Label: ACETAZOLAMIDE capsule, extended release

This product contains FD&C Yellow No. 6 which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 6 sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

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. Caution 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.Gradual ascent is desirable to try to avoid acute mountain sickness. If rapid ascent is undertaken and acetazolamide 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, i.e., high altitude pulmonary edema (HAPE) or high altitude cerebral edema.

Caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported (see WARNINGS).

Both increases and decreases in blood glucose have been described in patients treated with acetazolamide. This should be taken into consideration in patients with impaired glucose tolerance or diabetes mellitus.

Acetazolamide treatment may cause electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis. Therefore, periodic monitoring of serum electrolytes is recommended. Particular caution is recommended in patients with conditions that are associated with, or predispose a patient to, electrolyte and acid/base imbalances, such as patients with impaired renal function (including elderly patients; see PRECAUTIONS, Geriatric Use), patients with diabetes mellitus, and patients with impaired alveolar ventilation.

Some adverse reactions to acetazolamide, such as drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery.

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.

Drug Interactions

Aspirin - See WARNINGS

Acetazolamide modifies phenytoin metabolism with increased serum levels of phenytoin. This may increase or enhance the occurrence of osteomalacia in some patients receiving chronic phenytoin therapy. Caution is advised in patients receiving chronic concomitant therapy. By decreasing the gastrointestinal absorption of primidone, acetazolamide may decrease serum concentrations of primidone and its metabolites, with a consequent possible decrease in anticonvulsant effect. Caution is advised when beginning, discontinuing, or changing the dose of acetazolamide in patients receiving primidone.

Because of possible additive effects with other carbonic anhydrase inhibitors, concomitant use is not advisable.

Acetazolamide may increase the effects of other folic acid antagonists.

Acetazolamide decreases urinary excretion of amphetamine and may enhance the magnitude and duration of their effect.

Acetazolamide reduces urinary excretion of quinidine and may enhance its effect.

Acetazolamide may prevent the urinary antiseptic effect of methenamine.

Acetazolamide increases lithium excretion and the lithium may be decreased.

Acetazolamide and sodium bicarbonate used concurrently increase the risk of renal calculus formation.

Acetazolamide may elevate cyclosporine levels.

Drug/laboratory test interactions

Sulfonamides may give false negative or decreased values for urinary phenolsulfonphthalein and phenol red elimination values for urinary protein, serum non-protein, and serum uric acid. Acetazolamide may produce an increased level of crystals in the urine.

Acetazolamide interferes with the HPLC method of assay for theophylline. Interference with the theophylline assay by acetazolamide depends on the solvent used in the extraction; acetazolamide may not interfere with other assay methods for theophylline.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of acetazolamide has 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

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 reactions 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. Acetazolamide should only be used by nursing women if the potential benefit justifies the potential risk to the child.

Pediatric Use

The safety and effectiveness of acetazolamide extended-release capsules in pediatric patients below the age of 12 years have not been established. Growth retardation has been reported in children receiving long-term therapy, believed secondary to chronic acidosis.

Geriatric Use

Metabolic acidosis, which can be severe, may occur in the elderly with reduced renal function.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

Body as a whole:

 Headache, malaise, fatigue, fever, pain at injection site, flushing, growth retardation in children, flaccid paralysis, anaphylaxis.

Digestive:

Gastrointestinal disturbances such as nausea, vomiting, diarrhea.

Hematological/Lymphatic:

Blood dyscrasias such as aplastic anemia, agranulocytosis, leukopenia, thrombocytopenic purpura, melena.

Hepato-biliary disorders:

Abnormal liver function, cholestatic jaundice, hepatic insufficiency, fulminant hepatic necrosis.

Metabolic/Nutritional:

Metabolic acidosis, electrolyte imbalance, including hypokalemia, hyponatremia, osteomalacia with long-term phenytoin therapy, loss of appetite, taste alteration, hyper/hypoglycemia.

Nervous:

Drowsiness, paresthesia (including numbness and tingling of extremities and face), depression, excitement, ataxia, confusion, convulsions, dizziness.

Skin:

Allergic skin reactions including urticaria, photosensitivity, Stevens- Johnson syndrome, toxic epidermal necrolysis.

Special senses:

Hearing disturbances, tinnitus, transient myopia. Transient myopia is the result of forward movement of the ciliary body leading to a narrowing of the angle.

Urogenital:

 Crystalluria, increased risk of nephrolithiasis with long-term therapy, hematuria, glycosuria, renal failure, polyuria.

Glaucoma

The recommended dosage is 1 capsule (500 mg) two times a day. Usually 1 capsule is administered in the morning and 1 capsule in the evening. It may be necessary to adjust the dose, but it has usually been found that dosage in excess of 2 capsules (1 g) does not produce an increased effect. The dosage should be adjusted with careful individual attention both to symptomatology and intraocular tension. In all cases, continuous supervision by a physician is advisable.

In those unusual instances where adequate control is not obtained by the twice-a-day administration of acetazolamide extended-release capsules, the desired control may be established by means of acetazolamide (tablets or parenteral). Use tablets or parenteral in accordance with the more frequent dosage schedules recommended for these dosage forms, such as 250 mg every four hours, or an initial dose of 500 mg followed by 250 mg or 125 mg every four hours, depending on the case in question.

Acute Mountain Sickness

Dosage is 500 mg to 1000 mg daily, in divided doses using tablets or extended-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.