ACETAZOLAMIDE
DIAMOX 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
DIAMOX is N-(5-Sulfamoyl-1,3,4-thiadiazol- 2yl)-acetamide. Its molecular weight
is 222.24. Its chemical formula is C4H6N4O3S2.
DIAMOX is available as oral tablets containing 125 mg and 250 mg of
acetazolamide respectively and the following inactive ingredients: Corn Starch,
Dibasic Calcium Phosphate, Magnesium Stearate, Povidone, and Sodium Starch
Glycolate.
DIAMOX is also available for intravenous use, and is supplied as a sterile
powder requiring reconstitution. Each vial contains an amount of acetazolamide
sodium equivalent to 500 mg of acetazolamide. The bulk solution is adjusted to
pH 9.2 using sodium hydroxide and, if necessary, hydrochloric acid prior to
lyophilization.
ACTIONS/CLINICAL PHARMACOLOGY:
DIAMOX acetazolamide is a potent carbonic anhydrase inhibitor, effective in the
control of fluid secretion (eg, some types of glaucoma), in the treatment of
certain convulsive disorders (eg, epilepsy) and in the promotion of diuresis in
instances of abnormal fluid retention (eg, cardiac edema).
DIAMOX is not a mercurial diuretic. Rather, it is a non bacteriostatic
sulfonamide possessing a chemical structure and pharmacological activity
distinctly different from the bacteriostatic sulfonamides.
DIAMOX 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 results in a drop
in intraocular pressure, a reaction considered desirable in cases of glaucoma
and even in certain non glaucomatous conditions. Evidence seems to indicate that
DIAMOX has utility as an adjuvant in the treatment of certain dysfunctions of
the central nervous system (eg, epilepsy). Inhibition of carbonic anhydrase in
this area appears to retard abnormal, paroxysmal, excessive discharge from
central nervous system neurons. The diuretic effect of DIAMOX 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 HCO3 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.
Placebo-controlled clinical trials have shown that prophylactic administration
of DIAMOX at a dose of 250 mg every eight to 12 hours (or a 500 mg controlled-
release capsule once daily) before and during rapid ascent to altitude results
in fewer and/or less severe symptoms (such as headache, nausea, shortness of
breath, dizziness, drowsiness, and fatigue) of acute mountain sickness (AMS).
Pulmonary function (eg, minute ventilation, expired vital capacity, and peak
flow) is greater in the DIAMOX treated group, both in subjects with AMS and
asymptomatic subjects. The DIAMOX treated climbers also had less difficulty in
sleeping.
INDICATIONS AND USAGE:
For adjunctive treatment of: edema due to congestive heart failure; drug-induced
edema; centrencephalic epilepsies (petit mal, unlocalized seizures); chronic
simple (open- angle) glaucoma, secondary glaucoma, and preoperatively in acute
angle-closure glaucoma where delay of surgery is desired in order to lower
intraocular pressure. DIAMOX is also indicated for the prevention or
amelioration of symptoms associated with acute mountain sickness in climbers
attempting rapid ascent and in those who are very susceptible to acute mountain
sickness despite gradual ascent.
CONTRAINDICATIONS:
DIAMOX 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.
Long-term administration of DIAMOX is contraindicated in patients with chronic
noncongestive angle-closure 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 Stevens-Johnson 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 high-dose aspirin and
DIAMOX 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,
Stevens-Johnson 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, DIAMOX acetazolamide which may precipitate or aggravate
acidosis, should be used with caution.
Gradual ascent is desirable to try to avoid acute mountain sickness. If rapid
ascent is undertaken and DIAMOX is used, it should be noted that such use does
not obviate the need for prompt descent if severe forms of high altitude
sickness occur, ie, high altitude pulmonary edema (HAPE) or high altitude
cerebral edema.
Caution is advised for patients receiving concomitant high-dose aspirin and
DIAMOX 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 DIAMOX 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: Long-term studies in
animals to evaluate the carcinogenic potential of DIAMOX acetazolamide have not
been conducted. In a bacterial mutagenicity assay, DIAMOX 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: 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 well-controlled 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 DIAMOX, 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 DIAMOX 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 Stevens-Johnson
syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis,
agranulocytosis, aplastic anemia and other blood dyscrasias (see WARNINGS).
OVERDOSAGE:
No data are available regarding DIAMOX overdosage in humans as no cases of acute
poisoning with this drug have been reported. Animal data suggest that DIAMOX is
remarkably 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, DIAMOX may be dialyzable. This may be particularly important in the
management of DIAMOX overdosage when complicated by the presence of renal
failure.
DOSAGE AND ADMINISTRATION:
PREPARATION AND STORAGE OF PARENTERAL SOLUTION: Each 500 mg vial containing
DIAMOX sterile acetazolamide sodium parenteral 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 deg C (36 to 46 deg F), or 12 hours at room temperature 15 to 30 deg C
(59 to 86 deg F). CONTAINS NO PRESERVATIVE. The direct intravenous route of
administration is preferred. Intramuscular administration is not recommended.
GLAUCOMA: DIAMOX should be used as an adjunct to the usual therapy. The dosage
employed in the treatment of Chronic Simple (open-angle) Glaucoma ranges from
250 mg to 1 g of DIAMOX 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 (closed-angle) Glaucoma, the preferred dosage is 250
mg every four hours, although some cases have responded to 250 mg twice daily on
short-term 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 DIAMOX 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 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 DIAMOX 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 DIAMOX 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. DIAMOX 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
DIAMOX does not elimi10:44 AM 3/13/04nate the need for other therapy such as digitalis, bed
rest, and salt restriction.
DRUG-INDUCED EDEMA: Recommended dosage is 250 to 375 mg of DIAMOX once a day
for one or two days, alternating with a day of rest.
ACUTE MOUNTAIN SICKNESS: Dosage is 500 mg to 1000 mg daily, in divided doses
using tablets or sustained-release capsules as appropriate. In circumstances of
rapid ascent, such as in rescue or military operations, the higher dose level of
1000 mg is recommended. It is preferable to initiate dosing 24 to 48 hours
before ascent and to continue for 48 hours while at high altitude, or longer as
necessary to control symptoms.
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 the 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.