SUMMARY OF PRODUCT CHARACTERISTICS

Furo/SPC/03 12-Nov-17 1 1. NAME OF THE MEDICINAL PRODUCT

Furosemide Norameda 10 mg/ml solution for injection/infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml solution contains 10 mg furosemide. Each 2 ml sterile solution for injection/infusion contains 20 mg of furosemide. Each 5 ml sterile solution for injection/infusion contains 50 mg of furosemide.

Excipient with known effect: Contains less than 1 mmol of sodium (23 mg) per dose. For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection/infusion. A clear and colourless to almost colourless solution, essentially free from visible particles. pH of the solution is between 8.00 and 9.30.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

When a prompt diuresis is required in emergencies or when oral therapy is precluded. - Oedema caused by cardiac or hepatic diseases. - Oedema caused by renal diseases (in case of nephrotic syndrome, treatment of the underlying disease is essential). - Pulmonary oedema (e.g. in case of acute heart failure).

Furosemide is indicated in adults and adolescents over 15 years.

4.2 Posology and method of administration

Posology

Adults and adolescents over 15 years In the absence of conditions requiring a reduced dose (see below) the initial dose recommended for adults and adolescents over 15 years, is of 20 mg to 40 mg furosemide by intravenous (or in exceptional cases intramuscular) administration; the maximum dose varying according to individual response. If larger doses are required, they should be given increasing by 20 mg increments and not given more often than every two hours.

In adults, the recommended maximum daily dose of furosemide administration is 1500 mg.

Weight loss induced by enhanced diuresis should not exceed 1 kg/day.

Paediatric population The intravenous administration of furosemide to children and adolescents below 15 years is only recommended in exceptional cases. The dosage will be adapted to the body weight, and the recommended dose ranges from 0.5 to 1 mg/kg body weight daily up to a maximum total daily dose of 20 mg.

Furo/SPC/03 12-Nov-17 2 Renal impairment In patients with severe impairment of renal function (serum creatinine > 5 mg/dl) it is recommended that an infusion rate of 2.5 mg furosemide per minute is not exceeded.

Elderly The recommended initial dose is 20 mg/day, increasing gradually until the required response is achieved.

Special dosage recommendations: For adults, the dose is based on the following conditions: - Oedema associated to chronic and acute congestive heart failure The recommended initial dose is 20 to 40 mg daily. This dose can be adapted to the patient´s response, as necessary. The dose should be given in two or three individual doses per day for chronic heart failure and as a bolus for acute congestive heart failure. - Oedema associated with renal disease. The recommended initial dose is 20 to 40 mg daily. This dose can be adapted to the response as necessary. The total daily dose can be administered as a single dose or as several doses throughout the day. If this does not lead to an optimal fluid excretion increase, furosemide must be administered in continuous intravenous infusion, with an initial rate of 50 mg to 100 mg per hour. Before beginning the administration of furosemide, hypovolaemia, hypotension and acid-base and electrolytic imbalances must be corrected. In dialyzed patients, the usual maintenance dose ranges from 250 mg to 1,500 mg daily. In patients with nephrotic syndrome the dosage must be determined with caution, because of the risk of a higher incidence of adverse events. - Oedema associated with hepatic disease When intravenous treatment is absolutely needed, the initial dose should range from 20 mg to 40 mg. This dose can be adapted to the response as necessary. The total daily dose can be administered as a single dose or in several doses. Furosemide can be used in combination with aldosterone antagonists in cases in which these agents in monotherapy are not sufficient. In order to avoid complications such as orthostatic intolerance or acid- base and electrolytic imbalances or hepatic encephalopathy, the dose must be carefully adjusted to achieve a gradual fluid loss. The dose may produce in adults a daily body weight loss of approximately 0.5 kg. - Pulmonary oedema (in acute heart failure) The initial dose to be administered is 40 mg furosemide by intravenous application. If required by the condition of the patient, another injection of 20 to 40 mg furosemide is given after 30 – 60 minutes. Furosemide should be used in addition to other therapeutic measures.

Method of administration

Intravenous or intramuscular

The parenteral administration of furosemide is indicated in cases where oral administration is not feasible or not efficient (for example in case of reduced intestinal absorption) or when a quick effect is required. To achieve optimum efficacy and suppress counter-regulation, a continuous furosemide infusion is generally to be preferred to repeated bolus injections. Where continuous furosemide infusion is not feasible for follow-up treatment after one or several acute bolus doses, a follow-up regimen with low doses given at short intervals (approx. 4 hours) is to be preferred to a regimen with higher bolus doses at longer intervals. Intravenous furosemide must be injected or infused slowly; a rate of 4 mg per minute must not be exceeded and should never be given in association with other medicinal products in the same syringe. Generally, furosemide should be administered intravenously. Intramuscular administration must be restricted to exceptional cases where neither oral nor intravenous administration is feasible. It must be noted that intramuscular injection is not suitable for the treatment of acute conditions such as pulmonary oedema.

