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Furosemid Biotika

SUMMARY OF PRODUCT CHARACTERISTICS 

1. NAME OF THE MEDICINAL PRODUCT 

                            Furosemid Biotika

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
Active substance: Furosemide 20 mg in 2 ml.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM 
Solution for injection 
Clear, colourless or pale khaki solution. 

4. CLINICAL PARTICULARS
4. 1 Therapeutic indications 
Acute and chronic edema, edema in cardiac insufficiency , nephrotic syndrome or liver cirrhosis, late gestosis, acute left ventricular failure, (pulmonary edema), cerebral edema, chronic renal insufficiency, hypercalcemia, and hyperkalemia. 
This medicine is for treatment of adults and children. 

4.2 Posology and method of administration 
a) Dosage for children: 
The dose of 1-2 mg / kg per day is administered intravenously in children, if necessary, repeatedly. The maximum daily dose is 6 mg / kg of body weight. 

b) Dosage for adults: 
Dosage is individual and depends on the functional state of the kidney, previous diuretic therapy 
 and the desired diuretic effect. In a good renal function the diuretic effect is reached with 20-40 mg dose of furosemide administered intravenously in injection or infusion. In inadequate diuretic response the same or increased dose may be repeated at 6-8 hour intervals. 
In acute pulmonary edema the initial dose is 40 mg of furosemide. In the lack of effect the same or double dose is 
applied in 2 to 3 hour intervals. The speed of application should not exceed 4 mg of furosemide per minute. 

4.3 Contraindications 
 Hypersensitivity to furosemide and to sulfonamides (the possibility of cross-sensitivity). Acute glomerulonephritis, renal insufficiency with hepatic coma with anuria.  Hyponatremia and hypokalemia, metabolic alkalosis. 

4.4 Special warnings and precautions for use 
Intravenous form of administration is chosen if oral administration is not possible (coma, vomiting), if absorption from the gastrointestinal tract is insufficient, or if rapid onset of therapeutic response is necessary(forced diuresis in intoxications). 
 In patients with liver cirrhosis and ascites, furosemide may cause severe electrolyte imbalance (hypokalemia, hyponatremia, azotemia), and coma.  Treatment should be initiated only when the current laboratory control and treatment of electrolyte imbalance are managed. 
 In diabetes mellitus is necessary to adjust glycemia with oral antidiabetic agents or insulin 
 and in hyperuricemia simultaneous administration of allopurinol is needed. Caution is necessary in patients treated with cardiac glycosides. 

4.5 Interactions with other medicinal products and other forms of interaction
Furosemide-induced hypokalemia may enhance the arrhythmogenic effect cardiac glycosides.  Furosemide enhances the hypotensive effect of antihypertensive therapy. Ototoxic effects of furosemide may be potentiated by the current application of aminoglycoside antibiotics with ototoxic effect (eg, gentamicin). 
 Nephrotoxic effect of some cephalosporin antibiotics (Cefalotin) might be potentiated by furosemide administration.  Diuretics of different types can increase plasma levels of lithium to toxic levels.  If a long-term treatment with lithium medication is necessary, the dose of lithium need to be reduced and plasma levels of lithium shall be regularly checked. Repeated administration of furosemide may increase plasma levels of barbiturates in patients with epilepsy.
  Long-term antiepileptic medication reduces the diuretic effect.  Furosemide may reduce plasma levels of theophylline. 
 Probenecid and indomethacin can reduce the diuretic and hypotensive effect of furosemide.  Furosemide reduces the vasoconstrictive effects of norepinephrine. Co-administration of furosemide and sucralphate may reduce diuretic and hypotensive effect of furosemide.  Both substances should be applied at two-hour interval. In patients who received chloral hydrate during the previous 24 hours, furosemide injection may cause tachycardia, elevate blood pressure, flushing heat and sweating.  Furosemide may increase the toxicity of simultaneously administrated high doses of acetylsalicylic acid. 

