PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Diagnostic Agents, Other
    Osmotic Diuretics
    Osmotic Therapy
    Other Irrigating Solutions

    BOXED WARNING

    Acute bronchospasm, asthma, requires an experienced clinician

    Inhaled mannitol acts as a bronchoconstrictor and may cause severe bronchospasm in susceptible patients. Use of inhaled mannitol during diagnostic use or during the BRONCHITOL Tolerance Testing requires an experienced clinician (e.g., test should only be conducted by trained professionals) under the supervision of a physician familiar with all aspects of the test and the management of acute bronchospasm. Do not leave patients unattended during the test. Medications and equipment to treat severe bronchospasm must be present in the testing area. The diagnostic test for bronchial hyper-responsiveness with mannitol should not be performed in any patient with clinically apparent asthma or very low baseline pulmonary function tests (e.g., FEV1 of less than 1 to 1.5 L or less than 70% of the predicted values). If a patient receiving the test for bronchial hyper-responsiveness has a 10% or greater reduction in FEV1 (from pre-challenge FEV1) on administration of the 0 mg capsule, discontinue the test and administer a dose of a short acting inhaled beta-agonist; continue appropriate monitoring. Short acting inhaled beta-agonists should also be administered to patients with either a positive response to bronchial challenge testing or significant respiratory symptoms. Monitor patients until fully recovered to within baseline. In addition, because of the risk of bronchospasm, inhaled mannitol is contraindicated for use in cystic fibrosis (CF) patients who fail the BRONCHITOL Tolerance Test (BTT). Prior to prescribing inhaled mannitol for CF, perform the BTT to identify patients who are appropriate for maintenance treatment with inhaled mannitol. The BTT must be administered under the supervision of a healthcare practitioner who can treat severe bronchospasm. In clinical trials, 896 adult patients with CF underwent the BTT and 72 patients (8%) failed or did not complete the BTT. Bronchospasm may occur during continued treatment with inhaled mannitol, even in patients who have passed the BTT. An inhaled short-acting bronchodilator must be administered 5 to 15 minutes before administration of each mannitol dose during maintenance therapy. In clinical studies, bronchospasm or bronchial hyperreactivity was reported in 4 of 414 adult CF patients (1%) receiving inhaled mannitol as maintenance therapy and in 2 of 347 adult patients (0.6%) receiving control (50 mg inhaled mannitol), even though these patients had passed the BTT. If bronchospasm occurs following dosing of inhaled mannitol, discontinue immediately and treat with an inhaled short-acting bronchodilator or as medically appropriate.

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral osmotic diuretic; also uses as an orally inhaled bronchoconstrictor
    Used parenterally to reduce intracranial pressure, cerebral edema, and intraocular pressure; can promote diuresis in acute renal failure; enhances renal elimination of some drugs
    Mannitol inhalation testing kit aides in diagnosis of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma; another inhalation product is used as add-on chronic therapy to improve pulmonary function in adults with cystic fibrosis who have passed a BRONCHITOL Tolerance Test (BTT)

    COMMON BRAND NAMES

    Aridol, Osmitrol, Resectisol

    HOW SUPPLIED

    Aridol Respiratory (Inhalation) Pwd: 0-5-10-20-40mg
    Mannitol Irrigation Inj Sol: 25%
    Mannitol/Osmitrol Intravenous Inj Sol: 5%, 10%, 15%, 20%, 25%
    Resectisol Intravesical Sol: 5%
    Resectisol Irrigation Sol: 5%

    DOSAGE & INDICATIONS

    For the promotion of diuresis in the prevention and/or treatment of oliguria in acute renal failure before irreversible renal failure occurs.
    NOTE: Data supporting the routine use of mannitol for the prevention or treatment of acute renal failure is lacking; many experts do not recommend its use for this indication.[31943] [64578] [64579] [64580] However, there is some evidence that mannitol may be renoprotective in select situations if administered prior to kidney insult.[31937]
    For the treatment of acute renal failure (oliguria).
    Intravenous dosage
    Adults

    50 to 100 g IV of 15% to 25%; doses of 200 g IV may be necessary. Adjust rate to maintain adequate urine flow (30 to 50 mL/hour). In marked oliguria or inadequate renal function, use a test dose of 0.2 g/kg IV of 15% to 25% over 3 to 5 minutes to produce adequate urine flow (30 to 50 mL/hour); if urine flow does not increase within 2 to 3 hours, a second test dose may be given. Reevaluate patients with inadequate response.

    Children and Adolescents 12 to 17 years

    50 to 100 g IV of 15% to 25%; doses of 200 g IV may be necessary. Adjust rate to maintain adequate urine flow (30 to 50 mL/hour). In marked oliguria or inadequate renal function, use a test dose of 0.2 g/kg IV of 15% to 25% over 3 to 5 minutes to produce adequate urine flow (30 to 50 mL/hour); if urine flow does not increase within 2 to 3 hours, a second test dose may be given. Reevaluate patients with inadequate response.

    For the prevention of acute renal failure (oliguria) during surgery, immediately postoperatively, or after trauma.
    Intravenous dosage
    Adults

    50 to 100 g IV of 5% to 25%; the concentration and amount depends on the fluid requirements of the patient.[64581]

    Children and Adolescents 12 to 17 years

    50 to 100 g IV of 5% to 25%; the concentration and amount depends on the fluid requirements of the patient.[64581]

    For renoprotection during renal transplantation†.
    Intravenous dosage
    Adults

    50 g of 20% IV immediately before arterial clamp removal for a cadaveric kidney recipient and 12.5 to 25 g IV administered immediately before arterial clamping for a live donor.[31932] 

    Children and Adolescents

    0.5 to 1 g/kg IV of 20% given over 30 to 60 minutes before arterial clamp removal for a cadaveric kidney recipient.[31932]

    For the prevention of acute renal failure (oliguria) in patients with hemolytic transfusion reactions.
    Intravenous dosage
    Adults

    20 g IV over 5 minutes; may repeat if no diuresis occurs. Once urine flow is adequate (30 to 50 mL/hour), give IV fluids containing no more than 50 to 75 mEq of sodium/L at a rate equal to the desired urine output until fluids can be taken orally.

    Children and Adolescents 12 to 17 years

    20 g IV over 5 minutes; may repeat if no diuresis occurs. Once urine flow is adequate (30 to 50 mL/hour), give IV fluids containing no more than 50 to 75 mEq of sodium/L at a rate equal to the desired urine output until fluids can be taken orally.