Furo/SPC/03 12-Nov-17 3 4.3 Contraindication

- Hypersensitivity to furosemide or any of the excipients listed in section 6.1. - Patients with anuria or renal failure with anuria not responding to furosemide. - Renal failure as a result of poisoning by nephrotoxic or hepatotoxic agents. - Renal failure associated with hepatic coma. - Patients with severe hypokalaemia or severe hyponatraemia. - Patients with hypovolaemia (with or without hypotension) or dehydration. - Patients in pre-comatose and comatose state associated with hepatic encephalopathy. - Patients with hypersensitivity to sulphonamides (e.g. Sulfonyureas or antibiotics of sulphonamides group) may show cross-sensitivity to furosemide. - Breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

Careful monitoring is required in case of: - Patients with partial obstruction of urinary outflow (e.g. prostatic hypertrophy, hydronephrosis, ureterostenosis). Urinary output must be secured ; - Patients with hypotension or at increased risk from pronounced fall in blood pressure (patients with coronary artery stenosis or cerebral artery stenosis); - Patients with manifest or latent diabetes mellitus or variation of glycaemia (regular monitoring of blood glucose levels necessary); - Patients with gout and hyperuricaemia (regular monitoring of uric acid levels in serum necessary); - Patients with hepatic disease or hepatorenal syndrome (renal impairment associated to severe hepatic disease); - Hypoproteinaemia (associated to nephrotic syndrome, furosemide´s effect may be reduced and its ototoxicity increased); - Co-administration with lithium salts (monitoring of lithium levels is required, see section 4.5); - Acute porphyria (the use of diuretics is considered to be unsafe in acute porphyria and caution should be exercised); - Too vigorous diuresis may cause orthostatic hypotension or acute hypotensive episode; - Where indicated, steps should be taken to correct hypotension or hypovolaemia before commencing therapy.

Cautious dose titration is required: - Electrolyte variations (e.g. hypokalaemia, hyponatraemia); - Fluid variations, dehydration, blood volume reduction with circulatory collapse and possibility of thrombosis and embolism, particular in elderly, with excessive use; - Ototoxicity (if administered faster than 4 mg/ml - other ototoxic compounds administered concomitantly can increase this risk, see section 4.5; - Administration of high dosages; - Administration in progressive and severe renal disease; - Administration with sorbitol. Concomitant administration of both substances may lead to increased dehydratation (sorbitol might cause additional fluid loss by inducing diarrhoea); - Administration in Lupus Erythematosus; - Medication that prolong the QT interval.

Caution should be observed in patients liable to electrolyte deficiency. Regular monitoring of serum sodium, potassium and creatinine is generally recommended during furosemide therapy; particularly close monitoring is required in patients at high risk of developing electrolyte imbalances or in case of significant additional fluid loss. (e.g. due to vomiting or diarrhoea). Hypovolaemia or dehydration as well as any significant electrolyte and acid-base disturbances must be corrected. This may require temporary discontinuation of furosemide. In patients who are at high risk for radiocontrast nephropathy, furosemide is not recommended to be used for diuresis as part of the preventative measures against radiocontrast-induced nephropathy.

Furo/SPC/03 12-Nov-17 4 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 (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).

Photosensitivity: Cases of photosensitivity reactions have been reported. If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Paediatric population Premature infants (possible development of nephrocalcinosis /nephrolithiasis; renal function must be monitored and renal ultrasonography performed). In premature infants with respiratory distress syndrome, diuretic treatment with furosemide during the first weeks of life can increase the risk of persistent ductus arteriosus Botalli.

This medicinal product contains less than 1 mmol sodium (23 mg) per 40 mg, i.e. essentially ‘sodium- free’.

4.5 Interaction with other medicinal products and other forms of interaction

Not recommended combinations

Lithium: Lithium excretion levels may be reduced by furosemide, resulting in increased cardiotoxic effect and lithium toxicity. Therefore, this combination is not recommended (see section 4.4). If this combination is deemed necessary lithium levels should be carefully monitored and lithium dosage should be adjusted. Ototoxic drugs (e.g. aminoglycosides, cisplatin): Furosemide may intensify the ototoxicity of certain drugs, for example cisplatin or aminoglycoside antibiotics such as kanamycin, gentamicin and tobramycin, in particular in patients with renal impairment. Since this may lead to irreversible damage, these drugs must only be used with furosemide if there are compelling medical reasons. Chloral Hydrate: In isolated cases, the intravenous administration of furosemide in a 24 hour period prior to chloral hydrate administration may lead to flush, hyperhidrosis, anxiety, nausea, increase in blood pressure and tachycardia. Therefore, the simultaneous administration of furosemide and chloral hydrate is not recommended.

Combinations requiring a caution for use

Carbamazepine and aminoglutethimide: Concomitant administration of carbamazepine or aminoglutethimide may increase the risk of hyponatraemia.

Other anti-hypertensive agents: The effect of other certain anti-hypertensive agents (diuretics and other drugs that low blood pressure) may be potentiated by concurrent administration of furosemide.

Furo/SPC/03 12-Nov-17 5 Inhibitors of the angiotensin converting enzyme (ACE) and Angiotensin II receptor antagonists: The effects of other antihypertensives can be potentiated by concomitant administration of furosemide. Severe fall in blood pressure with shock in extreme cases and deterioration of renal function (acute renal failure in isolated cases) have been observed in combination with ACE inhibitors, when the ACE inhibitor was administered for the first time, or for the first time at high dosage (first dose hypotension). If possible, furosemide therapy should be temporarily discontinued (or at least the dose reduced) for three days before therapy with an ACE inhibitor or an Angiotensin II receptor antagonists is initiated or the dose of an ACE inhibitor or Angiotensin II receptor antagonists is increased.

Patients taking diuretics may suffer accentuated hypotension and deterioration of renal function; renal impairment may also occur during the first concurrent administration, or with the first administration of high doses of ACE or of an antagonist of the angiotensin II receptor.

Thiazides: A synergetic effect of diuresis occurs as result of interaction of furosemide and thiazides.

Anti-diabetic agents: A decrease in glucose tolerance may occur, since furosemide may reduce these drugs action.

Metformin: The blood levels of metformin may be increased by furosemide. Inversely, metformin may reduce furosemide concentration. The risk is linked to an increased occurrence of lactic acidosis in case of functional renal insufficiency.

