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ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Pronunciation

(MAN i tole)

Generic Available (U.S.)

Yes: Excludes powder for inhalation

Index Terms

• D-Mannitol

U.S. Brand Names

• Aridol™
• Osmitrol

Canadian Brand Names

• Osmitrol®

Pharmacologic Category

• Diagnostic Agent
• Diuretic, Osmotic
• Genitourinary Irrigant

Pharmacologic Category Synonyms

• Osmotic Diuretic

Use: Labeled Indications

Injection: Reduction of increased intracranial pressure associated with cerebral edema; reduction of increased intraocular pressure; promoting urinary excretion of toxic substances; genitourinary irrigant in transurethral prostatic resection or other transurethral surgical procedures

Note: Although FDA-labeled indications, the use of mannitol for the prevention of acute renal failure and/or promotion of diuresis is not routinely recommended (Kellum, 2008).

Genitourinary irrigation solution: Irrigation in transurethral prostatic resection or other transurethral surgical procedures

Powder for inhalation: Assessment of bronchial hyper-responsiveness

Pregnancy Risk Factor

C

Pregnancy Considerations

Reproduction studies have not been conducted.

Lactation

Excretion in breast milk unknown/use caution

Contraindications

Injection: Hypersensitivity to mannitol or any component of the formulation; severe renal disease (anuria); severe dehydration; active intracranial bleeding except during craniotomy; progressive heart failure, pulmonary congestion, or renal dysfunction after mannitol administration; severe pulmonary edema or congestion

Genitourinary irrigation solution: Anuria

Powder for inhalation: Hypersensitivity to mannitol, gelatin, or any component of the formulation; conditions that may be compromised by induced bronchospasm or repeated spirometry (eg, aortic or cerebral aneurysm, uncontrolled hypertension, recent MI or cerebral vascular accident)

Warnings/Precautions

Boxed warnings:

• Bronchospasm: See “Dosage form specific issues” below

Concerns related to adverse effects:

• Fluid/electrolyte loss: Excess amounts can lead to profound diuresis with fluid and electrolyte loss; close medical supervision and dose evaluation are required. Watch for and correct electrolyte disturbances; adjust dose to avoid dehydration.

• Nephrotoxicity: May cause renal dysfunction especially with high doses; use caution in patients taking other nephrotoxic agents, with sepsis or pre-existing renal disease. To minimize adverse renal effects, adjust to keep serum osmolality less than 320 mOsm/L. Discontinue if evidence of acute tubular necrosis.

Disease-related concerns:

• Cerebral edema: In patients being treated for cerebral edema, mannitol may accumulate in the brain (causing rebound increases in intracranial pressure) if circulating for long periods of time as with continuous infusion; intermittent boluses preferred. Cardiovascular status should also be evaluated; do not administer electrolyte-free mannitol solutions with blood. If hypotension occurs, monitor cerebral perfusion pressure to ensure adequate.

Dosage form specific issues:

• Powder for inhalation (Aridol™): Bronchospasm: [U.S. Boxed Warning] Use may result in severe bronchospasm; use only for bronchial challenge testing. Testing should only be done by trained professionals. Not for use in patients with asthma or very low baseline pulmonary function. Medications (eg, short-acting inhaled beta-agonist) and equipment for the treatment of severe bronchospasm should be readily available. Use with caution in patients with conditions that may increase sensitivity to bronchoconstriction (eg, severe cough, ventilatory impairment, spirometry-induced bronchoconstriction, hemoptysis of unknown origin, pneumothorax, recent abdominal, thoracic, or intraocular surgery, unstable angina, active upper or lower respiratory tract infection). Patients who have ≥10% reduction in FEV₁ on administration of the 0 mg capsule, patients with a positive response to bronchial challenge testing, or patients who develop significant respiratory symptoms should receive short acting inhaled beta-agonist; monitor until full recovery to baseline. Bronchial challenge testing should not be performed in children <6 years of age as these patients are unable to provide reliable spirometric results.

Other warnings/precautions:

• Adequate renal function: Should not be administered until adequacy of renal function and urine flow is established; use 1-2 test doses to assess renal response.

