Furosemide 20mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Furosemide 20mg Tablets.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 20 mg furosemide.
Excipient(s) with known effect
Each tablets contains 45 mg of lactose monohydrate. For full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Tablet.
White, circular, flat bevelled edge tablet with ‘F’ scoreline 20’ embossed on one face and plain on the reverse.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
In the treatment of oedema associated with congestive heart failure, cirrhosis of the liver, renal disease including nephrotic syndrome.
In the treatment of peripheral oedema due to mild to moderate hypertension (alone, or in combination with other antihypertensive agents in the treatment of more severe cases).
Management of oliguria due to acute or chronic renal insufficiency.
4.2 Posology and method of administration
Posology
Adults and children over 12 years:
Oedema: The usual initial daily dose is 40 mg in the morning; ordinarily a prompt diuresis ensues. This may require adjustment until the effective dose is achieved. Diuresis lasts for approximately four hours following administration and hence the time of administration can be adjusted to suit the patient's requirements. In mild cases 20 mg daily or 40 mg on alternate days may be sufficient, whereas in cases of resistant oedema daily doses of 80 mg and above may be used.
In patients with chronic renal insufficiency, an initial daily dose of 250 mg is employed. If a satisfactory diuresis is not produced then the dose may be increased in steps of 250 mg at four to six hourly intervals up to a maximum daily dose of 1,500 mg in 24 hours. In exceptional cases up to 2,000 mg in 24 hours may be given.
Hypertension: 20-40 mg twice daily; if 40 mg twice daily does not lead to a clinically satisfactory response, the addition of other antihypertensive agents, rather than an increase in the dose of furosemide should be considered.
Children under 12 years: The oral dose for children ranges from 1-3 mg/kg body weight daily, up to a maximum total dose of 40mg per day.
Elderly: The usual adult dose, but caution is advised as furosemide is excreted more slowly in the elderly. Dosage should be titrated until the required response is achieved.
Dosage adjustment may be necessary in patients with
• hypoproteinaemia
• liver congestion/dysfunction
Concomitant administration of the following with furosemide should be considered (see section 4.4): Colestyramine and colestipol - Administer 2 to 3 hours apart.
Method of administration
For oral administration only. The tablets should be swallowed with water.
4.3 Contraindications
Furosemide is contra-indicated in the following circumstances:
- Hypersensitivity to the active substance or any of its excipients listed in section 6.1, sulphonamides, or sulphonamide derivatives/amiloride
- Anuria and impaired renal function (creatinine clearance below 30mL/min per 1.73 m2 body surface area) and renal failure resulting from poisoning by nephrotoxic and/or hepatotoxic agents
- Electrolyte deficiency (severe hyponatraemia: severe hypokalaemia, hypovolaemia), dehydration and/or hypotension (see section 4.4)
- Concomitant potassium supplements or potassium sparing diuretics (see section 4.5)
- Pre-coma/coma associated with hepatic cirrhosis or encephalopathy
- Addison’s disease
- Digitalis intoxication (see also section 4.5)
- Porphyria
- Breast-feeding women (see section 4.6)
4.4 Special warnings and precautions for use
Hypotension and/or hypovolaemia (see also section 4.3)
Where indicated, steps should be taken to correct hypotension or hypovolaemia, or any acid-base disturbances before commencing therapy. Regular monitoring of fluid and electrolyte balance is recommended.
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.
Dose titration/adjustment (see section 4.2)
- Patients with hypoproteinaemia (such as that associated with the nephrotic syndrome) require careful dose titration (reduced furosemide effect: increased risk of ototoxicity)
- In moderate liver congestion dosage adjustment may be needed Caution required:
- Use with caution in patients with impaired hepatic or renal function and hepato-renal syndrome, diabetes mellitus or adrenal disease. Latent diabetes may become manifest or the insulin requirements of diabetic patients may increase (see sections 4.2 & 4.3 and below - monitoring required).
- Use with care in elderly patients or those with potential obstruction in the urinary tract including prostatic hypertrophy or impairment of micturition.
- Hypotension may occur if ACE inhibitors are added to furosemide therapy. The dose of furosemide should be reduced or the drug stopped before initiating the ACE inhibitor.
- Use with caution in patients with a history of gout. Discontinue furosemide if bone marrow depression occurs.
Clinical monitoring requirements (see also section 4.8):
Regular monitoring for
- blood dyscrasias. If these occur, stop furosemide immediately
- liver damage
- idiosyncratic reactions
In premature infants there is a risk of development of nephrocalcinosis / nephrolithiasis. Renal function must be monitored and renal ultrasonography performed.
