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 into a large central vein. 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 : 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 as a single dose administered 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 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. Preparation Tear outer wrap at notch and remove solution container. Visually inspect flexible container. Do not administer unless the solution is clear and the seal is intact. If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for minute leaks prior to use by squeezing the bag firmly. If leaks are detected, discard solution as sterility may be impaired. Admixing Mannitol Injection with other medications is not recommended. Inspect Mannitol Injection visually for particulate matter and discoloration prior to administration. If particulates or discoloration are present, discard the bag. Manitol Injection solutions may crystalize when exposed to low temperatures. Inspect Mannitol Injection for crystals prior to administration. If crystals are visible, re-dissolve by warming the solution up to 70°C with agitation. Heat solution by using a dry-heat cabinet with overwrap intact. The use of a water bath is not recommended. Allow the solution to cool to body temperature or less before administering. Reinspect Mannitol Injection for crystals prior to administration. Discard the solution if all the crystals cannot be dissolved. Administration Close flow control clamp of administration set. Remove cover from outlet port at bottom of container. Insert piercing pin of administration set into port with a twisting motion until the set is firmly seated. NOTE: See full directions on administration set carton. Use administration sets with a final in-line filter because of the potential for mannitol crystals to form. Suspend container from hanger. Squeeze and release drip chamber to establish proper fluid level in chamber. Open flow control clamp and clear air from set. Close clamp. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture. Regulate rate of administration with flow control clamp. To prevent air embolism, use a non-vented infusion set or close the vent on a vented set, avoid multiple connections, do not connect flexible containers in series, fully evacuate residual gas in the container prior to administration, do not pressurize the flexible container to increase flow rates, and if administration is controlled by pumping device, turn off pump before the container runs dry. For single use only; discard unused portion. 2.2 Recommended Dosage Prior to administration of Mannitol Injection, evaluate r…

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 preexisting renal failure, 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 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 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 …

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 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 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 Agents : 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., 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 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 from voluntary reports or clinical studies have been reported with Mannitol Injection. Because many 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 :, anaphylaxis, hypotension, dyspnea, hypertension, pyrexia, chills, sweating, urticaria/rash, pruritus [see Warnings and Precautions (5.1) ] Renal Failure : acute kidney injury, osmotic nephrosis, azotemia, anuria, hematuria, oliguria, polyuria, urinary retention [see Warnings and Precautions (5.2) ] CNS Toxicity : coma, seizures, confusion, lethargy; rebound increase in intracranial pressure; dizziness, headache [see Warnings and Precautions (5.3) ] Fluid and Electrolyte Imbalances : hypovolemia (dehydration), hypervolemia, peripheral edema, , hyponatremia, hypernatremia, hyperkalemia, hypokalemia; metabolic acidosis [see Warning and Precautions (5.4) ] Infusion Site Reactions : venous thrombosis, phlebitis, inflammation, pain, rash, erythema, pruritus; compartment syndrome and swelling associated with extravasation [see Warnings and Precautions (5.6) ] Cardiac and Respiratory Disorders : cardiac arrest, congestive cardiac failure, pulmonary edema, palpitations, tachycardia, angina-like chest pain Musculoskeletal Disorders: musculoskeletal stiffness, myalgia Gastrointestinal Disorders : thirst, dry mouth, nausea, vomiting General Disorders : asthenia, malaise The 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 name ICU Medical, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.