Cardiac glycosides (e.g. digoxin) and other medicinal products that may csuse prolongation of th QT- interval:

A decrease of potassium levels may increase digitalis toxicity; for this reason, potassium levels should be monitored. Some electrolyte disturbances may increase the toxicity of certain concomitantly administered drugs that may cause prolongation of the QT interval. e.g. (class Ia antiarrhythmics and class III antiarrhythmics like amiodarone, sotalol, dofetilide, ibutilide and quinolones). Monitoring of potassium plasma levels and ECG are recommended.

Fibrates: Blood levels of furosemide and of fibric acid derivates (for example clofibrate and fenofibrate) may be increased during concurrent administration (particularly in case of hypoalbuminaemia). The increase of its effect/toxicity should be monitored.

Non-steroidal anti-inflammatory agents and high doses of salicylates: Non-steroidal anti-inflammatory agents (including coxibs) may induce acute renal failure in cases of pre-existing hypovolaemia and reduce its diuretic, natriuretic and antihypertensive effect. When co- administered with high doses of salicylates, the predisposition for salicylic toxicity may be increased due to a reduced renal excretion or to a modified renal function.

Nephrotoxic drugs (e.g. polymyxins, aminoglycosides, cephalosporins organoplatins, immunosuppressants, iodinated contrast media, foscarnet, pentamidine): Furosemide may intensify the nephrotoxic effects of nephrotoxic drugs

Nephrotoxicity of cisplatin may be enhanced if furosemide in 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

Drugs that undergo significant renal tubular secretion: Probenecid, methotrexate and other drugs which, like furosemide, undergo significant renal tubular secretion may reduce the effect of furosemide. Conversely, furosemide may decrease renal elimination of these products. In case of high-dose treatment (in particular, of both furosemide and the other

Furo/SPC/03 12-Nov-17 6 medicinal products), this may lead to increased serum levels and an increased risk of adverse effects due to furosemide or the concomitant medication.

Peripheral adrenergic inhibitors: These agents´ effects may be enhanced by the simultaneous administration of furosemide. Phenobarbital and phenytoin: Attenuation of the effect of furosemide may occur following concurrent administration of these drugs.

Tubocurarine, curarine derivatives and succinyl choline: The muscle relaxing effect of these agents may be enhanced by furosemide.

Glucocorticoids, carbenoxolone, laxatives and liquorice: Co-administration of furosemide with glucocorticoids, carbenoxolone,large amount of liquorice or prolonge use of laxatives may increase potassium loss. In the association with glucocorticoids, hypokalaemia should be considered and its aggravation with the overuse of laxatives. Since, this may lead to irreversible hearing damages, this combination should only be used if there are compelling medical reasons. Potassium levels should be monitored.

Sucralfate: Simultaneous administration of sucralfate and furosemide may reduce the natriuretic and antihypertensive effects of furosemide. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of furosemide is achieved. The intake of furosemide and sucralfate should be separated by at least two hours.

Oral anticoagulants: Furosemid increases the effects of oral anticoagulants.

Theophylline: The effects of theophylline and of curare-type muscle relaxants may be potentiated.

Pressor amines (e.g. adrenaline (epinephrine), noradrenaline (norepinephrine)): Concomitant use of furosemide may attenuate the effects of pressor amines.

Other interactions: Concomitant use of ciclosporin and furosemide is associated with increased risk of gouty arthritis.

4.6 Fertility, pregnancy and lactation

Pregnancy Furosemide should not be given during pregnancy unless there are compelling medical reasons. Furosemide crosses the placental barrier, and can therefore cause a diuresis of the fetus. Treatment during pregnancy requires monitoring of fetal growth. Treatment of pregnancy hypertension and oedema is in general not recommended, as physiological hypovolemia can be induced which causes reduction of placental perfusion. If use of furosemide is essential for the treatment of cardiac or renal insufficiency during pregnancy, careful monitoring of electrolytes, haematocrit and fetal growth is essential. Possible displacement of bilirubin from albumin binding and thus elevated risk of nuclear icterus in hyperbilirubinaemia is discussed for furosemide. Furosemide can predispose the fetus to hypercalciuria, nephrocalcinosis, and secondary hyperparathyroidism Furosemide reaches 100% of the maternal serum concentration in cord blood. No malformations in humans which might be associated with exposure to furosemide have been reported to date. However, there is limited experience to allow a conclusive evaluation of a potential damaging effect in the embryo/fetus.

Breastfeeding

Furo/SPC/03 12-Nov-17 7 Furosemide passes into breast milk and may inhibit lactation. Women must not breast-feed if they are treated with furosemide (see section 4.3).

4.7 Effects on ability to drive and use machines

Patients respond individually to furosemide The ability to drive or operate machines can incidentally be reduced because of treatment with furosemide, especially at the start of therapy, change of medication or in combination with alcohol.

4.8 Undesirable effects

The evaluation of adverse reactions is based on the following definition of frequency: 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); not known (cannot be estimated from the available data). As with other diuretics, certain undesirable effects may occur, such as:

Investigations Rare: serum cholesterol and triglyceride levels may rise during furosemide treatment.

Cardiac disorders In particular, at the initial state of treatment and in elderly, a very intense diuresis may cause a reduction in blood pressure which, if pronounced may cause signs and symptoms such as orthostatic hypotension, acute hypotension, sensations of pressure in the head, dizziness, circulatory collapse, thrombophlebitis or sudden death (with i.m. or i.v. administration).

