Mannitol 25 % Injection Fresenius 50 ml Solution for injection.

u2022 Renal failure u2013 Prophylaxis against acute renal failure in conditions such as cardiovascular operations, severe traumatic injury, operations in the presence of severe jaundice, and management of haemolytic transfusion reactions.

u2022 Differential diagnosis of acute oliguria. If either glomerular or tubular function is too severely compromised, mannitol will not increase urine flow.

u2022 Reduction of cerebrospinal and intraocular fluid pressures.

Warm before use to dissolve crystals. Do not use unless solution is clear. Use filter type administration set for large volumes. The adult dose for promotion of diuresis ranges from 50 to 200 g over a 24 hour period of infusion or slow injection. The rate is generally adjusted to maintain a urinary output of at least 30 to 50 ml per hour. It should be preceded by a test dose in patients with marked oliguria or questionable adequacy of renal function. The recommended test dose is 200 mg/kg (approximately 65 ml of a 20 % or 50 ml of a 25 % solution for an adult patient), slowly injected over 3 to 5 minutes. If the first or a second test dose fails to promote a urinary flow greater than 30 ml per hour for 2 to 3 hours, the patient's status should be re-evaluated prior to continuation of therapy.

For the prevention of acute renal failure during various types of surgery or for the treatment of oliguria, the total dose is 50 to 100 g of mannitol for an adult patient.

For the reduction of intracranial pressure and brain mass prior to neurosurgery, or for the reduction of intraocular tension during an acute attack of congestive glaucoma or for ophthalmic surgery, the recommended dose is 1,5 to 2 g/kg given as a 15 %, 20 % or 25 % solution over a period of 30 to 60 minutes.

u2022 Hypersensitivity to mannitol or to any of the excipients listed in section 6.1.

u2022 Renal disease of sufficient severity to produce anuria and marked pulmonary congestion.

u2022 MANNITOL 25 % INJECTION FRESENIUS is contraindicated in patients with pulmonary congestion or oedema, intracranial bleeding (except during craniotomy), metabolic oedema with abnormal capillary fragility, severely dehydrated patients, or patients with renal failure unless a test dose has produced a diuretic response.

u2022 MANNITOL 25 % INJECTION FRESENIUS is also contraindicated in patients with congestive heart failure because in patients with diminished cardiac reserve, expansion of the extracellular fluid may lead to fulminating heart failure.

u2022 MANNITOL 25 % INJECTION FRESENIUS should not be administered with whole blood.

u2022 Progressive renal damage or dysfunction after the institution of mannitol therapy, including oliguria and azotaemia.

u2022 Pre-existing plasma hyperosmolarity.

u2022 Disturbance of the blood-brain barrier.

MANNITOL 25 % INJECTION FRESENIUS is a hyperosmolar solution. This solution may not be mixed with other parenteral medicines. It may, however, be diluted with water for injection or sodium chloride 0,45 % solution if necessary. Hyperosmotic solutions of mannitol should be administered slowly by intravenous injection and should not be mixed with blood in the transfusion apparatus. Patients should be closely observed for signs of electrolyte and fluid imbalance, especially in patients with diminished cardiac reserve.

The expansion of extracellular volume can precipitate pulmonary oedema and patients with diminished cardiac reserve are at special risk. The shift of fluid from the intracellular to extracellular compartment can cause tissue dehydration. Dehydration of the brain, particularly in patients with renal failure, may give rise to central nervous system (CNS) symptoms.

Hypersensitivity Anaphylactic/anaphylactoid reactions, including anaphylaxis, as well as other hypersensitivity/infusion reactions have been reported with MANNITOL 25 % INJECTION FRESENIUS. Fatal outcome has been reported (see section 4.8). The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develops. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Mannitol occurs in nature (e.g. in some fruits and vegetables) and is widely used as an excipient in medicines and cosmetics. Therefore, patients may be sensitised without having received intravenous treatment with MANNITOL 25 % INJECTION FRESENIUS.

