Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Baxter Healthcare, Caxton Way, Thetford, Norfolk, IP24 3SE, United Kingdom
Mannitol 15% w/v Solution for infusion is contra-indicated in patients presenting with:
Anaphylactic/anaphylactoid reactions, including anaphylaxis, as well as other hypersensitivity/infusion reactions have been reported with mannitol. 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 drugs and cosmetics. Therefore, patients may be sensitized without having received intravenous treatment with mannitol.
CNS toxicity manifested by, e.g. confusion, lethargy, coma has been reported in patients treated with mannitol, in particular in the presence of impaired renal function. Fatal outcomes have been reported.
CNS toxicity may result from:
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 preexisting 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.
Reversible, acute oligoanuric renal failure, has occurred in patients with normal pretreatment renal function who received large intravenous doses of mannitol.
Although the osmotic nephrosis associated with mannitol 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. Serum osmolar gap and renal function should be closely monitored and appropriate action initiated, should signs of worsening renal function or haematuria appear.
Mannitol 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 infusion, the patient’s clinical status should be closely reviewed for developing renal impairment, and the mannitol infusion suspended, if necessary.
The cardiovascular status of the patient should be carefully evaluated before rapidly administering Mannitol 15% w/v Solution for infusion.
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.
If the patient’s cardiac or pulmonary function deteriorates, treatment should be discontinued.
Mannitol-induced osmotic diuresis may cause or worsen dehydration/hypovolaemia and hemoconcentration. Administration of mannitol may also cause hyperosmolarity.
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 treatment include:
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, for example,
The risk for developing encephalopathy as a complication of hyponatraemia is increased, for example,
By sustaining diuresis, mannitol administration may obscure and intensify inadequate hydration or hypovolaemia.
Infusion site reactions have occurred with the use of mannitol. 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.
In patients with shock and renal dysfunction, mannitol should not be administered until volume (fluid; blood) and electrolytes have been replaced.
The acid base balance, renal function and serum osmolarity must be monitored carefully when mannitol is used.
Patients receiving mannitol 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.
Mannitol should not be given concomitantly with blood because it may cause agglutination and crenation of blood cells.
When exposed to low temperatures, solutions of mannitol may crystallize. Inspect for crystals prior to administration. If crystals are visible, redissolve by warming the solution up to 37°C, followed by gentle agitation. See section 4.2.
Mannitol can cause false low results in some tests systems for inorganic phosphorus blood concentrations.
Mannitol produces false positive results in tests for blood ethylene glycol concentrations in which mannitol is initially oxidized to an aldehyde.
Safety and effectiveness in the paediatric population have not been established in clinical studies.
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 drug therapy.
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.
Pressurizing 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.
Concurrent use of other diuretics may potentiate the effects of mannitol and dose adjustments may be required.
Mannitol promotes urine flow, which will mainly affect drugs that are renally reabsorbed to a large extent-thereby increasing their clearance and reducing their exposure.
Mannitol increases urinary excretion of lithium and, therefore, concomitant use of mannitol may impair the response to lithium.
Although an interaction in humans is unlikely, patients receiving concomitant cyclosporine and aminoglycoside should be closely monitored for signs of nephrotoxicity.
Concomitant use of neurotoxic agents (e.g. aminoglycoside) and mannitol may potentiate the toxicity of neurotoxic agents. (See also section 4.4).
The development of electrolyte imbalances (e.g., hyperkalaemia, hypokalaemia) associated with mannitol administration may alter the effects of agents that are sensitive to such imbalances (e.g., digoxin, agents that may cause QT prolongation, neuromuscular blocking agents).
Other potential interactions are with tubocurarine and depolarising neuromuscular blocking drugs (enhancement of their effects by mannitol), oral anticoagulants (mannitol 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).
There are no relevant published data from the use of mannitol in pregnant women.
There are no relevant published data from animal studies with respect to mannitol effect on pregnancy and/or embryo/foetal development and/or parturition and/or postnatal development.
Mannitol should not be used during pregnancy unless clearly needed.
There is no information on excretion of mannitol in breast milk.
Mannitol should not be used during lactation unless clearly needed.
Not relevant.
The following adverse reactions have been reported in post-marketing experience. The frequency of the adverse drug reactions listed in this section cannot be estimated from the available data.
Not known: Allergic reaction, Anaphylactic reaction including anaphylactic shock*
Not known: Fluid and electrolytes imbalance**: Dehydration, Oedema. Metabolic acidosis
Not known: Headache, Dizziness, Rebound intracranial pressure increase, CNS toxicity manifested by: Convulsions, Coma, Confusion, Lethargy.
Not known: Blurred vision
Not known: Cardiac arrhythmia, Congestive heart failure, Palpitations
Not known: Hypotension, Hypertension
Not known: Pulmonary oedema, Rhinitis
Not known: Mouth dry, Thirst, Nausea, Vomiting
Not known: Skin necrosis, Urticaria
Not known: Cramps
Not known: Excessive diuresis, Nephrosis osmotic, Urinary retention, Acute renal failure, Azotemia, Anuria, Haematuria, Oliguria, Polyuria
Not known: Chills, Chest pain (angina-like chest pain), Fever, Asthenia, Malaise, Infusion site reactions including: infusion thrombophlebitis, infusion site inflammation, infusion site pain, infusion site rash, infusion site erythema, infusion site pruritus. Compartment syndrome (associated with extravasation and swelling at the injection site)
* It can be manifested with skin, gastrointestinal, and severe circulatory (hypotension), and respiratory manifestations (e.g. dyspnea). Other hypersensitivity/infusion reactions, include hypertension, pyrexia, chills, sweating, cough, musculoskeletal stiffness and myalgia, urticaria/rash, pruritus, generalized pain, discomfort, nausea, vomiting, and headache.
** including hypervolaemia, peripheral oedema, dehydration, hyponatraemia, hypernatraemia, hyperkalaemia, hypokalaemia.
Severe anaphylaxis with cardiac arrest, and fatal outcome.
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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.
Additives may be incompatible with Mannitol 15% w/v Solution for infusion.
Incompatibility of the medicinal product to be added with the solution in the Viaflo container must be assessed before addition.
Before adding a medicinal product, verify it is soluble and stable in water at the pH of the mannitol solution (4.5 to 7.0).
Mannitol 15% w/v Solution for infusion should not be administered simultaneously with, before, or after administration of blood through the same infusion equipment, due to risk of pseudoagglutination. See section 4.4.
The instructions for use of the medicinal product to be added must be consulted.
As an example, cefepime, imipenem, cilastin and filgrastim are incompatible with mannitol solutions, but this list is not exhaustive. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
The addition of potassium and sodium chloride to mannitol may lead to precipitation of mannitol.
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