2.1 Important Preparation and Administration Instructions

• Mannitol Injection is for intravenous infusion preferably into a large central vein [see Warnings and Precautions (5.6), Description (11)].
• Prior to administration of Mannitol Injection, evaluate renal, cardiac, and pulmonary status of the patient and correct fluid and electrolyte imbalances [see Dosage and Administration (2.2)].
• Do not administer Mannitol Injection simultaneously with blood products through the same administration set because of the possibility of pseudoagglutination or hemolysis.

2.2 Recommended Dosage

Prior to administration of Mannitol Injection, evaluate renal, cardiac and pulmonary status of the patient and correct fluid and electrolyte imbalances.

The total dosage, concentration, and rate of administration depend on the age, weight, and condition of the patient being treated, including fluid requirement, electrolyte balance, serum osmolality, urinary output, and concomitant therapy.

The following outline of administration and dosage is only a general guide to therapy.

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, hypotension and dyspnea resulting in cardiac arrest and death have been reported with Mannitol Injection [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 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 Mannitol Injection 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 Mannitol Injection. Avoid concomitant administration of nephrotoxic drugs (e.g., aminoglycosides) or other diuretics with Mannitol Injection, if possible [see Drug Interactions (7.1, 7.2)].

Patients with oliguric acute kidney injury who subsequently develop anuria while receiving mannitol are at risk of congestive heart failure, pulmonary edema, hypertensive crisis, coma and death.

During and following Mannitol Injection infusion for the reduction in intracranial pressure, monitor the patient clinically and review laboratory tests for changes in fluid and electrolyte status. Discontinue Mannitol Injection 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 Mannitol Injection 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 Mannitol Injection may potentiate neurotoxicity. Avoid concomitant use of neurotoxic drugs, if possible [see Drug Interactions (7.3)].

During and following Mannitol Injection infusion for the reduction in intracranial pressure, monitor the patient clinically and laboratory tests for changes in fluid and electrolyte status. Discontinue Mannitol Injection if CNS toxicity develops [see Warnings and Precautions (5.5)].

5.4 Fluid and Electrolyte Imbalances, Hyperosmolarity

Depending on dosage and duration, administration of Mannitol Injection 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 Mannitol Injection 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 Mannitol Injection 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 Mannitol Injection administration due to decreased glomerular filtration rate and limited ability to concentrate urine [see Use in Specific Populations (8.4)].

During and following Mannitol Injection infusion for the reduction in intracranial pressure, monitor fluid, acid-base balance and electrolyte status and discontinue Mannitol Injection if imbalances occur [see Warnings and Precautions (5.5)].

5.5 Monitoring/Laboratory Tests

During and following infusion of Mannitol Injection for reduction of intracranial pressure and monitor:

• serum osmolarity, serum electrolytes (sodium, potassium, calcium, and phosphate) and acid base balance
• the osmol gap
• signs and symptoms of hypo- or hypervolemia, including urine output
• renal, cardiac, and pulmonary function
• intracranial pressure

Discontinue Mannitol Injection 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 Mannitol Injection 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 Mannitol Injection [see Adverse Reactions (6)]. Administration through a large central vein is preferred with mannitol [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)].

7.1 Nephrotoxic Drugs

Concomitant administration of nephrotoxic drugs (e.g., aminoglycosides, cyclosporine) increases the risk of renal failure following administration of mannitol. Avoid use of nephrotoxic drugs with Mannitol Injection, if possible [see Warnings and Precautions (5.2)].

7.2 Diuretics

Concomitant administration of other diuretics may potentiate the renal toxicity of mannitol. Avoid use of other diuretics with Mannitol Injection, if possible [see Warnings and Precautions (5.2)].

7.3 Neurotoxic Drugs

Concomitant administration of systemic neurotoxic drugs (e.g., aminoglycosides) with Mannitol Injection may potentiate the CNS toxicity of mannitol. Avoid concomitant administration of neurotoxic drugs with mannitol [see Warnings and Precautions (5.3)].

7.4 Drugs Affected by Electrolyte Imbalances

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, drugs that prolong the QT interval, neuromuscular blocking agents) [see Warnings and Precautions (5.4)]. During and following Mannitol Injection infusion, monitor serum electrolytes and discontinue Mannitol Injection if cardiac status worsens [see Warnings and Precautions (5.5)].

7.5 Renally Eliminated Drugs

Mannitol may increase the elimination, and decrease the effectiveness of treatment with, drugs that undergo significant renal elimination. Concomitant administration of mannitol with lithium may initially increase the elimination of lithium but may also increase the risk of lithium toxicity in patients who develop hypovolemia or renal impairment. Consider holding lithium therapy during treatment with Mannitol Injection. If lithium therapy cannot be held, monitor serum lithium concentrations frequently for signs of lithium toxicity. Mannitol therapy may increase the elimination of digoxin leading to a potential decrease in effectiveness of the treatment. Monitor digoxin serum concentrations.

7.6 Interference with Laboratory Tests

High concentrations of mannitol can cause false low results for inorganic phosphorus blood concentrations when an assay based on the conversion of phosphate (orthophosphate) to the phosphomolybdate complex is used [see Warnings and Precautions (5.7)].

Mannitol may produce false positive results in tests for blood ethylene glycol concentrations in which mannitol is initially oxidized to an aldehyde [see Warnings and Precautions (5.7)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Mannitol Injection is approved for use in the pediatric population for the reduction of intracranial and intraocular pressure. Studies have not defined the optimal dose of Mannitol Injection in the pediatric population. The safety profile for mannitol use in pediatric patients is similar to adults at dosages described in labeling. However, pediatric patients less than two years of age, particularly preterm and term neonates, may be at higher risk for fluid and electrolyte abnormalities following Mannitol Injection administration due to decreased glomerular filtration rate and limited ability to concentrate urine [see Warnings and Precautions (5.4)].

8.5 Geriatric Use

Mannitol is known to be substantially excreted by the kidney and the risk of adverse reactions to this drug may be greater in elderly patients with impaired renal function. Evaluate the renal, cardiac, and pulmonary status of the patient and correct fluid and electrolyte imbalances prior to administration of Mannitol Injection [see Warnings and Precautions (5.2, 5.3, 5.4, 5.5)].

8.6 Renal Impairment

Patients with pre-existing renal disease, patients with conditions that put them at high risk of renal failure, or those receiving potentially nephrotoxic drugs or other diuretics, are at increased risk of renal failure with administration of mannitol. Evaluate the renal, cardiac, and pulmonary status of the patient and correct fluid and electrolyte imbalances prior to administration of Mannitol Injection [see Warnings and Precautions (5.2, 5.3, 5.4, 5.5)].

12.1 Mechanism of Action

Mannitol, when administered intravenously, exerts its osmotic diuretic effect as a solute of relatively small molecular size being largely confined to the extracellular space. Mannitol hinders tubular reabsorption of water and enhances excretion of sodium and chloride by elevating the osmolarity of the glomerular filtrate.

This increase in extracellular osmolarity affected by the intravenous administration of mannitol will induce the movement of intracellular water to the extracellular and vascular spaces. This action underlies the role of mannitol in reducing intracranial pressure, intracranial edema, and intraocular pressure.

12.3 Pharmacokinetics

Protect from freezing. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]