CNS toxicity CNS toxicity manifested by confusion, lethargy and/or coma has been reported in patients treated with MANNITOL 25 % INJECTION FRESENIUS in particular in the presence of impaired renal function. Fatal outcomes have been reported. CNS toxicity may result from:

• high serum mannitol concentrations
• serum hyperosmolarity resulting in intracellular dehydration within the CNS
• hyponatraemia or other disturbances of electrolyte and acid/base balance secondary to mannitol administration.

At high concentrations, mannitol may cross the blood-brain barrier and interfere with the ability of the brain to maintain the pH of the cerebrospinal fluid especially in the presence of acidosis.

In patients with pre-existing compromised blood-brain barrier, the risk of increasing cerebral oedema (general or focal) associated with repeated or continued use of mannitol must be individually weighed against the expected benefits. A rebound increase of intracranial pressure may occur several hours after the use of mannitol. Patients with compromised blood-brain barrier are at increased risk.

Risk of renal complications Reversible, acute oligoanuric renal failure has occurred in patients with normal pretreatment renal function who received large intravenous doses of MANNITOL 25 % INJECTION FRESENIUS. Although the osmotic nephrosis associated with MANNITOL 25 % INJECTION FRESENIUS administration is in principle reversible, osmotic nephrosis in general is known to potentially proceed to chronic or even end-stage renal failure. Patients with pre-existing renal disease, or those receiving potentially nephrotoxic medicinal products, are at increased risk of renal failure following administration of MANNITOL 25 % INJECTION FRESENIUS. Serum osmolar gap and renal function should be closely monitored and appropriate action initiated, should signs of worsening renal function or haematuria appear. MANNITOL 25 % INJECTION FRESENIUS should be administered with caution to patients with severely impaired renal function. A test dose should be employed and therapy with mannitol continued only if an adequate urine flow is achieved (see section 4.2). If the urine output declines or haematuria is observed during MANNITOL 25 % INJECTION FRESENIUS, the patient's clinical status should be closely reviewed for developing renal impairment, and the injection suspended, if necessary.

Risk of hypervolaemia The cardiovascular status of the patient should be carefully evaluated before rapidly administering MANNITOL 25 % INJECTION FRESENIUS. High doses and/or high rates of infusion, as well as accumulation of mannitol (due to insufficient renal excretion of mannitol), may result in hypervolaemia, overexpansion of the extracellular fluid, which may lead to or exacerbate existing congestive heart failure. Accumulation of mannitol may result if urine output continues to decline during administration and this may worsen existing or latent congestive heart failure. The infusion of MANNITOL 25 % INJECTION FRESENIUS should be terminated if the patient develops signs of progressive renal dysfunction, heart failure or pulmonary congestion.

Risk of water and electrolyte imbalances and hyperosmolarity Mannitol-induced osmotic diuresis may cause or worsen dehydration/hypovolaemia and haemoconcentration. Acute water toxicity and hyperosmolarity may follow the intravenous administration of MANNITOL 25 % INJECTION FRESENIUS if renal flow is inadequate. Should patient serum osmolarity increase during treatment, the effects of mannitol on diuresis and reduction of intracranial and intraocular pressure may be impaired. In addition, depending on dosage and duration of administration, electrolyte and acid/base imbalances may result from transcellular shifts of water and electrolytes, osmotic diuresis and/or other mechanisms. Such imbalances may be severe and potentially fatal. Imbalances that may result from MANNITOL 25 % INJECTION FRESENIUS treatment include:

• hypernatraemia, dehydration and haemoconcentration (resulting from excessive water loss).

