MANNITOL: 1,976 Adverse Event Reports & Safety Profile

D-mannitol (referred to throughout as mannitol), the active ingredient in ARIDOL is a hexahydric alcohol, that is a sugar alcohol, with the following chemical name (2R,3R,4R,5R)-hexane-1,2,3,4,5,6-hexol and chemical structure: Mannitol is a white or almost white crystalline powder of free-flowing granules with an empirical formula of C 6 H 14 O 6 and molecular weight of 182.2. Mannitol is freely soluble in water, and very slightly soluble in alcohol. Mannitol shows polymorphism. The ARIDOL Bronchial Challenge Test Kit contains one single patient use dry powder inhaler and 3 consecutively numbered foil blister packs containing a total of 19 capsules of mannitol for oral inhalation. All except the 0 mg printed hard gelatin capsules contain dry powder mannitol for oral inhalation. The accompanying dry powder inhaler is a plastic device used for inhaling the capsules. All doses are to be administered using the same device supplied with each kit without washing or sterilizing the device at anytime during the test. To use the delivery system, a mannitol capsule is placed in the well of the inhaler, and the capsule is pierced by pressing and releasing the buttons ONCE on the side of the device. The mannitol dry powder is dispersed into the air stream when the patient inhales deeply through the mouthpiece. There are no inactive ingredients in the mannitol capsules supplied with the ARIDOL Bronchial Challenge Test Kit.

The

0 mg capsule and the bodies of the 5, 10, 20 and 40 mg capsules are clear. The white caps (5 mg) contain titanium dioxide. The yellow caps (10 mg) contain titanium dioxide and yellow iron oxide. The pink caps (20 mg) and red caps (40 mg) contain titanium dioxide and red iron dioxide. The inhaler is a plastic device used for administering mannitol to the lungs. The amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow rate and inspiratory time. Under standardized in vitro testing at a fixed flow rate of 60 L/min for 2 seconds, the delivered dose from the inhaler from each of the 5, 10, 20 and 40 mg capsules is approximately 3.4, 7.7, 16.5 and 34.1 mg, respectively. Peak inspiratory flow rates (PIFR) achievable through the inhaler were evaluated in healthy and asthmatic individuals ranging from 7 to 65 years of age and with % FEV 1 of predicted ranging from 67% to 123%. PIFR achieved in the study was at least 70.8 L/min in all subjects assessed. The mean PIFR was 118.2 L/min and approximately ninety percent of each population studied generated a PIFR through the device exceeding 90 L/min. Aridol-kit-1

INDICATIONS AND USAGE For Intravenous Injection Mannitol Injection, USP is indicated for the following therapeutic uses:

• The promotion of diuresis, in the prevention and/or treatment of the oliguric phase of acute renal failure before irreversible renal failure becomes established.
• The reduction of intracranial pressure and treatment of cerebral edema by reducing brain mass.
• The reduction of elevated intraocular pressure when it cannot be lowered by other means.
• The promotion of urinary excretion of toxic substances.

For Urologic Irrigation

Mannitol solution, 2.5% is indicated as an irrigation solution in transurethral prostatic resection or other transurethral surgical procedures.

For Intravenous Injection Mannitol

Injection, USP is indicated for the following therapeutic uses:

• The promotion of diuresis, in the prevention and/or treatment of the oliguric phase of acute renal failure before irreversible renal failure becomes established.
• The reduction of intracranial pressure and treatment of cerebral edema by reducing brain mass.
• The reduction of elevated intraocular pressure when it cannot be lowered by other means.
• The promotion of urinary excretion of toxic substances.

For Urologic Irrigation

Mannitol solution, 2.5% is indicated as an irrigation solution in transurethral prostatic resection or other transurethral surgical procedures.

DOSAGE AND ADMINISTRATION For Intravenous Injection General Recommendations –Give mannitol injection only intravenously. 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. Usual adult dosage ranges from 50 to 200 g in 24 hours but in most instances an adequate response will be achieved at a dosage of approximately 100 g in 24 hours. The rate is usually adjusted to maintain an adequate urine flow (at least 30 to 50 mL/hr).

