5 WARNINGS AND PRECAUTIONS

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 (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 to chronic or even end-stage renal failure. Monitor renal function closely during infusion of Mannitol Injection. 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 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 Mannitol Injection infusion for 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, or coma has been reported in patients treated with mannitol, with fatal outcomes identified, 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 20% Mannitol Injection USP 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 nephrotoxic 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 infusion of Mannitol Injection 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)].

The obligatory diuretic response following rapid infusion of Mannitol Injection may further aggravate preexisting hemoconcentration. Excessive loss of water and electrolytes may lead to serious imbalances. Serum sodium and potassium should be carefully monitored during mannitol administration.

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 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 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)]. Mannitol Injection 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)].

7 DRUG INTERACTIONS

7.1 Nephrotoxic Drugs

Concomitant administration of nephrotoxic drugs (e.g., cyclosporine, aminoglycosides) 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 use of systemic neurotoxic drugs with Mannitol Injection, if possible [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 infusion of Mannitol Injection, monitor serum electrolytes and discontinue Mannitol Injection if cardiac status worsens [see Warnings and Precautions (5.5)].

7.5 Renally Eliminated Drugs

Mannitol therapy 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 if patients develop hypovolemia or renal impairment. In patients receiving lithium, consider holding lithium doses during treatment with Mannitol Injection. In patients requiring concomitant administration of lithium and Mannitol Injection, frequently monitor serum lithium concentrations and for signs of lithium toxicity.

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.
Mannitol may produce false positive results in tests for blood ethylene glycol concentrations in which mannitol is initially oxidized to an aldehyde.

11 DESCRIPTION

Mannitol Injection 20%, USP is a sterile, nonpyrogenic solution of Mannitol, USP in 250 mL and 500 mL single-dose EXCEL® flexible containers for intravenous administration as an osmotic diuretic. It contains no antimicrobial agents. Mannitol is a six-carbon sugar alcohol prepared commercially by the reduction of dextrose.

Each 100 mL contains:

Mannitol USP 20 g; Water for Injection USP qs

pH: 5.3 (4.5-7.0); Calculated Osmolarity 1100 mOsmol/liter

Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.

The formula of the active ingredient is:

Ingredient	Molecular Formula	Molecular Weight
Mannitol USP		182.17

The EXCEL® plastic container is made from a multilayered film specifically developed for parenteral drugs. It contains no plasticizers. The solution contact layer is a rubberized copolymer of ethylene and propylene. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. The container-solution unit is a closed system and is not dependent upon entry of external air during administration. The container is overwrapped to provide protection from the physical environment and to provide an additional moisture barrier when necessary. Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mannitol, when administered intravenously, exerts its osmotic 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 effected 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 elevated intraocular pressure.

12.3 Pharmacokinetics

Distribution

Mannitol distributes largely in the extracellular space in 20 to 40 minutes after intravenous administration. The volume of distribution of mannitol is approximately 17 L in adults.

Elimination

In subjects with normal renal function, the total clearance is 87 to 109 mL/min. The elimination half-life of mannitol is 0.5 to 2.5 hours.

Metabolism

Only relatively small amount of the dose administered is metabolized after intravenous administration of mannitol to healthy subjects.

Excretion

Mannitol is eliminated primarily via the kidneys in unchanged form. Mannitol is filtered by the glomeruli, exhibits less than 10% of tubular reabsorption, and is not secreted by tubular cells. Following intravenous administration, approximately 80% of an administered dose of mannitol is estimated to be excreted in the urine in three hours with lesser amounts thereafter.

Specific Populations

Patients with Renal Impairment

In patients with renal impairment, the elimination half-life of mannitol is prolonged. In a published study, in patients with renal impairment including acute renal failure and end stage renal failure, the elimination half-life of mannitol was estimated at about 36 hours, based on serum osmolarity. In patients with renal impairment on dialysis, the elimination half-life of mannitol was reduced to 6 and 21 hours during hemodialysis and peritoneal dialysis, respectively [see Use in Specific Populations (8.6), Overdosage (10)].

16 HOW SUPPLIED/STORAGE AND HANDLING

Mannitol Injection USP, 20% (0.2 grams/mL) as a clear and colorless solution is supplied in sterile and nonpyrogenic 250 mL and 500 mL single-dose EXCEL® Containers.
Not made with natural rubber latex, PVC or DEHP.

NDC	REF	Size
0264-7578-10	L5781	500 mL
0264-7578-20	L5782	250 mL

The 500 mL and 250 mL containers are packaged 24 per case.

Store at room temperature (25°C).

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing.