Osmitrol

6 ADVERSE REACTIONS The following adverse reactions from voluntary reports or clinical studies have been reported with OSMITROL. 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 : 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 : phlebitis, inflammation, pain, rash, erythema, pruritus; compartment syndrome and swelling associated with extravasation [see Warnings and Precautions (5.6) ] • Cardiac and Respiratory Disorders : congestive cardiac failure, pulmonary edema, palpitations • Gastrointestinal Disorders : thirst, dry mouth • 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 Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS OSMITROL 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 OSMITROL is a sterile, nonpyrogenic solution of Mannitol, USP in a single-dose flexible container 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. The pH is adjusted with sodium hydroxide or hydrochloric acid. Composition, osmolarity, and pH are shown in Table 1 . Table 11 Size Composition Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Osmolarity pH (mL) Mannitol, USP (g/L) (mOsmol/L) (calc) 5% OSMITROL 1000 50 274 5.0 (4.5 TO 7.0) 10% OSMITROL 500 100 549 5.0 (4.5 TO 7.0) 15% OSMITROL 500 150 823 5.0 (4.5 TO 7.0) 20% OSMITROL 250 200 1098 5.0 (4.5 TO 7.0) 500 The plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146 Plastic). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. Osmitrol Injection Structural Formula

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 gram/kg administered every 6 to 8 hours as an intravenous infusion over 30 minutes. • Reduction of Intraocular Pressure : 1.5 to 2 grams/kg of a 15% or 20% w/v solution as a single dose administered intravenously over at least 30 minutes. 2.1 Important Preparation and Administration Instructions • OSMITROL is for intravenous infusion preferably into a large central vein [see Warnings and Precautions (5.5) , Description (11) ]. • Prior to administration of OSMITROL, evaluate renal, cardiac and pulmonary status of the patient and correct fluid and electrolyte imbalances [see Dosage and Administration (2.2) ]. • Do not administer OSMITROL simultaneously with blood products through the same administration set because of the possibility of pseudoagglutination or hemolysis. Preparation 1. Tear overwrap down side at slit and remove solution container. 2. Visually inspect the container. Do not administer unless solution is clear and seal is intact. o If the outlet port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. o 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. 3. Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired. 4. Admixing OSMITROL with other medications is not recommended. 5. Inspect OSMITROL visually for particulate matter and discoloration prior to administration. If particulates or discoloration are present, discard the bag. 6. OSMITROL solutions may crystallize when exposed to low temperature. At higher concentrations, the solutions have a greater tendency to crystallize. Inspect OSMITROL for crystals prior to administration. If crystals are visible, re-dissolve by warming the solution up to 70°C, with agitation. Solutions should not be heated in water or in a microwave oven due to potential for product contamination or damage. Allow the solution to cool to room or body temperature before re-inspection for crystals and use. Administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. 4. Use administration sets with a final in-line filter because of the potential for OSMITROL crystals to form. 5. 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 a pumping device, turn off pump before the container runs dry. 6. For single use only; discard unused portion. 2.2 Recommended Dosage Prior to administration of OSMITROL, 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 Usually a maximum reduction in intracranial pressure can be achieved with a dose of 0.25 gram/kg given intravenously as an intravenous infusion over 30 minutes which may be repeated every six to eight hours. During and following OSMITROL infusion, monitor fluid and electrolytes, serum osmolarity, and renal, cardiac and pulmonary function. Discontinue OSMITROL 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 grams/kg of a 20% w/v solution (7.5 to 10 mL/kg) or as a 15% w/v solution (10 to 13 mL/kg) as a single dose administered intravenously over at least 30 minutes. When used preoperatively, administer OSMITROL sixty to ninety minutes before surgery to achieve maximal reduction of intraocular pressure before operation.

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

10 OVERDOSAGE Signs and symptoms of overdose with OSMITROL include renal failure and AKI, 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 OSMITROL 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. OSMITROL is dialyzable (hemodialysis and peritoneal dialysis), hemodialysis may increase OSMITROL elimination.

