Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Mercury Pharma International Ltd, 4045, Kingswood Road, City West Business Park, Co Dublin, Ireland
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, the Lapp lactase deficiency or glucose-galactose malabsorption.
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.
Particularly in the elderly people or in patients liable to electrolyte deficiency
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).
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.
Adverse effect on carbohydrate metabolism – exacerbation of existing carbohydrate intolerance or diabetes mellitus. Regular monitoring of blood glucose levels is desirable.
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:
Serum cholesterol and triglycerides may rise but usually return to normal within 6 months of starting furosemide.
In risperidone placebo-controlled trials in elderly people 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).
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 furosemide.
The toxic effects of nephrotoxic drugs may be increased by concomitant administration of 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 used for 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.
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.
Furosemide is contraindicated as it passes into breast milk and may inhibit lactation.
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.
Undesirable effects can occur with the following frequencies: 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, including isolated reports), not known (cannot be estimated from the available data).
Uncommon: Thrombocytopenia
Rare: Eosinophilia, Leukopenia, Bone marrow depression (necessitates withdrawal of treatment). The haemopoietic status should be therefore be regularly monitored.
Very Rare: Aplastic anaemia or haemolytic anaemia, Agranulocytosis
Rare: Paraesthesia, Hyperosmolar coma
Not known: Dizziness, fainting and loss of consciousness (caused by symptomatic hypotension).
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. Insulin requirements of diabetic patients may increase.
Uncommon: Visual disturbance
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 intravenons furosemide has been given too rapidly.
Uncommon: Deafness (sometimes irreversible)
Uncommon: Cardiac arrhythmias
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. The diuretic effect of furosemide can result in hypovolaemia and dehydration, especially in the elderly. There is an increased risk of thrombosis.
In isolated cases, intrahepatic cholestasis, an increase in liver transaminases or acute pancreatitis may develop.
Hepatic encephalopathy in patients with hepatocellular insufficiency may occur (see Section 4.3).
Rare: Vasculitis
Uncommon: Photosensitivity
Rare: Skin and mucous membrane reactions may occasionally occur, e.g. 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, AGEP (acute generalized exanthematous pustulosis) and DRESS (Drug rash with eosinophilia and systemic symptoms).
Not Known: Bullous Pemphigoid
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 increase excretion of water. In addition, excretion of other electrolytes (in particular potassium, calcium and magnesium) is increased.
Metabolic acidosis can also occur. The risk of this abnormality increases at higher dosages and is influenced by the underlying disorder (e.g. cirrhosis of the liver, heart failure), concomitant medication (see section 4.5) and diet.
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
Symptoms of electrolyte imbalance depend on the type of disturbance:
Sodium deficiency can occur; this can manifest itself in the form of confusion, muscle cramps, muscle weakness, loss of appetite, dizziness, drowsiness and vomiting.
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.
Magnesium and calcium deficiency result very rarely in tetany and heart rhythm disturbances.
Serum calcium levels may be reduced; in very rare cases tetany has been observed.
Nephrocalcinosis/Nephrolithiasis has been reported in premature infants.
Serum cholesterol (reduction of serum HDL-cholesterol, elevation of serum LDL-cholesterol) and triglyceride levels may rise during furosemide treatment. During long term therapy they will usually return to normal within six months
As with other diuretics, treatment with furosemide may lead to transitory increase in blood creatinine and urea levels. Serum levels of uric acid may increase and attacks of gout may occur.
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.
Uncommon: Fatigue
Rare: Severe anaphylactic or anaphylactoid reactions (e.g. with shock) occurs rarely, Fever, Malaise
Uncommon: Dry mouth, thirst, nausea, bowel motility disturbances, vomiting, diarrhea, constipation.
Rare: Acute Pancreatitis, Gastro-intestinal disorders such as nausea, malaise or gastric upset (vomiting or diarrhoea) and constipation may occur but not usually severe enough to necessitate withdrawal of treatment.
Uncommon: Serum creatinine and urea levels can be temporarily elevated during treatment with furosemide.
Rare: Interstitial nephritis, acute renal failure.
Increased urine production, urinary incontinence, can be caused or symptoms can be exacerbated in patients with urinary tract obstruction. Acute urine retention, possibly accompanied by complications, can occur for example in patients with bladder disorders, prostatic hyperplasia or narrowing of the urethra.
In premature infants with respiratory distress syndrome, administration of Furosemide in the initial weeks after birth entails an increased risk of a persistent patent ductus arteriosus.
In premature infants, furosemide can be precipitated as nephrocalcinosis/kidney stones.
Rare complications may include minor psychiatric disturbances.
Pre-existing metabolic alkalosis (e.g. in decompensated cirrhosis of the liver) may be aggravated by furosemide treatment.
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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Furosemide may precipitate solutions of low pH, and therefore dextrose solutions are not suitable infusion fluids for furosemide injection. The injection solution should not be mixed with other drugs in infusion bottles.
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