Frusol 40mg/5ml Oral Solution
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Frusol 40mg/5ml Oral Solution
2. QAUALITATIVE AND QUANTITATIVE COMPOSITION
Each 5ml contains 40 milligrams Furosemide Excipient(s) with known effect:
Each 5ml Oral Solution contains 0.5ml ethanol and 2.5g liquid maltitol.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM Oral Solution
4 CLINICAL PARTICULARS
4.1. Therapeutic Indications
Furosemide is indicated in all conditions requiring prompt diuresis, including cardiac, pulmonary, hepatic and renal oedema, peripheral oedema due to mechanical obstruction or venous insufficiency and hypertension.
It is also indicated for the maintenance therapy of mild oedema of any origin.
4.2. Posology and method of administration
Posology
Adults
The usual initial daily dose is 40mg. This may be adjusted until an effective dose is achieved.
Paediatric population
1 to 3mg/Kg body weight daily up to a maximum total dose of 40mg/day. Elderly
In the elderly, Furosemide is generally eliminated more slowly. Dosage should be titrated until the required response is achieved.
Method of administration
For oral use.
Suitable for administration via nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes. For further instructions see section 6.6.
The medication should be administered in the morning to avoid nocturnal diuresis.
4.3 Contraindications
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Contra-indicated conditions |
See also |
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Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or sulphonamides, sulphonamide derivatives. |
- |
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Hypovolaemia and dehydration (with or without accompanying hypotension) |
Section 4.4 |
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Severe hypokalaemia: severe hyponatraemia |
Section 4.4 |
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Comatose or pre-comatose states associated with hepatic cirrhosis |
Section 4.4 |
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Anuria or renal failure with anuria not responding to furosemide, renal failure as a result of poisoning by nephrotoxic or hepatotoxic agents | |
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Impaired renal function with a creatinine clearance below 30ml/min per 1.73 m2 body surface area |
Section 4.4 |
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Addison’s disease |
Section 4.4 |
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Digitalis intoxication |
Section 4.5 |
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Concomitant potassium supplements or potassium sparing diuretics |
Section 4.5 |
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Breast-feeding women |
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
Furosemide is not recommended
• 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 elderly patients with dementia taking risperidone - Increased mortality (see below and section 4.5)
Particular caution and/or dose reduction required:
• elderly patients (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)
• impaired hepatic function - hepatic failure and alcoholic cirrhosis particularly predispose to hypokalaemia and hypomagnesaemia (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)
• hypoproteinemia e.g. nephrotic 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
• premature infants - possible development of nephrocalcinosis/ nephrolithiasis (see below - monitoring of renal function required)
• some diuretics have been considered unsafe in acute porphyria
Avoidance with other medicines (see also section 4.5 for other interactions)
• 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
• concurrent risperidone in elderly patients with dementia has resulted in increased mortality - no mechanism for and no consistent pattern of deaths identified (see section 4.5)
Laboratory and other monitoring requirements:
• Serum sodium
Particularly in the elderly 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. If used in premature infants there is a risk of nephrocalcinosis/nephrolithiasis so renal function must be monitored and renal ultrasonography performed
• 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 hypomagnesemia (as well as hypokalaemia). During long-term therapy (especially at high doses) magnesium, calcium, chloride, bicarbonate and uric acid should be regularly measured.
Clinical monitoring requirements (see also section 4.8):
Regular monitoring for
• blood dyscrasias. If these occur, stop furosemide immediately
• liver damage
• idiosyncratic reactions
Excipient Warnings
• Ethanol (Alcohol) - This medicinal product contains 10% v/v ethanol (alcohol), i.e. up to 0.4g per 5ml of dose.
• Liquid Maltitol - This medicinal product also contains liquid maltitol. Patients with a rare hereditary problem of fructose intolerance should not take this medicine
4.5. Interaction with other medicinal products and other forms of interaction
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). Increased risk of first dose hypotension with post-synaptic alpha-blockers (eg prazosin).
Antipsychotics - furosemide-induced hypokalaemia increases the risk of cardiac toxicity. Avoid concurrent use with pimozide. Increased risk of ventricular arrhythmias with pimozide (avoid concurrent use), amisulpride or sertindole. Enhanced hypotensive effect with phenothiazines.
In placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone. No consistent pattern for cause of death was observed but caution should be exercised and the risks and benefits of this combination considered prior to the decision to use.
