Mannitol

1 INDICATIONS AND USAGE Mannitol Injection is indicated for the reduction of: • intracranial pressure and treatment of cerebral edema. • elevated intraocular pressure. Mannitol Injection is an osmotic diuretic, indicated for the reduction of: • intracranial pressure and treatment of cerebral edema. ( 1 ) • elevated intraocular pressure. ( 1 )

2 DOSAGE AND ADMINISTRATION Administration Instructions ( 2.1 ) : • For intravenous infusion, preferably through a central venous catheter. • Prior to administration, evaluate renal, cardiac and pulmonary status and correct fluid and electrolyte imbalances. Recommended Dosage ( 2.2 ) : • The dosage, concentration and rate of administration depend on the age, weight and condition of the patient, including fluid requirement, urinary output and concomitant therapy. • Reduction of Intracranial Pressure and Treatment of Cerebral Edema : 0.25 g/kg administered every 6 to 8 hours as an intravenous infusion over at least 30 minutes. • Reduction of Intraocular Pressure: 1.5 to 2 g/kg administered as a single dose intravenously over at least 30 minutes. Administer 60 to 90 minutes before surgery to achieve maximal effect. 2.1 Important Preparation and Administration Instructions • Mannitol Injection is for intravenous infusion preferably through a central venous catheter [see Warnings and Precautions (5.6) , Description (11) ] . • Prior to the 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 or through the same administration set because of the possibility of pseduoagglutination or hemolysis. If it is essential that blood be given simultaneously, at least 20 mEq of sodium chloride should be added to each liter of mannitol solution to avoid pseudoagglutination. • Do not transfer Mannitol Injection into polyvinylchloride (PVC) bags; a white flocculent precipitate may form from contact with PVC surfaces. • Administer Mannitol Injection using an administration set with a filter to ensure against infusion of mannitol crystals. Preparation 1. Visually inspect the container before preparation and again before administration. Do not administer unless solution is clear, the container undamaged, and the fliptop vial seal intact. 2. Crystals may form in Mannitol Injection, especially if the solution is exposed to low temperatures. If crystallization occurs, warm the vial in water at 80°C and periodically shake vigorously to dissolve the crystals. Mannitol Injection may be autoclaved at 121°C for 20 minutes at 15 psi. Cool to body temperature or less before administering. Re-inspect Mannitol Injection for crystals prior to administration. Discard the solution if all the crystals cannot be dissolved. 3. Remove cover from fliptop vial and cleanse stopper with antiseptic before use. 4. Additives may be incompatible. Consult with pharmacist, if available. 5. For single use only; discard unused portion. 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. Reduction of Intracranial Pressure and Treatment of Cerebral Edema Usually a maximum reduction in intracranial pressure can be achieved with a dose of 0.25 g/kg administered as an intravenous infusion over at least 30 minutes, which may be repeated every six to eight hours. During and following infusion of Mannitol Injection, monitor fluid and electrolytes, serum osmolarity, and renal, cardiac, and pulmonary function. Discontinue Mannitol Injection if renal, cardiac, or pulmonary status worsens or CNS toxicity develops [see Warnings and Precautions (5.2 , 5.3 , 5.4 , 5.5) ] . Reduction of Intraocular Pressure The recommended dosage is 1.5 to 2 g/kg as a single dose administered as an intravenous infusion over at least 30 minutes. When used preoperatively,…

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 disease, conditions that put patients at risk for renal failure and concomitant use of nephrotoxic drugs or other diuretics. Avoid use of nephrotoxic drugs. Discontinue Mannitol Injection 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 Mannitol Injection 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 Mannitol Injection 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 cause 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 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. Patients with pre-existing renal disease, patients with conditions that put them at risk for renal failure, or those receiving potentially nephrotoxic drugs or other diuretics, are at increased risk for 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) ] . 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 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 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 …

4 CONTRAINDICATIONS Mannitol Injection is contraindicated in patients with: • Known hypersensitivity to mannitol [see Warnings and Precautions (5.1) ]. • Anuria [see Warnings and Precautions (5.2) ]. • Severe hypovolemia [see Warnings and Precautions (5.4) ]. • Pre-existing severe pulmonary vascular congestion or pulmonary edema [see Warnings and Precautions (5.5) ] . • Active intracranial bleeding except during craniotomy. • Known hypersensitivity to mannitol. ( 4 , 5.1 ) • Anuria. ( 4 , 5.2 ) • Severe hypovolemia. ( 4 , 5.4 ) • Pre-existing severe pulmonary vascular congestion or pulmonary edema. ( 4 , 5.5 ) • Active intracranial bleeding except during craniotomy. ( 4 )

7 DRUG INTERACTIONS • Nephrotoxic Drugs and Diuretics : May increase the risk of renal failure; avoid concomitant use. ( 7.1 , 7.2 ) • Neurotoxic Drugs : May potentiate CNS toxicity of mannitol; avoid concomitant use. ( 7.3 ) • Drugs Affected by Electrolyte Imbalances : May result in cardiac adverse reactions; monitor serum electrolytes and discontinue Mannitol Injection if cardiac status worsens. ( 7.4 ) • Renally Eliminated Drugs : Concomitant use may decrease the effectiveness of agents that undergo significant renal elimination. However, concomitant use of mannitol and lithium may increase risk of lithium toxicity. If concomitant use is necessary, frequently monitor lithium concentrations and for signs of toxicity. ( 7.5 ) 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 concomitant administration 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.

8.1 Pregnancy Risk Summary The available case report data with mannitol over decades of use have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Mannitol crosses the placenta and may cause fluid shifts that could potentially result in adverse effects in the fetus (see Data ) .No adverse developmental effects from mannitol were reported in published animal studies; however, fluid shifts occurred in fetal ewes in response to maternal infusion of mannitol. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Published literature reports the presence of mannitol in amniotic fluid when mannitol is administered to pregnant women during the third trimester of pregnancy.

6 ADVERSE REACTIONS The following adverse reactions associated with the use mannitol were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions: Cardiac arrest, anaphylaxis, hypotension, dyspnea, hypertension, pyrexia, chills, sweating, cough, musculoskeletal stiffness, myalgia, urticaria/rash, pruritus, generalized pain, discomfort, nausea, vomiting, headache [see Warnings and Precautions (5.1) ] Renal failure: Acute kidney injury, osmotic nephrosis, anuria, oliguria, urinary retention [see Warnings and Precautions (5.2) ] CNS toxicity: Coma, seizures, confusion, lethargy, rebound increase in intracranial pressure, headache, dizziness [see Warnings and Precautions (5.3) ] Fluid and electrolyte imbalances: Metabolic acidosis, dehydration (hypovolemia), hypervolemia, hyponatremia, hypernatremia, hyperkalemia, hypokalemia [see Warnings and Precautions (5.4) ] Infusion site reactions: Venous thrombosis, thrombophlebitis extending from the site of injection, compartment syndrome and swelling associated with extravasation [see Warnings and Precautions 5.6) ] Cardiac and respiratory disorders: Tachycardia, angina-like chest pain, congestive heart failure, pulmonary congestion, hypotension, edema, rhinitis Gastrointestinal disorders: Dryness of mouth, nausea, vomiting General disorders: Thirst Most common adverse reactions are hypersensitivity reactions, renal failure, CNS toxicity, hypo/hypervolemia, hypo/hypernatremia, hypo/hyperkalemia, and infusion site reactions. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.