    For the reduction of increased intracranial pressure (ICP) and treatment of cerebral edema.
    Intravenous dosage
    Adults

    0.25 to 2 g/kg/dose IV over 30 to 60 minutes and repeated every 6 to 8 hours as needed.[33007] [63784] Maintain a serum osmolality less than 320 mOsm/kg.[31479] Monitor fluid and electrolytes, serum osmolarity, and renal, cardiac, and pulmonary function during and after the infusion. Discontinue mannitol if renal, cardiac, or pulmonary status worsens or CNS toxicity develops.[33007]

    Infants, Children, and Adolescents

    0.25 to 2 g/kg/dose IV over 20 to 60 minutes and repeated every 6 to 8 hours as needed.[33007] [44772] [49188] [63784] Alternatively, 30 to 60 g/m2/dose IV.[49188] Maintain a serum osmolality less than 320 mOsm/kg, ICP less than 20 mmHg, and CPP 40 to 50 mmHg.[31479] [64013] Monitor fluid and electrolytes, serum osmolarity, and renal, cardiac, and pulmonary function during and after the infusion. Discontinue mannitol if renal, cardiac, or pulmonary status worsens or CNS toxicity develops.[33007] Mannitol is commonly used to manage elevated ICP in pediatric traumatic brain injury; however, it has not been subjected to contemporary controlled clinical trials in children for this indication and hence was not addressed in guidelines.[64013]

    For the reduction of increased intraocular pressure.
    Intravenous dosage
    Adults

    0.25 to 2 g/kg IV of 15% to 25% solution over at least 30 minutes. When used preoperatively, administer 60 to 90 minutes before surgery to achieve maximal reduction of intraocular pressure.

    Infants, Children, and Adolescents

    1 to 2 g/kg IV of 15% to 25% solution over at least 30 minutes. Alternatively, 30 to 60 g/m2 IV. When used preoperatively, administer 60 to 90 minutes before surgery to achieve maximal reduction of intraocular pressure. Monitor fluid and electrolyte balance.[33007] [49188] [64552]

    For toxin excretion enhancement (e.g., urinary excretion of salicylates, barbiturates, bromides, lithium).
    Intravenous dosage
    Adults

    50 to 200 g IV of 5% to 25% at a rate to maintain a urine output of 100 to 500 mL/hour.  Discontinue mannitol if benefits are not observed after 200 g IV. May give a test dose of 12.5 to 25 g IV of 20% to 25% over 3 to 5 minutes with the balance of 50 g IV of 20% over 1 hour. Then, 5% continuous IV infusion at a rate sufficient to maintain urine output at 150 to 500 mL/hour. Monitor serum osmolarity, serum electrolytes, urine output, and fluid status.[31940]

    For antihemolytic urologic irrigation for transurethral prostatic resection or other transurethral surgical procedures.
    Bladder instillation
    Adults

    Irrigate the bladder with 2.5% to 5% solution.

    For glomerular filtration rate estimation without imaging.
    Intravenous dosage
    Adults

    7.2% solution IV at 20 mL/minute.[49188]

    For bronchial airway hyperreactivity diagnosis in patients who do not have clinically apparent asthma.
    Oral Inhalation dosage (mannitol inhalation powder; i.e., Aridol Test Kit product ONLY)
    Adults

    Initiate test with the 0 mg capsule via oral inhalation using the provided inhaler device, and continue according to the graduated dose steps until the patient has a positive response or a total cumulative dose of 635 mg (negative test). Administer a standard dose of a short-acting inhaled beta-agonist to patients with either a positive response to testing or significant respiratory symptoms, and monitor until fully recovered to within baseline. The inhalation dose steps are: Dose #1 = 0 mg (capsules/dose = 1); Dose #2 = 5 mg (capsules/dose = 1); Dose #3 = 10 mg (capsules/dose = 1); Dose #4 = 20 mg (capsules/dose = 1); Dose #5 = 40 mg (capsules/dose = 1); Dose #6 = 80 mg (capsules/dose = 2 x 40 mg); Dose #7 = 160 mg (capsules/dose = 4 x 40 mg); Dose #8 = 160 mg (capsules/dose = 4 x 40 mg); and Dose #9 = 160 mg (capsules/dose = 4 x 40 mg).

    Children and Adolescents 6 to 17 years

    Initiate test with the 0 mg capsule via oral inhalation using the provided inhaler device, and continue according to the graduated dose steps until the patient has a positive response or a total cumulative dose of 635 mg (negative test). Administer a standard dose of a short-acting inhaled beta-agonist to patients with either a positive response to testing or significant respiratory symptoms, and monitor until fully recovered to within baseline. The inhalation dose steps are: Dose #1 = 0 mg (capsules/dose = 1); Dose #2 = 5 mg (capsules/dose = 1); Dose #3 = 10 mg (capsules/dose = 1); Dose #4 = 20 mg (capsules/dose = 1); Dose #5 = 40 mg (capsules/dose = 1); Dose #6 = 80 mg (capsules/dose = 2 x 40 mg); Dose #7 = 160 mg (capsules/dose = 4 x 40 mg); Dose #8 = 160 mg (capsules/dose = 4 x 40 mg); and Dose #9 = 160 mg (capsules/dose = 4 x 40 mg).

    For add-on maintenance therapy to improve pulmonary function in patients with cystic fibrosis.
    Oral Inhalation dosage (mannitol inhalation powder; i.e., BRONCHITOL product only)
    Adults

    400 mg (contents of 10 inhalation capsules containing 40 mg mannitol/capsule) via oral inhalation twice daily (morning and evening, with evening dose at least 2 to 3 hours before bedtime). Administer an inhaled short-acting bronchodilator 5 to 15 minutes before every mannitol dose. Each capsule is inhaled individually using the provided inhaler device. LIMIT OF USE: Use only in patients who have passed the BRONCHITOL Tolerance Test.

    For the adjunctive treatment of edema†.
    Intravenous dosage
    Adults

    10% to 20% continuous IV infusion at 25 to 75 mL/hour. Give IV loop diuretics prior to mannitol. Monitor cardiovascular status, urine output, serum electrolytes, and serum osmolarity during the infusion. In patients with symptomatic hyponatremia, 25 g IV bolus as a 20% solution every 1 hour as needed. Alternatively, 20% continuous IV infusion at 100 to 125 mL/hour.[31940] [31946] Others recommend 100 g IV as 10% to 20% solution over 2 to 6 hours. Each 50 g of mannitol transfers 1,000 mL of water intracellularly to extracellularly.[31946]

    Children and Adolescents

    0.5 to 2 g/kg IV of 15% to 20% over 2 to 6 hours has been used. Children with nephrotic syndrome resistant to standard treatments, including diuretics, (n = 3) responded to 5 mL/kg/day IV of 20% over 1 hour. These patients also received a daily dose of furosemide 2 mg/kg.

