Acetazolamide = Diamox

  

Generic Name: Acetazolamide sodium

Dosage Form: injection, powder, lyophilized, for solution

For Intravenous use

Rx Only

Acetazolamide Description

Acetazolamide, an inhibitor of the enzyme carbonic anhydrase, is a white to faintly yellowish white

crystalline, odorless powder, weakly acidic, very slightly soluble in water and slightly soluble in alcohol.

The chemical name for Acetazolamide is N(

5Sulfamoyl1,

3, 4thiadiazol2yl)

acetamide

 

 

 

Acetazolamide is available for intravenous use, and is supplied as a sterile powder requiring

reconstitution. Each vial contains Acetazolamide sodium equivalent to 500 mg of Acetazolamide. The bulk

solution is adjusted to pH 9.6 using sodium hydroxide NF and, if necessary, hydrochloric acid NF prior to

lyophilization.

Acetazolamide Clinical

Pharmacology

Acetazolamide is a potent carbonic anhydrase inhibitor, effective in the control of fluid secretion (e.g.,

some types of glaucoma), in the treatment of certain convulsive disorders (e.g., epilepsy) and in the

promotion of diuresis in instances of abnormal fluid retention (e.g., cardiac edema).

Acetazolamide is not a mercurial diuretic. Rather, it is a nonbacteriostatic sulfonamide possessing a

chemical structure and pharmacological activity distinctly different from the bacteriostatic sulfonamides.

Acetazolamide is an enzyme inhibitor that acts specifically on carbonic anhydrase, the enzyme that

catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic

acid. In the eye, this inhibitory action of Acetazolamide decreases the secretion of aqueous humor and

4 6 4 3 2

   

 

results in a drop in intraocular pressure, a reaction considered desirable in cases of glaucoma and even in

certain nonglaucomatous conditions. Evidence seems to indicate that Acetazolamide has utility as an

adjuvant in the treatment of certain dysfunctions of the central nervous system (e.g., epilepsy). Inhibition

of carbonic anhydrase in this area appears to retard abnormal, paroxysmal, excessive discharge from

central nervous system neurons. The diuretic effect of Acetazolamide is due to its action in the kidney on

the reversible reaction involving hydration of carbon dioxide and dehydration of carbonic acid.

The result is renal loss of HCO ion, which carries out sodium, water, and potassium. Alkalinization of the

urine and promotion of diuresis are thus effected. Alteration in ammonia metabolism occurs due to

increased reabsorption of ammonia by the renal tubules as a result of urinary alkalinization.

INDICATIONS & USAGE

For adjunctive treatment of: edema due to congestive heart failure; druginduced

edema; centrencephalic

epilepsies (petit mal, unlocalized seizures); chronic simple (openangle)

glaucoma, secondary glaucoma,

and preoperatively in acute angleclosure

glaucoma where delay of surgery is desired in order to lower

intraocular pressure.

Contraindications

Hypersensitivity to Acetazolamide or any excipients in the formulation. Since Acetazolamide is a

sulfonamide derivative, cross sensitivity between Acetazolamide, sulfonamides and other sulfonamide

derivatives is possible.

Acetazolamide therapy is contraindicated in situations in which sodium and/or potassium blood serum

levels are depressed, in cases of marked kidney and liver disease or dysfunction, in suprarenal gland

failure, and in hyperchloremic acidosis. It is contraindicated in patients with cirrhosis because of the risk of

development of hepatic encephalopathy.

Longterm

administration of Acetazolamide is contraindicated in patients with chronic noncongestive

angleclosure

glaucoma since it may permit organic closure of the angle to occur while the worsening

glaucoma is masked by lowered intraocular pressure.

Warnings

Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including StevensJohnson

syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic

anemia, and other blood dyscrasias. Sensitizations may recur when a sulfonamide is readministered

irrespective of the route of administration. If signs of hypersensitivity or other serious reactions occur,

discontinue use of this drug.

Caution is advised for patients receiving concomitant highdose

aspirin and Acetazolamide, as anorexia,

tachypnea, lethargy, coma and death have been reported.

Precautions

GENERAL

Increasing the dose does not increase the diuresis and may increase the incidence of drowsiness and/or

 

paresthesia. Increasing the dose often results in a decrease in diuresis. Under certain circumstances,

however, very large doses have been given in conjunction with other diuretics in order to secure diuresis

in complete refractory failure.

Information for Patients

Adverse reactions common to all sulfonamide derivatives may occur: anaphylaxis, fever, rash (including

erythema multiforme, StevensJohnson

syndrome, toxic epidermal necrolysis), crystalluria, renal calculus,

bone marrow depression, thrombocytopenic purpura, hemolytic anemia, leukopenia, pancytopenia and

agranulocytosis. Precaution is advised for early detection of such reactions and the drug should be

discontinued and appropriate therapy instituted.