4.6 Pregnancy and lactation 
 Furosemide  crosses the placenta and may cause increased production of fetal urine. 
 In pregnancy can be used only in those cases where the benefits of treatment outweigh the possible adverse effect in fetus (eg, pulmonary edema or heart failure). 
 Furosemide passes at low concentrations into breast milk, therefore the patient treated with furosemide should not breastfeed. The diuretic effect of furosemide can be reduced in newborns, and thus the risk of ototoxicity might be increased.  

4.7 Effects on ability to drive and use machines 
Furosemide does not affect the ability to drive or operate machinery. 

4.8 Undesirable effects 
 Furosemide may cause hypokalemia in patients.  Risk group are people with low potassium intake in the diet, or patients where the loss of potassium is not replaced by oral or parenteral form, or potassium-sparing diuretics are not used.  Decreased level of potassium is manifested by various symptoms: usually it's fatigue, lethargy and muscle weakness.  Severe hypokalemia is associated with cardiac arrhythmias of ventricular type (ventricular extrasystoles, ventricular tachycardia). Furosemide may cause acute hyponatremia due to excessive loss of sodium if inappropriately high doses are used.  Chronic sodium depletion results from the prolonged use of potent diuretics.  Both disorders are characterized by weakness, lethargy, somnolence, muscle spasms, postural hypotension, hyponatremia, hyperkalemia, elevated serum urea and elevated hematocrit.  A serious complication is dilutional hyponatremia, which puts patients at risk. 
 Furosemide may cause a loss of magnesium (hypomagnesaemia) in patients.  Decreased levels of magnesium in serum and tissues may result, as in the case of increased potassium loss, to heart arrhythmias. Furosemide increases Furosemidexcretion in the urine.  In patients with latent or manifest symptoms of hypoparathyroidism tetany symptoms may arise. The long-term treatment may develop osteoporosis.  Current kidney disease with reduced formation of 1.25 OH-cholecalciferol which results to decrease in Furosemidabsorption from the gut, might develop osteoporosis. In about 7% of patients anorexia, nausea, vomiting and epigastric pain are present.  Constipation or diarrhea occurs in about 4% of patients. Furosemide in high doses increases levels of amylase, cases of acute pancreatitis and cholestatic jaundice. Leukopenia, agranulocytosis, thrombocytopenia, anemia, hemolytic anemia, or aplastic anemia have been reported occasionally.
 Furosemide may like thiazide diuretics cause carbohydrate metabolism disorders, hyperglycemia, glycosuria and might  aggravate diabetes mellitus. These disorders occur mainly in patients with latent diabetes, with hypokalemia, and in prolonged use of furosemide. The course is usually reversible. 
 Hyperosmolar coma in high doses has been rarely described. In this case a high hyperglycemia, hypokalemia, and dehydration are developed. Furosemide increased serum uric acid.  This may cause hyperuricemia attack in predisposed patients.  Like other diuretics, furosemide may alter lipid spectrum. Furosemide increases serum triglycerides and cholesterol. It increases concentration of low density lipoprotein, LDL-cholesterol and decreases HDL-cholesterol.  Furosemide in high doses causes tinnitus and deafness in patients Particularly affected are middle and upper acoustic frequencies, the perception of deep tones is slightly damaged only.  Damage is usually transitory, but it can also cause permanent hearing loss.  Danger of permanent hearing damage is increased by concomitant use of other ototoxic drugs and in patients with renal insufficiency who are treated with high doses of furosemide. To prevent this undesirable effect it is necessary to follow the dosage and rate of administration. Infusion rate should not exceed 4 mg / min.  Adverse reactions to skin are often characterized by rashes of various types, by pruritus, urticaria and by fotoalergic reactions. Most of them are of light nature, but rarely erythema multiforme, exfoliative dermatitis and purpura might occur.  Rarely at high doses blurred vision or xanthopia (yellow vision) are found.  In patients with micturition disorders, eg due to prostatic hypertrophy, can occur acute urinary retention.  Increased urination may bother patients during night. Cases of interstitial nephritis have been reported. Changes in water and electrolyte balance, particularly hypokalaemia and hypomagnesaemia can lead to arrhythmias.  Hypotensive effect and increased hematocrit, may be involved in the development of cerebral or peripheral ischemia in patients with the advanced atherosclerosis.
 After rapid intravenous administration cardiac arrest has been reported. 

