2.1 Important Administration Instructions

Magnesium Sulfate in 5% Dextrose Injection is:

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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.

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For intravenous use only

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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

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The recommended loading dosage of Magnesium Sulfate in 5% Dextrose Injection in patients with eclampsia or preeclampsia is 4 grams to 6 grams over 15 minutes followed by a recommended maintenance dosage of 1 grams to 2 grams every hour.

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Obtain serum magnesium concentrations and assess clinical status to adjust the dosage.

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In patients with eclampsia, consider targeting the maintenance dosage to achieve serum magnesium concentrations of 3 mg 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.

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For patients with eclampsia, therapy should continue until seizures cease.

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The maximum recommended dosage is 30 grams to 40 grams of magnesium sulfate over 24 hours.

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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

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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.

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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.

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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.

5.1 Fetal-Neonatal Toxicity with Prolonged Use

Continuous administration of magnesium sulfate beyond 5 to 7 days in pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus, including skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported.

Neonates of women receiving Magnesium Sulfate in 5% Dextrose Injection (especially with prolonged maternal use) are at risk for magnesium toxicity including hyporeflexia, hypotonia, and respiratory depression. There is one reported case of neonatal death as the result of magnesium toxicity after transplacental exposure.

The shortest duration of magnesium sulfate treatment that can lead to fetal harm is not known. Administration of Magnesium Sulfate in 5% Dextrose Injection beyond 5 to 7 days is not recommended.

5.2 Risk of Magnesium Toxicity

Patients receiving Magnesium Sulfate in 5% Dextrose Injection are at risk for magnesium toxicity including respiratory depression, acute renal failure and rarely, pulmonary edema.

Monitor clinical signs of magnesium toxicity (for example, facial edema, diminished strength of deep tendon reflexes, respiratory depression) and magnesium concentrations during infusions of Magnesium Sulfate in 5% Dextrose Injection. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more per minute). Serum magnesium concentrations usually sufficient to control convulsions range from 3 to 6 mg per 100 mL (2.5 to 5 mEq per liter). The strength of the deep tendon reflexes begins to diminish when serum magnesium concentrations exceed 4 mEq per liter. Reflexes may be absent at concentration of 10 mEq per liter, at which point respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of magnesium toxicity in patients with preeclampsia and eclampsia. If there is significant magnesium toxicity, stop the Magnesium Sulfate in 5% Dextrose Injection infusion and recheck serum magnesium concentration.

Patients with renal impairment are at greater risk of magnesium toxicity because magnesium is excreted by the body solely by the kidneys [see Use in Specific Populations (8.6)]. Urine output should be maintained at a level of 100 mL per 4 hours. Monitoring serum magnesium levels and the patient’s clinical status is essential to avoid the consequences of overdosage in patients with preeclampsia. Discontinuation of the magnesium infusion is recommended when urine output is less than 100 mL every 4 hours to avoid magnesium toxicity, especially if serum creatinine is increasing progressively.

5.3 Risk of Elevated Blood Glucose

Solutions containing dextrose should be used with caution in patients with known prediabetes or diabetes mellitus given the risk of elevated blood glucose.

5.4 Co-administration with Unapproved Tocolytics

Do not use Magnesium Sulfate in 5% Dextrose Injection with unapproved tocolytics (e.g., beta adrenergic agents such as terbutaline, or with calcium channel blockers such as nifedipine). Serious adverse events including pulmonary edema and hypotension have occurred [see Drug Interactions (7)].

5.5 Aluminum Toxicity

Magnesium Sulfate in 5% Dextrose Injection contains aluminum that may be toxic (Magnesium Sulfate in 5% Dextrose Injection contains less than 25 mcg/L of aluminum). Aluminum may reach toxic concentrations with prolonged parenteral administration in patients with renal impairment.

Patients with renal impairment who receive parenteral concentrations of aluminum at greater than 4 to 5 mcg/kg/day, accumulate aluminum at concentrations associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

5.6 Exacerbation of Myasthenia Gravis

Magnesium Sulfate in 5% Dextrose Injection is contraindicated in patients with known myasthenia gravis.

Use of magnesium sulfate in patients with underlying myasthenia gravis can precipitate a myasthenic crisis. Myasthenic crisis is a life-threatening condition characterized by neuromuscular respiratory failure. Symptoms of myasthenic crisis may include difficulty swallowing, ptosis, facial droop, weakness and/or difficulty breathing that may require intubation.

If myasthenic crisis is suspected, discontinue use of Magnesium Sulfate in 5% Dextrose Injection immediately. Secure the patient’s airway. Consider intensive care unit admission and elective intubation, if respiratory failure is anticipated. Once the airway is secure, confirm the diagnosis. Therapies include plasmapheresis and plasma exchange or intravenous immunoglobulin (IVIG) and immunomodulating therapy in addition to high-dose glucocorticoids.

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.

12.2 Pharmacodynamics

With intravenous administration of magnesium sulfate the onset of anticonvulsant action is immediate and lasts about 30 minutes. The estimated magnesium concentration (above baseline) required to elicit half-maximum effect (EC50) on systolic and diastolic blood pressure in pregnant women with preeclampsia that received intravenous magnesium sulfate therapy was reported to be 1.5 and 1.8 mEq per liter (1.9 and 2.2 mg per dL), respectively, in a published study. Effective anticonvulsant serum concentrations range from 2.5 to 7.5 mEq per liter.

Drug Interaction Studies

The following information is based upon published case reports and clinical studies that could not be confirmed by an adequately controlled study, but still warrant consideration given the potential risks involved [see Drug Interactions (7)].

Neuromuscular Blocking Agents:

Potentiation and prolongation of neuromuscular blockade requiring modification of the neuromuscular blocking agent dosage and/or increased reversal agent requirements were reported in preeclamptic women who received magnesium sulfate treatment who underwent subsequent surgery (for example, caesarian section) with anesthesia that included either a depolarizing (d-tubocurarine, succinylcholine) or nondepolarizing neuromuscular blocking agent (vecuronium, rocuronium).

Narcotics and/or Propofol:

Potentiation and prolongation of analgesic and/or sedative effects as well as a reduced requirement for an intravenous narcotic (fentanyl, sufentanil, tramadol), intrathecal narcotic (fentanyl), and/or intravenous propofol was reported in magnesium sulfate treated patients who required surgery or intensive care that also included narcotic and/or propofol therapy.

Dihydropyridine Calcium Channel Blockers:

An exaggerated hypotensive response (blood pressure 80 to 93/49 to 60 mm Hg) was reported in preeclamptic women who received oral nifedipine in addition to magnesium sulfate treatment. Blood pressure returned to previous levels within approximately 30 minutes with supportive care.

12.3 Pharmacokinetics

Distribution

Approximately 1 to 2% of total body magnesium is located in the extracellular fluid space. Magnesium is 30% bound to albumin.

Elimination

The average half-life and systemic clearance of magnesium sulfate in preeclamptic women is approximately 4 to 5 hours and 4 to 5 liters per hour, respectively.

Excretion:

Magnesium is excreted solely by the kidney at a rate proportional to the serum concentration and glomerular filtration.

Specific Populations

Patients with Renal Impairment:

Plasma magnesium concentrations of 7 to 12.3 mEq per liter (8.6 to 15.1 mg per dL) were reported in preeclamptic women with a urine output less than 100 mL per 4 hours that received 20 grams of magnesium sulfate intravenously over 2 to 8 hours in a published study [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with Magnesium Sulfate in 5% Dextrose Injection have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.