In patients with pulmonary obstruction or emphysema where alveolar ventilation may be impaired,

Acetazolamide which may precipitate or aggravate acidosis should be used with caution.

Caution is advised for patients receiving concomitant highdose

aspirin and Acetazolamide, as anorexia,

tachypnea, lethargy, coma and death have been reported (see WARNINGS).

Laboratory Tests

To monitor for hematologic reactions common to all sulfonamides, it is recommended that a baseline CBC

and platelet count be obtained on patients prior to initiating Acetazolamide therapy and at regular intervals

during therapy. If significant changes occur, early discontinuance and institution of appropriate therapy are

important. Periodic monitoring of serum electrolytes is recommended.

Carcinogenesis & Mutagenesis & Impairment Of Fertility

Longterm

studies in animals to evaluate the carcinogenic potential of Acetazolamide have not been

conducted. In a bacterial mutagenicity assay, Acetazolamide was not mutagenic when evaluated with and

without metabolic activation.

The drug had no effect on fertility when administered in the diet to male and female rats at a daily intake

of up to 4 times the recommended human dose of 1000 mg in a 50 kg individual.

Pregnancy

Teratogenic Effects

Pregnancy Category C: Acetazolamide, administered orally or parenterally, has been shown to be

teratogenic (defects of the limbs) in mice, rats, hamsters and rabbits. There are no adequate and wellcontrolled

studies in pregnant women. Acetazolamide should be used in pregnancy only if the potential

benefit justifies the potential risk to the fetus.

Nursing Mothers

Because of the potential for serious adverse reaction in nursing infants from Acetazolamide, a decision

should be made whether to discontinue nursing or to discontinue the drug taking into account the

importance of the drug to the mother.

  

Pediatric Use

The safety and effectiveness of Acetazolamide in children have not been established.

Adverse Reactions

Adverse reactions, occurring most often early in therapy, include paresthesias, particularly a “tingling”

feeling in the extremities, hearing dysfunction or tinnitus, loss of appetite, taste alteration and

gastrointestinal disturbances such as nausea, vomiting and diarrhea; polyuria, and occasional instances of

drowsiness and confusion.

Metabolic acidosis and electrolyte imbalance may occur.

Transient myopia has been reported. This condition invariably subsides upon diminution or discontinuance

of the medication. Other occasional adverse reactions include urticaria, melena, hematuria, glycosuria,

hepatic insufficiency, flaccid paralysis, photosensitivity and convulsions. Also see PRECAUTIONS :

Information for Patients for possible reactions common to sulfonamide derivatives. Fatalities have

occurred although rarely, due to severe reactions to sulfonamides including StevensJohnson

syndrome,

toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood

dyscrasias (see WARNINGS).

Overdosage

No data are available regarding Acetazolamide overdosage in humans as no cases of acute poisoning

with this drug have been reported.

Animal data suggest that Acetazolamide is remarkable nontoxic. No specific antidote is known. Treatment

should be symptomatic and supportive.

Electrolyte imbalance, development of an acidotic state, and central nervous effects might be expected to

occur. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored.

Supportive measures are required to restore electrolyte and pH balance. The acidotic state can usually be

corrected by the administration of bicarbonate.

Despite its high intraerythrocytic distribution and plasma protein binding properties, Acetazolamide may be

dialyzable. This may be particularly important in the management of Acetazolamide overdosage when

complicated by the presence of renal failure.

DOSAGE & ADMINISTRATION

Preparation and Storage of Parenteral Solution

Each 500 mg vial containing sterile Acetazolamide sodium should be reconstituted with at least 5 mL of

Sterile Water for Injection prior to use. Reconstituted solutions retain their physical and chemical

properties for 3 days under refrigeration at 2° to 8°C (36° to 46°F), or 12 hours at room temperature 20°

to 25°C (68° to 77°F). CONTAINS NO PRESERVATIVE. The direct intravenous route of administration

is preferred. Intramuscular administration is not recommended.

Glaucoma: Acetazolamide should be used as an adjunct to the usual therapy. The dosage employed in

the treatment of chronic simple (openangle)

glaucoma ranges from 250 mg to 1 g of Acetazolamide per

   

24 hours, usually in divided doses for amounts over 250 mg. It has usually been found that a dosage in

excess of 1 g per 24 hours does not produce an increased effect. In all cases, the dosage should be

adjusted with careful individual attention both to symptomatology and ocular tension. Continuous

supervision by a physician is advisable.

In treatment of secondary glaucoma and in the preoperative treatment of some cases of acute congestive

(closedangle)

glaucoma, the preferred dosage is 250 mg every four hours, although some cases have

responded to 250 mg twice daily on shortterm

therapy.

In some acute cases, it may be more satisfactory to administer an initial dose of 500 mg followed by 125

or 250 mg every four hours depending on the individual case. Intravenous therapy may be used for rapid

relief of ocular tension in acute cases. A complementary effect has been noted when Acetazolamide has

been used in conjunction with miotics or mydriatics as the case demanded.

