mannitol (Rx)

Frequency Not Defined

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

Renal failure: acute kidney injury, osmotic nephrosis, azotemia, anuria, hematuria, oliguria, polyuria

CNS toxicity: Headache, coma, seizures, confusion, lethargy; rebound increase in intracranial pressure; dizziness

Fluid and electrolyte imbalances: Hypovolemia, hypervolemia, peripheral edema, dehydration, hyponatremia, hypernatremia, hyperkalemia, hypokalemia; metabolic acidosis

Infusion site reactions: Infection, venous thrombosis or phlebitis, inflammation, pain, rash, erythema, pruritus, compartment syndrome and swelling associated with extravasation

Cardiac and respiratory disorders: Rhinitis, congestive cardiac failure, pulmonary edema, palpitations, hypotension, hypertension, tachycardia, and angina-like chest pains

Gastrointestinal disorders: Thirst, dry mouth, nausea, vomiting

Other: Asthenia, malaise, fever, chills, urticaria

Contraindications

Hypersensitivity

Anuria

Severe hypovolemia

Pre-existing severe pulmonary vascular congestion or pulmonary edema

Active intracranial bleeding, except during craniotomy

Cautions

Infusion of hypertonic solutions through a peripheral vein, at a concentration of 10% w/v or greater, may result in peripheral venous irritation, including phlebitis; other severe infusion site reactions, such as compartment syndrome and swelling associated with extravasation, can occur; administer, preferably, into a large central vein

Do not mix with blood

Serious hypersensitivity reactions, including anaphylaxis, hypotension and dyspnea resulting in cardiac arrest and death reported; stop infusion immediately if signs or symptoms of suspected hypersensitivity reaction develop

Renal complications

• Renal complications, including irreversible renal failure reported in patients receiving mannitol
• Reversible, oliguric acute kidney injury (AKI) has occurred with normal pretreatment renal function in patient who received large IV mannitol doses
• 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 mannitol infusion
• Patients with pre-existing renal disease, conditions at high risk for renal failure, or those receiving potentially nephrotoxic drugs or other diuretics, are at increased risk of renal failure following administration
• Avoid coadministration of nephrotoxic drugs or other diuretics, if possible
• Patients with oliguric AKI who subsequently develop anuria while receiving mannitol are at risk of CHF, pulmonary edema, hypertensive crisis, coma, and death
• During and following mannitol infusion for reduction in intracranial pressure, clinically monitor and review laboratory tests for changes in fluid and electrolyte status
• Discontinue if renal function worsens

Central nervous system toxicity

• CNS toxicity manifested by, confusion, lethargy, or coma reported in patients, some resulting in death, in particular in 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
• At high concentrations, mannitol may cross blood brain barrier and interfere with ability of brain to maintain pH of cerebrospinal fluid especially in presence of acidosis
• In patients with preexisting compromise of blood brain barrier, risk of increasing cerebral edema (general and focal) associated with repeated or continued use of product must be individually weighed against expected benefits
• A rebound increase of intracranial pressure may occur several hours after infusion; patients with a compromised blood brain barrier are at increased risk
• Concomitant administration of neurotoxic drugs (eg, aminoglycosides) may potentiate neurotoxicity; avoid concomitant use of neurotoxic drugs, if possible

Fluid electrolyte imbalance

• Depending on dosage and duration, administration may result in hypervolemia leading to or exacerbating existing congestive heart failure
• Accumulation of mannitol due to insufficient renal excretion increases risk of hypervolemia; mannitol-induced osmotic diuresis may cause or worsen dehydration/hypovolemia and hemoconcentration; therapy may also cause hyperosmolarity
• 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

• Metabolic acidosis/alkalosis

  • Pediatric patients <2 years, particularly preterm and term neonates, may be at higher risk for fluid and electrolyte abnormalities following administration due to decreased glomerular filtration rate and limited ability to concentrate urine
  • During and following infusion for reduction in intracranial pressure, monitor fluid and electrolyte status and discontinue therapy if imbalances occur

