MANNITOL

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

INDICATIONS AND USAGE For Intravenous Injection Mannitol Injection, USP is indicated for the following therapeutic uses: • The promotion of diuresis, in the prevention and/or treatment of the oliguric phase of acute renal failure before irreversible renal failure becomes established. • The reduction of intracranial pressure and treatment of cerebral edema by reducing brain mass. • The reduction of elevated intraocular pressure when it cannot be lowered by other means. • The promotion of urinary excretion of toxic substances. For Urologic Irrigation Mannitol solution, 2.5% is indicated as an irrigation solution in transurethral prostatic resection or other transurethral surgical procedures.

For Intravenous Injection Mannitol Injection, USP is indicated for the following therapeutic uses: • The promotion of diuresis, in the prevention and/or treatment of the oliguric phase of acute renal failure before irreversible renal failure becomes established. • The reduction of intracranial pressure and treatment of cerebral edema by reducing brain mass. • The reduction of elevated intraocular pressure when it cannot be lowered by other means. • The promotion of urinary excretion of toxic substances.

For Urologic Irrigation Mannitol solution, 2.5% is indicated as an irrigation solution in transurethral prostatic resection or other transurethral surgical procedures.

DOSAGE AND ADMINISTRATION For Intravenous Injection General Recommendations –Give mannitol injection only intravenously. The total dosage, concentration and rate of administration should be governed by the nature and severity of the condition being treated, fluid requirement and urinary output. Usual adult dosage ranges from 50 to 200 g in 24 hours but in most instances an adequate response will be achieved at a dosage of approximately 100 g in 24 hours. The rate is usually adjusted to maintain an adequate urine flow (at least 30 to 50 mL/hr). Test Dose –In marked oliguria or inadequate renal function a test dose of mannitol should be given. The test dose may be approximately 0.2 g/kg (about 50 mL of a 25% solution) infused in three to five minutes to produce an adequate urine flow (at least 30 to 50 mL/hr). If urine flow does not increase within two or three hours a second test dose may be given. If there is an inadequate response the patient should be reevaluated. Prevention of Acute Renal Failure (Oliguria) –When used during surgery, immediately postoperatively or following trauma, 50 to100 g of mannitol as a 5 to 25% solution maybe given. The concentration and amount will depend upon the fluid requirements of the patient. Following suspected or actual hemolytic transfusion reactions 20 g of mannitol may be given intravenously over a five minute period to provoke diuresis. If diuresis does not occur the 20 g dose may be repeated. If there is an adequate urine flow (30 to 50 mL/hr) then intravenous fluids containing not more than 50 to 75 mEq of sodium per liter should be given in sufficient volume to match the desired urine flow (100 mL/hr) until fluids can be taken orally. Treatment of Oliguria –The usual dose for treatment of oliguria is 50 to 100 g as a 15 to 25% solution. Reduction of Intracranial Pressure, Cerebral Edema or Intraocular Pressure –A 25% solution of mannitol is recommended since its effectiveness depends on establishing intravascular hyperosmolarity. When used before or after surgery, a total dose of 1.5 to 2 g/kg can be given over a period of 30 to 60 minutes. Careful evaluation must be made of the circulatory and renal reserve prior to and during use of mannitol at this relatively high dose and rapid infusion rate. Careful attention must be paid to fluid and electrolyte balance, body weight, and total input and output before and after infusion of mannitol. Evidence of reduced cerebral spinal fluid pressure may be observed within 15 minutes after starting infusion. Maximal reduction of intraocular pressure occurs 30 to 60 minutes after injection. Urinary Excretion of Toxic Substances –Mannitol in 5 to 25% solutions is used as an infusion as long as indicated if the level of urinary output remains high. The concentration will depend upon the fluid requirement and urinary output. Intravenous water and electrolytes must be given to replace the loss of these substances in the urine, sweat and expired air. If benefits are not observed after 200 g of mannitol are given, discontinue it. mannitol-image For Urologic Irrigation A 2.5% solution is used. The use of 2.5% mannitol solution minimizes the hemolytic effect of water alone, the entrance of hemolyzed blood into the circulation, and the resulting hemoglobinemia which is considered a major factor in producing serious renal complications. PREPARATION OF DILUTIONS FOR UROLOGIC IRRIGATION Concentration How Prepared 2.5% Add contents of two 50 mL vials (25% mannitol) to 900 mL Sterile Water for Injection.