Laboratory monitoring requirements:
- frequent BUN in first few months of treatment, periodically thereafter
- serum electrolytes with replacement as appropriate
Other alterations in lab values
- Serum creatinine and urea levels tend to rise during treatment
- Serum cholesterol and triglycerides may rise but usually return to normal within 6 months of starting furosemide
- Furosemide should be discontinued before a glucose tolerance test
This product contains lactose. 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
Cardiac glycosides - Furosemide may enhance the toxicity of cardiac glycosides by electrolyte disturbance particularly potassium and magnesium.
Antihypertensives - enhanced hypotensive effect possible with all types. Concurrent use with ACE inhibitors can result in marked falls in blood pressure. Furosemide should be stopped or the dose reduced before starting an ACE-inhibitor. There is a risk of a first-dose effect with post-synaptic alpha blockers e.g. prazosin. Furosemide may interact with ACE inhibitors causing impaired renal function.
Antibiotics - increased risk of ototoxicity with aminoglycosides, polymixins or vancomycin. The nephrotoxic effect of cephaloridine and the aminoglycoside antibiotics may be increased by furosemide. Furosemide can decrease vancomycin serum levels after cardiac surgery.
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.
Lithium - The renal clearance of lithium is decreased by furosemide, resulting in increased and possibly toxic serum levels. Concomitant administration should be avoided unless plasma levels can be monitored.
Antihistamines - hypokalaemia may potentiate cardiac toxicity of certain drugs such as antihistamines
Antiarrythmics (including amiodarone, disopyramide, flecanaide and sotalol) - risk of cardiac toxicity (because of furosemide-induced hypokalaemia). It may also antagonise the action of antiarrhythmics such as lidocaine, mexiletine and tocainide.
Drugs associated with QTprolongation - cardiac toxicity may be increased by furosemide-induced hypokalaemia and/or hypomagnesaemia.
Vasodilators - enhanced hypotensive effect with moxisylyte (thymoxamine) or hydralazine.
Renin inhibitors - aliskiren reduces plasma concentrations of furosemide. Nitrates - enhanced hypotensive effect.
Chelating agents - sucralfate may decrease the gastro-intestinal absorption of furosemide - the 2 drugs should be taken at least 2 hours apart.
Lipid regulating drugs - Bile acid sequestrants (eg colestyramine: colestipol) -reduced absorption of furosemide - administer 2 to 3 hours apart.
NSAIDs - increased risk of nephrotoxicity (especially if there is hypovolaemia). Indometacin and ketorolac may antagonise the effects of furosemide. In patients with dehydration or hypovolaemia, NSAIDs may cause acute renal insufficiency.
Salicylates - effects may be potentiated by furosemide.
Antidepressants - enhanced hypotensive effect with MAOIs. Increased risk of postural hypotension with TCAs (tricyclic antidepressants). Possible increased risk of hypokalaemia with reboxetine.
Antidiabetics - hypoglycaemic effects antagonised by furosemide.
Insulin - requirements may be increased (see section 4.4).
Antiepileptics - increased risk of hyponatraemia with carbamazepine. Diuretic effect reduced by phenytoin.
Antifungals - increased risk of hypokalaemia with amphoterecin.
Anxiolytics and hypnotics - enhanced hypotensive effect. Chloral or triclorfos may displace thyroid hormone from binding site.
CNS stimulants (drugs used for ADHD) - hypokalaemia increases the risk of ventricular arrhythmias.
Corticosteroids - diuretic effect antagonised (sodium retention) and increased risk of hypokalaemia.
Cytotoxics - increased risk of nephrotoxicity and ototoxicity with platinum compounds.
Other diuretics - profound diuresis possible when furosemide given with metolazone. Increased risk of hypokalaemia with thiazides.
Dopaminergics - enhanced hypotensive effect with levodopa.
Immunomodulators - enhanced hypotensive effect with aldesleukin.
Muscle relaxants - enhanced hypotensive effect with baclofen or tizanidine (see also Anaesthetic agents below - curare).
Oestrogens andprogestogens - diuretic effect antagonized.
Prostaglandins - enhanced hypotensive effect with alprostadil.
Sympathomimetics - increased risk of hypokalaemia with high doses of beta2 sympathomimetics (such as bambuterol, femoterol, salbutamol, salmeterol and terbutaline).