    †Indicates off-label use

    MAXIMUM DOSAGE

    When administering intravenous (IV) mannitol, the total dosage, concentration, and rate of administration should be governed by the nature and severity of the condition being treated, fluid requirement, and urinary output. While the usual adult dosage ranges from 20 to 100 grams IV in a 24-hour period, there is no absolute maximum dosage; however doses in excess of 200 grams/day IV or 400 grams/48 hours IV have been associated with acute renal failure. In patients with increased intracranial pressure or cerebral edema, the plasma osmolality should not exceed 320 mOsm/kg.

    Adults

    Aridol test kit for bronchial challenge: 635 mg (19 capsules)/day via oral inhalation; BRONCHITOL for cystic fibrosis: 800 mg (20 capsules)/day via oral inhalation.

    Geriatric

    Aridol test kit for bronchial challenge: 635 mg (19 capsules)/day via oral inhalation; BRONCHITOL for cystic fibrosis: 800 mg (20 capsules)/day via oral inhalation.

    Adolescents

    Aridol test kit for bronchial challenge: 635 mg (19 capsules)/day via oral inhalation.

    Children

    6 to 12 years: Aridol test kit for bronchial challenge: 635 mg (19 capsules)/day via oral inhalation.
    Less than 6 years: Safety and efficacy of inhaled mannitol have not been established.

    Infants

    Safety and efficacy of inhaled mannitol have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Intravenous mannitol: Contraindicated in patients with anuria. In all other patients, monitor renal function closely and discontinue use if renal dysfunction develops.[33007]
    Inhaled mannitol: No specific dose adjustments are available for patients with cystic fibrosis; however, an increase in systemic exposure of mannitol can be expected in patients with renal impairment based on the kidney being the primary route of mannitol elimination.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear.

    Intravenous Administration

    Preparation
    Inspect for crystals prior to administration. Higher concentrations of mannitol (more than 15%) have a greater tendency to crystallize, particularly when exposed to low temperature.
    Flexible containers: If crystals are visible, dissolve by warming the solution up to 70 degrees C (158 degrees F) with agitation. Some formulations recommend warming to a temperature no greater than 60 degrees C (140 degrees F).[63872] Heat the solution using a dry-heat cabinet with the overwrap intact. Do not heat in water or a microwave oven due to the potential for contamination or damage. If the crystals cannot be completely redissolved, discard the container.
    Vials for injection: If crystals are visible, dissolve by warming bottles in hot water at 80 degrees C (176 degrees F) and shaking vigorously. Mannitol 25% may be autoclaved at 121 degrees C (250 degrees F) for 20 minutes at 15 psi.
    Allow the solution to cool to room or body temperature before reinspecting for crystals and use.
    For flexible bags stored in overwrap, there may be some opacity of the plastic due to moisture absorption during the sterilization process. This is normal and does not affect the solution quality or safety; the opacity will diminish gradually.[33007]
    Do not place 25% solution in polyvinylchloride (PVC) bags; a white flocculent precipitate may form from contact with PVC surfaces.[64552]
    Do not admix mannitol with other medications. Mannitol may precipitate with the addition of sodium chloride to the 20% solution.
     
    Intermittent IV Infusion
    Administer using a sterile, filter-type administration set to prevent the unintentional administration of mannitol crystals.[33007] [64552] The size of the filter used varies and ranges from 0.2-micron up to 5-micron.[60616] Consult institution-specific recommendations.
    Infusion into a large central vein is preferred.[33007] If central access is unavailable, administer via a large peripheral vein using a small-bore needle.[63872]
    Specific infusion rates and administration times are indication-dependent.[33007]
    For glomerular filtration rate (GFR) estimation, dilute 100 mL of 20% solution (20 g) with 180 mL of 0.9% Sodium Chloride Injection or 200 mL of 10% solution (20 g) with 80 mL of 0.9% Sodium Chloride Injection. Infuse the resulting 280 mL of 7.2% solution IV at a rate of 20 mL/minute. Collect urine by catheter and analyze for mannitol excreted in mg/minute. Draw a blood sample at the start and end of the time period and determine the concentration of mannitol in mg/mL of plasma. GFR is the number of mL of plasma that must have been filtered to account for the amount excreted per minute in the urine. Normal clearance rates are about 125 mL/minute for men and 116 mL/minute for women.[49188]
    Do not administer mannitol simultaneously with blood products through the same administration set due to the possibility of pseudoagglutination or hemolysis.[33007] If coadministration is essential, add at least 20 mEq of sodium chloride to each liter of mannitol solution to avoid pseudoagglutination.[49188]
    To prevent air embolism, use a non-vented infusion set or close the vent on a vented set, avoid multiple connections, do not connect flexible containers in series, fully evacuate residual gas in the container prior to administration, do not pressurize the flexible container to increase flow rates, and if administration is controlled by a pump, turn off pump before the container runs dry.[33007]
    Storage: For single use only; discard unused portion.[33007]

    Inhalation Administration
    Oral Inhalation Administration

    Aridol Test Kit
    Prior to bronchial challenge testing with mannitol, standard spirometry should be performed and the reproducibility of the resting FEV1 established.
    The mannitol bronchial challenge test kit contains a single patient use inhaler necessary to perform 1 bronchial challenge test.
    The inhaler should be discarded after use.
    Mannitol capsules should never be swallowed.
    The airway response to the test is measured using forced expiratory volume in one second (FEV1).
    Administration of Aridol
    For more complete instructions, refer to the FDA-approved labeling.
    If a nose clip is preferred, apply the nose clip to the subject and direct the subject to breathe through the mouth.
    Insert the 0 mg capsule (contains no mannitol) into the inhalation device; puncture capsule by depressing buttons on the side of the device slowly. Only puncture once as a second puncture may fragment the capsules.
    The patient should exhale completely before inhaling from the device using a controlled rapid deep inspiration.
    At the end of the deep inspiration, start the 60-second timer, the subject should hold their breath for 5 seconds and exhale through the mouth before removal of the nose clip.
    At the end of 60 seconds, measure the FEV1 in duplicate (the measurement after inhaling the 0 mg capsule is the baseline FEV1)
    Repeat the steps above after the mannitol capsule dose steps (see below) until the patient has a positive response or the cumulative dose of 635 mg of mannitol has been administered (negative test).
    A positive response is achieved when the patient experiences a 15% reduction in FEV1 from (0 mg) baseline (or a 10% incremental reduction in FEV1 between consecutive doses). The test result is expressed as a PD15.
    Patients with either a positive response or significant respiratory symptoms should receive a standard dose of a short acting inhaled beta-agonist and monitored until fully recovered to within baseline.
     
