymoxamine) or hydralazine
Other diuretics: profound diures is possible when furosemide given with metolazone.
Increased risk of hypokalaemia with thiazides.
Renin inhibitors: aliskiren reduces plasma concentrations of furosemide
Nitrates: enhanced hypotensive effect
Lithium: In common with other diuretics, serum lithium levels may be
increased when lithium is given concomitantly with furosemide, 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.
Chelating agents: sucralfate may decrease the gastro-intestinal absorption of furosemide – the 2 drugs should be taken at least 2 hours apart
NSAIDs: increased risk of nephrotoxicity. Indometacin and ketorolac may antagonise the effects of furosemide (avoid if possible see section 4.4). NSAIDs may attenuate the action of furosemide and may cause acute renal failure in cases of pre-existing hypovolaemia or dehydration.
Salicylates: effects may be potentiated by furosemide. Salycylic toxicity may be increased by furosemide
Antibiotics: increased risk of ototoxicity with aminoglycosides, polymixins or vancomycin – only use concurrently if compelling reasons. Increased risk of nephrotoxicity with aminoglycosides or cefaloridine. Furosemide can decrease vancomycin serum levels after cardiac surgery. Increased risk of hyponatraemia with trimethoprim. Impairment of renal function may develop in patients receiving concurrent treatment with furosemide and high doses of certain cephalosporins.
Antidepressants: enhanced hypotensive effect with MAOIs. Increased risk of postural hypotension with TCAs (tricyclic antidepressants). Increased risk of hypokalaemia with reboxetine
Antidiabetics: hypoglycaemic effects antagonised by furosemide
Antiepileptics: increased risk of hyponatraemia with carbamazepine. Diuretic effect reduced by phenytoin.
Antihistamines: hypokalaemia with increased risk of cardiac toxicity
Antifungals: increased risk of hypokalaemia and nephrotoxicity with amphotericin
Anxiolytics and hypnotics: enhanced hypotensive effect. Chloral or triclorfos may displace thyroid hormone from binding site.
CNS stimulants (drugs usedfor ADHD): hypokalaemia increases the risk of ventricular arrhythmias
Corticosteroids: diuretic effect anatgonised (sodium retention) and increased risk of hypokalaemia
Glychyrrizin: (contained in liquorice) may and increase the risk of developing hypokalaemia.
Cytotoxics: increased risk of nephrotoxicity and ototoxicity with platinum compounds/cisplatin. 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.
Anti-metabolites: effects of furosemide may be reduced by methotrexate and furosemide may reduce renal clearance of methotrexate
Dopaminergics: enhanced hypotensive effect with levodopa.
Immunomodulators: enhanced hypotensive effect with aldesleukin. Increased risk of hyperkalaemia with ciclosprin and tacrolimus.
Increased risk of gouty arthritis with ciclosporin
Muscle relaxants: enhanced hypotensive effect with baclofen or tizanidine. Increased effect of curare-like muscle relaxants
Oestrogens: diuretic effect antagonised
Progestogens (drosperidone): increased risk of hyperkalaemia
Prostaglandins: enhanced hypotensive effect with alprostadil
Sympathomimetics: increased risk of hypokalaemia with high doses of beta2 sympathomimetics
Theophylline: enhanced hypotensive effect
Probenecid: effects of furosemide may be reduced by probenecid and furosemide may reduce renal clearance of probenecid.
Anaesthetic agents: general anaesthetic agents may enhance the hypotensive effects of furosemide. The effects of curare may be enhanced by furosemide.
Alcohol: enhanced hypotensive effect
Laxative abuse: increases the risk of potassium loss
Others: Concomitant administration of aminoglutethimide may increase the risk of hyponatraemia.
4.6 Fertility, pregnancy and lactation
Pregnancy
Furosemide crosses the placental barrier and should not be given during pregnancy unless there are compelling medical reasons. It should only be used for the pathological causes of oedema which are not directly or indirectly linked to the pregnancy. The treatment with diuretics of oedema and hypertension caused by pregnancy is undesirable because placental perfusion can be reduced, so, if used, monitoring of fetal growth is required. However, furosemide has been given after the first trimester of pregnancy for oedema, hypertension and toxaemia of pregnancy without causing fetal or newborn adverse effects.
Breast-feeding (see section 4.3)
Furosemide is contraindicated as it passes into breast milk and may inhibit lactation.