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 OSMITROL 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., cyclosporine, aminoglycosides) increases the risk of renal failure following administration of mannitol. Avoid use of nephrotoxic drugs with OSMITROL, 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 OSMITROL, if possible [see Warnings and Precautions (5.2) ]. 7.3 Neurotoxic Drugs Concomitant administration of systemic neurotoxic drugs (e.g., aminoglycosides) with OSMITROL may potentiate the CNS toxicity of mannitol. Avoid use of systemic neurotoxic drugs with OSMITROL, 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 OSMITROL infusion, monitor serum electrolytes and discontinue OSMITROL 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 OSMITROL. In patients requiring concomitant administration of lithium and OSMITROL, 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.

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 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. 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) ].

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.

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) ].

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3 DOSAGE FORMS AND STRENGTHS OSMITROL Injection: • 5% (0.05 grams/mL): 5 grams of mannitol, USP per 100 mL in a single-dose 1000 mL flexible container • 10% (0.1 grams/mL): 10 grams of mannitol, USP per 100 mL in a single-dose 500 mL flexible container • 15% (0.15 grams/mL): 15 grams of mannitol, USP per 100 mL in a single-dose 500 mL flexible container • 20% (0.2 grams/mL): 20 grams of mannitol, USP per 100 mL in single-dose 250 mL and 500 mL flexible containers Injection ( 3 ): • 5% (0.05 grams/mL): 5 grams of mannitol, USP per 100 mL in a single-dose 1000 mL flexible container • 10% (0.1 grams/mL): 10 grams of mannitol, USP per 100 mL in a single-dose 500 mL flexible container • 15% (0.15 grams/mL): 15 grams of mannitol, USP per 100 mL in a single-dose 500 mL flexible container • 20% (0.2 grams/mL): 20 grams of mannitol, USP per 100 mL in single-dose 250 mL and 500 mL flexible containers

Osmitrol Mannitol MANNITOL MANNITOL WATER SODIUM HYDROXIDE HYDROCHLORIC ACID Osmitrol Mannitol MANNITOL MANNITOL WATER SODIUM HYDROXIDE HYDROCHLORIC ACID Osmitrol Mannitol MANNITOL MANNITOL WATER SODIUM HYDROXIDE HYDROCHLORIC ACID Osmitrol Mannitol MANNITOL MANNITOL WATER SODIUM HYDROXIDE HYDROCHLORIC ACID