    Aridol Inhalation Dose Steps:
    Dose #1 = 0 mg (capsules/dose = 1)
    Dose #2 = 5 mg (capsules/dose = 1)
    Dose #3 = 10 mg (capsules/dose = 1)
    Dose #4 = 20 mg (capsules/dose = 1)
    Dose #5 = 40 mg (capsules/dose = 1)
    Dose #6 = 80 mg (capsules/dose = 2 x 40 mg)
    Dose #7 = 160 mg (capsules/dose = 4 x 40 mg)
    Dose #8 = 160 mg (capsules/dose = 4 x 40 mg)
    Dose #9 = 160 mg (capsules/dose = 4 x 40 mg)
     
    BRONCHITOL inhalation powder
    The BTT (BRONCHITOL tolerance test) must be performed prior to administration to identify patients who experience bronchospasm, a decrease in FEV1, or a decrease in oxygen saturation with administration of mannitol. If a patient experiences any of these events during the BTT, the patient has failed the BTT and mannitol should NOT be prescribed. If a patient passes the BTT, they are a candidate for mannitol therapy.
    Each capsule for inhalation contains 40 mg of mannitol inhalation powder. Only use the capsules with the provided inhaler.
    Mannitol capsules should never be swallowed.
     
    Administration of BRONCHITOL doses:
    For more complete instructions, refer to the FDA-approved labeling and the manufacturer "Instructions for Use".
    An inhaled short-acting bronchodilator, such as albuterol, must be administered 5 to 15 minutes before every dose of mannitol.
    Administer doses twice daily in the morning and evening, with the later dose given at least 2 to 3 hours before bedtime. Each adult dose will require use of 10 capsules.
    Administration steps for each dose:
    Step 1: Remove cap.
    Step 2: Twist open inhaler by turning the mouthpiece to the right.
    Step 3: Take 1 capsule out of the blister pack and put it in the chamber; do not place capsule into the mouthpiece of the inhaler.
    Step 4: Hold inhaler upright and turn the mouthpiece to the left until it locks in place.
    Step 5: Push both piercing buttons at the same time. Release both piercing buttons at the same time. Keep inhaler upright. Never keep piercing buttons pressed.
    Step 6: Exhale fully. Do not breathe out into inhaler.
    Step 7: Close lips around the mouthpiece and take a steady deep breath in through the mouth; do not breathe through your nose. Remove inhaler from mouth. Hold breath for 5 seconds before exhaling, do not exhale into inhaler. A rattling sound should be heard while breathing in. If not, tap bottom of inhaler firmly and repeat steps 6 and 7.
    Step 8: Open the inhaler by turning the cap to the right. If powder is left in capsule, repeat steps 6 and 7. After the capsule is empty, throw it away.
    Step 9: Repeat steps 3 to 8 for all 10 capsules in 1 blister pack. Inhale contents of each capsule one after another until all 10 capsules in the blister pack are used.
    Step 10: After inhaling contents of all 10 capsules, close mouthpiece and place cap on inhaler.
    The BRONCHITOL inhaler should be discarded and replaced after 7 days of use.
    The inhaler should not need cleaning; however, if it does refer to the manufacturer "Instructions for Use".

    Other Administration Route(s)

    Bladder administration
    Add the contents of two 50-mL vials of 25% mannitol injection to 900 mL of Sterile Water for Injection to make a 2.5% irrigating solution. Only use clear solutions.
    Instill solution into the bladder via an indwelling urethral catheter.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Aridol:
    - Do not freeze
    - Do not refrigerate
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Osmitrol :
    - Avoid excessive heat (above 104 degrees F)
    - Protect from freezing
    - Store at 77 degrees F; brief exposure up to 104 degrees F does not adversely affect product
    Resectisol:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from freezing
    - Store at 77 degrees F; brief exposure up to 104 degrees F does not adversely affect product

    CONTRAINDICATIONS / PRECAUTIONS

    Intracranial bleeding

    Intravenous mannitol is contraindicated in active intracranial bleeding except during craniotomy.[33007] Mannitol may increase cerebral blood flow and the risk of postoperative bleeding in neurosurgical patients.[49188]

    Heart failure, pulmonary edema

    Intravenous mannitol is contraindicated in preexisting severe pulmonary vascular congestion or pulmonary edema. Depending on dose and duration, mannitol administration may result in hypervolemia leading to or exacerbating existing congestive heart failure.[33007] Mannitol is contraindicated in patients who develop progressive heart failure or pulmonary congestion after mannitol therapy. Accumulation of mannitol due to insufficient renal excretion increases the risk of hypervolemia. Monitor fluid and electrolyte status during mannitol therapy in patients with increased intracranial pressure, and discontinue mannitol if renal, cardiac, or pulmonary status worsens.[33007]

    Anuria, dehydration, electrolyte imbalance, hypovolemia, renal disease, renal failure, renal impairment

    Intravenous mannitol is contraindicated in patients with anuria or severe hypovolemia or dehydration. Use intravenous mannitol with caution in patients with renal impairment. Do not administer intravenous mannitol in patients with renal disease until fluid or electrolyte imbalance is corrected. Monitor renal function closely during mannitol infusion, including signs of urine output reduction. If urine output declines during mannitol infusion, closely monitor the patient for developing renal impairment, and suspend the infusion if necessary. Patients with preexisting renal disease, 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. Renal complications, including oliguric acute kidney injury (AKI) and irreversible renal failure, have occurred in patients receiving intravenous mannitol. Patients with oliguric AKI who subsequently develop anuria while receiving mannitol are at risk for congestive heart failure, pulmonary edema, hypertensive crisis, coma, and death. Mannitol-induced osmotic diuresis may worsen dehydration or hypovolemia and hemoconcentration. Mannitol may also cause electrolyte and acid-base imbalances and hyperosmolarity. Such imbalances can be fatal. When used for the reduction of intracranial pressure (ICP), monitor serum osmolarity, serum electrolytes, acid-base balance, osmol gap, and ICP during and after infusion. In addition, monitor for signs of hyper- or hypovolemia, including urine output. Discontinue mannitol if pulmonary, cardiac, or renal status worsens, if electrolyte or acid-base imbalances occur, or if CNS toxicity (e.g., confusion, lethargy, coma) develops. In the presence of impaired renal function, CNS toxicity may result from high serum mannitol concentrations, serum hyperosmolarity and subsequent intracellular dehydration within the CNS, or electrolyte and acid/base imbalance. At high concentrations, mannitol may cross the blood-brain barrier and interfere with the ability of the brain to maintain cerebrospinal fluid pH. In those with compromise of the blood-brain barrier, the risk of cerebral edema must be weighed against the expected benefits of mannitol use. A rebound increase of ICP may occur several hours after mannitol infusion.[33007] [49188]