4.7 Effects on ability to drive and use machines
Reduced mental alertness, dizziness and blurred vision have been reported, particularly at the start of treatment, with dose changes and in combination with alcohol. Patients should be advised that if affected, they should not drive, operate machinery or take part in activities where these effects could put themselves or others at risk.
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 (>1/1000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000, including isolated reports); not known (cannot be estimated from the available data):
| System Organ Class | Adverse Drug Reactions- Frequency Category | |||
| Uncommon (> 1/1000 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) | |
| Blood and lymphatic system disorders | Thrombocytopenia | Eosinophilia Leucopenia Bone marrow depression (necessitates withdrawal of treatment). The haemopoietic status should be regularly monitored. | Aplastic anaemia Haemolytic anaemia Agranulocytosis | |
| Immune system disorders | Severe anaphylactic or anaphylactoid reactions (e.g. with shock) | |||
| Nervous system disorders | Paraesthesia Hyperosmolar coma | Impairment of concentration and reactions Light-headedness Sensations of pressure in the head Headache Drowsiness Weakness Confusion Dizziness, fainting and loss of consciousness (caused by symptomatic hypotension) | |
| Endocrine disorders | Decrease in glucose tolerance | ||
| Eye disorders Visual disturbance | Disorders of vision | ||
| Ear and Deafness labyrinth (sometimes disorders irreversible) | Hearing disorders Tinnitus | ||
| Cardiac Cardiac disorders arrhythmias | Reduction in blood pressure Disorders of cardiac rhythm |
| Hepatobiliary disorders | Intrahepatic cholestasis Increase in liver transaminases Acute pancreatitis Hepatic encephalopathy | ||
| Vascular disorders | Vasculitis | Orthostatic intolerance Thrombosis |
| Skin and subcutaneous tissue disorders | Photosensitivity | Itching Urticaria Other rashes or bullous lesions Fever Hypersensitivity to light Exsudative erythema multiforme (Lyell’s syndrome and Stevens-Johnson syndrome) Bullous exanthema Exfoliative dermatitis Purpura DRESS (Drug rash with eosinophilia and systemic symptoms) | AGEP (acute generalised exanthematous pustulosis) |
| Metabolism and nutrition disorders: | Electrolyte and water imbalance1 Hyponatraemia Hypokalaemia Hypochloraemia Hypomagnesaemia Metabolic alkalosis Hypovolaemia2 cholesterol and triglyceride levels3 Decrease in glucose 4 tolerance Hyperuricaemia Gout | |||
| Congenital, familial and genetic disorders | Persistence of patent ductus arteriosus (in premature infants) | |||
| Gastrointestinal disorders | Nausea Vomiting Diarrhoea Dry mouth Thirst Bowel motility disturbances Constipation | Acute pancreatitis | ||
| 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) |
Additional information
1 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.
2
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 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 OverdoseSymptoms:
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 those designated to reduce absorption (e.g. activated charcoal).
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: diuretics, ATC code: C03CA01
The evidence from many experimental studies suggests that furosemide acts along the entire nephron with the exception of the distal exchange site. The main effect is on the ascending limb of the loop of Henle with a complex effect on renal circulation. Blood-flow is diverted from the juxta-medullary region to the outer cortex. The principle renal action of furosemide is to inhibit active chloride transport in the thick ascending limb. Re-absorption of sodium chloride from the nephron is reduced and a hypotonic or isotonic urine produced. It has been established that prostaglandin (PG) biosynthesis and the renin-angiotensin system are affected by furosemide administration and that furosemide alters the renal permeability of the glomerulus to serum proteins.
5.2 Pharmacokinetic properties
5.2 Pharmacokinetic propertiesFurosemide 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 radiolabelled 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 1015% 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.
6.1 List of excipients
Sodium chloride, sodium hydroxide and water for injections.
6.2 Incompatibilities
Not known.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
Store in a cool dry place. Protect from light.
6.5 Nature and contents of container
Sterile amber glass ampoules.
2ml in packs of 10 and 25.
5ml in packs of 5.
6.6 Special precautions for disposal
6.6 Special precautions for disposalDiuresal* Injection should not be mixed with any other preparation.
Opened ampoules should be used immediately, and any material remaining should be discarded.
7 MARKETING AUTHORISATION HOLDER
Ennogen Pharma Limited
Unit G4,
Riverside Industrial Estate,
Riverside Way,
Dartford
DA1 5BS
8 MARKETING AUTHORISATION NUMBER(S)
PL 40147/0040
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
11/08/2012