Mannitol (Page 3 of 4)
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.
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)].
10 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.
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:
| Conc. (%) | g/100 mL | mOsmol/liter (calc.) | pH * |
|---|---|---|---|
| |||
| 25 | 25 | 1372 | 5.9 (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.
Mannitol, USP is chemically designated D-mannitol (C6 H14 O6 ), 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 H2 O.
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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