magnesium sulfate in dextrose

1 INDICATIONS AND USAGE Magnesium Sulfate in 5% Dextrose Injection is indicated for: • Prevention of eclampsia in patients with preeclampsia • Treatment of seizures and prevention of recurrent seizures in patients with eclampsia Magnesium Sulfate in 5% Dextrose Injection is indicated for ( 1 ): • Prevention of eclampsia in patients with preeclampsia ( 1 ) • Treatment of seizures and prevention of recurrent seizures in patients with eclampsia ( 1 )

2 DOSAGE AND ADMINISTRATION • Administer via intravenous infusion pump ( 2.1 ) • Recommended loading dosage is 4 to 6 grams over 15 minutes followed by a recommended maintenance dosage of 1 to 2 grams every hour; maximum recommended dosage is 30 to 40 grams over 24 hours ( 2.2 ) • Obtain serum magnesium concentrations and assess clinical status to adjust the dose ( 2.2 ) • Administration beyond 5 to 7 days is not recommended ( 2.2 , 5.1 ) • In patients with severe renal impairment and/or urine output less than 0.5 mL/kg/hour, administer a 4 gram loading dose followed by a maintenance dosage of 1 gram every hour; do not exceed the maximum recommended dosage of 20 grams over 48 hours ( 2.3 ) • Do not administer Magnesium Sulfate in 5% Dextrose Injection with incompatible drugs through the same intravenous line, specifically with salicylates and alkali carbonates ( 2.4 ) 2.1 Important Administration Instructions Magnesium Sulfate in 5% Dextrose Injection is: • A clear solution. Visually inspect Magnesium Sulfate in 5% Dextrose Injection for particulate matter and discoloration prior to administration. Do not administer unless solution is clear and colorless to slightly yellow. • For intravenous use only • Administered via intravenous infusion pump Magnesium Sulfate in 5% Dextrose Injection does not require dilution prior to intravenous administration. After removing the overwrap, check for minute leaks by squeezing the container fully. Do not administer Magnesium Sulfate in 5% Dextrose Injection if there is a leak or there is greater than 2 mL of water in the overwrap [see Description (11) ]. Do not administer Magnesium Sulfate in 5% Dextrose Injection with incompatible drugs through the same intravenous line [see Dosage and Administration (2.4) ] . Do not use Magnesium Sulfate in 5% Dextrose Injection in series connections. 2.2 Recommended Dosage • The recommended loading dosage of Magnesium Sulfate in 5% Dextrose Injection in patients with eclampsia or preeclampsia is 4 to 6 grams over 15 minutes followed by a recommended maintenance dosage of 1 to 2 grams every hour. • Obtain serum magnesium concentrations and assess clinical status to adjust the dosage. • In patients with eclampsia, consider targeting the maintenance dosage to achieve serum magnesium concentrations of 3 to 6 mg per 100 mL (2.5 to 5 mEq per liter). For patients with recurrent eclampsia, consider giving an additional 2 gram intravenous bolus. • For patients with eclampsia, therapy should continue until seizures cease. • The maximum recommended dosage is 30 to 40 grams of magnesium sulfate over 24 hours. • Administration of Magnesium Sulfate in 5% Dextrose Injection beyond 5 to 7 days is not recommended [see Warnings and Precautions (5.1) ] . 2.3 Dosage in Patients with Severe Renal Impairment and/or Oliguria • In patients with severe renal impairment and/or a urine output less than 0.5 mL/kg/hour, initiate Magnesium Sulfate in 5% Dextrose Injection with a 4 gram loading dose followed by a maintenance dosage of 1 gram every hour. • Titrate the magnesium sulfate maintenance dosage to maintain concentrations in the target range through frequent monitoring of magnesium concentrations and observation for clinical signs of magnesium toxicity (e.g., facial edema, diminished strength of deep tendon reflexes, respiratory depression). A lower maintenance dosage requirement is likely in these patients. • Do not exceed the maximum recommended dosage of 20 grams of Magnesium Sulfate in 5% Dextrose Injection over 48 hours. 2.4 Drug Incompatibilities Magnesium Sulfate in 5% Dextrose Injection is not compatible with administration of a variety of solutions and forms precipitates of magnesium salts. Before using Magnesium Sulfate in 5% Dextrose Injection with another parenteral product, investigate potential incompatibilities. Incompatible products that should not be coadministered include salicylates and alkali carbonates.