4.9. Overdose 
Furosemide overdose may cause hypokalemia, hyponatremia, hypocalcaemia 
 and hypomagnesemia (see section 4.8) in patients.  Furosemide in high doses causes 
 tinnitus and deafness (see section 4.8)in patients. 
Treatment of overdosage consists of treatment of internal environment dysbalance.  Furosemide can not be dialyzed. 

5. PHARMACOLOGICAL PROPERTIES 
5.1 Pharmacodynamic properties 
Pharmacotherapeutic group: Sulphonamide diuretic
ATC code: C03CA01
Mechanism of effect 
Furosemide belongs to the loop diuretics.  It is also effective in significantly reduced kidney function. Furosemide inhibits the reabsorption of chloride and sodium in the medullary part of ascending limb of loop of Henle. Another site of action are distal and proximal tubule.  It increases excretion of sodium, chloride and water, as well as potassium, Furosemidand magnesium.  Furosemide increases the blood flow in the kidney and its redistribution in the kidney cortex. It  reduces left ventricular filling pressure, which is achieved earlier than the diuretic effect.  It acts hypotensively.
 
5.2 Pharmacokinetic properties 
 Furosemide in plasma is largely bound to plasma proteins, on average 97% and only 2-4% are unbound fraction of the drug.  Volume of distribution is approximately 170-270 ml / kg.  Diseases leading to 
decrease in plasma albumin levels (eg, nephrotic syndrome or liver cirrhosis), increase the amount of unbound fraction and increase the volume of distribution.  Plasma clearance is approximately 200 ml / min.  The half-life in healthy individuals is 45-60 minutes.  The greater part of the dose is excreted unchanged into urine.  Approximately 7-15% of the applied dose is transformed to glucuronide.  Part of furosemide is excreted unchanged in the faeces (approximately 10%). Clearance of furosemide is influenced by different factors. Clearance is reduced in neonates and in elderly, likely due to reduced glomerular filtration. 
 Kidney disesase or heart disease, reduce the clearance.  The half-life in renal, heart or liver impairment is extended. It can reach up to 20-24 hours.  Pharmacological effect of furosemide correlates better with the concentration of the substance in the urine than in plasma.  The effect depends on the amount of unbound fraction, which gets to the site of action in kidney tubules.  After intravenous administration, the pharmacological effect is reached approximately in 5 minutes and lasts about 2 hours.  Furosemide passes into the placenta and breast milk.  Clearance of furosemide can not be affected by hemodialysis. 

5.3 Preclinical safety data
Experiments on pregnant females of several animal species at doses exceeding the therapeutic dose have documented an increased incidence of fetal death and abortion.  In mice and rabbits, the increased incidence of renal pelvic distension and ureteral distension has been observed.

6. PHARMACEUTICAL PARTICULARS 
6.1 List of excipients 
Sodium hydroxide, sodium chloride, water for injection. 
Sodium content in the product: 3.688 mg / ml, corresponding to 0.160 mmol / l. 

6.2 Incompatibilities 
 In infusion preparation, furosemide must not be mixed with substances which reduce the pH of the solution (eg, vitamin B, vitamin C, adrenaline, noradrenaline, local anesthetics, antihistamines, etc.). 
pH of the solution must not drop below 7, because the active ingredient may precipitate. 

6.3 Shelf life 
3 years

6.4 Special precautions for storage 
Store at 10-25 ° C.  Store in original package to protect from light. 

6.5 Nature and contents of container 
Brown glass ampoule, insert a PVC box. 
Package size: 5 ampoules of 2 ml 

6.6 Special precautions for disposal
No special requirements.

7. MARKETING AUTHORISATION HOLDER 
BB Pharma Pod Višňovkou 1662/21, 140 00 Prague 4, Czech Republic 
8. MARKETING AUTHORISATION NUMBER(S) 
50/804/92-S/C

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
December 18th, 1992/ June 24th1998