Blood and lymphatic system disorders Uncommon: thrombocytopenia; thrombocytopenia may become manifest, especially with an increase of haemorrhage tendency. Rare: eosinophilia, leukopenia, bone marrow depression; occurrence of this symptom necessitates withdrawal of treatment. Very rare: haemolytic anaemia, aplastic anaemia, agranulocytosis. Severe fluid depletion may lead to haemoconcentration with a tendency for thromboses to develop especially in elder patients.

Nervous system disorders Rare: paraesthesia, vertigo, dizziness, sleepiness, confusion, sensations of pressure in the head.

Eye disorders Rare: aggravation of myopia, blurred vision; disturbances of vision with hypovolaemia symptoms.

Ear and labyrinth disorders Rare: dysacusis and/or syrigmus (tinnitus aurium) due to furosemide are rare and usually transitory; incidence is higher in rapid intravenous administration, particularly in patients with renal failure or hypoproteinaemia (e.g. in nephrotic syndrome).

Gastrointestinal disorders Rare: nausea, vomiting, diarrhoea, anorexia, gastric distress, constipation, dry mouth.

Hepato-biliary disorders Very rare: acute pancreatitis, intrahepatic cholestasis, cholestasis jaundice, hepatic ischaemia, increases in hepatic transaminases.

Renal and urinary disorders

Furo/SPC/03 12-Nov-17 8 Diuretics may exacerbate or reveal acute retention of urine symptoms (bladder-emptying disorders, prostatic hyperplasia or narrowing of the urethra), vasculitis, glycosuria, transitorily increase of blood creatinine and urea levels. Rare: interstitial nephritis

Immune system disorders Rare: severe anaphylactic and anaphylactoid reactions such as anaphylactic shock (for treatment see section 4.9).

Skin and subcutaneous tissue disorders Uncommon: pruritus, dermal and mucosal reactions (e.g. bullous exanthema, rash, urticaria, purpura, erythema multiforme, exfoliative dermatitis, photosensitivity) Rare: vasculitis, lupus erythematosus exacerbation or activation.

Musculoskeletal and connective tissue disorders Rare: leg muscle cramps, asthenia. chronic arthritis.

Endocrine disorders Glucose tolerance may decrease with furosemide. In patients with diabetes mellitus this may lead to a deterioration of the metabolic control; latent diabetes mellitus may become manifest.

Metabolism and nutrition disorders Hypokalaemia, hyponatraemia and metabolic alkalosismay occur, especially after prolonged therapy or when high doses are administered. Regular monitoring of serum electrolytes (especially potassium, sodium and calcium) is therefore indicated. Potassium depletion may occur, especially due to poor potassium diet. Particulary when the supply of potassium is concomitantly reduced and/or extrarenal potassium losses are increased (e.g. in vomiting or chronic diarrhoea) hypokalaemia may occur as a result of increased renal potassium losses. Underlying disorders (e.g. cirrhotic disease or heart failure), concomitant medication (see section 4.5) and nutrition may cause predisposition to potassium deficiency. In such cases, adequate monitoring is necessary as well as therapy substitution.

As a result of increased renal sodium losses, hyponatraemia with corresponding symptoms may occur, particularly if the supply of sodium chloride is restricted.

Increased renal calcium losses can lead to hypocalcaemia, which may induce tetania in rare cases.

In patients with increased renal magnesium losses, tetania or cardiac arrhythmias were observed in rare cases as a consequence of hypomagnesaemia.

Uric acid levels may increase and gout attacks may occur.

Metabolic alkalosis may develop, or pre-existing metabolic alkalosis (for e.g. decompensated hepatic cirrhosis) may become more severe with furosemide.

General disorders and administration site conditions Rare: febrile conditions; following i.m. injection local reactions such as pain may appear.

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 national reporting system listed in Appendix V

Furo/SPC/03 12-Nov-17 9

4.9 Overdose

The clinical picture in acute or chronic overdose depends primarily on the extent and consequences of electrolyte and fluid loss (e.g. hypovolaemia, dehydration, haemoconcentration, cardiac arrhythmias - including AV blockage and ventricular fibrillation) due to excessive diuresis. Symptoms: Symptoms of these disturbances include severe hypotension (progressing to shock), acute renal failure, thrombosis, delirious states, flaccid paralysis, apathy and confusion. Treatment: At the first signs of shock (hypotension, sudoresis, nausea, cyanosis) the injection should be immediately interrupted, place the patient head down and allow free breathing. Fluid replacement and correction of the electrolyte imbalance; monitoring of metabolic functions, and maintenance of urinary flux.

Medicinal treatment in case of anaphylactic shock: dilute 1 ml of 1:1000 adrenaline solution in 10 ml and inject slowly 1 ml of the solution (corresponding to 0.1 mg of adrenaline), control pulse and tension and monitor eventual arrhythmias. Adrenaline administration may be repeated, if necessary. Subsequently, inject intravenously a glucocorticoid (for example 250 mg of methylprednisolone), repeating if necessary.

Paediatric population Adapt the above-mentioned dosages for children, according body weight.

Correct hypovolaemia with available means and complement with artificial ventilation, oxygen and in case of anaphylactic shock with anti-histamines.

No specific antidote to furosemide is known. If overdose during parenteral treatment has taken place, in principle the treatment consists on follow up and supportive therapy. Haemodialysis does not accelerate furosemide elimination.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: High-ceiling diuretics, sulfonamides, plain. ATC code: C03CA01 Mechanism of action Furosemide is a strong diuretic agent of fast action. From a pharmacological point of view, furosemide inhibits the co-transport system (reabsorption) of the following electrolytes Na+, K+ and 2CL-, located on the luminal cell membrane on the ascending limb of the loop of Henle. Consequently, furosemide´s efficiency depends on the drug reaching the tubular lumen through an anionic transport mechanism. The diuretic effect results on the inhibition of sodium chloride reabsorption in this segment of the loop of Henle. As a result, the fraction of excreted sodium may ascend to 35 % of sodium glomerular filtration. The secondary effects of increased elimination of sodium are: increase of urinary excretion and increase of potassium distal secretion at the distal tube. Excretion of calcium and magnesium salts is also increased.