    Gelatin hypersensitivity, mannitol hypersensitivity

    Mannitol is contraindicated in patients with known mannitol hypersensitivity.[33007] [50722] The inhaled mannitol testing kit is also contraindicated in patients with gelatin hypersensitivity.[50722] Discontinue mannitol immediately and institute appropriate therapeutic countermeasures if signs or symptoms of a hypersensitivity reaction develop.[33007]

    Acute bronchospasm, asthma, requires an experienced clinician

    Inhaled mannitol acts as a bronchoconstrictor and may cause severe bronchospasm in susceptible patients. Use of inhaled mannitol during diagnostic use or during the BRONCHITOL Tolerance Testing requires an experienced clinician (e.g., test should only be conducted by trained professionals) under the supervision of a physician familiar with all aspects of the test and the management of acute bronchospasm. Do not leave patients unattended during the test. Medications and equipment to treat severe bronchospasm must be present in the testing area. The diagnostic test for bronchial hyper-responsiveness with mannitol should not be performed in any patient with clinically apparent asthma or very low baseline pulmonary function tests (e.g., FEV1 of less than 1 to 1.5 L or less than 70% of the predicted values). If a patient receiving the test for bronchial hyper-responsiveness has a 10% or greater reduction in FEV1 (from pre-challenge FEV1) on administration of the 0 mg capsule, discontinue the test and administer a dose of a short acting inhaled beta-agonist; continue appropriate monitoring. Short acting inhaled beta-agonists should also be administered to patients with either a positive response to bronchial challenge testing or significant respiratory symptoms. Monitor patients until fully recovered to within baseline. In addition, because of the risk of bronchospasm, inhaled mannitol is contraindicated for use in cystic fibrosis (CF) patients who fail the BRONCHITOL Tolerance Test (BTT). Prior to prescribing inhaled mannitol for CF, perform the BTT to identify patients who are appropriate for maintenance treatment with inhaled mannitol. The BTT must be administered under the supervision of a healthcare practitioner who can treat severe bronchospasm. In clinical trials, 896 adult patients with CF underwent the BTT and 72 patients (8%) failed or did not complete the BTT. Bronchospasm may occur during continued treatment with inhaled mannitol, even in patients who have passed the BTT. An inhaled short-acting bronchodilator must be administered 5 to 15 minutes before administration of each mannitol dose during maintenance therapy. In clinical studies, bronchospasm or bronchial hyperreactivity was reported in 4 of 414 adult CF patients (1%) receiving inhaled mannitol as maintenance therapy and in 2 of 347 adult patients (0.6%) receiving control (50 mg inhaled mannitol), even though these patients had passed the BTT. If bronchospasm occurs following dosing of inhaled mannitol, discontinue immediately and treat with an inhaled short-acting bronchodilator or as medically appropriate.

    Acute myocardial infarction, aneurysm, hypertension, stroke

    Inhaled mannitol used for the test for bronchial hyper-responsiveness is contraindicated in patients with conditions that may be compromised by induced bronchospasm or repeated spirometry maneuvers, including aortic or cerebral aneurysm, uncontrolled hypertension, recent or acute myocardial infarction, or cerebral vascular accident (stroke).

    Angina, pneumothorax, respiratory infection, surgery

    Use inhaled mannitol with caution in patients with conditions that may increase sensitivity to bronchoconstriction or other potential effects of mannitol such as severe cough, ventilatory impairment, hemoptysis of unknown origin, pneumothorax, recent abdominal, thoracic, or intraocular surgery, unstable angina, or active upper or lower respiratory infection.[50722] Hemoptysis has been reported in patients receiving inhaled mannitol for the treatment of cystic fibrosis (CF). Inhaled mannitol for CF treatment has not been studied in patients with a history of episodes of significant hemoptysis (volume greater than 60 mL) in the previous 3 months and should be discontinued in the event of hemoptysis during treatment.

    Geriatric

    In general, mannitol use in the geriatric patient should be cautious, reflecting the greater frequency of decreased renal, pulmonary, and cardiac function, and concomitant disease or other drug therapy in this population. Systemically administered mannitol is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Evaluate the renal, cardiac, and pulmonary status of the patient and correct fluid and electrolyte imbalances prior to administration.[33007] The clinical program for bronchial challenge testing with inhaled mannitol did not include a sufficient number of subjects 50 years of age and older to determine whether they respond differently from younger subjects; therefore, the safety and efficacy of inhaled mannitol in the older adult population cannot be adequately assessed.[50722]

    Children, infants, neonates, premature neonates

    Studies have not defined the optimal dose of intravenous mannitol in the pediatric population and while the safety profile of mannitol in pediatric patients is similar to adults at FDA-approved dosages, precautions are warranted. Infants and children younger than 2 years of age, particularly premature neonates and neonates, may be a higher risk for fluid and electrolyte abnormalities, due to a decreased glomerular filtration rate and limited ability to concentrate urine. Monitor fluid and electrolyte status closely and discontinue treatment if abnormalities occur.[33007] Mannitol may increase cerebral blood flow and worsen intracranial hypertension in children who develop generalized cerebral hyperemia in the first 24 to 48 hours after injury.[49188] In addition, do not perform bronchial challenge testing with inhaled mannitol in pediatric patients younger than 6 years due to their inability to provide spirometric measurements.[50722] The safety and effectiveness of inhaled mannitol for cystic fibrosis (CF) have not been established in pediatric patients younger than 18 years. Two clinical trials included 154 CF pediatric patients less than 18 years of age (range; 6 to 17 years) who received inhaled mannitol and 105 patients who received the control (50 mg inhaled mannitol). Hemoptysis was reported in 12 of 154 (7.8%) of pediatric patients who received inhaled mannitol and in 2 of 105 (1.9%) patients who received control.