Anti-arrhythmics (including amiodarone, disopyramide, flecainide 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 hypomagnesemia) 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 diuresis possible when furosemide given with metolazone. Increased risk of hypokalaemia with thiazides. Contraindicated with potassium sparing diuretics (eg amiloride spironolactone) - increased risk of hyperkalaemia (see section 4.3). Concurrent use with tetracyclines may increase the risk of rising BUN (see section 4.4 - monitoring).
Renin inhibitors - aliskiren reduces plasma concentrations of furosemide.
Nitrates - enhanced hypotensive effect.
Lithium - furosemide reduces lithium excretion with increased plasma lithium concentrations (risk of cardio- and/or neuro-toxicity). Avoid concomitant administration unless plasma levels are monitored.
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 (especially with pre-existing hypovolaemia/dehydration. Indometacin and ketorolac may antagonise the effects of furosemide (avoid if possible see section 4.4).
Salicylates - effects may be potentiated by furosemide. Salicylic 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.
Antiviral - plasma concentrations of diuretics may be increased by nelfinavir, ritonavir or saquinavir.
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 hydrate or triclofos may displace thyroid hormone from binding site.
CNS stimulants (drugs used for ADHD) - hypokalaemia increases the risk of ventricular arrhythmias.
Corticosteroids - diuretic effect anatgonised (sodium retention) and increased risk of hypokalaemia.
Cytotoxics - increased risk of nephrotoxicity and ototoxicity with platinum compounds/cisplatin.
Anti-metabolites - effects of furosemide may be reduced by methotrexate and furosemide may reduce renal clearance of methotrexate
Potassium salts - contraindicated - increased risk of hyperkalaemia (see section 4.3)
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 (drospirenone) - 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.
Warfarin and clofibrate - compete with furosemide in binding to serum albumin - possibly significant if this is low (eg nephrotic syndrome).
Aminoglutethimide - concomitant use may increase the risk of hyponatraemia
Alcohol - enhanced hypotensive effect
Laxative abuse - increases the risk of potassium loss
4.6. Pregnancy and Lactation
Frusol must not be given during pregnancy unless there are compelling medical reasons
Furosemide may inhibit lactation and may pass into breast milk. Women must not breastfeed if they are treated with furosemide.
4.7. Effects on Ability to Drive and Use Machines
Mental alertness may be reduced and the ability to drive or operate machinery may be impaired.
4.8. Undesirable Effects
The side effects are generally minor and Furosemide is well tolerated.
General
Side effects of a minor nature such as nausea, malaise, gastric upset (vomiting or diarrhoea) may occur but are not usually severe enough to necessitate withdrawal of treatment.
Disturbance of electrolytes and water balance (see also section 4.4). Furosemide leads to increased excretion of sodium, chloride, water and other electrolytes (in particular potassium, calcium and magnesium). Symptomatic electrolyte disturbances and metabolic acidosis may develop either gradually or acutely (with higher furosemide doses). Pre-existing metabolic alkalosis (e.g. in decompensated cirrhosis of the liver) may be aggravated by furosemide treatment.
Signs of electrolyte disturbances include increased thirst, headache, hypotension, confusion, muscle cramps, tetany, muscle weakness, disorders of cardiac rhythm and gastrointestinal symptoms.
The diuretic action of furosemide may lead to or contribute to hypovolaemia and dehydration, especially in dehydrated patients. Severe fluid depletion may lead to haemoconcentration with a tendency for thrombosis to develop.
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.
Other blood biochemistry
Treatment with furosemide may lead to transitory increases in blood creatinine and urea levels and to an increase in cholesterol and triglyceride levels. Serum levels of uric acid may increase and attacks of gout may occur (see section 4.4).
Bladder outlet obstruction
Increased production of urine may provoke or aggravate any obstruction of urinary outflow (including prostatic hyperplasia or narrowing of the urethra) and acute retention of urine with possible secondary complications may occur.
Haematological
Aplastic anaemia and bone marrow depression has been reported as a rare complication and necessitate withdrawal of treatment.
Occasionally, thrombocytopenia may occur with rare cases of leucopenia and eosinophilia and isolated cases of agranulocytosis and haemolytic anaemia.
Tetany and reduced serum calcium
Serum calcium levels may be reduced; in very rare cases tetany has been observed. Nephrocalcinosis/nephrolithiasis has been reported in premature infants.
Control of glucose
Glucose tolerance may decrease with furosemide. In patients with diabetes mellitus this may lead to deterioration of metabolic control; latent diabetes mellitus may become manifest.
Hearing disorders
Hearing disorders and tinnitus, although usually transitory, may occur in rare cases, particularly in patients with renal failure with hypoproteinemia (e.g. in nephrotic syndrome.) See also section 4.4.