Pharmacodynamic effects Furosemide inhibits the feedback mechanism in the dense macula and induces dose-dependent stimulation of the renin-angiotensin-aldosterone system. In case of heart failure, furosemide induces an acute reduction of cardiac pre-load (through the enlargement of the blood vessels capacity). This early vascular effect seems to be mediated by prostaglandins and assumes an adequate renal function with activation of the renin-angiotensin system

Furo/SPC/03 12-Nov-17 10 and an intact synthesis of prostaglandins. Due to its natriuretic effect, furosemide reduces the vascular reactivity to catecholamine that is increased in hypertensive patients.

Clinical efficacy and safety The diuretic effect of furosemide is established within 15 minutes of an intravenous administration. A dose-dependent increase in diuresis and natriuresis was found in healthy individuals to whom furosemide was administerd (doses between 10 and 100 mg). The duration of action in healthy individuals after the administration of an intravenous 20 mg dose of furosemide is approximately 3 hours and 3 to 6 hours, when an oral 40 mg dose is given. In ill patients, the relation between tubular concentration of free furosemide and bound furosemide (determined through the urine excretion rate) andits natriuretic effect is translated in a sigmoid graphic, with a minimum effective excretion rate of approximately 10 micrograms per minute. Consequently, a continuous infusion of furosemide is more effective than repeated bolus injections. Above a certain bolus administration dose, the drugs effects do not significantly increase. The efficacy of furosemide is decreased in cases of reduced tubular secretion or in cases of intra-tubular binding of the drug to albumin.

5.2 Pharmacokinetic properties

Distribution Furosemide distribution volume is 0.1 to 1.2 litres per kg of body weight. The distribution volume may be increased depending on the concomitant illness. Protein binding (mostly to albumin) is higher than 98 %.

Elimination Furosemide is mostly eliminated as the non-conjugated form, mainly through secretion at the proximal tube. After intravenous administration, 60 % to 70 % of furosemide is eliminated by this manner. The glucuronic metabolite of furosemide represents 10 % to 20 % of the recovered substances in the urine. The remaining dose is eliminated in the faeces, probably after biliary secretion. After intravenous administration, the plasma half-life of furosemide ranges from 1 to 1.5 hours. Furosemide is excreted in breast milk. It crosses the placental barrier transferring itself slowly to the foetus. Furosemide achieves similar concentrations in the mother, foetus and newborn.

Renal impairment In case of renal impairment, furosemide´s elimination is slower and its half-life is increased. In patients with end-stage renal disease the average half-life is 9.7 hours. In several multi-organ failure the half life may range from 20-24 hours. In case of nephrotic syndrome, the lower concentration of plasma proteins leads to higher concentrations of unbound furosemide. On the other hand, the efficiency of furosemide is reduced in these patients, due to intratubular albumin binding and to reduced tubular secretion. Furosemide exhibits low dialysis in patients undergoing haemodialysis, peritoneal dialysis or CAPD (Chronic Ambulatory Peritoneal Dialysis).

Hepatic impairment In case of hepatic impairment, furosemide´s half-life increases 30 % to 90 %, mainly due to the higher distribution volume. Biliary elimination might be reduced (up to 50 %). In this group of patients, there is a wider variability of the pharmacokinetic parameters.

Congestive heart failure, severe hypertension, elderly Furosemide elimination is slower due to reduced renal function in patients with congestive heart failure, severe hypertension or in elderly.

Premature infants and new-born Depending on the maturity of the kidney, elimination of furosemide may be slow. In case of children with insufficient capacity of glucuronidation, the metabolism of the drug is also reduced. In term neonates the half-life is generally less than 12 hours.

Furo/SPC/03 12-Nov-17 11 5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on repeated dose toxicity, genotoxicity and carcinogenic potential In reproductive toxicology studies, a reduced number of differentiated glomeruli, skeletal anomalies of the scapulae, humerus and ribs (induced by hypokalaemia) were seen in fetal rats, as well as hydronephrosis that occurred in fetal mice and rabbits after administration of high doses. The results of a mouse study and one of the three rabbit studies showed an increased incidence and severity of hydronephrosis (distention of the renal pelvis and, in some cases, of the ureters) in fetuses derived from the treated dams as compared with those from the control group. Preterm rabbits given furosemide had a higher incidence of intraventricular haemorrhage than saline- treated littermates, possibly due to furosemide-induced intracranial hypotension.

6.0 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium hydroxide (for pH-adjustment) Sodium chloride Hydrochloric acid, concentrated (for pH-adjustment) Water for Injections

6.2 Incompatibilities

Furosemide should not be mixed with strong acid solutions (pH lower than 5.5), such as solutions containing ascorbic acid, noradrenaline and adrenaline, due to the risk of precipitation. This medicinal product should not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Shelf life of the finished medicinal product: 2 years After first opening: Once opened the product should be used immediately

After dilution: Chemical and physical in-use stability has been demonstrated for 48 hours at 25ºC and at 2 to 8°C, protected from light.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Keep the ampoules in the outer carton in order to protect from light. Do not freeze. For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container

Type I amber glass ampoules containing 2 ml or 5 ml solution.