For Intravenous Injection General Recommendations –Give mannitol injection only intravenously. The total dosage, concentration and rate of administration should be governed by the nature and severity of the condition being treated, fluid requirement and urinary output. Usual adult dosage ranges from 50 to 200 g in 24 hours but in most instances an adequate response will be achieved at a dosage of approximately 100 g in 24 hours. The rate is usually adjusted to …

3 DOSAGE FORMS AND STRENGTHS Mannitol Injection 20%, USP is a clear and colorless solution of 20 grams of mannitol, USP per 100 mL (0.2 grams/mL) in single-dose 250 mL and 500 mL flexible containers. Injection: 20% (0.2 grams/mL): 20 grams of mannitol, USP per 100 mL in single-dose 250 mL and 500 mL flexible containers.

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 )

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: cardiac arrest, anaphylaxis, hypotension, dyspnea, hypertension, pyrexia, chills, sweating, cough, musculoskeletal stiffness, myalgia, urticarial/rash, pruritus, generalized pain, discomfort, nausea, vomiting, and headache [ see Warnings and Precautions (5.1) ] • Renal Failure: acute kidney injury, osmotic nephrosis, azotemia, anuria, hematuria, oliguria, polyuria [see Warnings and Precautions (5.2) ] • CNS Toxicity : headache, coma, seizures, confusion, lethargy; rebound increase in intracranial pressure; dizziness [ see Warnings and Precautions (5.3) ] • Fluid and Electrolyte Imbalances : hypovolemia, hypervolemia, peripheral edema, dehydration, hyponatremia, hypernatremia, hyperkalemia, hypokalemia; metabolic acidosis [ see Warnings and Precautions (5.4) ] • Infusion Site Reactions : infection, venous thrombosis or phlebitis, inflammation, pain, rash, erythema, pruritus, compartment syndrome and swelling associated with extravasation [see Warnings and Precautions (5.6) ] • Cardiac and Respiratory Disorders : rhinitis, congestive cardiac failure, pulmonary edema, palpitations, hypotension, hypertension, tachycardia, and angina-like chest pains. • Gastrointestinal Disorders : thirst, dry mouth, nausea, vomiting • Other : asthenia, malaise, fever, chills, urticaria The most common adverse reactions are hypersensitivity reactions, renal failure, CNS toxicity, hypo/hypervolemia, hypo/hypernatremia, hypo/hyperkalemia, and infusion site reactions. To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-800-854-6851 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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) ] .

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.

11 DESCRIPTION Mannitol Injection, USP is a sterile, nonpyrogenic solution of mannitol in water for injection available in a concentration of 20% in flexible plastic containers. The content and characteristics of the available concentration is as follows: Concentration (%) g/100 mL mOsmol/liter (calc.) pH may contain sodium bicarbonate for pH adjustment. 20 20 1098 6.3 (4.5 to 7.0) The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only as a single-dose injection. When smaller doses are required the unused portion should be discarded. Mannitol Injection, USP is an osmotic diuretic for intravenous administration. Mannitol, USP is chemically designated D-mannitol (C 6 H 14 O 6 ), a white crystalline powder or free-flowing granules freely soluble in water. It has the following structural formula: Water for Injection, USP is chemically designated H 2 O. The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap, but not in amounts sufficient to affect the solution significantly. 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. 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. Chemical Structure

10 OVERDOSAGE Too rapid infusion of large amounts of mannitol will cause a shift of intracellular water into the extracellular compartment resulting in cellular dehydration and overexpansion of the intravascular space with hyponatremia, congestive heart failure and pulmonary edema. Repeated doses should not be given to patients with persistent oliguria as this can produce a hyperosmolar state and precipitate congestive heart failure and pulmonary edema due to volume overload. Dosage must be carefully monitored and adjusted in accordance with the clinical situation to avoid the consequences of overdosage [see Contraindications (4) , Warnings and Precautions (5) , Dosage and Administration (2) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Mannitol Injection, USP is supplied in single-dose containers as follows: 25% MANNITOL INJECTION, USP is supplied in the following dosage forms. NDC 51662-1468-1 25% MANNITOL INJECTION, USP 12.5g/50mL (250mg/mL) 50mL VIAL NDC 51662-1468-2 25% MANNITOL INJECTION, USP 12.5g/50mL (250mg/mL) 50mL VIAL, 1 VIAL PER POUCH NDC 51662-1468-3 25% MANNITOL INJECTION, USP 12.5g/50mL (250mg/mL) 50mL VIAL, 1 VIAL PER POUCH, 25 POUCHES PER CASE HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 NOTE: Crystals may form in mannitol solutions especially if the solutions are chilled. To dissolve the crystals, warm the bottle in hot water at 80°C and periodically shake vigorously. 25% Mannitol Injection, USP may be autoclaved at 121°C for 20 minutes at 15 psi. Remove cover from fliptop vial and cleanse stopper with antiseptic before use. Cool to body temperature or less before administering. When infusing 25% mannitol concentrations, the administration set should include a filter. Protect from freezing. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] INSTRUCTlONS FOR USE Remove cover and cleanse stopper with antiseptic before use.