Adverse Reactions

Injection: Frequency not defined:

Cardiovascular: Chest pain, CHF, circulatory overload, hyper-/hypotension, peripheral edema, tachycardia

Central nervous system: Chills, convulsions, dizziness, fever, headache

Dermatologic: Bullous eruption, urticaria

Endocrine & metabolic: Fluid and electrolyte imbalance, dehydration and hypovolemia secondary to rapid diuresis, hyperglycemia, hypernatremia, hyponatremia (dilutional), hyperosmolality-induced hyperkalemia, metabolic acidosis (dilutional), osmolar gap increased, water intoxication

Gastrointestinal: Nausea, vomiting, xerostomia

Genitourinary: Dysuria, polyuria

Local: Pain, thrombophlebitis, tissue necrosis

Ocular: Blurred vision

Renal: Acute renal failure, acute tubular necrosis (>200 g/day; serum osmolality >320 mOsm/L)

Respiratory: Pulmonary edema, rhinitis

Miscellaneous: Allergic reactions

Inhalation:

1% to 10%:

Cardiovascular: Chest discomfort (1%)

Central nervous system: Headache (adults 6%; children 3%), dizziness (1%)

Gastrointestinal: Nausea (adults 2%; children 3%), throat irritation (2%), retching (1%)

Respiratory: Cough (2%), pharyngolaryngeal pain (adults 2%; children 4%), rhinorrhea (2%), dyspnea (1%), wheezing (1%)

<1%, postmarketing, and/or case reports: FEV₁ decreased, gagging

Drug Interactions

Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy

MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification

Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Risk D: Consider therapy modification

Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Storage

Injection: Should be stored at room temperature of 15°C to 30°C (59°F to 86°F); do not freeze. In concentrations ≥15%, crystallization may occur at low temperatures; do not use solutions that contain crystals. Heating in a hot water bath and vigorous shaking may be utilized for resolubilization. Cool solutions to body temperature before using.

Irrigation: Store at room temperature of 25°C (77°F); excursions permitted up to 40°C. Avoid excessive heat; do not warm above 150°F (66°C). Do not freeze.

Powder for inhalation: Store at <25°C (<77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Do not freeze.

Compatibility

Y-site administration: Compatible: Allopurinol, amifostine, amphotericin B cholesteryl sulfate complex, aztreonam, bivalirudin, cisatracurium, cladribine, docetaxel, doripenem, etoposide, fenoldopam, fludarabine, fluorouracil, gemcitabine, hetastarch in lactate electrolyte injection (Hextend®), idarubicin, lansoprazole, linezolid, melphalan, ondansetron, oxaliplatin, paclitaxel, palonosetron, pemetrexed, piperacillin/tazobactam, propofol, remifentanil, sargramostim, teniposide, thiotepa, vinorelbine. Incompatible: Cefepime, doxorubicin liposome, filgrastim, pantoprazole.

Compatibility when admixed: Compatible: Amikacin, amphotericin B cholesteryl sulfate complex, cefamandole, cefoxitin, cimetidine, cisplatin, dopamine, doxapram, fosphenytoin, furosemide, gentamicin, metoclopramide, nizatidine, ofloxacin, ondansetron, penicillin G potassium, sodium bicarbonate, tobramycin, verapamil, vinorelbine. Incompatible: Furosemide, imipenem/cilastatin, meropenem. Variable (consult detailed reference): Etoposide with cisplatin and potassium chloride, potassium chloride.

Mechanism of Action

Produces an osmotic diuresis by increasing the osmotic pressure of glomerular filtrate, which inhibits tubular reabsorption of water and electrolytes and increases urinary output . Mechanism of action in reduction of intracranial pressure (ICP) is controversial. However, it is thought that mannitol reduces ICP by reducing blood viscosity which transiently increases cerebral blood flow and oxygen transport. This in turn reduces cerebral blood volume and ICP. Furthermore, mannitol reduces ICP by withdrawing water from the brain parenchyma and excretes water in the urine (Allen, 2009; Bratton, 2007; Miller, 2010).

Pharmacodynamics/Kinetics

Onset of action: Diuresis: Injection: 1-3 hours; Reduction in intracranial pressure: ~15-30 minutes

Duration: Reduction in intracranial pressure: 1.5-6 hours

Distribution: 34.3 L; remains confined to extracellular space (except in extreme concentrations); does not penetrate the blood-brain barrier (generally, penetration is low)

Metabolism: Minimally hepatic to glycogen

Bioavailability: Inhaled: 59% (relative to oral administration: 96%)

Half-life elimination: Terminal: 4.7 hours

Time to peak, plasma: Inhaled: 1.5 hours

Excretion: Urine (~55% to 87% as unchanged drug)

Dosage

Children: I.V.: Increased intracranial pressure (unlabeled use): 0.25-1 g/kg/dose; repeat as needed to maintain serum osmolality <300-320 mOsm/kg (Adelson, 2003; Broderick, 2007; Hegenbarth, 2008)

Children ≥6 years and Adults: Inhalation: Assessment of bronchial hyper-responsiveness: Administer in a stepwise fashion (measuring FEV₁ in duplicate after each administration) until the patient has a positive response or 635 mg of mannitol has been administered (whichever comes first).