    Pregnancy

    Available data with mannitol over decades of use during human pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, mannitol crosses the placenta and may cause fluid shifts that could potentially result in adverse effects in the fetus. The presence of mannitol in amniotic fluid has been reported when mannitol was administered to pregnant women during the third trimester of pregnancy. No adverse developmental effects from mannitol were reported in animal studies; however, fluid shifts occurred in fetal sheep in response to maternal infusion of mannitol.[33007] There are no available human data regarding inhaled mannitol to evaluate a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes.[50722] Based on animal reproduction studies, no evidence of structural alterations was observed when oral mannitol was administered to pregnant rats and mice during organogenesis at doses up to approximately 20 and 10 times, respectively, the maximum recommended daily inhalation dose (MRDID) in humans. There are risks to the mother associated with cystic fibrosis (CF) in pregnancy. Inhaled mannitol for the treatment of CF should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

    Breast-feeding

    There are no data available on the presence of mannitol in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for mannitol and any potential adverse effects on the breast-fed infant from mannitol or the underlying maternal condition.[33007]

    Laboratory test interference

    Mannitol injection may cause laboratory test interference. High concentrations of systemic mannitol can cause falsely 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 also produce false positive results in tests for blood ethylene glycol concentrations in which mannitol is initially oxidized to an aldehyde.[33007]

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    coma / Early / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    azotemia / Delayed / Incidence not known
    osmotic nephrosis / Early / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    anuria / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    cardiac arrest / Early / Incidence not known
    thrombosis / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known

    Moderate

    hemoptysis / Delayed / 7.8-10.4
    chest pain (unspecified) / Early / 1.0-1.0
    wheezing / Rapid / 1.0-1.0
    dyspnea / Early / 1.0-1.0
    confusion / Early / Incidence not known
    blurred vision / Early / Incidence not known
    hypovolemia / Early / Incidence not known
    hyponatremia / Delayed / Incidence not known
    hypervolemia / Delayed / Incidence not known
    hypernatremia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    metabolic acidosis / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    metabolic alkalosis / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known
    angina / Early / Incidence not known
    edema / Delayed / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    hematuria / Delayed / Incidence not known
    urinary retention / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    erythema / Early / Incidence not known