3 DOSAGE FORMS AND STRENGTHS Magnesium Sulfate in 5% Dextrose Injection, USP is a clear and colorless to slightly yellow solution supplied in single-dose flexible plastic containers: • 0.01 grams per mL (1%): ▪ 100 mL flexible plastic container containing 1 gram of magnesium sulfate in 5% dextrose injection Each 100 mL contains 5 grams of hydrous dextrose in water for injection. Supplied in premixed single-dose flexible plastic containers: ( 3 ) • 0.01 grams/mL (1%) in 100 mL flexible plastic container containing 1 gram of magnesium sulfate in 5% dextrose injection

4 CONTRAINDICATIONS Magnesium Sulfate in 5% Dextrose Injection is contraindicated in patients: • with heart block or myocardial damage • in diabetic coma • with myasthenia gravis [see Warnings and Precautions (5.6) ] • Heart block or myocardial damage ( 4 ) • Diabetic coma ( 4 ) • Myasthenia gravis ( 4 , 5.6 )

6 ADVERSE REACTIONS The following adverse reactions have been identified in clinical studies or postmarketing reports. Because these reactions are 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. Cardiovascular: hypotension, circulatory collapse, cardiac depression including bradycardia Central Nervous System: central nervous system depression leading to respiratory paralysis, visual disturbances, flushing, sweating, hypothermia Metabolic: hypocalcemia with signs of tetany, hypermagnesemia Neurologic: lethargy, sedation, somnolence, myasthenic crisis Neuromuscular: depressed deep tendon reflexes, flaccid paralysis Pulmonary: decreased respiratory rate, pulmonary edema The most common adverse reactions are flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system (CNS) depression proceeding to respiratory paralysis and hypocalcemia. Bradycardia, pulmonary edema, decreased respiratory rate, lethargy, sedation, somnolence, visual disturbances, and hypermagnesemia are also reported (6) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Table 1 presents the potential clinical impact of medications that may be commonly administered concomitantly with Magnesium Sulfate in 5% Dextrose Injection in the clinical setting. Table 1: Potential Clinically Significant Drug Interactions with Magnesium Sulfate in 5% Dextrose Injection For drug incompatibility information [see Dosage and Administration (2.4) ] . Neuromuscular Blocking Agents Clinical Impact: • Potentiation and prolongation of neuromuscular blockade is possible with the concomitant use of magnesium sulfate and neuromuscular blocking agents [see Clinical Pharmacology (12.2) ] . • The underlying mechanism of this interaction may involve suppression of peripheral neuromuscular function by decreasing acetylcholine release, reduction of endplate sensitivity, and decreased muscle fiber excitability with magnesium sulfate therapy. Intervention: • Monitor respiration and the depth of neuromuscular blockade frequently (e.g., train-of-four monitoring) when a neuromuscular blocking agent is used concomitantly with Magnesium Sulfate in 5% Dextrose Injection. • Adjust the dosage of the neuromuscular blocking agent accordingly to maintain the desired level of musculoskeletal activity. The amount of reversal agent(s) required to achieve adequate reversal of the neuromuscular blocking agent(s) may also be increased. Examples: • Depolarizing neuromuscular blockers: succinylcholine • Non-depolarizing neuromuscular blockers: atracurium, cisatracurium, pancuronium, rocuronium, vecuronium Narcotics and/or Propofol Clinical Impact: • Potentiation and prolongation of analgesia and CNS depression is possible with the concomitant use of Magnesium Sulfate in 5% Dextrose Injection with narcotics and/or propofol. The potential for magnesium sulfate to affect other CNS depressants is unknown [see Clinical Pharmacology (12.2) ] . • The underlying mechanism of this interaction may involve antagonism of N-methyl-D-aspartate (NMDA) by magnesium sulfate therapy. Intervention: • Monitor the depth of CNS depression frequently using a reliable instrument. • Adjust the narcotic and/or propofol dosage accordingly to maintain the desired level of analgesia and sedation. Examples: • Narcotics and propofol Dihydropyridine Calcium Channel Blockers Clinical Impact: • An exaggerated hypotensive response is possible with the concomitant use of Magnesium Sulfate in 5% Dextrose Injection with dihydropyridine calcium channel blockers. The potential for magnesium sulfate to affect other calcium channel blockers (e.g., diltiazem and verapamil) is unknown [see Clinical Pharmacology (12.2) ] . Intervention: • Monitor vital signs (heart rate, blood pressure, respiration) frequently. • Supportive care and/or discontinuation of the calcium channel blocker may be required. Examples: • Amlodipine, clevidipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, and nisoldipine Drugs that May Induce Magnesium Loss Clinical Impact: • Reduced magnesium concentrations may impact efficacy Intervention: • Monitor magnesium concentrations frequently and adjust the Magnesium Sulfate in 5% Dextrose Injection dosage to maintain concentrations in the target range [see Dosage and Administration (2) ] . Examples: • Alcohol, aminoglycosides, amphotericin B, cisplatin, cyclosporine, digitalis, loop diuretics, thiazide diuretics • Neuromuscular blocking agents : Potentiation and prolongation of neuromuscular blockade is possible with the concomitant use of Magnesium Sulfate in 5% Dextrose Injection ( 7 ) • Narcotics and/or propofol : Potentiation and prolongation of analgesia and CNS depression is possible with the concomitant use of Magnesium Sulfate in 5% Dextrose Injection ( 7 ) • Dihydropyridine calcium channel blockers : An exaggerated hypotensive response is possible with the concomitant use of Magnesium Sulfate in 5% Dextrose Injection ( 7 ) • Drugs that may induce magnesium loss with concomitant use of Magnesium Sulfate in 5% Dextrose Injectio …