Pack sizes: Ampoule of 2 ml. Each pack contains 10 or 25 ampoules. Ampoule of 5 ml. Each pack contains 10 or 25 ampoules. Furo/SPC/03 12-Nov-17 12

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Furosemide 10 mg/ml solution for injection/infusion may be mixed with neutral and weak alkaline solution with pH between 7 and 10, such as 0.9 % sodium chloride and Ringer’s lactate solution in non PVC bag. Any unused product or waste material should be disposed of in accordance with local requirements. Product containing visible particles should not be used. For single use only, discard any remaining contents after use. Furosemide 10 mg/ml solution for injection/infusion solution should not be mixed with any other drugs.

7. MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

8. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<[To be completed nationally]>

10. DATE OF REVISION OF THE TEXT

To be completed nationally]>

Furo/SPC/03 12-Nov-17 13 LABELLING

Furo/SPC/03 12-Nov-17 14

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

Furosemide Norameda 10 mg/ml solution for injection/infusion Furosemide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each ml solution for injection/infusion contains 10 mg furosemide. Each 2 ml ampoule contains 20 mg furosemide. Each 5 ml ampoule contains 50 mg furosemide.

3. LIST OF EXCIPIENTS

Sodium chloride, Sodium hydroxide, Hydrochloric acid, concentrated, Water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection/infusion 10 x 2 ml 10 x 5 ml 25 x 2 ml 25 x 5 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use. Intravenous or intramuscular use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

Expiry date

Furo/SPC/03 12-Nov-17 15

9. SPECIAL STORAGE CONDITIONS

Keep the ampoules in the outer carton in order to protect from light. Do not freeze

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

12. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

13. BATCH NUMBER

Batch No

14. GENERAL CLASSIFICATION FOR SUPPLY

<[To be completed nationally]>

15. INSTRUCTIONS ON USE

<[To be completed nationally]>

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

<2D barcode carrying the unique identifier included.>

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC: SN: NN:

Furo/SPC/03 12-Nov-17 16 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

AMPOULE

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Furosemide Norameda 10 mg/ml solution for injection/infusion Furosemide i.v., i.m.

2. METHOD OF ADMINISTRATION

Read the package leaflet before use

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

20 mg/2 ml 50 mg/5 ml

6. OTHER

Furo/SPC/03 12-Nov-17 17

PACKAGE LEAFLET

Furo/SPC/03 12-Nov-17 18 Package leaflet: Information for the patient

Furosemide Norameda 10 mg/ml solution for injection/infusion Furosemide

Read all of this leaflet carefully before you start using this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet 1. What Furosemide Norameda is and what it is used for 2. What you need to know before you use Furosemide Norameda 3. How to use Furosemide Norameda 4. Possible side effects 5. How to store Furosemide Norameda 6. Contents of the pack and other information

1. What Furosemide Norameda is and what it is used for

Furosemide Norameda 10 mg/ml solution for injection/infusion contains the active substance furosemide. Furosemide is one of a group of medicines called diuretics. Furosemide works by helping to produce more urine. This helps to relieve symptoms caused when your body contains too much fluid. Your doctor has prescribed Furosemide Norameda for one of the following reasons: - When quick and effective removal of excess fluid is needed. - You are not able to take this kind of medicine by mouth or in an emergency. - You have too much fluid around your heart, lungs, liver or kidneys. Furosemide injection/infusion must only be used under medical supervision

2. What you need to know before you use Furosemide Norameda

Do not use Furosemide Norameda if: - You are allergic to furosemide or any of the other ingredients of this medicine (listed in section 6). - You are allergic to sulphonamide antibiotics. - You are severely dehydrated (you have lost lots of body fluid for example by suffering from severe diarrhea or being sick). - You have kidney failure and are not producing urine, despite treatment with furosemide. - You have kidney failure as a consequence of poisoning with kidney or liver toxic substances. - You have very low levels of potassium or sodium in your blood. - You have kidney failure. - You are breastfeeding. - The patient is in a coma caused by liver failure.

Warnings and precautions

Talk to your doctor or pharmacist or nurse before using Furosemide Norameda.

Take special care with Furosemide Norameda if: - You normally have problems passing water due to an obstruction (such as Furo/SPC/03 12-Nov-17 19 an enlarged prostate). - You have diabetes. - You have a low blood pressure or sometimes have sudden falls in blood pressure vessels in your heart or brain are to narrow). - You have liver disease (such as cirrhosis). - You have kidney problems (such as nephrotic syndrome). - You are dehydrated (you have lost body fluids by suffering from severe diarrhoea or being sick), this might lead to collapse or blood clots. - You have gout (painful or inflamed joints) due to high levels of uric acid (by-product of metabolism) in your blood. - You have the inflammatory disease called “systemic lupus erythematosus (SLE)” - You have hearing problems. - You are using sorbitol (sugar substitute for people with diabetes). - You have porphyria (disease where the production of the oxygen binding molecule of the red blood cells is disrupted and urine is purple-coloured). - Your skin has an increased sensitivity to sunlight (photosensitivity).

If any of above points apply to you, your doctor may want to change your treatment or give you special advice. Your doctors may recommend regular blood tests of your blood sugar levels or your blood uric acid levels. They will also check your blood levels of important body salts such as potassium and sodium which are particularly important if you are being sick or have diarrhea.

Children If given to premature babies furosemide can cause kidney stones or calcification. In premature babies the channel between the lung artery and the aorta which is open in the unborn baby might stay open.

