Urea (Systemic)


VA CLASSIFICATION
Primary: CV709
Secondary: OP115

Commonly used brand name(s): Ureaphil.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Diuretic—

antiglaucoma agent (systemic)—

Indications

Accepted

Edema, cerebral (treatment)—Urea is indicated to treat cerebral edema and reduce brain mass and intracranial pressure. {01} {05}

Glaucoma, malignant (treatment) or
Glaucoma, secondary (treatment)—Urea is indicated to reduce elevated intraocular pressure (IOP) after other methods have failed or in preparation for intraocular surgery. {01}


Pharmacology/Pharmacokinetics

Mechanism of action/Effect:

Cerebral edema—Elevates blood plasma osmolality, resulting in enhanced flow of water from tissues, including the brain and cerebrospinal fluid, into interstitial fluid and plasma. As a result, cerebral edema, elevated intracranial pressure, and cerebrospinal fluid volume and pressure may be reduced. {01} {05} This effect is evident early in the course of infusion as long as a gradient between plasma and intracellular urea exists. As urea diffuses into the cells and the gradient diminishes, the effect diminishes. {09}

Glaucoma—Elevates blood plasma osmolality, resulting in enhanced flow of water from the eye into plasma and a consequent reduction in intraocular pressure. {01} {05}


Other actions/effects:

As the concentration of urea in glomerular filtrate increases, reabsorption of a proportional amount of water is prevented, resulting in increases in rate and volume of urine flow. {01}

Distribution:

Urea is distributed into extracellular and intracellular fluids including lymph, bile, cerebral spinal fluid (CSF), and blood in approximately equal concentrations.{05} Urea also crosses the placenta and penetrates the eyes, but it is unknown whether urea is excreted in the milk of lactating women.{05}

Biotransformation:

Urea may be partially metabolized in the gastrointestinal tract by hydrolysis to ammonia and carbon dioxide, which may be resynthesized into urea. {05}

Half-life:

1.17 hours.

Onset of action:

Reduction of intraocular and intracranial pressure—Within 10 minutes after infusion is started.

Time to peak effect:

1 to 2 hours. {05}

Duration of action:

Diuresis—3 to 10 hours after infusion is stopped. {05}

Reduction in cerebrospinal fluid pressure—3 to 10 hours after infusion is stopped. {05}

Reduction in intraocular pressure—5 to 6 hours. {05}

Elimination:
    Renal (reabsorption about 50%).{05}


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans. {01}

Studies have not been done in animals. {01}

FDA Pregnancy Category C. {01}

Breast-feeding

It is not known whether urea is distributed into breast milk, {01} but it is expected that distribution likely occurs. {05} Problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of urea have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the usefulness of urea in children are not expected.


Geriatrics


Urea should not be infused into veins of the lower extremities, especially in elderly patients, since phlebitis and thrombosis of superficial and deep veins may occur. In addition, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving urea. {01} {02}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Diuretics, other, including carbonic anhydrase inhibitors    (diuretic and IOP–reducing effects may be potentiated when these medications are used concurrently with urea; dosage adjustments may be necessary)


Lithium    (urea may increase renal excretion of lithium {05} {07} {08})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Blood urea nitrogen (BUN) {01}    (concentrations may be increased with excessive doses)


Potassium and
Sodium    (serum concentrations may be decreased with prolonged administration)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Dehydration, severe {01} {05}    (this condition may increase risk of urea-induced electrolyte depletion )


» Hepatic function impairment, severe    (blood ammonia concentrations may be elevated {01})


» Intracranial bleeding, active, except during craniotomy     (reduction of brain edema by urea may increase bleeding {01})


» Renal function impairment, severe {01}    (accumulation of urea solution may lead to circulatory overload {01})


Risk-benefit should be considered when the following medical problems exist
Cardiovascular function impairment    (sudden expansion of extracellular fluid may lead to congestive heart failure )


Hepatic function impairment    (blood ammonia concentrations may be elevated {05})


» Hereditary fructose intolerance (aldolase deficiency)—for infusions prepared with invert sugar injection only {05}
Hypovolemia    (may be masked and intensified)


Renal function impairment {03}    (accumulation of urea may lead to overexpansion of extracellular fluid and circulatory overload)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure measurements and
Electrolyte measurements, including sodium and potassium, and {01}{05}
Renal function determinations and
Urine output determinations {09}    (recommended during intravenous infusion of urea, especially with repeated doses {01})


Blood urea nitrogen (BUN) determinations {01}    (recommended before and frequently during intravenous administration; if a rapid increase occurs, the infusion should be slowed or stopped {05})




Side/Adverse Effects

Note: Most side/adverse effects are related to the rate of administration.
Thrombosis may occur with administration into the superficial and deep veins of the lower extremities, especially in elderly patients. {01}
Hemolysis may occur as a result of rapid administration {01} {05}; urea may also cause increased capillary bleeding, and rapid infusion has resulted in intraocular hemorrhage in patients with absolute glaucoma. {01}
Side effects can be minimized by maintaining adequate hydration and keeping the patient horizontal. {05}
Excessive diuresis can result from long-term urea therapy, which may lead to tissue dehydration, hypokalemia, and hyponatremia. {05}