8 USE IN SPECIFIC POPULATIONS Patients with severe renal impairment and/or a urine output less than 100 mL every 4 hours are at greater risk for increased magnesium concentrations that may lead to toxicity ( 8.6 ) 8.1 Pregnancy Risk Summary Magnesium Sulfate in 5% Dextrose Injection is indicated in pregnant women for the prevention of eclampsia in women with preeclampsia and the treatment of seizures and prevention of recurrent seizures in women with eclampsia. Fetal, neonatal, and maternal risks are discussed throughout the labeling. Clinical Considerations Labor or Delivery: Magnesium Sulfate in 5% Dextrose Injection is not approved for the treatment of pre-term labor. Administration of Magnesium Sulfate in 5% Dextrose Injection to pregnant women longer than 5 to 7 days may lead to hypocalcemia and bone abnormalities in the developing fetus, including skeletal demineralization and osteopenia [see Warnings and Precautions (5.1) ] . 8.2 Lactation The use of intravenous magnesium in pregnant women increases human milk magnesium concentrations only slightly and oral absorption of magnesium by the infant is poor. The effect of intravenous magnesium on milk production is unknown. The developmental and health benefits to the neonate of breastfeeding should be considered along with the mother's clinical need for Magnesium Sulfate in 5% Dextrose Injection and any potential adverse effects on the breastfed infant from Magnesium Sulfate in 5% Dextrose Injection or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Magnesium Sulfate in 5% Dextrose Injection have been established for the prevention of eclampsia in adolescents with preeclampsia and the treatment of seizures and prevention of recurrent seizures in adolescents with eclampsia. Dosing recommendation in pregnant adolescent patients are the same as for pregnant adult patients [see Dosage and Administration (2.2) ] . 8.6 Renal Impairment Magnesium is excreted solely by the kidneys. Patients with severe renal impairment (urine output less than 100 mL per 4 hours) are at greater risk for increased magnesium concentrations that may lead to magnesium toxicity [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . In patients with severe renal impairment, dosage reduction is recommended and the maximum recommended dosage is lower than patients with normal renal function [see Dosage and Administration (2.3) ] .

12.1 Mechanism of Action Magnesium prevents seizures in patients with preeclampsia and controls seizures in patients with eclampsia by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Magnesium has a depressant effect on the central nervous system [see Drug Interactions (7) ] . Magnesium acts peripherally to produce vasodilation.