Anaphylaxis and allergic reactions
Severe anaphylactic or anaphylactoid reactions (e.g. with shock) occur rarely. The incidence of allergic reactions such as skin rash, photosensitivity, vasculitis, fever, interstitial nephritis, or shock is very low but treatment should be withdrawn when these occur.
Hepato-biliary disorders
Pure intra hepatic cholestasis, hepatic function abnormal, increase in liver transaminases. Isolated cases of acute pancreatitis and jaundice have been reported after long term diuretic therapy.
Skin and mucous membrane
Skin and mucous membrane reactions may occasionally occur, e.g. itching, urticaria, other rashes or bullous lesions, erythema multiforme, exfoliative dermatitis, purpura. Steven-Johnson’s syndrome, toxic epidermal necrolysis may occasionally occur.
Nervous system disorders
Rarely, paraesthesia may occur. Psychiatric disorder NOC.
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. Risk of nephrocalcinosis/nephroliathiasis (see Tetany and reduced serum calcium and section 4.4 re monitoring).
Renal and urinary disorders Reduced diuresis, urinary incontinence.
Hepatic encephalopathy in patients with hepatocellular insufficiency may occur.
4.9. Overdose
Overdosing may lead to dehydration and electrolyte depletion through excessive diuresis. Severe potassium loss may lead to serious cardiac arrhythmias.
Treatment of overdose consists of fluid replacement and electrolyte imbalance correction.
5 PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic Properties
Pharmacotherapeutic group:
High-Ceiling Diuretic Sulfonamide - CO3C A 01
Furosemide is a potent loop diuretic which inhibits sodium and chloride reabsorption at the Loop of Henle. The drug eliminates both positive and negative free water production. Furosemide acts at the luminal face of the epithelial cells by inhibiting co-transport mechanisms for the entry of sodium and chloride. Furosemide gains access to its site of action by being transported through the secretory pathway for organic acids in the proximal tubule. It reduces the renal excretion of uric acid. Furosemide causes an increased loss of potassium in the urine and also increases the excretion of ammonia by the kidney.
5.2. Pharmacokinetic Properties
When oral doses of Furosemide are given to normal subjects the mean bioavailability of the drug is approximately 52% but the range is wide. In plasma, Furosemide is extensively bound to proteins mainly to albumin. The unbound fraction in plasma averages 2 - 4% at therapeutic concentrations. The volume of distribution ranges between 170 - 270ml/Kg. The half life of the B phase ranges from 45 - 60 min. The total plasma clearance is about 200ml/min. Renal excretion of unchanged drug and elimination by metabolism plus faecal excretion contribute almost equally to the total plasma clearance. Furosemide is in part cleared by the kidneys in the form of the glucuronide conjugate.
5.3.
Pre-clinical Safety Data
Furosemide is a widely used diuretic which has been available for over thirty years and its safety profile in man is well established.
6 PHARMACEUTICAL PARTICULARS
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Ethanol, sodium hydroxide, cherry flavour (containing ethanol and propylene glycol), liquid maltitol (E965), disodium hydrogen phosphate (E339), citric acid monohydrate (E330) and purified water.
6.2. Incompatibilities
None known
6.3. Shelf life
24 months
3 months after opening
6.4. Special precautions for storage
Store at or below 25°C.
6.5. Nature and Contents of Container
Bottles: Amber (Type III) glass
Closures: HDPE, EPE wadded, tamper evident, child resistant
Capacity: 150ml.
6.6. Special precautions for disposal and other handling
Keep out of the sight and reach of children.
Instruction for administration via nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes:
Ensure that the enteral feeding tube is free from obstruction before administration.
1. Flush the enteral tube with water, a minimum flush volume of 5mL is required.
2. Administer the required dose of Furosemide Oral Solution gently and slowly into enteral tube, with a suitable measuring device.
3. Flush the enteral tube with water again. A minimum flush volume of 5mL is required. However, for large bore size tubes (18 Fr) a minimum flush volume of 10mL should be used.
This product has not been tested with latex NG or PEG tubes and therefore should not be used with tubes made from latex.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Rosemont Pharmaceuticals Ltd
Yorkdale Industrial Park
Braithwaite Street
Leeds
LS11 9XE
UK
8. MARKETING AUTHORISATION NUMBER
PL 00427/0110
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06/04/1998 / 31/03/2003
10 DATE OF REVISION OF THE TEXT
01/06/2015