Test

Dose –In marked oliguria or inadequate renal function a test dose of mannitol should be given. The test dose may be approximately 0.2 g/kg (about 50 mL of a 25% solution) infused in three to five minutes to produce an adequate urine flow (at least 30 to 50 mL/hr). If urine flow does not increase within two or three hours a second test dose may be given. If there is an inadequate response the patient should be reevaluated. Prevention of Acute Renal Failure (Oliguria) –When used during surgery, immediately postoperatively or following trauma, 50 to100 g of mannitol as a 5 to 25% solution maybe given. The concentration and amount will depend upon the fluid requirements of the patient. Following suspected or actual hemolytic transfusion reactions 20 g of mannitol may be given intravenously over a five minute period to provoke diuresis. If diuresis does not occur the 20 g dose may be repeated. If there is an adequate urine flow (30 to 50 mL/hr) then intravenous fluids containing not more than 50 to 75 mEq of sodium per liter should be given in sufficient volume to match the desired urine flow (100 mL/hr) until fluids can be taken orally. Treatment of Oliguria –The usual dose for treatment of oliguria is 50 to 100 g as a 15 to 25% solution. Reduction of Intracranial Pressure, Cerebral Edema or Intraocular Pressure –A 25% solution of mannitol is recommended since its effectiveness depends on establishing intravascular hyperosmolarity. When used before or after surgery, a total dose of 1.5 to 2 g/kg can be given over a period of 30 to 60 minutes. Careful evaluation must be made of the circulatory and renal reserve prior to and during use of mannitol at this relatively high dose and rapid infusion rate. Careful attention must be paid to fluid and electrolyte balance, body weight, and total input and output before and after infusion of mannitol. Evidence of reduced cerebral spinal fluid pressure may be observed within 15 minutes after starting infusion. Maximal reduction of intraocular pressure occurs 30 to 60 minutes after injection.

Urinary

Excretion of Toxic Substances –Mannitol in 5 to 25% solutions is used as an infusion as long as indicated if the level of urinary output remains high. The concentration will depend upon the fluid requirement and urinary output. Intravenous water and electrolytes must be given to replace the loss of these substances in the urine, sweat and expired air. If benefits are not observed after 200 g of mannitol are given, discontinue it. mannitol-image For Urologic Irrigation A 2.5% solution is used. The use of 2.5% mannitol solution minimizes the hemolytic effect of water alone, the entrance of hemolyzed blood into the circulation, and the resulting hemoglobinemia which is considered a major factor in producing serious renal complications.

Preparation Of Dilutions For Urologic Irrigation

Concentration How Prepared 2.5% Add contents of two 50 mL vials (25% mannitol) to 900 mL Sterile Water for Injection.

For Intravenous Injection General

Recommendations –Give mannitol injection only intravenously. 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. Usual adult dosage ranges from 50 to 200 g in 24 hours but in most instances an adequate response will be achieved at a dosage of approximately 100 g in 24 hours. The rate is usually adjusted to maintain an adequate urine flow (at least 30 to 50 mL/hr).

Test

Dose –In marked oliguria or inadequate renal function a test dose of mannitol should be given. The test dose may be approximately 0.2 g/kg (about 50 mL of a 25% solution) infused in three to five minutes to produce an adequate urine flow (at least 30 to 50 mL/hr). If urine flow does not increase within two or three hours a second test dose may be given. If there is an inadequate response the patient should be reevaluated. Prevention of Acute Renal Failure (Oliguria) –When used during surgery, immediately postoperatively or following trauma, 50 to100 g of mannitol as a 5 to 25% solution maybe given. The concentration and amount will depend upon the fluid requirements of the patient. Following suspected or actual hemolytic transfusion reactions 20 g of mannitol may be given intravenously over a five minute period to provoke diuresis. If diuresis does not occur the 20 g dose may be repeated. If there is an adequate urine flow (30 to 50 mL/hr) then intravenous fluids containing not more than 50 to 75 mEq of sodium per liter should be given in sufficient volume to match the desired urine flow (100 mL/hr) until fluids can be taken orally. Treatment of Oliguria –The usual dose for treatment of oliguria is 50 to 100 g as a 15 to 25% solution. Reduction of Intracranial Pressure, Cerebral Edema or Intraocular Pressure –A 25% solution of mannitol is recommended since its effectiveness depends on establishing intravascular hyperosmolarity. When used before or after surgery, a total dose of 1.5 to 2 g/kg can be given over a period of 30 to 60 minutes. Careful evaluation must be made of the circulatory and renal reserve prior to and during use of mannitol at this relatively high dose and rapid infusion rate. Careful attention must be paid to fluid and electrolyte balance, body weight, and total input and output before and after infusion of mannitol. Evidence of reduced cerebral spinal fluid pressure may be observed within 15 minutes after starting infusion. Maximal reduction of intraocular pressure occurs 30 to 60 minutes after injection.

