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Methazolamide
METHAZOLAMIDE TABLETS, USP 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-thiadiazol-2( 3H)-ylidene]-acetamide.
Methazolamide is available for oral
administration
as 25 mg and 50 mg
tablets containing the following inactive ingredients: Acacia,
Alginic Acid, Corn Starch, Dibasic Calcium Phosphate, Gelatin and
Magnesium Stearate.
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 (Cmax) 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) were 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 extra-cellular fluid. The mean apparent volume of distribution (Varea/F) ranges from 17 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 20-25% of the total clearance of drug. After repeated BID-TID dosing, methazolamide accumulates to steady state concentrations in seven 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 two to four hours, has a peak effect in six to eight hours, and a total duration of ten to eighteen 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
cell. Urinary citrate excretion is decreased by approximately 40%
after doses of 100mg every 8 hours. Uric acid
output has been shown
to decrease 36% in the first 24 hour period.
Methazolamide 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.
The effective therapeutic dose administered varies from 50 mg to 100 mg 2-3 times daily. The drug may be used concomitantly with miotic and osmotic agents. HOW SUPPLIED Methazolamide Tablets, USP, 25 mg, are square white tablets engraved with engraved Ji on one side and embossed LL on the other side, supplied as follows: NDC 0005-3519-23 - Bottle of 100 Methazolamide Tablets, USP, 50 mg, are round white scored tablets engraved with LL on one side and J above and 2 below the score on the other side, supplied as follows: NDC 0005-3520-23 - Bottle of 100 Methazolamide is not available for parenteral use. Store at Controlled Room Temperature 15-30° C(59-86° F).
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, hernaturia, glycosuria, hepatic insufficiency, flaccid paralysis, photosensitivity, convulsions, and rarely, crystalluria and renal calculi. Also see PATIENT INFORMATION 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).
Methazolamide should be used with caution in patients on steroid therapy because of the potential for developing hypokalemia. 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 (see 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. Hypersensitivity reactions may recur when a sulfonamide is re-administered, 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.
General Potassium excretion is increased initially upon administration of methazolamide and in patients with cirrhosis or hepatic insufficiency could precipitate a hepatic coma. In patients with pulmonary obstruction or emphysema, where alveolar ventilation may be impaired, methazolamide should be used with caution because it may precipitate or aggravate acidosis. 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. Caution is advised for patients receiving high-dose aspirin and methazolamide concomitantly. 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 methazolamide 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 also recommended. Drug Interactions Methazolamide should be used with caution in patients on steroid therapy because of the potential for developing hypokalemia. 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 (see Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate methazolamide's carcinogenic potential and its effect on fertility have not been conducted. Methazolamide was not mutagenic in the Ames bacterial test. Pregnancy Teratogenic Effects: Pregnancy Category C: Methazolamide has been shown to be teratogenic (skeletal anomalies) in rats when given in doses approximately 40 times the human dose. There are no adequate and well controlled studies in pregnant women. Methazolamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is excreted inhuman milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from methazolamide, 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 methazolamide
in children have not been established.
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