Furosemide Injection BP 10 mg/ml (For IM/IV injection use only)
COMPOSITION
Each ml contains:
Furosemide BP 10 mg
Water for Injections BP q. s.
DESCRIPTION
A clear, colourless to slightly yellowish coloured solution.
PHARMACODYNAMIC
Pharmacotherapeutic group: High-ceiling diuretic sulfonamides, loop diuretics.
ATC code: C03CA01
Mechanism of action:
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.
Pharmacodynamic effects:
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.
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.
PHARMACOKINETICS
Absorption:
Approximately 65% of the dose is absorbed after oral administration. The plasma half-life is biphasic with a terminal elimination phase of about 1½ hours.
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.
Distribution:
Furosemide is up to 99% bound to plasma proteins.
Biotransformation:
Furosemide is bound to plasma albumin and little biotransformation takes place.
Elimination:
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 mainly eliminated via the kidneys (80-90%) mainly excreted in the urine, largely unchanged; but also excreted in the bile, non-renal elimination being considerably increased in renal failure. Furosemide crosses the placental barrier and is excreted in the milk.
A small fraction of the dose undergoes biliary elimination and 10-15% of the activity can be recovered from the faeces.
Hepatic impairment
Where liver disease is present, biliary elimination is reduced up to 50%.
Renal impairment
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.
Paediatric population
A sustained diuretic effect is seen in the newborn, possibly due to immature tubular function.
THERAPEUTIC INDICATION
- Furosemide is a potent diuretic and is recommended for use when prompt and effective diuresis is required.
- Furosemide Injection are appropriate for use in emergencies or where oral therapy is not feasible. The indications include cardiac, pulmonary, hepatic and renal oedema.
- Furosemide Injection is for use in the management of oliguria due to acute or chronic renal insufficiency with a glomerular filtration rate below 20ml/minute.
DOSAGE AND ADMINISTRATION
General: The dose used must be the lowest that is sufficient to achieve the desired effect.
Route of administration: intravenous or intramuscular
Adults:
Initially, doses of 20 – 50mg may be administered by the intramuscular route, or by slow intravenous injection at a rate not exceeding 4mg/minute. The diuretic effect of furosemide is proportional to the dosage and, if larger doses are required, they should be given as a controlled infusion at a rate not exceeding 4mg/minute and titrated according to the response.
Children:
Parenteral doses for children range from 0.5 to 1.5 mg/kg body weight daily up to a maximum total daily dose of 20 mg.
Elderly:
In the elderly furosemide is generally eliminated more slowly. Dosage should be titrated until the required response is achieved.
OVERDOSE
Symptoms
Overdose can cause massive diuresis resulting in dehydration, volume depletion and electrolyte disturbances with consequent hypotension and cardiac toxicity. High doses have the potential to cause transient deafness and may precipitate gout (disturbed uric acid secretion).
Management
Benefits of gastric decontamination are uncertain. In patients presenting within 1 hour of ingestion, consider activated charcoal (50g for adults: 1g/kg for children).
Observe for a minimum of 4 hours – monitor pulse and blood pressure.
Treat hypotension and dehydration with appropriate IV fluids.
Monitor urinary output and serum electrolytes (including chloride and bicarbonate). Correct electrolyte imbalances. Monitor 12 lead ECG in patients with significant electrolyte disturbances.
CONTRAINDICATION
- Patients with hypovolaemia or dehydration, 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, severe hypokalaemia, severe hyponatraemia, pre-comatose and comatose states associated with hepatic encephalopathy and breast-feeding women.
- Hypersensitivity to the furosemide or to any of the excipients.
- Patients allergic to sulphonamides may show cross-sensitivity to furosemide.
WARNING AND PRECAUTIONS
Particularly careful monitoring is necessary in:
- patients with hypotension.
- patients who are at risk from a pronounced fall in blood pressure.
- patients with latent or manifest diabetes. Furosemide may necessitate adjustment of control by hypoglycaemic agents in cases of diabetes mellitus.
- 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).
- The use of diuretics is considered to be unsafe in acute porphyria therefore caution should be exercised.
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 when compared to patients treated with risperidone alone or furosemide alone.
Cautions should be exercised and the risks and benefits of this combination or co-treatment should be considered prior to the decision to use. Dehydration should be avoided.
The possibility exists of exacerbation or activation of systemic lupus erythematosus hence caution should be taken when administering frusemide to patients with a history of SLE.
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.
This medicinal product contains less than 1 mmol sodium (= 23 mg) per dose, that is to say essentially ‘sodium- free’.
PREGNANCY, LACTATION AND FERTILITY
Pregnancy
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.
Breast-feeding
Furosemide passes into breast milk and may inhibit lactation. Women must not breast-feed if they are treated with furosemide.
Fertility
The safety of furosemide during fertility has not been established.
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.
DRUG INTERACTION
General
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.
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. 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 diuresis possible when furosemide given with metolazone. Increased risk of hypokalaemia with thiazides.
Renin inhibitors: aliskiren reduces the plasma concentrations of furosemide given orally. Reduced effect of furosemide might be observed in patients treated with both aliskiren and oral furosemide, and it is recommended to monitor for reduced diuretic effect and adjust the dose accordingly.
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. Indomethacin and ketorolac may antagonise the effects of furosemide. 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. Salicylic toxicity may be increased by furosemide
Antibiotics: increased risk of ototoxicity with aminoglycosides, polymyxins 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 beta 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.
ADVERSE EFFECTS
| Category | Frequency | Adverse Effect |
| Metabolism and nutrition disorders | Very Common | electrolyte disturbances (including symptomatic) dehydration and hypovolaemia, especially in elderly patients. Blood creatinine increased; blood triglyceride increased. |
| Common | hyponatremia, hypochloremia, hypokalaemia, blood cholesterol increased. Blood uric acid increased and attacks of gout, urine volume increased. | |
| Vascular Disorders | Very Common | Hypotension including orthostatic hypotension. |
| Renal and urinary disorders | Common | urine volume increased |
| Nervous system disorders | Common | hepatic encephalopathy in patients with hepatocellular insufficiency. |
| Blood and the lymphatic system disorders | Common | haemoconcentration. |
PRESENTATION
FUROMID Injections are supplied in 2 ml and 4 ml amber color Type I USP ampoule.
STORAGE AND OTHER INFORMATION
Store in a cool and dry place. Protect from light.
Store at below 30°C temperature.
Caution: Not to be used if container is found leaking or solution is hazy or contain any visible solid particles. Keep this medicine out of the sight and reach of children.