Other medicines and Furosemide Norameda Tell your doctor or pharmacist, if you are using, have recently used or might use any other medicines. This is important because some medicines should not be taken together with Furosemide Norameda. In particular, tell your doctor or pharmacist if you are taking: - Lithium – for mood disorders, as its effect and side effects may be increased by furosemide. Your doctor will check your lithium levels and may change your dose. - Heart medicines, such as digoxin; your doctor may need to change your dose. - Any medicines for high blood pressure, including thiazide diuretics (such as bendroflumethiazide or hydrochlorothiazide), ACE inhibitors (such as lisinopril), angiotensin II antagonists (such as losartan), as furosemide may cause your blood pressure to fall too low. Your doctor may need to change your dose of furosemide. - Cholesterol or lipid-lowering medicines such as colestyramine, colestipol and fibrates such as clofibrate, as the effect of furosemide may be reduced. - Medicines for diabetes such as metformin and insulin, as your sugar levels may be increased. - Anti-inflammatory medicines, including NSAIDS (such as diclofenac, ibuprofen, celecoxib), as they can reduce the effects of furosemide; high doses of pain killers such as acetylsalicylic acid (aspirin) may increase the side effects of furosemide. - Medicines used to treat inflammation or allergy known as corticosteroids (such as prednisolone, dexamethasone), carbenoxolone (for stomach ulcers) or laxatives, in combination with furosemide will affect levels of potassium in your body. Your doctor will do blood tests to check your potassium levels. - Injections given during operations, including tubocurarine, curarine derivates and succinylcholine. - Chloral hydrate (for sleeping problems) – giving furosemide injection at the same time as chloral hydrate is not recommended since side effects such as flushing, increased sweating, anxiety, nausea, increased blood pressure and rapid heart rate may occur. - Phenytoin or Phenobarbital – for epilepsy, as the effect of furosemide may be decreased; Carbamazepine – used to treat epilepsy or schizophrenia, as it may increase the side effects of furosemide.

Furo/SPC/03 12-Nov-17 20 - Theophylline – for asthma, as its effect may be increased by furosemide. - Medicines which may affect your kidneys such as antibiotics (cephalosporins, aminoglycoside, polymyxins, quinolones), immunosuppressant drugs, foscarnet (used to treat viral infections), pentamidine (used to treat diseases caused by one-celled organisms known as protozoa) or iodated contrast media – furosemide may make worse the side effects of these drugs on the kidneys. - Probenecid – used with some other medicines to protect the kidney, as it may reduce the effects of furosemide. - Methotrexate – used in some cancers and for severe arthritis, as it may reduce the effects of furosemide. - Drugs to raise your blood pressure (pressor amines such as adrenaline, noradrenaline), as they may not work as well when you take them with furosemide. Aminoglutethimide – used to treat Cushing’s syndrome, as it may increase the side effects of furosemide. - Sucralfate – used to treat stomach ulcers. Do not take furosemide within two hours of taking sucralfate as the effect of furosemide may be decreased. - Ciclosporin – used to prevent rejection of transplants, as you are at risk of gouty arthritis (painful joints) - Cisplatin – used in cancer chemotherapy or aminoglycoside antibiotics such as kanamycin, gentamicin and tobramycin, as the side effects of these medicines on hearing (ototoxicity) may be made worse by furosemide, in particular in patients with kidney problems. - Drugs that alter your heart rate such as amiodarone, sotalol, dofetilide, ibutilide, as their effect may be increased by furosemide. - Risperidone – used for the treatment of mental disorders.

Using Furosemide Norameda with food and drink and alcohol

Food is not expected to influence this medicine when it is given into a vein. Chronic moderate to heavy drinking raises blood pressure and reduces the effectiveness of antihypertensive drugs. Patients may experience dizziness and fainting shortly after drinking alcohol whilst on treatment.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Furosemide should not be used during pregnancy unless there are very good medical reasons for using it. Furosemide passes into breast milk. You should not breast-feed while receiving it

Driving and using machines

The ability to drive or operate machinery can be reduced because of treatment with Furosemide, especially at the start of therapy, when medication is changed or in combination with alcohol. If your mental alertness is affected in any way during treatment with Furosemide, you should not drive or operate machinery.

Furosemide Norameda contains sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per dose (40mg), i.e. essentially ‘sodium- free’.

3. How to use Furosemide Norameda

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist or nurse, if you are not sure. Your medicine is normally given by a doctor or nurse: - as a slow injection into a vein (intravenous) or - exceptionally into a muscle (intramuscular).

Furo/SPC/03 12-Nov-17 21 Your doctor will decide how much you need, when it is to be given to you and the duration of treatment. This will depend on your age, weight, medical history, other medicines that you are taking and type and severity of your disease.

Adults The recommended dose is 20 to 40 mg. If your doctor thinks a higher dose is needed, you may be given further 20 mg injections. This is usually given every 2 hours, until the desired fluid loss occurs. In some cases, instead of injections, your doctor may recommend this medicine is given by continuous infusion into a vein (a drip). The recommended maximum daily dose of furosemide administration is 1500 mg.

Use in children and adolescents over 15 years For children (children below 15 will only be treated in exceptional cases), the dose depends on the child´s weight. The first dose is 0.5 to 1 mg per kilogram of body weight per day up to a maximum total daily dose of 20 mg. For adolescents over 15 years of age the usual first recommended dose is 20 to 40 mg

Patients with renal impairment: In patients with severe impairment of renal function (serum creatinine > 5 mg/dl) it is recommended that an infusion rate of 2.5 mg furosemide per minute is not exceeded.

Elderly: The elderly are usually given 20 mg/day at first. This can be gradually increased until the desired fluid loss occurs.

Weight loss by loss of body fluid should not be more than 1 kg of body weight per day.

If you use more Furosemide Norameda than you should

If you think you have been given too much of this medicine, tell your doctor straight away. Signs which may occur if you have been given too much of this medicine are dryness of the mouth, increased thirst, irregular heartbeat, mood changes, muscle cramps or pain, feeling or being sick, unusual tiredness or weakness, a weak pulse or loss of appetite.