11 DESCRIPTION Magnesium Sulfate in 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution of magnesium sulfate heptahydrate and dextrose in water for injection for intravenous use. Each 100 mL contains 1 gram of magnesium sulfate heptahydrate and dextrose, hydrous 5 grams in water for injection [see How Supplied/Storage and Handling (16) ] . Magnesium Sulfate in 5% Dextrose Injection, USP may contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 4.5 (3.5 to 6.5). Magnesium Sulfate, USP heptahydrate is chemically known as sulfuric acid magnesium salt (1:1), heptahydrate and chemically designated MgSO 4 ∙ 7H 2 O, with a molecular weight of 246.47. It occurs as colorless crystals or white powder freely soluble in water. Dextrose, USP is chemically designated D-glucose, monohydrate, a hexose sugar freely soluble in water. The molecular formula is C 6 H 12 O 6 ∙ H 2 O and the molecular weight is 198.17. It has the following structural formula: Water for Injection, USP is chemically designated H 2 O. Not made with natural rubber latex, DEHP or PVC. The plastic container is a copolymer of ethylene and propylene formulated and developed for parenteral drugs. The copolymer contains no plasticizers. The safety of the plastic container has been confirmed by biological evaluation procedures. The material passes Class Vl testing as specified in the U.S. Pharmacopeia for Biological Tests — Plastic Containers. The container/solution unit is a closed system and is not dependent upon entry of external air during administration. The container has two ports, one is for the intravenous administration set covered by a tamper proof barrier and the other is a blocked port. Refer to the directions for use of the container to properly identify the ports [see How Supplied/Storage and Handling (16) ]. No vapor barrier is necessary. Structural Formula

10 OVERDOSAGE Manifestations of magnesium toxicity include a drop in blood pressure, difficulty breathing, and disappearance of the patellar reflex. As serum magnesium rises above 4 mEq per liter, the deep tendon reflexes decrease. As the serum magnesium level approaches 10 mEq per liter, the tendon reflexes disappear and respiratory paralysis may occur [see Warnings and Precautions (5.2) ] . Other signs and symptoms of magnesium overdosage include flushing, sweating, hypotension, weakness, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis, cardiac arrest, and prolongation of PR and QRS intervals. Patients with renal impairment and underlying neuromuscular diseases such as myasthenia gravis may experience magnesium intoxication at lower magnesium concentrations (Magnesium Sulfate in 5% Dextrose Injection is contraindicated in patients with myasthenia gravis). If patient is experiencing magnesium toxicity, immediately discontinue Magnesium Sulfate in 5% Dextrose Injection. Artificial respiration may be required. Administer an injectable calcium salt to counteract the potential hazards of magnesium toxicity [see Warnings and Precautions (5.2) ] . Hypermagnesemia in the newborn (after administration of Magnesium Sulfate in 5% Dextrose Injection to the mother) may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.

16 HOW SUPPLIED/STORAGE AND HANDLING Magnesium Sulfate in 5% Dextrose Injection, USP is a clear solution supplied in single-dose 100 mL fill PAB® containers packaged 24 per case (see Table 2). PAB is a registered trademark of B. Braun Medical Inc. Table 2: How Supplied Information Magnesium Sulfate As the heptahydrate; Concentration NDC Number REF: Container Size Partial fill container 100 mL in 150 mL. Total Magnesium Sulfate Total Magnesium Ion Magnesium Ion Concentration Osmolarity Osmolarity was calculated. 0.01 grams/mL (1%) 0264-4400-54 D4400-54 100 mL 1 gram 8.1 mEq 8.1 mEq/100 mL 333 mOsmol/liter Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Protect from freezing. Handling Directions For Use of PAB® Container CAUTION: DO NOT ADD SUPPLEMENTARY MEDICATION. WHENEVER POSSIBLE USE CENTRAL ROUTE. Aseptic technique is required. Before use, perform the following checks: Read the label. Ensure solution is the one ordered and is within the expiration date. Inspect the solution in good light for cloudiness, haze or particulate matter; check the container for leakage or damage. Any container which is suspect should not be used. Use only if solution is clear and container and seals are intact. Single dose plastic container. Discard unused portion. Consult Package Insert for complete product information. WARNING: DO NOT USE PLASTIC CONTAINER IN SERIES CONNECTION. This solution is intended for intravenous administration using sterile equipment. It is recommended that intravenous administration apparatus be replaced at least once every 24 hours. 1. Identify Two Ports (See Figure A). 2. To Attach Administration Set To aseptically remove the set port closure: hold container below the set port and grasp the foil tab between the thumb and forefinger then pull the tab in two steps as shown in Figure B Steps 1 and 2 . 3. Push spike through the diaphragm of the port (See Figure C) . Hang container using hole on the lower flap. Prime set in accordance with the Directions for Use provided with the set in use. PAB® containers can be safely transported in a standard 6-inch carrier through a pneumatic tube system that is well maintained and running properly. Figure A Figure B Figure C