    Mild

    cough / Delayed / 2.0-15.0
    headache / Early / 6.0-6.0
    arthralgia / Delayed / 3.1-3.1
    rhinorrhea / Early / 2.0-2.0
    nausea / Early / 2.0-2.0
    throat irritation / Early / 2.0-2.0
    infection / Delayed / 1.2-1.2
    dizziness / Early / 1.0-1.0
    lethargy / Early / Incidence not known
    xerostomia / Early / Incidence not known
    polydipsia / Early / Incidence not known
    malaise / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    polyuria / Early / Incidence not known
    vomiting / Early / Incidence not known
    rash / Early / Incidence not known
    fever / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    myalgia / Early / Incidence not known
    chills / Rapid / Incidence not known
    injection site reaction / Rapid / Incidence not known
    rhinitis / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Acetazolamide: (Moderate) Carbonic anhydrase inhibitors promote electrolyte excretion including hydrogen ions, sodium, and potassium. They can enhance the sodium depleting effects of other diuretics when used concurrently. Pre-existing hypokalemia and hyperuricemia can also be potentiated by carbonic anhydrase inhibitors. Monitor serum potassium to determine the need for potassium supplementation and alteration in drug therapy.
    Acyclovir: (Major) Avoid use of mannitol and acyclovir, if possible. Concomitant administration of nephrotoxic drugs, such as acyclovir, increases the risk of renal failure after administration of mannitol.
    Adefovir: (Major) Avoid use of mannitol and adefovir, if possible. Concomitant administration of nephrotoxic drugs, such as adefovir, increases the risk of renal failure after administration of mannitol.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Amiloride: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Aminoglycosides: (Major) Avoid concomitant use of mannitol and aminoglycosides, if possible. Concomitant administration of systemic therapy may increase the risk of ototoxicity and nephrotoxicity. In addition, systemic mannitol may alter the serum and tissue concentrations of aminoglycosides and increase the risk for aminoglycoside toxicity. If use together is necessary, monitor renal function and serum aminoglycoside concentrations. Audiologic monitoring may be advisable during high dose therapy or therapy of long duration, when hearing loss is suspected, or in selected risk groups (e.g., neonates). Studies to evaluate a potential interaction between inhaled formulations of mannitol and tobramycin have not been conducted.
    Aminosalicylate sodium, Aminosalicylic acid: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Amlodipine; Celecoxib: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Amphotericin B: (Major) Avoid use of mannitol and amphotericin, if possible. Concomitant administration of nephrotoxic drugs, such as amphotericin, increases the risk of renal failure after administration of mannitol.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with mannitol. Electrolyte abnormalities (e.g., hypokalemia) caused by mannitol may increase the risk for QT prolongation and torsade de pointes. Monitor electrocardiograms and serum electrolytes more frequently if concurrent use cannot be avoided.
    Aspirin, ASA: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Aspirin, ASA; Butalbital; Caffeine: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Aspirin, ASA; Caffeine: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Aspirin, ASA; Caffeine; Orphenadrine: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Aspirin, ASA; Carisoprodol: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Aspirin, ASA; Dipyridamole: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Aspirin, ASA; Omeprazole: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Aspirin, ASA; Oxycodone: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Aspirin, ASA; Pravastatin: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Atenolol; Chlorthalidone: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Azelastine; Fluticasone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Azilsartan; Chlorthalidone: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Bacitracin: (Major) Avoid use of mannitol and systemic bacitracin, if possible. Concomitant administration of nephrotoxic drugs, such as bacitracin, increases the risk of renal failure after administration of mannitol.
    Barbiturates: (Minor) Mannitol promotes the urinary excretion of barbiturates, and it may be used as an adjunct in patients with barbiturate toxicity.
    Beclomethasone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Benazepril; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Bendroflumethiazide; Nadolol: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Betamethasone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Bismuth Subsalicylate: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Budesonide: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Budesonide; Formoterol: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Bumetanide: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Bupivacaine; Meloxicam: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Candesartan; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Carbonic anhydrase inhibitors: (Moderate) Carbonic anhydrase inhibitors promote electrolyte excretion including hydrogen ions, sodium, and potassium. They can enhance the sodium depleting effects of other diuretics when used concurrently. Pre-existing hypokalemia and hyperuricemia can also be potentiated by carbonic anhydrase inhibitors. Monitor serum potassium to determine the need for potassium supplementation and alteration in drug therapy.
    Cardiac glycosides: (Moderate) Mannitol-induced diuresis increases the excretion of potassium and can lead to hypokalemia. Administration of mannitol to patients receiving cardiac glycosides can increase the risk of developing cardiac toxicity secondary to mannitol-induced hypokalemia. Serum potassium concentrations should be monitored.
    Celecoxib: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Chlorothiazide: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Chlorthalidone: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Chlorthalidone; Clonidine: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Choline Salicylate; Magnesium Salicylate: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Ciclesonide: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Cidofovir: (Major) Avoid use of mannitol and cidofovir, if possible. Concomitant administration of nephrotoxic drugs, such as cidofovir, increases the risk of renal failure after administration of mannitol.
    Cisplatin: (Major) Avoid use of mannitol and cisplatin, if possible. Concomitant administration of nephrotoxic drugs, such as cisplatin, increases the risk of renal failure after administration of mannitol.
    Clindamycin: (Major) Avoid concomitant use of mannitol and clindamycin; coadministration may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
    Clofarabine: (Major) Avoid the concomitant use of clofarabine and mannitol; coadministration may result in additive nephrotoxicity. The kidney is the primary route of elimination for both oral and IV mannitol.
    Corticosteroids: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Cortisone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Cyclosporine: (Major) Avoid use of mannitol and cyclosporine, if possible. Concomitant administration of nephrotoxic drugs, such as cyclosporine, increases the risk of renal failure after administration of mannitol.
    Deflazacort: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Dexamethasone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and mannitol together with caution as both drugs can cause metabolic acidosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Diclofenac: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Diclofenac; Misoprostol: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Diflunisal: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Diphenhydramine; Ibuprofen: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Diphenhydramine; Naproxen: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Diuretics: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Enalapril; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Epoprostenol: (Moderate) Further reductions in blood pressure may occur when epoprostenol is administered with diuretics.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Ethacrynic Acid: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Etodolac: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Famotidine; Ibuprofen: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Fenoprofen: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Fludrocortisone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Flunisolide: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Flurbiprofen: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Fluticasone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Fluticasone; Salmeterol: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Fluticasone; Vilanterol: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Formoterol; Mometasone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Foscarnet: (Major) Avoid use of mannitol and foscarnet, if possible. Concomitant administration of nephrotoxic drugs, such as foscarnet, increases the risk of renal failure after administration of mannitol.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Furosemide: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Ganciclovir: (Major) Avoid use of mannitol and ganciclovir, if possible. Concomitant administration of nephrotoxic drugs, such as ganciclovir, increases the risk of renal failure after administration of mannitol.
    Hetastarch; Dextrose; Electrolytes: (Moderate) Diuretics may interfere with the kidneys ability to regulate magnesium concentrations. Long-term use of diuretics may impair the magnesium-conserving ability of the kidneys and lead to hypomagnesemia.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Hydrochlorothiazide, HCTZ; Moexipril: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Hydrocodone; Ibuprofen: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Hydrocortisone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Ibuprofen: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Ibuprofen; Oxycodone: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Ibuprofen; Pseudoephedrine: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Iloprost: (Moderate) Further reductions in blood pressure may occur when inhaled iloprost is administered to patients receiving other antihypertensive agents.
    Imipramine: (Minor) Mannitol promotes the urinary excretion of imipramine, and it may be used as an adjunct in patients with imipramine toxicity.
    Inamrinone: (Moderate) Hypokalemia may occur due to excessive diuresis during inamrinone therapy. Fluid and electrolyte changes and renal function should be carefully monitored during inamrinone therapy.
    Indapamide: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Indomethacin: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Isocarboxazid: (Moderate) Exaggerated hypotensive effects may result when MAOIs are used in combination with other antihypertensive drugs, including diuretics; patients should be observed for symptoms of orthostatic hypotension
    Ketoprofen: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Ketorolac: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Lansoprazole; Naproxen: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Levomethadyl: (Major) Mannitol-induced diuresis increases the excretion of potassium and can lead to hypokalemia. Administration of mannitol to patients receiving levomethadyl can increase the risk of developing cardiac toxicity secondary to mannitol-induced hypokalemia. Serum potassium concentrations should be monitored.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Lithium: (Major) Concomitant use of mannitol and lithium may initially increase the elimination of lithium but may also increase the risk of lithium toxicity if the patient develops hypovolemia or renal impairment. Consider holding lithium doses during mannitol treatment. In patients requiring concomitant use, frequently monitor serum lithium concentrations and for signs of lithium toxicity.
    Losartan; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Magnesium Salicylate: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Magnesium Salts: (Moderate) Diuretics may interfere with the kidneys ability to regulate magnesium concentrations. Long-term use of diuretics may impair the magnesium-conserving ability of the kidneys and lead to hypomagnesemia.
    Magnesium: (Moderate) Diuretics may interfere with the kidneys ability to regulate magnesium concentrations. Long-term use of diuretics may impair the magnesium-conserving ability of the kidneys and lead to hypomagnesemia.
    Meclofenamate Sodium: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Mefenamic Acid: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Meloxicam: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Methazolamide: (Moderate) Carbonic anhydrase inhibitors promote electrolyte excretion including hydrogen ions, sodium, and potassium. They can enhance the sodium depleting effects of other diuretics when used concurrently. Pre-existing hypokalemia and hyperuricemia can also be potentiated by carbonic anhydrase inhibitors. Monitor serum potassium to determine the need for potassium supplementation and alteration in drug therapy.
    Methyclothiazide: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Methylprednisolone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Metolazone: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Mometasone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Monoamine oxidase inhibitors: (Moderate) Exaggerated hypotensive effects may result when MAOIs are used in combination with other antihypertensive drugs, including diuretics; patients should be observed for symptoms of orthostatic hypotension
    Nabumetone: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Naproxen: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Naproxen; Esomeprazole: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Naproxen; Pseudoephedrine: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Nifedipine: (Moderate) Nifedipine can have additive hypotensive effects with other antihypertensive agents (including diuretics). This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Nitrates: (Moderate) Nitrates can cause hypotension. This action may be additive with other agents that can cause hypotension such as diuretics.
    Nonsteroidal antiinflammatory drugs: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Octreotide: (Moderate) Patients receiving diuretics or other agents to control fluid and electrolyte balance may require dosage adjustments while receiving octreotide due to additive effects.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Oxaprozin: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Pamidronate: (Major) Avoid use of mannitol and pamidronate, if possible. Concomitant administration of nephrotoxic drugs, such as pamidronate, increases the risk of renal failure after administration of mannitol.
    Pentamidine: (Major) Avoid use of mannitol and pentamidine, if possible. Concomitant administration of nephrotoxic drugs, such as pentamidine, increases the risk of renal failure after administration of mannitol.
    Phenelzine: (Moderate) Exaggerated hypotensive effects may result when MAOIs are used in combination with other antihypertensive drugs, including diuretics; patients should be observed for symptoms of orthostatic hypotension
    Piroxicam: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Prednisolone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Prednisone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Propranolol; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Quinapril; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Rofecoxib: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Salicylates: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Salsalate: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
    Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Moderate) Diuretics may interfere with the kidneys ability to regulate magnesium concentrations. Long-term use of diuretics may impair the magnesium-conserving ability of the kidneys and lead to hypomagnesemia.
    Sotalol: (Major) Diuretics should be used cautiously with sotalol and should be accompanied by close monitoring of electrolyte balance because hypokalemia and hypomagnesemia have been associated with an increased risk of proarrhythmia.
    Spironolactone: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Sulindac: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Sumatriptan; Naproxen: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Tolmetin: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Tolterodine: (Minor) Diuretics can increase urinary frequency, which may aggravate bladder symptoms.
    Torsemide: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Tranylcypromine: (Moderate) Exaggerated hypotensive effects may result when MAOIs are used in combination with other antihypertensive drugs, including diuretics; patients should be observed for symptoms of orthostatic hypotension
    Triamcinolone: (Moderate) Corticosteroids may accentuate the electrolyte loss associated with diuretic therapy resulting in hypokalemia. Also, corticotropin may cause calcium loss and sodium and fluid retention. Mannitol itself can cause hypernatremia. Close monitoring of electrolytes should occur in patients receiving these drugs concomitantly.
    Triamterene: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Triamterene; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Valacyclovir: (Major) Avoid use of mannitol and valacyclovir, if possible. Concomitant administration of nephrotoxic drugs, such as valacyclovir, increases the risk of renal failure after administration of mannitol.
    Valdecoxib: (Major) Avoid use of mannitol and nonsteroidal anti-inflammatory drugs (NSAIDs), if possible. If use together is necessary, carefully monitor the patient for signs and symptoms of decreased renal function and diuretic efficacy. Concomitant administration of nephrotoxic drugs, such as NSAIDs, increases the risk of renal failure after administration of mannitol. NSAIDs may reduce the natriuretic effect of diuretics in some patients. NSAIDS have been associated with an inhibition of prostaglandin synthesis, which may result in reduced renal blood flow leading to renal insufficiency and increases in blood pressure that are often accompanied by peripheral edema and weight gain.
    Valsartan; Hydrochlorothiazide, HCTZ: (Major) Avoid use of other diuretics with mannitol, if possible. Concomitant administration may potentiate the renal toxicity of mannitol.
    Vancomycin: (Major) Avoid use of mannitol and vancomycin, if possible. Concomitant administration of nephrotoxic drugs, such as vancomycin, increases the risk of renal failure after administration of mannitol.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with mannitol is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug used in photodynamic therapy. Once activated, highly reactive, short-lived singlet oxygen and reactive oxygen radicals are generated. Concomitant use of drugs that quench active oxygen species or scavenge radicals, such as mannitol, would be expected to decrease verteporfin activity.
    Voclosporin: (Major) Avoid concomitant use of mannitol and voclosporin; coadministration may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
    Ziconotide: (Moderate) Patients taking diuretics with ziconotide may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, consideration of diuretic cessation is warranted in addition to ziconotide discontinuation.
    Zoledronic Acid: (Major) Avoid use of mannitol and zoledronic acid, if possible. Concomitant administration of nephrotoxic drugs, such as zoledronic acid, increases the risk of renal failure after administration of mannitol.