Urinary

Excretion of Toxic Substances –Mannitol in 5 to 25% solutions is used as an infusion as long as indicated if the level of urinary output remains high. The concentration will depend upon the fluid requirement and urinary output. Intravenous water and electrolytes must be given to replace the loss of these substances in the urine, sweat and expired air. If benefits are not observed after 200 g of mannitol are given, discontinue it. mannitol-image

Mannitol Injection is contraindicated in patients with:

• Known hypersensitivity to mannitol [see Warnings and Precautions (5.1) ].
• Anuria [see Warnings and Precautions (5.2) ].
• Severe hypovolemia [see Warnings and Precautions (5.4) ].
• Pre-existing severe pulmonary vascular congestion or pulmonary edema [see Warnings and Precautions (5.5) ] .
• Active intracranial bleeding except during craniotomy.
• Known hypersensitivity to mannitol. ( 4 , 5.1 )
• Anuria. ( 4 , 5.2 )
• Severe hypovolemia. ( 4 , 5.4 )
• Pre-existing severe pulmonary vascular congestion or pulmonary edema. ( 4 , 5.5 )
• Active intracranial bleeding except during craniotomy. ( 4 )

REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling:

• Severe Bronchospasm [ see Warnings and Precautions ( 5.1 )]. Most common adverse reactions (rate ≥1%) were headache, pharyngolaryngeal pain, throat irritation, nausea, cough, rhinorrhea, dyspnea, chest discomfort, wheezing, retching and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Methapharm, Inc. at 1-866-701-4636 or email at [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population for the ARIDOL bronchial challenge test consisted of 1,082 subjects (577 females and 505 males) including patients with asthma, symptoms suggestive of asthma, and healthy individuals from 6 to 83 years of age who participated in the two clinical trials (Studies 1 and 2). The racial distribution of subjects was 84% Caucasian, 5% Asian, 4% Black, and 7% Other. Pediatric and adolescents patients comprised 23% of the total study population with 118 pediatric patients aged 6-11 years and 128 adolescents aged 12-17 years. Adverse reactions were reported at the time of the testing procedure and for one day thereafter. No serious adverse reactions were reported following bronchial challenge testing with ARIDOL in either trial. Five adult subjects (0.6%) discontinued from the studies within a day following bronchial challenge testing with ARIDOL because of cough, decreased lung function, feeling jittery, sore throat, and throat irritation. One adult subject (0.3%) discontinued following the methacholine bronchial challenge test because of dizziness. One pediatric subject (0.4%) discontinued from the studies within a day following bronchial challenge testing with ARIDOL because of retching.

Table

2 displays the combined common adverse reactions (≥1%) within a day after bronchial challenge testing with ARIDOL or methacholine in the overall population for Studies 1 and 2.

Table

2: Adverse reactions with an incidence ≥1% within a day after bronchial challenge testing (overall population, Studies 1 and 2 combined)

Adverse Reactions

Treatment ARIDOL (N=1046) n (%)

Methacholine

Challenge (N=420) n (%)

Headache

59 (6) 4 (1) Pharyngolaryngeal pain 25 (2) 0 Throat irritation 19 (2) 1 (<1)

Nausea

19 (2) 0 Cough 17 (2) 8 (2)

Rhinorrhea

16 (2) 0 Dyspnea 15 (1) 21 (5) Chest discomfort 13 (1) 18 (4)

Wheezing

8 (1) 6 (1)

Retching

6 (1) 0 Dizziness 5 (1) 13 (3) The maximum reduction in FEV 1 following bronchial challenge testing with ARIDOL was 46%, compared to 54% for exercise testing and 67% for the methacholine challenge. The incidences in decreases in FEV 1 ≥30% and ≥60% following ARIDOL, methacholine, and exercise challenges for Studies 1 and 2 is shown in Table 3.

Table

3: Incidence of decreases in FEV 1 ≥30% or ≥60% (overall population, Studies 1 and 2) Challenge No. Exposed N (%) with Fall in FEV 1 ≥30% N (%) with Fall in FEV 1 ≥60% Study 1 Exercise 435 27 (6%) 0 Methacholine 420 51 (12%) 3 (1%) ARIDOL 419 3 (1%) 0 Study 2 ARIDOL asthmatics 536 23 (4%) 0 ARIDOL Non-asthmatics 91 0 0 There were no differences in the incidence of adverse reactions based on gender or race. The clinical trials did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently compared to subjects below 65 years of age.