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Confusion{01} , fast heartbeat, fever, or {01} nervousness
    
electrolyte imbalance (confusion; irregular heartbeat; muscle cramps or pain; numbness, tingling, pain, or weakness in hands or feet; seizures; trembling; unusual tiredness or weakness; weakness and heaviness of legs){05}
    
phlebitis or thrombosis, chemical, or {01} extravasation {01} (redness, swelling, or pain at injection site)—for intravenous injection only
    
subdural or subarachnoid hemorrhage, possible (blurred vision; severe headache){05}

Note: Confusion, fast heartbeat, fever, or nervousness may be caused by too rapid intravenous infusion.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Dryness of mouth or increased thirst
    
headache {01}
    
nausea or vomiting {01}

Incidence less frequent
    
Dizziness or faintness {01}
    
drowsiness — with prolonged urea administration in patients with sickle cell crisis
    
skin blemishes

Note: In some cases, headache, nausea or vomiting, blurred vision, and dizziness may be symptoms of subdural or subarachnoid hemorrhage.






Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing ).

Treatment of overdose
In the event of overdose as reflected by elevated blood urea nitrogen (BUN) concentrations, recommended treatment consists of the following: discontinuation of medication; patient evaluation, and institution of corrective measures. {01}


General Dosing Information

For intravenous injection only
The dose used depends on the fluid and electrolyte and renal status of the patient.

An infusion rate of not greater than 4 mL per minute is recommended, since rapid infusion may cause hemolysis and cerebral vasomotor symptoms. {01}

When urea is used preoperatively for reduction of intraocular or intracranial pressure, the dose should be started about 60 minutes prior to ocular surgery and at the time of scalp incision during intracranial surgery to achieve maximum reduction of pressure.

Urea should not be infused into veins of the lower extremities, especially in elderly patients, since phlebitis and thrombosis of superficial and deep veins may occur. Large veins should be used for infusion. {01}

Caution should be used to prevent extravasation of urea infusion solution at the site of injection, which may result in irritation and tissue necrosis.

Use of an indwelling urethral catheter is recommended in comatose patients to ensure bladder emptying and adequacy of urine output. {09}

The simultaneous use of hypothermia and urea infusion to lower intracranial pressure may increase the risk of venous thrombosis and hemoglobinuria. {01}

Patients exhibiting a temporary reduction in urine volume are generally able to maintain satisfactory elimination of urea. If diuresis does not follow the injection of urea within 6 to 12 hours, the drug should be withdrawn pending further evaluation of renal function. {01}


Parenteral Dosage Forms

UREA STERILE USP

Usual adult and adolescent dose
Diuretic or
Antiglaucoma agent
Intravenous infusion, 500 mg to 1.5 grams per kg of body weight as a 30% solution {01} in 5 or 10% Dextrose Injection USP or 10% invert sugar injection, administered at a rate not exceeding 4 mL per minute. {01}{05}


Usual adult prescribing limits
The total daily dose should not exceed 120 grams urea. {01}{05}

Usual pediatric dose
Diuretic
Intravenous infusion, 0.5 to 1.5 grams per kg of body weight as a 30% solution in 5 or 10% Dextrose Injection USP, or 10% invert sugar injection, administered at a rate not exceeding 4 mL per minute. In infants up to 2 years of age, as little as 0.1 g/kg may be adequate. {01}{05}


Size(s) usually available:
U.S.—


40 grams (Rx) [Ureaphil]

Canada—
Not commercially available.

Packaging and storage:
Prior to reconstitution, store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing. {01}

Preparation of dosage form:
For preparation of product for injection, see manufacturer's package insert.

Use of 5% or 10% dextrose injection or invert sugar injection as a diluent reduces the risk of hemolysis that may occur with rapid administration of urea. However, invert sugar injection is contraindicated in patients with fructose intolerance due to aldolase deficiency. {01}{05}

One gram of urea is equivalent to approximately 16.7 mOsm (calculated on basis of urea being reconstituted with water for injection).

The number of mOsm of urea per liter of specified diluent is as follows:

Urea
(%)
Diluent
Total
mOsm/liter
(approx)
30
5% Dextrose injection
5250
30
10% Dextrose injection
5500
30
10% Invert sugar injection
5550
{05}

Stability:
See manufacturer's package insert and/or label for stability of reconstituted solution.

Each dose of urea should be freshly prepared. Discard any unused portion. {01}

Incompatibilities:
When blood and urea are administered simultaneously, the urea infusion solution should not be administered through the same administration set through which the blood is being infused. {01}

Additional information:
Following reconstitution of urea powder for injection with 5 or 10% dextrose or 10% invert sugar injection, the solutions have a pH of 5.5 to 7. {05}



Revised: 02/23/00



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Product Information: Ureaphil®, sterile urea, USP. Abbott Labs, North Chicago, IL, (PI revised 03/95), reviewed 2/2000.
  1. General concept per Geriatrics Advisory Panel (1985-1990), 1990 revision.
  1. not used
  1. USAN, 1990: 592.
  1. American Hospital Formulary Service Drug Information, 1999: 2330–2332.
  1. USP/NF, 1990: 1856, 1439.
  1. Facts and comparisons, 1989: 139i-139j.
  1. Hansten's drug interactions. 5th ed., 1985: 414.
  1. Panel comments, 1990.
  1. Manufacturer comment, 1990.
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