    PREGNANCY AND LACTATION

    Pregnancy

    Available data with mannitol over decades of use during human pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, mannitol crosses the placenta and may cause fluid shifts that could potentially result in adverse effects in the fetus. The presence of mannitol in amniotic fluid has been reported when mannitol was administered to pregnant women during the third trimester of pregnancy. No adverse developmental effects from mannitol were reported in animal studies; however, fluid shifts occurred in fetal sheep in response to maternal infusion of mannitol.[33007] There are no available human data regarding inhaled mannitol to evaluate a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes.[50722] Based on animal reproduction studies, no evidence of structural alterations was observed when oral mannitol was administered to pregnant rats and mice during organogenesis at doses up to approximately 20 and 10 times, respectively, the maximum recommended daily inhalation dose (MRDID) in humans. There are risks to the mother associated with cystic fibrosis (CF) in pregnancy. Inhaled mannitol for the treatment of CF should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

    There are no data available on the presence of mannitol in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for mannitol and any potential adverse effects on the breast-fed infant from mannitol or the underlying maternal condition.[33007]

    MECHANISM OF ACTION

    Intravenous mannitol exerts its osmotic diuretic 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. The increase in extracellular osmolarity induces 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.
     
    Orally inhaled mannitol acts as a bronchoconstrictor; the precise mechanisms are not known.[50722]

    PHARMACOKINETICS

    Mannitol is administered intravenously and via oral inhalation. Mannitol distributes largely in the extracellular compartment and does not appear to cross the blood-brain barrier unless very high concentrations exist or the patient has acidosis. Systemic Vd ranges from 17 to 34 L in adults. Mannitol is metabolized in a CYP-independent manner through the glycolytic pathway via dehydrogenation to fructose. Metabolism is minimal. This is evident from a urinary excretion of about 87% of unchanged drug after an intravenous dose to healthy patients. The majority of a dose is freely filtered by the kidneys, with less than 10% tubular reabsorption. The half-life of intravenous mannitol ranges from 30 to 150 minutes; total clearance is 87 to 109 mL/minute. The mean terminal elimination half-life for mannitol in plasma remains unchanged regardless of the route of administration (oral, inhalation, and intravenous). The urinary excretion rate vs. time profile for mannitol is consistent for all routes of administration.[33007] [50722]
     
    Affected cytochrome P450 isoenzymes and drug transporters: None

    Intravenous Route

    Mannitol distributes into the extracellular space within 20 to 40 minutes of intravenous administration.[33007] Diuresis generally occurs in 1 to 3 hours. A decrease in the cerebrospinal fluid pressure will occur in approximately 15 minutes and will persist for 3 to 8 hours after the infusion is stopped. Elevated intraocular pressure can be reduced in 30 to 60 minutes, and the effect can last for 4 to 8 hours.

    Inhalation Route

    The rate and extent of absorption of mannitol after oral inhalation were generally similar to that observed after oral administration. The absolute bioavailability of mannitol powder after oral inhalation was 59%, while the relative bioavailability of inhaled mannitol in comparison to orally administered mannitol was 96%. After a dose of mannitol 635 mg via oral inhalation, the mean mannitol peak plasma concentration (Cmax) was 13.71 mcg/mL, while the mean extent of systemic exposure (AUC) was 73.15 mcg x hour/mL. The mean time to peak plasma concentration (Tmax) after oral inhalation was 1.5 hours. The elimination half-life of mannitol was 4.7 hours. About 55% of the total dose was excreted in the urine as unchanged mannitol.[50722]