MANNITOL Drug Interactions: What You Need to Know

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> .

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> .

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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> . Mannitol may produce false positive results in tests for blood ethylene glycol concentrations in which mannitol is initially oxidized to an aldehyde <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> .

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 )

AND PRECAUTIONS Hypersensitivity Reactions, including anaphylaxis: Stop infusion immediately if hypersensitivity reactions develop. ( 5.1 )

Renal Complications Including Renal

Failure: Risk factors include preexisting renal failure, concomitant use of nephrotoxic drugs or other diuretics. Avoid use of nephrotoxic drugs.

Discontinue Mannitol

Injection if renal function worsens. (5.2, 8.6)

Central Nervous

System (CNS) Toxicity: Confusion, lethargy and coma may occur during or after infusion. Concomitant neurotoxic drugs may potentiate toxicity. Avoid use of neurotoxic drugs.

Discontinue Mannitol

Injection if CNS toxicity develops. ( 5.3 ) Fluid and Electrolyte Imbalances, Hyperosmolarity: Hypervolemia may exacerbate congestive heart failure, hyponatremia can lead to encephalopathy; hypo/hyperkalemia can result in cardiac adverse reactions in sensitive patients.

Discontinue Mannitol

Injection if fluid and/or electrolyte imbalances occur. ( 5.4 )

Monitoring/Laboratory

Tests: Monitor fluid and electrolytes, serum osmolarity and renal, cardiac and pulmonary function. Discontinue if toxicity develops. ( 5.5 )

Infusion Site

Reactions: May include irritation and inflammation, as well as severe reactions (compartment syndrome) when associated with extravasation. ( 5.6 ) Interference with Laboratory Tests: High concentrations of mannitol may cause false low results of inorganic phosphorus blood concentrations. Mannitol may produce false positive results for blood ethylene glycol. ( 5.7 , 7.6 )

5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, hypotension and dyspnea resulting in cardiac arrest and death have been reported with Mannitol Injection [ see Adverse Reactions (6 ) ] . Stop the infusion immediately if signs or symptoms of a suspected hypersensitivity reaction develop. Initiate appropriate therapeutic countermeasures as clinically indicated.

5.2 Renal Complications Including Renal Failure Renal complications, including irreversible renal failure have been reported in patients receiving mannitol. Reversible, oliguric acute kidney injury (AKI) has occurred in patients with normal pretreatment renal function who received large intravenous doses of mannitol. Although the osmotic nephrosis associated with mannitol administration is in principle reversible, osmotic nephrosis in general is known to potentially proceed to chronic or even end-stage renal failure. Monitor renal function closely during infusion of Mannitol Injection. 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 following administration of Mannitol Injection. Avoid concomitant administration of nephrotoxic drugs (e.g., aminoglycosides) or, other diuretics with Mannitol Injection, if possible <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 , 7.2 )]</span>. Patients with oliguric AKI who subsequently develop anuria while receiving mannitol are at risk of congestive heart failure, pulmonary edema, hypertensive crisis, coma and death. During and following Mannitol Injection infusion for reduction in intracranial pressure, monitor the patient clinically and review laboratory tests for changes in fluid and electrolyte status.

Discontinue Mannitol

Injection if renal function worsens [see Warnings and Precautions (5.5) ] .

5.3 Central Nervous System (CNS) Toxicity CNS toxicity manifested by, e.g., confusion, lethargy, or coma has been reported in patients treated with mannitol, with fatal outcomes identified, in particular in the presence of impaired renal function CNS toxicity may result from high serum mannitol concentrations, serum hyperosmolarity resulting in intracellular dehydration within CNS, hyponatremia or other disturbances of electrolyte and acid/base balance secondary to mannitol administration [ see Warnings and Precautions (5.4) ] . At high concentrations, mannitol may cross the blood brain barrier and interfere with the ability of the brain to maintain the pH of the cerebrospinal fluid especially in the presence of acidosis. In patients with preexisting compromise of the blood brain barrier, the risk of increasing cerebral edema (general and focal) associated with repeated or continued use of 20% Mannitol Injection USP must be individually weighed against the expected benefits. A rebound increase of intracranial pressure may occur several hours after the infusion. Patients with a compromised blood brain barrier are at increased risk. Concomitant administration of nephrotoxic drugs (e.g., aminoglycosides) with Mannitol Injection may potentiate neurotoxicity. Avoid concomitant use of neurotoxic drugs, if possible <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span> . During and following infusion of Mannitol Injection for the reduction in intracranial pressure, monitor the patient clinically and laboratory tests for changes in fluid and electrolyte status.