Theophylline - enhanced hypotensive effect.
Probenecid - reduced renal clearance of furosemide and decreased diuretic effect.
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.
Liquorice - excess intake may increase the risk of hypokalaemia.
Fertility, pregnancy and lactation
4.6
Pregnancy
The teratogenic and embryotoxic potential of furosemide in humans is unknown. There is little evidence of safety of high-dose furosemide in human pregnancy, although the results of animal work, in general, show no hazardous effects.
Furosemide has been given after the first trimester of pregnancy for oedema, hypertension and toxaemia of pregnancy without causing foetal or new-born adverse effects. However, the drug should not be used in pregnant women unless the benefits to the patient outweigh the possible risk to the foetus which includes persistence of patent ductus arteriosus (section 4.8).
Breast-feeding
As it may inhibit lactation and passes into breast milk, furosemide should be used with caution in nursing mothers.
4.7 Effects on ability to drive and use machines
Reduced mental alertness and rarely dizziness and blurred vision have been reported. Patients so affected should not drive or operate machines.
4.8 Undesirable effects
Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); Frequency not known (cannot be estimated from the available data).
|
Blood and lymphatic system disorders: |
Uncommon: |
aplastic anaemia |
|
Rare: |
bone marrow depression (necessitates withdrawal of treatment), eosinophilia, leucopenia. | |
|
Very rare: |
haemolytic anaemia, agranulocytosis, thrombocytopenia | |
|
Metabolism and nutritional disorders: |
Very common: |
dehydration, hyponatraemia, hypochloremic metabolic alkalosis, hypocalcaemia, hypomagnesemia (incidences of the last three are reduced by triamterene) |
|
Common: |
Hypovolaemia, hypochloraemia |
|
Uncommon: |
impaired glucose tolerance (by hypokalaemia) hyperuricaemia, gout, reduction of serum HDL-cholesterol, elevation of serum LDL-cholesterol, elevation of serum triglycerides, hyperglycaemia | |
|
Very rare: |
tetany | |
|
Frequency not known: |
aggravated pre-existing metabolic alkalosis (in decompensated cirrhosis of the liver), fluid and electrolyte disturbances, excretion of potassium increased* | |
|
Psychiatric disorder: |
Rare: |
psychiatric disorder NOC |
|
Nervous system disorders: |
Rare: |
paraesthesia, confusion, headache |
|
Not known: |
dizziness, fainting and loss of consciousness (caused by symptomatic hypotension) | |
|
Eye disorders: |
Uncommon: |
visual disturbance, blurred vision, yellow vision. |
|
Ear and labyrinth disorders: |
Uncommon: |
deafness (sometimes irreversible) |
|
Rare: |
tinnitus and reversible or irreversible loss of hearing (although usually transitory, particularly in patients with renal failure, hypoproteinaemia (e.g. in nephritic syndrome) | |
|
Cardiac disorders: |
Uncommon: |
orthostatic intolerance, cardiac arrhythmias, increased risk or persistence of patent ductus arteriosus in premature infants. |
|
Vascular disorders: |
Very common: |
hypotension, (which, if pronounced may cause signs and symptoms such as impairment of concentration and reactions, lightheadedness, sensations of pressure in the head, headache, drowsiness, weakness, disorders of vision, dry mouth, orthostatic intolerance). |
|
Rare: |
vasculitis, thrombosis, shock | |
|
Gastrointestinal disorders: |
Uncommon: |
dry mouth, thirst, nausea, bowel motility disturbances, vomiting, diarrhoea, constipation |
|
Rare: |
acute pancreatitis (in long-term diuretic treatment, including furosemide). | |
|
Hepatobiliary disorders: |
Rare: |
pure intrahepatic cholestasis (jaundice), hepatic function abnormal. |
|
Skin and subcutaneous tissue disorders: |
Rare: |
rash, pruritus, photosensitivity, toxic epidermal necrolysis. |
|
Frequency not known: |
urticaria, erythema multiforme, purpura, exfoliative dermatitis, itching, allergic reactions, such as skin rashes, various forms of dermatitis including urticaria, bullous lesions, acute generalised exanthematous pustulosis (AGEP). When these occur treatment should be withdrawn. | |
|
Musculoskeletal and connective tissue disorders: |
Uncommon: |
muscle cramps, muscle weakness. |
|
Renal and urinary disorders: |
Very common: |
nephrocalcinosis in infants |
|
Uncommon: |
reduced diuresis, urinary incontinence, urinary obstruction (in patients with hyperplasia of the prostate, bladder inability to empty, urethral stricture unspecified). | |
|
Rare: |
acute renal failure. | |
|
Very rare: |
interstitial nephritis | |
|
Congenital, familial and genetic disorders: |
Rare: |
patent ductus arteriosus |
|
General disorders and administration site conditions: |
Uncommon: |
Fatigue |
|
Rare: |
malaise, fever, severe anaphylactoid or anaphylactic reactions (e.g. with shock). | |
|
Investigations: |
Common: |
creatinine increased, blood urea increased |
|
Rare: |
Transaminases increased, blood |
*Potassium deficiency manifests itself in neuromuscular symptoms (muscular weakness, paralysis), intestinal symptoms (vomiting, constipation, meterorism), renal symptoms (polyuria) or cardiac symptoms. Severe potassium depletion can result in paralytic ileus or confusion, which can result in coma.
