DIAMOX®
Acetazolamide
250mg tablet
500mg injection (as sodium salt)
Presentation
Acetazolamide tablets, 250mg: round, convex, white, cross scored, marked Lederle on reverse, diameter 11mm.
Acetazolamide Sodium Parenteral, 500 mg vial: cryodesiccated powder, white (solvent required)
Description
Diamox (acetazolamide) is a carbonic anhydrase inhibitor. It is N-[5-(aminosulphonyl)-1,3,4-thiadiazole-2-yl] acetamide.
It is a white to yellowish-white crystalline substance, sparingly soluble in cold water with a mp of 258-259°C, a weak acid, a pka of 7.2 and a molecular weight of 222.25 (C4H6N4O3S2).
Action
Diamox is a 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 oedema).
Diamox is not a mercurial diuretic. Rather it is a nonbacteriostatic sulphonamide possessing a chemical structure and pharmacological activity distinctly different from the bacteriostatic sulphonamides.
Diamox is an enzyme inhibitor that acts specifically on carbonic anhdyrase, 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 humour and results in a drop in intraocular pressure, a reaction considered desirable in cases of glaucoma and even in certain nonglaucomatous conditions. Evidence seems to indicate that Diamox has utility as an adjuvant in the 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 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 ions, that carry out sodium, water and potassium. Alkalinization of the urine and promotion of diuresis are thus effected.
Indications
For adjunctive treatment of: oedema due to congestive heart failure; drug-induced oedema; 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.
Contraindications
Situations in which sodium and/or potassium blood serum levels are depressed, in cases of marked kidney and liver disease or dysfunction, suprarenal gland failure, hyperchloraemic acidosis and hypersensitivity to sulphonamides.
Acetazolamide is contraindicated in patients with cirrhosis because of the risk of development of hepatic encephalophathy.
Long-term administration 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
Pharmacokinetic studies in four volunteers showed that the plasma protein binding and renal clearance of acetazolamide were significantly reduced during chronic salicylate dosing. Salicylate appears to competitively inhibit plasma protein binding of acetazolamide and simultaneously to inhibit acetazolamide renal secretion that may produce serious metabolic acidosis.
When acetazolamide and phenytoin are given together, accelerated development of osteomalacia has been reported. The concurrent use of these two agents should be avoided or else monitoring to detect osteomalacia should be instituted.
Precautions
Increasing the dose does not increase the diuresis and may increase the incidence of drowsiness and/or paraesthesia. 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.
Adverse reactions common to all sulphonamide derivatives may occur: fever, rash (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis), crystalluria, renal calculus, bone-marrow depression, thrombocytopenic purpura, haemolytic anaemia, leucopenia, pancytopenia, agranulocytosis, aplastic anaemia, renal and ureteral colic and renal lesions. The drug should be discontinued and appropriate therapy instituted if such reactions are detected. To monitor for haematological reactions common to all sulphonamides, it is recommended that a baseline CBC, platelet count and electrolyte levels be obtained on patients prior to initiating Diamox therapy and at regular intervals during therapy. If significant changes or toxic skin manifestations occur, early discontinuation and institution of appropriate therapy are important. Fatalities have occurred, although rarely, due to severe adverse reactions to sulphonamides
In patients with pulmonary obstruction or emphysema where alveolar ventilation may be impaired, Diamox, which may precipitate or aggravate acidosis, should be used with caution.
Precaution is advised for patients receiving concomitant high-dose aspirin and Diamox as anorexia, tachypnoea, lethargy and coma have been reported due to a possible drug interaction. (See WARNINGS).
Possible potentiation of the effects of folic acid antagonists, hypoglycaemics and oral anticoagulants. Concomitant administration with high-dose aspirin may potentiate the adverse reactions of Diamox. Adjustment of dose may be required when Diamox is given with cardiac glycosides or antihypertensive agents.
Use in Pregnancy
Pregnancy Category B3.
As there are no adequate and well-controlled studies in pregnant women, Diamox should not be used in pregnancy, especially during the first trimester.
Use during Lactation
Diamox has been detected in low levels in the milk of lactating women who have taken Diamox. Although it is unlikely that this will lead to any harmful effects in the infant, extreme caution should be utilized when Diamox is administered to lactating women.
Paediatrics
(See DOSAGE & ADMINISTRATION)
Adverse Effects
Adverse reactions during short-term therapy are minimal. Those effects that have been noted include: paraesthesias, particularly a tingling feeling in the extremities, some loss of appetite, polyuria, polydipsia, flushing, thirst, headaches, dizziness, fatigue, irritability and occasional instances of drowsiness and confusion. Rarely, photosensitivity has been reported.
During long-term therapy, metabolic acidosis and hypokalaemia may occur. This can usually be corrected by the administration of bicarbonate and/or potassium.
Transient myopia is rare and invariably subsides upon diminution or discontinuation of the medication. Other occasional adverse reactions include urticaria, melaena, haematuria, glycosuria, hepatic insufficiency, flaccid paralysis and convulsions.
Dosage and Administration
Preparation of Parenteral Solution
Each 500 mg vial should be reconstituted with at least 5 mL of sterile water for injection prior to use. The direct intravenous route of administration is preferred. Intramuscular administration may be employed but is painful, due to the alkaline pH of the solution.
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 1g 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 4 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 4 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 both adult and paediatric patients, in other types of seizures such as grand mal, mixed seizure patterns, myoclonic jerk pattern etc. The recommended dose in paediatric patients is 8-30 mg/kg daily in divided doses not to exceed 750 mg/day. In adults the recommended dose is 250-1000 mg daily in divided doses.
When Diamox is given in combination with any other anticonvulsant, it is suggested that the starting dose should be 250 mg once daily in addition to the existing medication. This can be increased to the levels indicated above.
The change from other medication to Diamox should be gradual 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 oedema fluid, do not increase the dose but allow for kidney recovery by omitting medication for a day.
Diamox yields best diuretic results when given on alternate days, or for 2 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 eliminate the need for other therapy such as digitalis, bed rest and salt restriction.
Drug-Induced Oedema
Recommended dosage is 250 to 375 mg once daily for one to two days, alternating with a day of rest.
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.
Overdosage
No specific antidote. Supportive measures with correction of electrolyte and fluid balance. Force fluids.
Pharmaceutical Precautions
Tablets: store below 30°C or 86°F
Parenteral: store below 30°C or 86°F, for unopened vial
Storage of parenteral solution: This product contains no preservative. Vial should be used once only - any residue should be discarded. To reduce microbiological hazard, use as soon as practicable after reconstitution. Storage of reconstituted solution is not recommended, but if storage is necessary hold at 2°-8°C (36°-47°F) for not more than 24 hours.
Package Quantities
Tablets, 250 mg: 100's
Injection, 500 mg vial (solvent required): 1's
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