Discontinue Mannitol

Injection if CNS toxicity develops. [see Warnings and Precautions (5.5) ] .

5.4 Fluid and Electrolyte Imbalances, Hyperosmolarity Depending on dosage and duration, administration of Mannitol Injection may result in hypervolemia leading to or exacerbating existing congestive heart failure. Accumulation of mannitol due to insufficient renal excretion increases the risk of hypervolemia. Mannitol-induced osmotic diuresis may cause or worsen dehydration/hypovolemia and hemoconcentration. Administration of Mannitol Injection may also cause hyperosmolarity <span class="opacity-50 text-xs">[see Description (11) ]</span> . The obligatory diuretic response following rapid infusion of Mannitol Injection may further aggravate preexisting hemoconcentration. Excessive loss of water and electrolytes may lead to serious imbalances. Serum sodium and potassium should be carefully monitored during mannitol administration. Depending on dosage and duration of administration, electrolyte and acid/base imbalances may also result from transcellular shifts in water and electrolytes, osmotic diuresis and/or other mechanisms. Such imbalances may be severe and potentially fatal. Imbalances that may result from Mannitol Injection administration include:

• Hypernatremia, dehydration and hemoconcentration
• Hyponatremia, which can lead to headache, nausea, seizures, lethargy, coma, cerebral edema, and death. Acute symptomatic hyponatremic encephalopathy is considered a medical emergency.
• Hypo/hyperkalemia. 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, agents that may cause QT prolongation, neuromuscular blocking agents) [see Drug Interactions (7.4) ] .
• Other electrolyte disturbances
• Metabolic acidosis/alkalosis Pediatric patients less than two years of age, particularly preterm and term neonates, may be at higher risk for fluid and electrolyte abnormalities following Mannitol Injection administration due to decreased glomerular filtration rate and limited ability to concentrate urine [see Use in Specific Populations (8.4) ] During and following Mannitol Injection infusion for the reduction in intracranial pressure, monitor fluid, acid-base balance and electrolyte status and discontinue Mannitol Injection if imbalances occur [see Warnings and Precautions (5.5) ] .

5.5 Monitoring/Laboratory Tests During and following infusion of Mannitol Injection for the reduction in intracranial pressure, monitor:

• serum osmolarity, serum electrolytes (including sodium, potassium, calcium and phosphate) and acid base balance
• the osmol gap
• signs of hypo- or hypervolemia, including urine output
• renal, cardiac and pulmonary function
• intracranial pressure Discontinue Mannitol Injection if renal, cardiac, or pulmonary status worsens, or CNS toxicity develops [see Contraindications (4) ] .

5.6 Infusion Site Reactions The infusion of hypertonic solutions through a peripheral vein, including Mannitol Injection, may result in peripheral venous irritation, including phlebitis. Other severe infusion site reactions, such as compartment syndrome and swelling associated with extravasation, can occur with administration of Mannitol Injection [ see Adverse Reactions (6) ] .

Mannitol

Injection is preferably for administration into a large central vein [see Dosage and Administration (2.1) ].

5.7 Interference with Laboratory Tests High concentrations of mannitol can cause false low results for inorganic phosphorus blood concentrations <span class="opacity-50 text-xs">[see Drug Interactions (7.6) ]</span>. Mannitol may produce false positive results in tests for blood ethylene glycol concentrations [ see Drug Interactions (7.6) ] .