Pediatric Patients Aged

6 to 17 Years: Overall, the types and severities of adverse reactions in children were similar to those observed in the adult population. As in the adult population, the adverse reactions of pharyngolaryngeal pain, nausea, and headache were the more common with incidences of 4%, 3%, and 3%, respectively. There were no major differences in the types of adverse reactions observed in children 6-11 years of age compared to adolescents 12-17 years old. The decrease in FEV 1 in pediatric patients and adolescents who received the ARIDOL bronchial challenge test was similar to that of the adult population with 5%, 15% and 9% of pediatric patients who had bronchial challenge testing with ARIDOL, methacholine and exercise, respectively, experiencing reduction in FEV 1 ≥30%. No patient who had bronchial challenge testing with ARIDOL or exercise had a decrease in FEV 1 ≥60%, whereas, one adolescent patient (aged 12 years) who received methacholine had a decrease in FEV 1 ≥60%.

6.2 Post-Marketing Experience The following adverse reactions have been identified post approval outside the U.S. of the ARIDOL Bronchial Challenge Test Kit: cough, gagging, wheeze, and decreased forced expiratory volume. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

Renal Complications Including Renal

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

Discontinue Mannitol

Injection if renal function worsens. (5.2, 8.6)

Central Nervous

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

Discontinue Mannitol

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

Discontinue Mannitol

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

Monitoring/Laboratory

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

Infusion Site

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

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

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

Discontinue Mannitol

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

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

Discontinue Mannitol

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

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

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

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

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

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

Mannitol

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

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

PRECAUTIONS General Crystals, if present in mannitol injection, 25%, may be dissolved by placing the vial in a hot water bath maintained at 60° to 80°C with occasional shaking. The resulting solution should be allowed to cool to body temperature before injection. An administration set with a filter should be used for intravenous infusions of solutions containing 20% or more of mannitol. NOTE: Use of any other method to heat the vial may result in its explosion. The cardiovascular status should be carefully evaluated before mannitol is administered by rapid intravenous injection or before and during transurethral resection since expansion of extracellular fluid may lead to fulminating congestive heart failure. By sustaining diuresis, mannitol may obscure and intensify inadequate hydration or hypovolemia. Unless it is essential, electrolyte-free mannitol solutions should not be combined with blood. When it is essential to give the combination, at least 20 mEq of sodium chloride should be added to each liter of mannitol solution to avoid pseudoagglutination. The contents of opened containers should be used promptly and unused contents should be discarded. A white flocculant mannitol precipitate may result from contact with PVC surfaces which act as nuclei for rapid rate crystallization of small crystals. This condition has also been reported to occur when mannitol has come in contact with other plastic and rough glass surfaces. Attempting to resolubilize the white flocculant precipitate with the aid of heat is not useful because crystallization may recur in a short period of time. Carcinogenesis, Mutagenesis, Impairment of Fertility In an early study of 1, 5 or 10% mannitol, given for 94 weeks in the diet of Wistar rats, a low incidence of benign thymomas occurred in females which was apparently treatment related. A subsequent life-time study at similar dose levels in Spraque-Dawley, Fischer and Wistar rats revealed no carcinogenic effect in the thymus. Mannitol had no mutagenic activity in a series of in vitro and in vivo test systems. Adequate studies measuring the effects of mannitol on fertility have not been done.

Pregnancy Pregnancy

Category B –Teratogenic studies in the mouse, rat and rabbit at oral doses up to 1600 mg/kg did not reveal harm to the fetus or adverse effects on reproduction due to mannitol. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mannitol is given to a nursing mother.

Pediatric Use

Dosage requirements in children below the age of 12 years have not been established.

General

Crystals, if present in mannitol injection, 25%, may be dissolved by placing the vial in a hot water bath maintained at 60° to 80°C with occasional shaking. The resulting solution should be allowed to cool to body temperature before injection. An administration set with a filter should be used for intravenous infusions of solutions containing 20% or more of mannitol. NOTE: Use of any other method to heat the vial may result in its explosion. The cardiovascular status should be carefully evaluated before mannitol is administered by rapid intravenous injection or before and during transurethral resection since expansion of extracellular fluid may lead to fulminating congestive heart failure. By sustaining diuresis, mannitol may obscure and intensify inadequate hydration or hypovolemia. Unless it is essential, electrolyte-free mannitol solutions should not be combined with blood. When it is essential to give the combination, at least 20 mEq of sodium chloride should be added to each liter of mannitol solution to avoid pseudoagglutination. The contents of opened containers should be used promptly and unused contents should be discarded. A white flocculant mannitol precipitate may result from contact with PVC surfaces which act as nuclei for rapid rate crystallization of small crystals. This condition has also been reported to occur when mannitol has come in contact with other plastic and rough glass surfaces. Attempting to resolubilize the white flocculant precipitate with the aid of heat is not useful because crystallization may recur in a short period of time.