NDA013684

Osmitrol

Mannitol

0338-0357

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Container Label 2D5604 NDC 0338-0351-04 5% OSMITROL Injection (5% Mannitol Injection USP) 1000 mL EACH 100 mL CONTAINS 5 g MANNITOL USP pH ADJUSTED WITH SODIUM HYDROXIDE OR HYDROCHLORIC ACID pH 5.0 (4.5 TO 7.0) OSMOLARITY 274 mOsmol/L (CALC) STERILE NONPYROGENIC SINGLE DOSE CONTAINER OSMOTIC DIURETIC DOSAGE INTRAVENOUSLY AS DIRECTED BY A PHYSICIAN SEE DIRECTIONS CAUTIONS SQUEEZE AND INSPECT INNER BAG WHICH MAINTAINS PRODUCT STERILITY DISCARD IF LEAKS ARE FOUND DO NOT ADMINISTER SIMULTANEOUSLY WITH BLOOD MUST NOT BE USED IN SERIES CONNECTIONS DO NOT USE UNLESS SOLUTION IS CLEAR RX ONLY STORE UNIT IN MOISTURE BARRIER OVERWRAP AT ROOM TEMPERATURE (25 ° C/77 º F) UNTIL READY TO USE AVOID EXCESSIVE HEAT SEE INSERT VIAFLEX CONTAINER PL 146 PLASTIC FOR PRODUCT INFORMATION 1-800-933-0303 BAXTER OSMITROL VIAFLEX AND PL 146 ARE TRADEMARKS OF BAXTER INTERNATIONAL INC BAXTER HEALTHCARE CORPORATION DEERFIELD IL 60015 USA MADE IN USA Container Label 2D5613 NDC 0338-0353-03 10% OSMITROL Injection (10% Mannitol Injection USP) 500 mL EACH 100 mL CONTAINS 10 g MANNITOL USP pH ADJUSTED WITH SODIUM HYDROXIDE OR HYDROCHLORIC ACID pH 5.0 (4.5 TO 7.0) HYPERTONIC OSMOLARITY 549 mOsmol/L (CALC) STERILE NONPYROGENIC SINGLE DOSE CONTAINER OSMOTIC DIURETIC DOSAGE INTRAVENOUSLY AS DIRECTED BY A PHYSICIAN SEE DIRECTIONS CAUTIONS SQUEEZE AND INSPECT INNER BAG WHICH MAINTAINS PRODUCT STERILITY DISCARD IF LEAKS ARE FOUND DO NOT ADMINISTER SIMULTANEOUSLY WITH BLOOD MUST NOT BE USED IN SERIES CONNECTIONS DO NOT USE UNLESS SOLUTION IS CLEAR RX ONLY STORE UNIT IN MOISTURE BARRIER OVERWRAP AT ROOM TEMPERATURE (25 ° C/77 º F) UNTIL READY TO USE AVOID EXCESSIVE HEAT SEE INSERT VIAFLEX CONTAINER PL 146 PLASTIC FOR PRODUCT INFORMATION 1-800-933-0303 BAXTER OSMITROL VIAFLEX AND PL 146 ARE TRADEMARKS OF BAXTER INTERNATIONAL INC BAXTER HEALTHCARE CORPORATION DEERFIELD IL 60015 USA MADE IN USA Container Label 2D5623 NDC 0338-0355-03 15% OSMITROL Injection (15% Mannitol Injection USP) 500 mL EACH 100 mL CONTAINS 15 g MANNITOL USP pH ADJUSTED WITH SODIUM HYDROXIDE OR HYDROCHLORIC ACID pH 5.0 (4.5 TO 7.0) OSMOLARITY 823 mOsmol/L (CALC) HYPERTONIC MAY CAUSE VEIN DAMAGE STERILE NONPYROGENIC SINGLE DOSE CONTAINER OSMOTIC DIURETIC DOSAGE INTRAVENOUSLY AS DIRECTED BY A PHYSICIAN USING A FILTER TYPE SET SEE DIRECTIONS CAUTIONS SQUEEZE AND INSPECT INNER BAG WHICH MAINTAINS PRODUCT STERILITY DISCARD IF LEAKS ARE FOUND DO NOT ADMINISTER SIMULTANEOUSLY WITH BLOOD MUST NOT BE USED IN SERIES CONNECTIONS DO NOT USE UNLESS SOLUTION IS CLEAR IF CRYSTALS ARE VISIBLE REDISSOLVE BY WARMING UNIT TO 70°C/158°F WITH AGITATION COOL TO ROOM TEMPERATURE AND REINSPECT FOR CRYSTALS BEFORE INFUSION RX ONLY STORE UNIT IN MOISTURE BARRIER OVERWRAP AT ROOM TEMPERATURE (25 ° C/77 º F) UNTIL READY TO USE AVOID EXCESSIVE HEAT SEE INSERT VIAFLEX CONTAINER PL 146 PLASTIC FOR PRODUCT INFORMATION 1-800-933-0303 BAXTER OSMITROL VIAFLEX AND PL 146 ARE TRADEMARKS OF BAXTER INTERNATIONAL INC BAXTER HEALTHCARE CORPORATION DEERFIELD IL 60015 USA MADE IN USA Container Label LOT EXP 2D5632 NDC 0338-0357-02 20% OSMITROL Injection (20% Mannitol Injection USP) 250 mL EACH 100 mL CONTAINS 20 g MANNITOL USP pH ADJUSTED WITH SODIUM HYDROXIDE OR HYDROCHLORIC ACID pH 5.0 (4.5 TO 7.0) OSMOLARITY 1098 mOsmol/L (CALC) HYPERTONIC MAY CAUSE VEIN DAMAGE STERILE NONPYROGENIC SINGLE DOSE CONTAINER OSMOTIC DIURETIC DOSAGE INTRAVENOUSLY AS DIRECTED BY A PHYSICIAN USING A FILTER TYPE SET SEE DIRECTIONS CAUTIONS SQUEEZE AND INSPECT INNER BAG WHICH MAINTAINS PRODUCT STERILITY DISCARD IF LEAKS ARE FOUND DO NOT ADMINISTER SIMULTANEOUSLY WITH BLOOD MUST NOT BE USED IN SERIES CONNECTIONS DO NOT USE UNLESS SOLUTION IS CLEAR IF CRYSTALS ARE VISIBLE REDISSOLVE BY WARMING UNIT TO 70°C/158°F WITH AGITATION COOL TO ROOM TEMPERATURE AND REINSPECT FOR CRYSTALS BEFORE INFUSION RX ONLY STORE UNIT IN MOISTURE BARRIER OVERWRAP AT ROOM TEMPERATURE (25 ° C/77 º F) UNTIL READY TO USE AVOID EXCESSIVE HEAT SEE INSERT VIAFLEX CONTAINER PL 146 PLASTIC FOR PRODUCT INFORMATION 1-800-933-0303 BAXTER OSMITROL VIAFLEX AND PL 146 ARE TRADEMARKS OF BAXTER INTERNATIONAL INC BAXTER HEALTHCARE CORPORATION DEERFIELD IL 60015 USA MADE IN USA Osmitrol Injection Representative Container Label NDC 0338-0351-04 Osmitrol Injection Representative Container Label NDC 0338-053-03 Osmitrol Injection Representative Container Label NDC 0338-0355-03 Osmitrol Injection Representative Container Label NDC 0338-0357-02

