Mannitol

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. 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. Image1.jpg

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)

11 DESCRIPTION Mannitol Injection, USP is a sterile, nonpyrogenic solution of mannitol in water for injection available in a fliptop vial for intravenous administration as an osmotic diuretic. The content and characteristics are as follows: The solution contains no bacteriostat, antimicrobial agent, or added buffer (except for pH adjustment) and is intended only as a single-dose injection. Mannitol, USP is chemically designated D-mannitol (C6H14O6), a white crystalline powder or free-flowing granules freely soluble in water. It has the following structural formula: Image2.jpg Formula1.jpg

2 DOSAGE AND ADMINISTRATION 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 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. 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. Remove cover from fliptop vial and cleanse stopper with antiseptic before use. Additives may be incompatible. Consult with pharmacist, if available. 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, administer Mannitol Injection 60 to 90 minutes before surgery to achieve maximal reduction of intraocular pressure before operation. 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.

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)

9 OVERDOSAGE Signs and symptoms of overdose with Mannitol Injection include renal failure and acute kidney injury, hypo/hypervolemia, hyperosmolarity and electrolyte imbalances, CNS toxicity (e.g., coma, seizures), some of which can be fatal [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.4)]. Management of overdosage with Mannitol Injection is symptomatic and supportive. Discontinue the infusion and institute appropriate corrective measures with particular attention to renal, cardiac, and pulmonary systems. Correct fluid and electrolyte imbalances. Mannitol Injection is dialyzable (hemodialysis and peritoneal dialysis), hemodialysis may increase mannitol elimination.

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 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. 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) See 17 for PATIENT COUNSELING INFORMATION. Revised: 3/2020

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Mannitol, when administered intravenously, exerts its osmotic diuretic effect as a solute of relatively small molecular size 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 Distribution Mannitol distributes largely to the extracellular space within 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/minute. The elimination half-life of mannitol is 0.5 to 2.5 hours Metabolism Only a relatively small amount of the mannitol dose is metabolized after intravenous administration 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 3 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)].

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3 DOSAGE FORMS AND STRENGTHS Mannitol Injection 25%, USP: 12.5 g/50 mL (0.25 g/mL) of mannitol as a clear and colorless solution in a single-dose vial. Mannitol Injection 25%, USP: 12.5 g/50 mL (0.25 g/mL) in a single-dose vial (3)

Mannitol Mannitol Mannitol Mannitol

NDA016269

Mannitol

Mannitol

0404-9905

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

Sample Package Label Label1.jpg

Recent Major Changes Indications and Usage (removed, revised) (1) 03/2020 Contraindications (4) 03/2020 Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7) 03/2020

These highlights do not include all the information needed to use MANNITOL INJECTION safely and effectively. See full prescribing information for MANNITOL INJECTION. MANNITOL injection, for intravenous use Initial U.S. Approval: 1964

8 USE IN SPECIFIC pOPULATIONS 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. 8.2 Lactation Risk Summary There are no data on the presence of mannitol in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Mannitol Injection and any potential adverse effects on the breastfed child from Mannitol Injection or from the underlying maternal condition. 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 administration of Mannitol Injection 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 for 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)].

16 HOW SUPPLIED/ STORAGE AND HANDLING Mannitol Injection 25%, USP is available as 12.5 g/50 mL (0.25 g/mL) of mannitol in a single-dose vial. Supplied as a tray of 25 vials (NDC 0409-4031-01). Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from freezing. Product repackaged by: Henry Schein, Inc., Bastian, VA 24314 From Original Manufacturer/Distributor's NDC and Unit of Sale To Henry Schein Repackaged Product NDC and Unit of Sale Total Strength/Total Volume (Concentration) per unit NDC 0409-4031-01 Supplied in a tray of 25 NDC 0404-9905-50 1 single dose vial in a bag (Vial bears NDC 0409-4031-16) 25% 12.5 mg/50mL (0.25 mg/mL)