methazolamide

Methazolamide, a sulfonamide derivative, is a white crystalline powder, weakly acidic, slightly soluble in water, alcohol and acetone. The chemical name for methazolamide is: N-[5-(aminosulfonyl)-3-methyl-1,3,4-thiadiazo1-2(3H)-ylidene]-acetamide and it has the following structural formula:

C ₅H ₈N ₄O ₃S ₂

236.26

Each tablet, for oral administration, contains 25 mg or 50 mg methazolamide. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate dihydrate, magnesium stearate (powder), and microcrystalline cellulose.

Methazolamide is a potent inhibitor of carbonic anhydrase.

Methazolamide is well absorbed from the gastrointestinal tract. Peak plasma concentrations are observed 1 to 2 hours after dosing. In a multiple-dose, pharmacokinetic study, administration of methazolamide 25 mg bid, 50 mg bid, and 100 mg bid demonstrated a linear relationship between plasma methazolamide levels and methazolamide dose. Peak plasma concentrations (C _max) for the 25 mg, 50 mg and 100 mg bid regimens were 2.5 mcg/mL, 5.1 mcg/mL, and 10.7 mcg/mL, respectively. The area under the plasma concentration-time curves (AUC) was 1130 mcg.min/mL, 2571 mcg.min/mL, and 5418 mcg.min/mL for the 25 mg, 50 mg, and 100 mg dosage regimens, respectively.

Methazolamide is distributed throughout the body including the plasma, cerebrospinal fluid, aqueous humor of the eye, red blood cells, bile and extracellular fluid. The mean apparent volume of distribution (V _area/F) ranges from 17 L to 23 L. Approximately 55% is bound to plasma proteins. The steady-state methazolamide red blood cell:plasma ratio varies with dose and was found to be 27:1, 16:1, and 10:1 following the administration of methazolamide 25 mg bid, 50 mg bid, and 100 mg bid, respectively.

The mean steady-state plasma elimination half-life for methazolamide is approximately 14 hours. At steady-state, approximately 25% of the dose is recovered unchanged in the urine over the dosing interval. Renal clearance accounts for 20% to 25% of the total clearance of drug. After repeated bid-tid dosing, methazolamide accumulates to steady-state concentrations in 7 days.

Methazolamide’s inhibitory action on carbonic anhydrase decreases the secretion of aqueous humor and results in a decrease in intraocular pressure. The onset of the decrease in intraocular pressure generally occurs within 2 to 4 hours, has a peak effect in 6 to 8 hours and a total duration of 10 to 18 hours.

Methazolamide is a sulfonamide derivative; however, it does not have any clinically significant antimicrobial properties. Although methazolamide achieves a high concentration in the cerebrospinal fluid, it is not considered an effective anticonvulsant.

Methazolamide has a weak and transient diuretic effect; therefore, use results in an increase in urinary volume, with excretion of sodium, potassium, and chloride. The drug should not be used as a diuretic. Inhibition of renal bicarbonate reabsorption produces an alkaline urine. Plasma bicarbonate decreases, and a relative, transient metabolic acidosis may occur due to a disequilibrium in carbon dioxide transport in the red blood cell. Urinary citrate excretion is decreased by approximately 40% after doses of 100 mg every 8 hours. Uric acid output has been shown to decrease 36% in the first 24 hour period.

Methazolamide Tablets USP is indicated in the treatment of ocular conditions where lowering intraocular pressure is likely to be of therapeutic benefit, such as chronic open-angle glaucoma, secondary glaucoma, and preoperatively in acute angle-closure glaucoma where lowering the intraocular pressure is desired before surgery.

Methazolamide therapy is contraindicated in situations in which sodium and/or potassium serum levels are depressed, in cases of marked kidney or liver disease or dysfunction, in adrenal gland failure, and in hyperchloremic acidosis. In patients with cirrhosis, use may precipitate the development of hepatic encephalopathy.

Long-term administration of methazolamide is contraindicated in patients with angle-closure glaucoma, since organic closure of the angle may occur in spite of lowered intraocular pressure.

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. Hypersensitivity reactions may recur when a sulfonamide is readministered, irrespective of the route of administration.

If hypersensitivity or other serious reactions occur, the use of this drug should be discontinued.

Caution is advised for patients receiving high-dose aspirin and methazolamide concomitantly, as anorexia, tachypnea, lethargy, coma, and death have been reported with concomitant use of high-dose aspirin and carbonic anhydrase inhibitors.

Adverse reactions, occurring most often early in therapy, include paresthesias, particularly a “tingling” feeling in the extremities; hearing dysfunction or tinnitus; fatigue; malaise; loss of appetite; taste alteration; 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, convulsions, and, rarely, crystalluria and renal calculi. 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).

No data are available regarding methazolamide overdosage in humans as no cases of acute poisoning with this drug have been reported. Animal data suggest that even a high dose of methazolamide is nontoxic. 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 may be required to restore electrolyte and pH balance.

The effective therapeutic dose administered varies from 50 mg to 100 mg two or three times daily. The drug may be used concomitantly with miotic and osmotic agents.

Methazolamide Tablets USP, 25 mg are round, white tablets, debossed “EFF” on one side and “21” on the other side and are supplied in bottles of 100, NDC 55806-021-03.

Methazolamide Tablets USP, 50 mg are round, white, scored tablets debossed “EFF” on one side and “20” on the other side and are supplied in bottles of 100, NDC 55806-020-03.

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

Dispense in a tight container as defined in the USP, with a child-resistant closure (as required).