Acetazolamide (Acetazolamide sodium) extended-release capsules are an inhibitor of the enzyme carbonic anhydrase.

Acetazolamide (Acetazolamide sodium) 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 (Acetazolamide sodium) is N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide and has the following chemical structure:

MW 222.24                                  CHNOS

Each Acetazolamide (Acetazolamide sodium) extended-release capsule intended for oral administration contains 500 mg of Acetazolamide (Acetazolamide sodium) . In addition, each capsule contains the following inactive ingredients: ammonio methacrylate copolymer dispersion type A and B, FD&C yellow #6, gelatin, microcrystalline cellulose, sodium lauryl sulfate, talc and titanium dioxide. The capsule is printed with black pharmaceutical ink which contains black iron oxide as a coloring agent.

Acetazolamide (Acetazolamide sodium) 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 (Acetazolamide sodium) 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.

Acetazolamide (Acetazolamide sodium) 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 (Acetazolamide sodium) 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 Acetazolamide (Acetazolamide sodium) has utility as an adjuvant in 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 (Acetazolamide sodium) 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 affected. Alteration in ammonia metabolism occurs due to increased reabsorption of ammonia by the renal tubules as a result of urinary alkalinization.

Acetazolamide (Acetazolamide sodium) extended-release capsules provide prolonged action to inhibit aqueous humor secretion for 18 to 24 hours after each dose, whereas tablets act for only eight to 12 hours. The prolonged continuous effect of Acetazolamide (Acetazolamide sodium) permits a reduction in dosage frequency.

Plasma concentrations of Acetazolamide (Acetazolamide sodium) peak from three to six hours after administration of Acetazolamide (Acetazolamide sodium) extended-release capsules, compared to one to four hours with tablets. Food does not affect bioavailability of Acetazolamide (Acetazolamide sodium) extended-release capsules.

Placebo-controlled clinical trials have shown that prophylactic administration of Acetazolamide (Acetazolamide sodium) 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 of acute mountain sickness (AMS) such as headache, nausea, shortness of breath, dizziness, drowsiness, and fatigue. Pulmonary function (e.g., minute ventilation, expired vital capacity, and peak flow) is greater in the Acetazolamide (Acetazolamide sodium) treated group, both in subjects with AMS and asymptomatic subjects. The Acetazolamide (Acetazolamide sodium) treated climbers also had less difficulty in sleeping.

For adjunctive treatment of: 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. Acetazolamide (Acetazolamide sodium) extended-release capsules are also indicated for the prevention or amelioration of symptoms associated with acute mountain sickness despite gradual ascent.

Hypersensitivity to Acetazolamide (Acetazolamide sodium) or any excipients in the formulation. Since Acetazolamide (Acetazolamide sodium) is a sulfonamide derivative, cross sensitivity between Acetazolamide (Acetazolamide sodium) , sulfonamides and other sulfonamide derivatives is possible.

Acetazolamide (Acetazolamide sodium) 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 Acetazolamide (Acetazolamide sodium) is contraindicated in patients with chronic non-congestive angle-closure glaucoma since it may permit organic closure of the angle to occur while the worsening glaucoma is masked by lowered intraocular pressure.

Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, anaphylaxis, 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 Acetazolamide (Acetazolamide sodium) , as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported.

Adverse reactions common to all sulfonamide derivatives may occur: anaphylaxis, fever, rash (including erythema multiforme, Steven-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 (Acetazolamide sodium) 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 (Acetazolamide sodium) 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 (Acetazolamide sodium) , as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported (see ).

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

Acetazolamide (Acetazolamide sodium) 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 ), patients with diabetes mellitus, and patients with impaired alveolar ventilation.

Some adverse reactions to Acetazolamide (Acetazolamide sodium) , such as drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery.

See

Acetazolamide (Acetazolamide sodium) 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 (Acetazolamide sodium) 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 (Acetazolamide sodium) in patients receiving primidone.

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

Acetazolamide (Acetazolamide sodium) may increase the effects of other folic acid antagonists.

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

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

Acetazolamide (Acetazolamide sodium) may prevent the urinary antiseptic effect of methenamine.

Acetazolamide (Acetazolamide sodium) increases lithium excretion and the lithium may be decreased.

Acetazolamide (Acetazolamide sodium) and sodium bicarbonate used concurrently increases the risk of renal calculus formation.

Acetazolamide (Acetazolamide sodium) may elevate cyclosporine levels.

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 (Acetazolamide sodium) may produce an increased level of crystals in the urine.

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

Long-term studies in animals to evaluate the carcinogenic potential of Acetazolamide (Acetazolamide sodium) has not been conducted. In a bacterial mutagenicity assay, Acetazolamide (Acetazolamide sodium) 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.

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.

No specific antidote is known. Treatment should be symptomatic and supportive.

Electrolyte imbalance, development of an acidotic state, and central nervous system 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 (Acetazolamide sodium) may be dialyzable. This may be particularly important in the management of Acetazolamide (Acetazolamide sodium) overdosage when complicated by the presence of renal failure.

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 (Acetazolamide sodium) extended-release capsules, the desired control may be established by means of Acetazolamide (Acetazolamide sodium) (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.

Acetazolamide (Acetazolamide sodium) Extended-Release Capsules, 500 mg are white to off-white pellets filled in empty hard gelatin capsules with orange opaque cap imprinted with "EP" in black ink and white opaque body imprinted with "107" in black ink and are supplied as follows:

NDC 0179-0050-70 -30 capsules in 1 Box, Unit Dose

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in well-closed containers.

Emcure Pharmaceuticals USA, Inc.

21-B Cotters Lane

East Brunswick, NJ 08816

Zydus Pharmaceuticals USA, Inc

Princeton, NJ 08540

KAISER FOUNDATION HOSPITALS

Livermore, CA 94551