Hyponatraemia A shift of sodium-free intracellular fluid into the extracellular compartment following MANNITOL 25 % INJECTION FRESENIUS infusion may lower serum sodium concentration and aggravate pre-existing hyponatraemia. Loss of sodium and potassium in the urine increases. Hyponatraemia can lead to headache, nausea, seizures, lethargy, coma, cerebral oedema, and death. Acute symptomatic hyponatraemic encephalopathy is considered a medical emergency. The risk for developing hyponatraemia is increased:

• in children
• in elderly patients
• in women
• post-operatively
• in persons with psychogenic polydipsia.

The risk for developing encephalopathy as a complication of hyponatraemia is increased:

• in paediatric patients (u2264 16 years of age)
• in women (in particular, premenopausal women)
• in patients with hypoxaemia
• in patients with underlying central nervous system disease.

Other electrolyte imbalances

• hypokalaemia
• hyperkalaemia
• metabolic acidosis
• metabolic alkalosis.

By sustaining diuresis, MANNITOL 25 % INJECTION FRESENIUS administration may obscure and intensify inadequate hydration or hypovolaemia.

Infusion reactions Infusion site reactions have occurred with the use of MANNITOL 25 % INJECTION FRESENIUS. They include signs and symptoms of infusion site irritation and inflammation, as well as severe reactions (compartment syndrome) when associated with extravasation. See section 4.8. Adding other medications or using an incorrect administration technique may cause febrile reactions due to possible introduction of pyrogens. In case of an adverse reaction, infusion must be stopped immediately. For information on incompatibilities and preparation of the product and additives, please see sections 6.2 and 6.6.

Volume and electrolyte replacement before use In patients with shock and renal dysfunction, MANNITOL 25 % INJECTION FRESENIUS should not be administered until volume (fluid and/or blood) and electrolytes have been replaced.

Monitoring The acid base balance, renal function and serum osmolarity must be monitored carefully when MANNITOL 25 % INJECTION FRESENIUS is used. Patients receiving MANNITOL 25 % INJECTION FRESENIUS should be monitored for any deterioration in renal, cardiac or pulmonary function and treatment discontinued in the case of adverse events.

Urinary output, fluid balance, central venous pressure and electrolyte balance (in particular serum sodium and potassium levels) should be carefully monitored.

Incompatibility with blood MANNITOL 25 % INJECTION FRESENIUS should not be given concomitantly with blood because it may cause agglutination and crenation of blood cells.

Crystallisation When exposed to low temperatures, MANNITOL 25 % INJECTION FRESENIUS may crystallise. Inspect for crystals prior to administration. If crystals are visible, re-dissolve by warming the solution up to 37 u00b0C, followed by gentle agitation. See section 4.2.

Laboratory test interferences MANNITOL 25 % INJECTION FRESENIUS can cause false low results in some test systems for inorganic phosphorus blood concentrations. MANNITOL 25 % INJECTION FRESENIUS produces false positive results in tests for blood ethylene glycol concentrations in which mannitol is initially oxidised to an aldehyde.

Paediatric use Safety and effectiveness in the paediatric population have not been established in clinical studies.

Geriatric use In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or medicine therapy.

Risk of air embolism Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is completed. Pressurising intravenous solutions contained in flexible plastic containers to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers.

MANNITOL 25 % INJECTION FRESENIUS should not be administered with whole blood.

Effect potentialisation Concurrent use of other diuretics may potentiate the effects of MANNITOL 25 % INJECTION FRESENIUS and dose adjustments may be required.

Effect inhibition MANNITOL 25 % INJECTION FRESENIUS promotes urine flow, which will mainly affect medicines that are renally reabsorbed to a large extent, thereby increasing their clearance and reducing their exposure. MANNITOL 25 % INJECTION FRESENIUS increases urinary excretion of lithium and therefore concomitant use may impair the response to lithium.

Nephrotoxicity of medicines due to fluid imbalance related to MANNITOL 25 % INJECTION FRESENIUS Although an interaction in humans is unlikely, patients receiving concomitant ciclosporin and aminoglycoside should be closely monitored for signs of nephrotoxicity.