• Imbalances resulting from therapy

  • 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 (eg, hyperkalemia, hypokalemia) associated with mannitol administration may result in cardiac adverse reactions in patients receiving drugs sensitive to such imbalances (e.g., digoxin, agents that may cause QT prolongation, neuromuscular blocking agents)

• During and following infusion for 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 therapy if renal, cardiac, or pulmonary status worsens or CNS toxicity develops

Drug interaction overview

• Nephrotoxic drugs

  • Coadministration of nephrotoxic drugs increases renal failure
  • If possible, avoid use with nephrotoxic drugs

• Diuretics

  • Coadministration of other diuretics may potentiate renal toxicity
  • If possible, avoid use of other diuretics

• Neurotoxic drugs

  • Coadministration of systemic neurotoxic drugs may potentiate CNS toxicity of mannitol
  • If possible, avoid use of neurotoxic drugs

• Drugs affected by electrolyte imbalances

  • Development of electrolyte imbalances (eg, hyperkalemia, hypokalemia) associated with mannitol administration may result in cardiac adverse reactions in patients receiving drugs that are sensitive to such imbalances (eg, digoxin, drugs that prolong the QT interval, neuromuscular blocking agents)
  • Monitor serum electrolytes during and following mannitol infusion; discontinue if cardiac status worsens

• Renally eliminated drugs

  • May increase elimination and decrease effectiveness of drugs that undergo significant renal elimination
  • Coadministration with lithium may initially increase lithium elimination, but may also increase risk of lithium toxicity if patients develop hypovolemia or renal impairment
  • Consider holding lithium doses during treatment with mannitol
  • If unable to avoid coadministration, frequently monitor serum lithium concentrations for signs of lithium toxicity

Pregnancy

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

Mannitol is present in amniotic fluid when administered to pregnant women during the third trimester of pregnancy

Animal data

• No adverse developmental effects from mannitol reported in published animal studies; however, fluid shifts occurred in fetal ewes in response to maternal infusion of drug

Lactation

There are no data on presence of mannitol in either human or animal milk, effects on breastfed infant, or on milk production

Consider developmental and health benefits of breastfeeding along with mother’s clinical need for drug and any potential adverse effects on breastfed infant from drug or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Osmotic diuretic

When administered IV, exerts its osmotic 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 will induce the movement of intracellular water to the extracellular and vascular space

Onset of Action

Diuresis: 1-3 hr after IV administration of mannitol. Lowering of

IOP reduction: 30-60 min

ICP reduction: 15 min

Duration

IOP reduction: 4-6 hr

ICP reduction: 3-8 hr

Other Information

Metabolism: liver (very slight)

Metabolites: glycogen

Half-life: 100 min

Excretion: urine (80%)

IV Incompatibilities:

Additive: etoposide w/ cisplatin & KCl(?), imipenem-cilastatin (may be used for shorter periods), meropenem (may be used for shorter periods)

Y-site: cefepime, doxorubicin liposomal, filgrastim

IV Compatibilities

Additive (partial list): cefoxitin, cimetidine, furosemide. metoclopramide, ondansetron

Y-site: allopurinol, cisatracurium, etoposide phosphate, linezolid, ondansetron, propofol, vinorelbine

IV Preparation

Infusion only

Use administration set with filter for infusion of injections containing 20% or more, since crystals may be present

For transurethral prostatic resection, mannitol irrigation solns are instilled into bladder via indwelling urethral catheter

IV Administration

Administer over 30-60 minutes

Administer IV using sterile, filter-type administration set to ensure against infusion of mannitol crystals

When administered peripherally, infuse slowly through a small bore needle, placed well within the lumen of a large vein to minimize venous irritation; carefully avoid infiltration

Do not admix with other drugs

Storage

Store at room temperature (25ºC)

Avoid excessive heat

Protect from freezing