Positive test: 15% reduction in FEV₁ from baseline or 10% incremental reduction in FEV₁ between consecutive doses

Negative test: Administration of full dose (635 mg) without reduction in FEV₁ sufficient to meet criteria for a positive test

Administration should be as follows:

Children ≥12 years and Adults:

I.V.:

Increased intracranial pressure: 0.25 g/kg/dose; may repeat every 6-8 hours as needed. Reported dosing range: 0.25-1 g/kg/dose (Adelson, 2003); maintain serum osmolality <300-320 mOsm/kg (Adelson, 2003; Broderick, 2007)

Reduction of intraocular pressure: 1.5-2 g/kg administered over 30 minutes

Severe traumatic brain injury (unlabeled use): ~1.4 g/kg as initial management prior to neurosurgery with concurrent fluid replacement (Cruz, 2001; Cruz, 2002; Cruz, 2004)

Topical: Transurethral irrigation: Use urogenital solution as required for irrigation

Elderly: Consider initiation at lower end of dosing range

Dosage adjustment in renal impairment: Contraindicated in severe renal impairment. Use caution in patients with underlying renal disease.

Dosage adjustment in hepatic impairment: No adjustment required.

Administration: I.V.

Vesicant; avoid extravasation. Do not administer with blood. Crenation and agglutination of red blood cells may occur if administered with whole blood. Inspect for crystals prior to administration. If crystals present redissolve by warming solution. Use filter-type administration set for infusion solutions containing mannitol ≥20%. For cerebral edema or elevated ICP, administer over 20-30 minutes.

Administration: Other

Inhalation (Aridol™): Administer using supplied single patient use inhaler; do not puncture capsule more than once; do not swallow capsules. A nose clip may be used if preferred. The patient should exhale completely, followed by a controlled rapid deep inspiration from the device; hold breath for 5 seconds and exhale through the mouth. Measure FEV₁ in duplicate 60 seconds after inhalation; repeat process until positive response or full dose (635 mg) has been administered.

Irrigation: Administer using only the appropriate transurethral urologic instrumentation.

Administration: I.V. Detail

pH: 4.5-7

Monitoring Parameters

Renal function, daily fluid I & O, serum electrolytes, serum and urine osmolality; for treatment of elevated intracranial pressure, maintain serum osmolality <300-320 mOsm/kg.

Bronchial challenge test: Standard spirometry prior to bronchial challenge test; FEV₁ in duplicate 60 seconds after administration of each step of test

Patient Education

Report immediately any nausea, dizziness, respiratory difficulty, chest pain, or pain at infusion site.

Additional Information

May autoclave or heat to redissolve crystals; mannitol 20% has an approximate osmolarity of 1100 mOsm/L and mannitol 25% has an approximate osmolarity of 1375 mOsm/L

Bronchial challenge testing: The dose of inhaled mannitol which causes a 15% reduction in FEV₁ is expressed as PD₁₅

Anesthesia and Critical Care Concerns/Other Considerations

Clinical Pearls/Comments: Other information:

May autoclave or heat mannitol solution to redissolve crystals.

Mannitol 20% has an approximate osmolarity of 1100 mOsm/L.

Mannitol 25% has an approximate osmolarity of 1375 mOsm/L.

Evidence-Based Information:

Management of Intracerebral Hemorrhage (ICH): The 2007 AHA/ASA Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults recommends mannitol as a treatment option to decrease intracranial pressure (ICP) (Class IIa recommendation).

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause dizziness

Mental Health: Effects on Psychiatric Treatment

Has been used to treat lithium toxicity/overdose but its overall effect in lowering serum lithium level is minimum; if toxicity is severe, hemodialysis is the treatment of choice

Nursing: Physical Assessment/Monitoring

Assess for adequate renal function and urine flow prior to administration. Infusion site must be closely monitored for extravasation; this is a vesicant. Renal and cardiovascular status should be monitored during infusion. Monitor for circulatory overload, CHF, rash, and water intoxication.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution: 20% [200 mg/mL] (250 mL, 500 mL); 25% [250 mg/mL] (50 mL)

Osmitrol: 5% [50 mg/mL] (1000 mL); 10% [100 mg/mL] (500 mL); 15% [150 mg/mL] (500 mL); 20% [200 mg/mL] (250 mL, 500 mL)

Injection, solution [preservative free]: 25% [250 mg/mL] (50 mL)

Powder, for oral inhalation [capsule/kit]:

Aridol™: 0 mg (1s) [empty], 5 mg (1s), 10 mg (1s), 20 mg (1s), 40 mg (15s) (19s)

Solution, genitourinary irrigation: 5% [50 mg/mL] (2000 mL)

References

Adelson PD, Bratton SL, Carney NA, et al, “Guidelines for the Acute Medical Management of Severe Traumatic Brain Injury in Infants, Children, and Adolescents,” Pediatr Crit Care Med, 2003, 4(3 Suppl):40-4.