Indications and Usage (removed, revised) ( 1 ) 11/2018 Contraindications ( 4 ) 11/2018 Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.4 , 5.5 , 5.6 , 5.7 ) 11/2018

Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA Printed in USA Baxter, Osmitrol, and Viaflex are trademarks of Baxter International Inc. 07-19-00-1127

17 PATIENT COUNSELING INFORMATION Inform patients or caregivers of the following risks of OSMITROL: • Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] • Renal Failure [see Warnings and Precautions (5.2) ] • CNS Toxicity [see Warnings and Precautions (5.3) ] • Fluid and Electrolyte Imbalances, Hyperosmolarity [see Warnings and Precautions (5.4) ] • Infusion Site Reactions [see Warnings and Precautions (5.6) ]

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 OSMITROL [see Warnings and Precautions (5.2 , 5.3 , 5.4 , 5.5 )].

8.4 Pediatric Use OSMITROL is approved for use in the pediatric population for the reduction of intracranial and intraocular pressure. Studies have not defined the optimal dose of OSMITROL 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 OSMITROL administration due to decreased glomerular filtration rate and limited ability to concentrate urine [see Warnings and Precautions (5.4 )].

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 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 OSMITROL and any potential adverse effects on the breastfed infant from OSMITROL or from the underlying maternal condition. 8.4 Pediatric Use OSMITROL is approved for use in the pediatric population for the reduction of intracranial and intraocular pressure. Studies have not defined the optimal dose of OSMITROL 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 OSMITROL administration 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 OSMITROL [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 OSMITROL [see Warnings and Precautions (5.2 , 5.3 , 5.4 , 5.5 )].

16 HOW SUPPLIED/STORAGE AND HANDLING OSMITROL injection is supplied in single-dose, flexible VIAFLEX plastic containers and is available as follows: Code Size (mL) NDC Product Name 2D5604 1000 0338-0351-04 5% (0.05 g/mL mannitol, USP) 2D5613 500 0338-0353-03 10% (0.1 g/mL mannitol, USP) 2D5623 500 0338-0355-03 15% (0.15 g/mL mannitol, USP) 2D5632 250 0338-0357-02 20% (0.2 g/mL mannitol, USP) 2D5633 500 0338-0357-03 20% (0.2 g/mL mannitol, USP) Do not remove container from overwrap until intended for use. Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Store at room temperature (25°C); brief exposure up to 40°C does not adversely affect the product.