Carcinogenesis, Mutagenesis, Impairment of Fertility In an early study of 1, 5 or 10% mannitol, given for 94 weeks in the diet of Wistar rats, a low incidence of benign thymomas occurred in females which was apparently treatment related. A subsequent life-time study at similar dose levels in Spraque-Dawley, Fischer and Wistar rats revealed no carcinogenic effect in the thymus. Mannitol had no mutagenic activity in a series of in vitro and in vivo test systems. Adequate studies measuring the effects of mannitol on fertility have not been done.

Pregnancy Pregnancy

Category B –Teratogenic studies in the mouse, rat and rabbit at oral doses up to 1600 mg/kg did not reveal harm to the fetus or adverse effects on reproduction due to mannitol. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mannitol is given to a nursing mother.

Pediatric Use

Dosage requirements in children below the age of 12 years have not been established.

For Urologic

Irrigation A 2.5% solution is used. The use of 2.5% mannitol solution minimizes the hemolytic effect of water alone, the entrance of hemolyzed blood into the circulation, and the resulting hemoglobinemia which is considered a major factor in producing serious renal complications.

Preparation Of Dilutions For Urologic Irrigation

Concentration How Prepared 2.5% Add contents of two 50 mL vials (25% mannitol) to 900 mL Sterile Water for Injection.

INTERACTIONS Nephrotoxic Drugs and Diuretics : May increase the risk of renal failure; avoid concomitant use. ( 7.1 , 7.2 )

Neurotoxic

Drugs : May potentiate CNS toxicity of mannitol; avoid concomitant use. ( 7.3 )

Drugs

Affected by Electrolyte Imbalances : May result in cardiac adverse reactions; monitor serum electrolytes and discontinue Mannitol Injection if cardiac status worsens. ( 7.4 )

Renally Eliminated

Agents : Concomitant use may decrease the effectiveness of agents that undergo significant renal elimination. However, concomitant use of mannitol and lithium may increase risk of lithium toxicity. If concomitant use is necessary, frequently monitor lithium concentrations and for signs of toxicity. ( 7.5 )

7.1 Nephrotoxic Drugs Concomitant administration of nephrotoxic drugs (e.g., aminoglycosides, cyclosporine) increases the risk of renal failure following administration of mannitol. Avoid use of nephrotoxic drugs with Mannitol Injection, if possible <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> .

7.2 Diuretics Concomitant administration of other diuretics may potentiate the renal toxicity of mannitol. Avoid use of other diuretics with Mannitol Injection, if possible <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.

7.3 Neurotoxic Drugs Concomitant administration of systemic neurotoxic drugs (e.g., aminoglycosides) with Mannitol Injection may potentiate the CNS toxicity of mannitol. Avoid concomitant administration of neurotoxic drugs with mannitol <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> .

7.4 Drugs Affected by Electrolyte Imbalances The development of electrolyte imbalances (e.g., hyperkalemia, hypokalemia) associated with mannitol administration may result in cardiac adverse reactions in patients receiving drugs that are sensitive to such imbalances (e.g., digoxin, drugs that prolong the QT interval, neuromuscular blocking agents) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> . During and following Mannitol Injection infusion, monitor serum electrolytes and discontinue Mannitol Injection if cardiac status worsens [ see Warnings and Precautions (5.5) ] .

7.5 Renally Eliminated Drugs Mannitol may increase the elimination, and decrease the effectiveness of treatment with, drugs that undergo significant renal elimination. Concomitant administration of mannitol with lithium may initially increase the elimination of lithium but may also increase the risk of lithium toxicity in patients who develop hypovolemia or renal impairment. Consider holding lithium therapy during treatment with Mannitol Injection. If lithium therapy cannot be held, monitor serum lithium concentrations frequently for signs of lithium toxicity. Mannitol therapy may increase the elimination of digoxin leading to a potential decrease in effectiveness of the treatment. Monitor digoxin serum concentrations.

7.6 Interference with Laboratory Tests High concentrations of mannitol can cause false low results for inorganic phosphorus blood concentrations when an assay based on the conversion of phosphate (orthophosphate) to the phosphomolybdate complex is used <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> . Mannitol may produce false positive results in tests for blood ethylene glycol concentrations in which mannitol is initially oxidized to an aldehyde <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> .

Active Ingredient Mannitol 30% Menthol 1.25%

Inactive Ingredients Lecithin, Ethylhexylglycerin, Ceteareth 20, Glyceryl stearate, Octyldodecanol, Phenoxyethanol, Propylene glycol, Isopropyl Palmitate, Caprylic/Capric triglyceride, Dimethicone, Polyethylene glycol 100 stearate, Water, Cetearyl alcohol.