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
Symptoms
Symptoms of overdose include dehydration, electrolyte depletion and hypotension due to excessive diuresis. In cirrhotic patients, over dosage may precipitate hepatic coma.
Management
Treatment should be aimed at fluid replacement and correction of electrolyte imbalance. The drug should be discontinued and electrolyte and water replacement instituted immediately; adjustment should be on the basis of careful monitoring. Gastric lavage may be useful if ingestion is recent.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: High-ceiling diuretics > Sulphonamide ATC Code: C03CA01
Furosemide is one of the high ceiling diuretics, a term used to denote a group of diuretics that have a distinctive action on renal tubular function. The peak diuresis is far greater than that observed with other agents.
Mechanism of action
The evidence from many experimental studies suggests that furosemide acts along the entire nephron with the exception of the distal exchange site. The main site of action is the thick ascending loop of Henle where they inhibit electrolyte re-absorption. It increases renal blood flow without increasing the filtration rate. Blood-flow is diverted from the juxta-medullary region to the outer cortex. Such a change in renal haemodynamics reduces fluid and electrolyte re-absorption in the proximal tubule and may augment the initial diuretic response.
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.
Pharmacodynamic effects
Furosemide is an inhibitor of carbonic anhydrase but this activity is too weak to contribute to a proximal diuresis except when massive doses are employed. Furosemide enhances the excretion of both calcium and magnesium to an extent approximately proportional to the increase in sodium excretion. Unlike the thiazides, high ceiling diuretics do not increase calcium re-absorption in the distal tubule. The calciuric action of these agents is the basis for their use in symptomatic hypercalcaemia.
5.2 Pharmacokinetic properties
Absorption
Furosemide is a weak carboxylic acid which exists mainly in the dissociated form in the gastrointestinal tract. Furosemide is incompletely (60-70%) but fairly rapidly absorbed from the gastrointestinal tract on oral administration and its effect is largely over within 4 hours. Bioavailability is about 65%. The optimal absorption site is the upper duodenum at pH 5.0.
Distribution
It is extensively bound to plasma proteins but is rapidly secreted by the organic acid transport system of the proximal tubule. In this manner it gains access to the tubular fluid and eventually to its site of action more distally.
Elimination
Furosemide is mainly eliminated via the kidneys (80-90%); a small fraction of the dose undergoes biliary elimination and 10-15% of the activity can be recovered from the faeces. 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 crosses the placental barrier and is excreted in milk.
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, but less than 20% residual renal function increases the elimination time.
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.
Preclinical safety data
5.3
Not relevant
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Magnesium stearate (E470b) Sodium starch glycollate Maize starch.
Starch paste 15%
6.2 Incompatibilities
Not Applicable
6.3 Shelf life
Tablet container: 5 Years Blister: 2 Years
6.4 Special precautions for storage
Tablet containers: Do not store above 25°C. Store in the original container. Keep the container tightly closed.
Blister packs: Do not store above 25°C. Store in the original package.
6.5 Nature and contents of container
Tablet container and cap (polypropylene container with low density polyethylene cap)
Pack sizes: 28, 56, 100, 250, 500 and 1000 tablets.
Blister (250 (pm white opaque PVC and 20 (pm hard temper aluminium foil). Pack sizes: 28 and 56 tablets.
6.6 Special precautions for disposal
Not applicable
7 MARKETING AUTHORISATION HOLDER
Activase Pharmaceuticals Limited 11 Boumpoulinas Nicosia 1060 Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 28444/0095
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
01/12/2010
10 DATE OF REVISION OF THE TEXT
07/11/2016