If you forget to use Furosemide Norameda

If you think you have missed an injection, speak to your doctor or nurse.

If you stop using Furosemide Norameda

If you stop treatment early before your doctor’s recommendation, your heart, lungs or kidneys, may be seriously affected by too much fluid. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. If you notice the following, contact the doctor or nurse immediately: Anaphylaxis, a severe allergic reaction which can cause skin rashes, swelling of the face, lips, tongue or throat, breathing difficulties, and loss of consciousness.

Uncommon side effects (may affect up to 1 in 100 patients) - Skin rashes (including itching, redness, peeling), a tendency to bruising or your skin being sensitive to sunlight - Blood cell changes can lead to failure of blood clotting (with increased risk of bleeding)

Furo/SPC/03 12-Nov-17 22 Rare side effects (may affect up to 1 in 1,000 patients): - Feeling or being sick, diarrhoea, constipation, loss of appetite, discomfort in the mouth and stomach. - Hearing problems and tinnitus (ringing in the ears) particularly in patients with kidney problems - Kidney damage (interstitial nephritis) - Very low white blood cell levels in the blood (which can lead to life threatening infections). Get medical help immediately if you have notice that you have an increased tendency to get infections or are unable to fight them off in the usual way. - Muscle problems, including leg cramps or muscle weakness - Pain or discomfort where the injection is given (particularly after injection into muscle) - The inflammatory disease lupus erythematosus may occur or get worse - Changes in blood test results for cholesterol and triglycerides - Feeling of numbness or tingling of the skin - Dizziness - High temperature - Blurred eye-sight, confusion, sleepiness - Dry mouth

Very rare side effects (may affect up to 1 in 10,000 patients): - Severe muscle problems including twitching, spasms, cramps (also called “tetanus”). - Blood cell changes can lead to anaemia, inability to fight infection - Pancreatitis (severe tummy pain) due to inflammation of the pancreas - Liver problems or changes in the levels of liver enzymes in the blood which may cause jaundice (yellow skin, dark urine, tiredness) The following side effects may also occur: - At the initial stage of treatment, low blood pressure making you feel faint or dizzy. It may also cause the feeling of pressure in the head, joint pain, blood clot formation, or collapse of your circulation (shock) - Low potassium levels in the blood. This can cause muscle weakness, tingling and numbness, slight inability to move a body part, being sick, constipation, increased gas in your gut, increased urine production, increased urge to drink, or slow or irregular heart rhythm. - Low sodium, calcium and magnesium levels in the blood. This may occur due to increased loss of sodium, calcium and magnesium with your urine. Low sodium levels cause a lack of interest, cramp in the calf, reduced appetite, weakness, sleepiness, being sick and confusion. Cramps can also be associated with low calcium levels or low magnesium levels in your body - Gout may occur or get worse - Existing problems passing water may be made worse - Diabetes may occur or get worse - Reduced volume of body fluid especially in elderly patients. Severe fluid loss may lead to increased concentration of the blood with a tendency for the development of blood clots

Reporting of side effects If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V.* By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Furosemide Norameda

This medicinal product does not require any special temperature storage conditions. Keep the ampoules in the outer carton in order to protect from light. Do not freeze.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after “EXP”. The expiry date refers to the last day of that month. Furo/SPC/03 12-Nov-17 23

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Single dose container should be used immediately after first opening. Discard any unused contents.

Storage information regarding the diluted medicinal product is provided in section 6 “The following information is intended for healthcare professionals only”.

6. Contents of the pack and other information

What Furosemide Norameda contains

- The active substance is furosemide. - The other ingredients are sodium hydroxide (for pH-adjustment), sodium chloride, concentrated hydrochloric acid (for pH-adjustment), water for injections.

What Furosemide Norameda looks like and contents of the pack

Furosemide 10 mg/ml solution for injection/infusion is a clear and colourless to almost colourless solution, essentially free from visible particles. It is available in amber coloured glass (Type I) ampoules containing 2ml or 5ml of solution. Each box contains 10 or 25 ampoules.

Not all packs sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

<[To be completed nationally]>

This medicinal product is authorised in the Member States of the EEA under the following names:

Estonia Furosemide Norameda Finland Furosemide Norameda 10 mg/ml injektioneste, liuos Hungary Furosemide Norameda 10 mg/ml oldatos injekció Latvia Furosemide Norameda 10 mg/ml ml šķīdums injekcijām Lithuania Furosemide Norameda 10 mg/ml injekcinis tirpalas Poland Furosemide Norameda Slovakia Furosemide Norameda 10 mg/ml injekčný roztok

This leaflet was last revised in {MM/YYYY

<[To be completed nationally]>

Other sources of information>

Detailed information on this medicine is available on the website of {name of MS Agency (link)} ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––

The following information is intended for healthcare professionals only

Single dose container. Use immediately after first opening. Discard any remaining contents after use. Product containing visible particles should not be used. Furo/SPC/03 12-Nov-17 24

Furosemide should not be mixed with strong acid solutions (pH lower than 5.5), such as solutions containing ascorbic acid, noradrenaline and adrenaline, due to the risk of precipitation. Furosemide 10 mg/ml solution for injection/infusion solution should not be mixed with any other drugs.

After dilution Furosemide Norameda 10 mg/ml solution for injection/infusion may be mixed with neutral and weak alkaline solution with pH between 7 and 10, such as 0.9% sodium chloride and Ringer’s lactate solution in non PVC bag.

Chemical and physical in-use stability after dilution has been demonstrated for 48 hours at 25ºC and at 2 to 8°C, protected from light.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Furo/SPC/03 12-Nov-17 25