Osmitrol

5 WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions, including anaphylaxis : Stop infusion immediately if hypersensitivity reactions develop. ( 5.1 ) • Renal Complications Including Renal Failure : Risk factors include pre-existing renal failure, concomitant use of nephrotoxic drugs or other diuretics. Avoid use of nephrotoxic drugs. Discontinue OSMITROL if renal function worsens. ( 5.2 , 8.6 ) • Central Nervous System (CNS) Toxicity : Confusion, lethargy and coma may occur during or after infusion. Concomitant neurotoxic drugs may potentiate toxicity. Avoid use of neurotoxic drugs. Discontinue OSMITROL if CNS toxicity develops. ( 5.3 ) • Fluid and Electrolyte Imbalances, Hyperosmolarity : Hypervolemia may exacerbate congestive heart failure, hyponatremia can lead to encephalopathy; hypo/hyperkalemia can result in cardiac adverse reactions in sensitive patients. Discontinue OSMITROL if fluid and/or electrolyte imbalances occur. ( 5.4 ) • Monitoring/Laboratory Tests : Monitor fluid and electrolytes, serum osmolarity and renal, cardiac and pulmonary function. Discontinue if toxicity develops. ( 5.5 ) • Infusion Site Reactions : May include irritation and inflammation, as well as severe reactions (compartment syndrome) when associated with extravasation. ( 5.6 ) • Interference with Laboratory Tests : High concentrations of mannitol may cause false low results of inorganic phosphorus blood concentrations. Mannitol may produce false positive results for blood ethylene glycol. ( 5.7 , 7.6 ) 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, hypotension and dyspnea resulting in cardiac arrest and death have been reported with OSMITROL [see Adverse Reactions (6) ]. Stop the infusion immediately if signs or symptoms of a suspected hypersensitivity reaction develop. Initiate appropriate therapeutic countermeasures as clinically indicated. 5.2 Renal Complications Including Renal Failure Renal complications, including irreversible renal failure have been reported in patients receiving mannitol. Reversible, oliguric acute kidney injury (AKI) 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 chronic or even end-stage renal failure. Monitor renal function closely, including signs of urine output reduction, during OSMITROL infusion. Patients with pre-existing renal disease, patients with conditions that put them at high risk for renal failure, or those receiving potentially nephrotoxic drugs or other diuretics, are at increased risk of renal failure following administration of OSMITROL. Avoid concomitant administration of nephrotoxic drugs (e.g., aminoglycosides) or, other diuretics with OSMITROL, if possible [see Drug Interactions (7.1 , 7.2 )]. Patients with oliguric AKI who subsequently develop anuria while receiving mannitol are at risk of congestive heart failure, pulmonary edema, hypertensive crisis, coma and death. During and following OSMITROL infusion for the reduction in intracranial pressure, monitor the patient clinically and laboratory tests for changes in fluid and electrolyte status. Discontinue OSMITROL if renal function worsens. [see Warnings and Precautions (5.5) ]. 5.3 Central Nervous System (CNS) Toxicity CNS toxicity manifested by, e.g., confusion, lethargy, coma has been reported in patients treated with mannitol, some resulting in death, in particular in the presence of impaired renal function CNS toxicity may result from high serum mannitol concentrations, serum hyperosmolarity resulting in intracellular dehydration within CNS, hyponatremia or other disturbances of electrolyte and acid/base balance secondary to mannitol administration [see Warnings and Precautions (5.4) ]. 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 compromise of the blood brain barrier, the risk of increasing cerebral edema (general and focal) associated with repeated or continued use of OSMITROL must be individually weighed against the expected benefits. A rebound increase of intracranial pressure may occur several hours after the infusion. Patients with a compromised blood brain barrier are at increased risk. Concomitant administration of neurotoxic drugs (e.g., aminoglycosides) with OSMITROL may potentiate neurotoxicity. Avoid concomitant use of neurotoxic drugs, if possible [see Drug Interactions (7.3) ]. During and following OSMITROL infusion for the reduction in intracranial pressure, monitor the patient clinically and laboratory tests for changes in fluid and electrolyte status. Discontinue OSMITROL if CNS toxicity develops [see Warnings and Precautions (5.5) ]. 5.4 Fluid and Electrolyte Imbalances, Hyperosmolarity Depending on dosage and duration, administration of OSMITROL may result in hypervolemia leading to or exacerbating existing congestive heart failure. Accumulation of mannitol due to insufficient renal excretion increases the risk of hypervolemia. Mannitol-induced osmotic diuresis may cause or worsen dehydration/hypovolemia and hemoconcentration. Administration of OSMITROL may also cause hyperosmolarity [see Description (11) ]. Depending on dosage and duration of administration, electrolyte and acid/base imbalances may also result from transcellular shifts in water and electrolytes, osmotic diuresis and/or other mechanisms. Such imbalances may be severe and potentially fatal. Imbalances that may result from OSMITROL administration include: • Hypernatremia, dehydration and hemoconcentration • Hyponatremia, which can lead to headache, nausea, seizures, lethargy, coma, cerebral edema, and death. Acute symptomatic hyponatremic encephalopathy is considered a medical emergency. • Hypo/hyperkalemia. The development of electrolyte imbalances (e.g., hyperkalemia, hypokalemia) associated with mannitol administration may result in cardiac adverse reactions in patients receiving drugs that are sensitive to such imbalances (e.g., digoxin, agents that may cause QT prolongation, neuromuscular blocking agents) [see Drug Interactions (7.4) ]. • Other electrolyte disturbances • Metabolic acidosis/alkalosis Pediatric patients less than two years of age, particularly preterm and term neonates, may be at higher risk for fluid and electrolyte abnormalities following OSMITROL administration due to decreased glomerular filtration rate and limited ability to concentrate urine [see Use in Specific Populations (8.4) ]. During and following OSMITROL infusion for the reduction in intracranial pressure, monitor fluid and electrolyte status and discontinue OSMITROL if imbalances occur [see Warnings and Precautions (5.5) ]. 5.5 Monitoring/Laboratory Tests During and following OSMITROL infusion for the reduction in intracranial pressure, monitor: • serum osmolarity, serum electrolytes (including sodium, potassium, calcium and phosphate) and acid base balance, • the osmol gap • signs of hypo- or hypervolemia, including urine output • renal, cardiac and pulmonary function • intracranial pressure Discontinue OSMITROL if renal, cardiac, or pulmonary status worsens or CNS toxicity develops [see Contraindications (4) ]. 5.6 Infusion Site Reactions The infusion of hypertonic solutions through a peripheral vein, including OSMITROL at a concentration of 10% w/v or greater, may result in peripheral venous irritation, including phlebitis. Other severe infusion site reactions, such as compartment syndrome and swelling associated with extravasation, can occur with administration of OSMITROL [see Adverse Reactions (6) ]. OSMITROL is preferably for administration into a large central vein [see Dosage and Administration (2.1) ]. 5.7 Interference with Laboratory Tests High concentrations of mannitol can cause false low results for inorganic phosphorus blood concentrations [see Drug Interactions (7.6) ]. Mannitol may produce false positive results in tests for blood ethylene glycol concentrations [see Drug Interactions (7.6) ].