Allen CH and Ward JD, “An Evidence-Based Approach to Management of Increased Intracranial Pressure,” Crit Care Clin, 1998, 14(3):485-96.

Bratton SL, Chestnut RM, Ghajar J, et al, “Guidelines for the Management of Severe Traumatic Brain Injury. II. Hyperosmolar Therapy,” J Neurotrauma, 2007, 24(Suppl 1):14-20.

Broderick J, Connolly S, Feldmann E, et al, “Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults: 2007 Update: A Guideline From the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group,” Stroke, 2007, 38(6):2001-23.

Cruz J, Minoja G, and Okuchi K, “Improving Clinical Outcomes from Acute Subdural Hematomas With the Emergency Preoperative Administration of High Doses of Mannitol: A Randomized Trial,” Neurosurgery, 2001, 49(4):864-71.

Cruz J, Minoja G, and Okuchi K, et al, “Major Clinical and Physiological Benefits of Early High Doses of Mannitol for Intraparenchymal Temporal Lobe Hemorrhages With Abnormal Pupillary Widening: A Randomized Trial,” Neurosurgery, 2002, 51(3):628-38.

Cruz J, Minoja G, Okuchi K, et al, “Successful Use of the New High-Dose Mannitol Treatment in Patients With Glasgow Coma Scale Scores of 3 and Bilateral Abnormal Pupillary Widening: A Randomized Trial,” J Neurosurg, 2004, 100(3):376-83.

Expert Panel Report 3, “Guidelines for the Diagnosis and Management of Asthma,” Clinical Practice Guidelines, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Publication No. 08-4051, prepublication 2007. Available at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm

Gadallah MF, Lynn M, and Work J, “Case Report: Mannitol Nephrotoxicity Syndrome: Role of Hemodialysis and Postulate of Mechanisms,” Am J Med Sci, 1995, 309(4):219-22.

Hegenbarth MA, “Preparing for Pediatric Emergencies: Drugs to Consider,” Pediatrics, 2008, 121(2):433-43.

Kellum JA, Cerda J, Kaplan LJ, et al, “Fluids for Prevention and Management of Acute Kidney Injury,” Int J Art Organ, 2008, 31(2):96-110.

Leuppi JD, Brannan JD, and Anderson SD, “Bronchial Provocation Tests: The Rationale for Using Inhaled Mannitol as a Test for Airway Hyperresponsiveness,” Swiss Med Wkly, 2002, 132(13-14):151-8.

Leuppi JD, Tandjung R, Anderson SD, et al, “Prediction of Treatment-Response to Inhaled Corticosteroids by Mannitol-Challenge Test in COPD: A Proof of Concept,” Pulm Pharmacol Ther, 2005, 18(2):83-8.

Miller RD, Fleisher LA, Wiener-Kronish JP, et al, eds, Miller's Anesthesia, 7th ed, Philadelphia: Churchill Livingstone, 2009.

Palmquist KL, Quattrocchi FP, and Looney LA, “Compatibility of Furosemide With 20% Mannitol,” Am J Health Syst Pharm, 1995, 52(6):648,50.

Procaccio F, Stocchetti N, Citerio G, et al, “Guidelines for the Treatment of Adults With Severe Head Trauma (Part II). Criteria for Medical Treatment,” J Neurosurg Sci, 2000, 44(1):11-8.

International Brand Names

• Anol (TW)
• Ardeaosmosol MA (CZ)
• D-Mannitol (KP)
• Diurecide (PE)
• Isotol (IT)
• Manitol (ID)
• Mannisol (HN)
• Mannisol B (PL)
• Mannit (AT)
• Mannit-Losung (DE)
• Mannitol (KP, PL)
• Mannits (EE)
• Osmitrol (AU, NZ)
• Osmofusin-M (BG)
• Photoderm Max Bio (MX)

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Last full review/revision May 2011

Content last modified May 2011