Epilepsy: It is not clearly known whether the beneficial effects observed in epilepsy are due to direct

inhibition of carbonic anhydrase in the central nervous system or whether they are due to the slight

degree of acidosis produced by the divided dosage. The best results to date have been seen in petit mal

in children. Good results, however, have been seen in patients, both in children and adult, in other types

of seizures such as grand mal, mixed seizure patterns, myoclonic jerk patterns, etc. The suggested total

daily dose is 8 to 30 mg per kg in divided doses. Although some patients respond to a low dose, the

optimum range appears to be from 375 to 1000 mg daily. However, some investigators feel that daily

doses in excess of 1 g do not produce any better results than a 1 g dose. When Acetazolamide is given in

combination with other anticonvulsants, it is suggested that the starting dose should be 250 mg once daily

in addition to the existing medications. This can be increased to levels as indicated above.

The change from other medications to Acetazolamide should be gradual and in accordance with usual

practice in epilepsy therapy.

Congestive Heart Failure: For diuresis in congestive heart failure, the starting dose is usually 250 to 375

mg once daily in the morning (5 mg/kg). If, after an initial response, the patient fails to continue to lose

edema fluid, do not increase the dose but allow for kidney recovery by skipping medication for a day.

Acetazolamide yields best diuretic results when given on alternate days, or for two days alternating with a

day of rest.

Failures in therapy may be due to overdosage or too frequent dosage. The use of Acetazolamide does

not eliminate the need for other therapy such as digitalis, bed rest, and salt restriction.

DrugInduced

Edema: Recommended dosage is 250 to 375 mg of Acetazolamide once a day for one or

two days, alternating with a day of rest.

Note: The dosage recommendations for glaucoma and epilepsy differ considerably from those for

congestive heart failure, since the first two conditions are not dependent upon carbonic anhydrase

inhibition in the kidney which requires intermittent dosage if it is to recover from inhibitory effect of the

therapeutic agent.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to

administration, whenever solution and container permit.

Dosage :

Usual Adult Dose for Edema

250 to 375 mg oral or IV once a day.

When continued acetazolamide therapy for edema is desired, it is recommended that every second or third dose be skipped to allow the kidney to recover.

Usual Adult Dose for Acute Mountain Sickness

Oral tablet: 125 to 250 mg orally every 6 to 12 hours.

-or-

SR capsule: 500 mg orally every 12 to 24 hours.

The maximum recommended dose is 1 gram/day.

For rapid ascent, higher doses are beneficial for preventing acute mountain sickness beginning 24 to 48 hours before ascent and continuing for 48 hours while at high altitude.

Usual Adult Dose for Glaucoma

Open-angle Glaucoma:

tablet or IV injection: 250 mg 1 to 4 times a day.

- or-

SR capsule: 500 mg once or twice a day.

Closed-angle glaucoma:

250 to 500 mg IV, may repeat in 2 to 4 hours to a maximum of I gram/day.

Usual Adult Dose for Seizure Prophylaxis

8 to 30 mg/kg/day in 1 to 4 divided doses. Do not exceed 1 gram per day.

If this patient is already taking other anticonvulsants, the recommended starting dosage is 250 mg once a day. If acetazolamide is used alone, most patients with good renal function respond to daily doses ranging from 375 to 1000 mg. The optimum dosage for this patient with renal dysfunction is not known, and will depend on this patient's clinical response and tolerance.

Acetazolamide is primarily used for the treatment of refractory epilepsy in combination with other drugs. Although it may be useful in partial, myoclonic, absence, and primary generalized tonic-clonic seizures uncontrolled by other marketed agents, it has been inadequately studied by current standards for these conditions.

Usual Pediatric Dose for Glaucoma

>= 1 year:

Oral: 8 to 30 mg/kg/day or 300 to 900 mg/m²/day divided every 8 hours.

-or-

IV: 20 to 40 mg/kg/day divided every 6 hours.

Maximum dose: 1 gram/day.

Usual Pediatric Dose for Edema

>= 1 year:

Oral or IV: 5 mg/kg or 150 mg/m² once a day.

Usual Pediatric Dose for Epilepsy

>= 1 year:

Oral: 8 to 30 mg/kg/day in 1 to 4 divided doses. Maximum dose is 1 gram/day.

Usual Pediatric Dose for Hydrocephalus

<1y:

Oral or IV: 20 to 100 mg/kg/day divided every 6 to 8 hours. Maximum dose is 2 grams/day.

Renal Dose Adjustments

CrCl < 10 mL/min: Not recommended.

CrCl 10 to 50 mL/min: The dosage interval should be doubled.

Liver Dose Adjustments

Not recommended for patients with severe liver disease. Patients with mild liver disease should be monitored carefully.

Dialysis

Acetazolamide is moderately dialyzable (20 to 50%).