Neurotoxic medicines Concomitant use of neurotoxic medicines (e.g. aminoglycoside) and MANNITOL 25 % INJECTION FRESENIUS may potentiate the toxicity of neurotoxic medicines. (See also section 4.4.)

Medicines affected by electrolyte imbalances The development of electrolyte imbalances (e.g. hyperkalaemia, hypokalaemia) associated with MANNITOL 25 % INJECTION FRESENIUS administration may alter the effects of medicines that are sensitive to such imbalances (e.g. digoxin, agents that may cause QT prolongation, neuromuscular blocking medicines).

Other potential interactions are with tubocurarine and depolarising neuromuscular blocking medicines (enhancement of their effects by MANNITOL 25 % INJECTION FRESENIUS) oral anticoagulants, (MANNITOL 25 % INJECTION FRESENIUS may reduce their effects by increasing the concentration of clotting factors secondary to dehydration) and digoxin (if hypokalaemia follows mannitol treatment there is a risk of digoxin toxicity).

Safety and efficacy in pregnancy and lactation have not been established.

There is no information of the effects of MANNITOL 25 % INJECTION FRESENIUS on the ability to operate a vehicle or other heavy machinery.

Immune system disorders Frequency unknown: Allergic reaction, anaphylactic reaction including anaphylactic shock.

Metabolism and nutrition disorders Frequency unknown: Fluid and electrolyte imbalance, dehydration, oedema, circulatory overload, hyponatraemia, metabolic acidosis and electrolyte loss.

Nervous system disorders Frequency unknown: Headache, dizziness and rebound intracranial pressure increase. Central nervous system symptoms including convulsions, coma, confusion and lethargy.

Eye disorders Frequency unknown: Blurred vision.

Cardiac disorders Frequency unknown: Cardiac dysrhythmia, congestive heart failure, palpitations, tachycardia and angina-like chest pains.

Vascular disorders Frequency unknown: Hypotension and hypertension.

Respiratory, thoracic and mediastinal disorders Frequency unknown: Pulmonary oedema and rhinitis.

Gastrointestinal disorders Frequency unknown: Dryness of mouth, thirst, nausea and vomiting.

Skin and subcutaneous tissue disorders Frequency unknown: Urticaria and skin necrosis.

Musculoskeletal and connective tissue disorders Frequency unknown: Arm pain and cramps.

Renal and urinary disorders Frequency unknown: Excessive diuresis, osmotic nephrosis, urinary retention, acute renal failure, azotaemia, anuria, haematuria, oliguria and polyuria.

General disorders and administration site conditions Frequency unknown: Chills, fever, asthenia, malaise, tissue dehydration, infusion site reactions including infusion thrombophlebitis, infusion site inflammation, infusion site pain, infusion site rash, infusion site erythema, infusion site pruritis and compartment syndrome (associated with extravasation and oedema at the injection site).

Reporting of suspected adverse reactions: Healthcare providers are asked to report any suspected adverse drug reactions to the Holder of the Certificate of Registration at the following email address: [email protected] and to the relevant medicineu2019s regulatory authority in the country where the product is marketed.

Reporting suspected adverse reactions after authorisation of MANNITOL 25 % INJECTION FRESENIUS is important. It allows continued monitoring of the benefit/risk balance of MANNITOL 25 % INJECTION FRESENIUS. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c 6.04 Adverse Drug Reactions Reporting Form u201d, found online under SAHPRAu2019s publications : ttps://www.sahpra.org.za/Publications/Index/8.

Symptoms: Hypotension, polyuria that rapidly converts to oliguria, stupor, convulsions, pulmonary oedema, hyperosmolarity and hyponatraemia.

Treatment: Discontinue infusion immediately. Institute supportive measures to correct fluid and electrolyte imbalances. Haemodialysis is beneficial to clear mannitol and reduce serum osmolarity. See section 4.4.