AcetaZOLAMIDE

Pronunciation

(a set a ZOLE a mide)

U.S. Brand Names

Diamox® Sequels®

Generic Available

Yes: Injection, tablet

Canadian Brand Names

Apo-Acetazolamide®; Diamox®

Use

Treatment of glaucoma (chronic simple open-angle, secondary glaucoma, preoperatively in acute angle-closure); drug-induced edema or edema due to congestive heart failure (adjunctive therapy); centrencephalic epilepsies (immediate release dosage form); prevention or amelioration of symptoms associated with acute mountain sickness

Use - Unlabeled/Investigational

Urine alkalinization; respiratory stimulant in COPD

Pregnancy Risk Factor

Pregnancy Implications

Teratogenic in animal studies, however, there are no adequate and well-controlled studies in pregnant women.

Lactation

Enters breast milk/not recommended (AAP rates "compatible")

Contraindications

Hypersensitivity to acetazolamide, sulfonamides, or any component of the formulation; hepatic disease or insufficiency; decreased sodium and/or potassium levels; adrenocortical insufficiency, cirrhosis; hyperchloremic acidosis, severe renal disease or dysfunction; severe pulmonary obstruction; long-term use in noncongestive angle-closure glaucoma

Warnings/Precautions

Use in impaired hepatic function may result in coma. Use with caution in patients with respiratory acidosis and diabetes mellitus. Impairment of mental alertness and/or physical coordination may occur. Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe.

I.M. administration is painful because of the alkaline pH of the drug; use by this route is not recommended

Drug may cause substantial increase in blood glucose in some diabetic patients; malaise and complaints of tiredness and myalgia are signs of excessive dosing and acidosis in the elderly

Adverse Reactions

Frequency not defined.

Cardiovascular: Flushing

Central nervous system: Ataxia, confusion, convulsions, depression, dizziness, drowsiness, excitement, fatigue, headache, malaise

Dermatologic: Allergic skin reactions, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Electrolyte imbalance, growth retardation (children), hyperglycemia, hypoglycemia, hypokalemia, hyponatremia, metabolic acidosis

Gastrointestinal: Appetite decreased, diarrhea, melena, nausea, taste alternation, vomiting

Genitourinary: Crystalluria, glycosuria, hematuria, polyuria, renal failure

Hematologic: Agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia, thrombocytopenic purpura

Hepatic: Cholestatic jaundice, fulminant hepatic necrosis, hepatic insufficiency, liver function tests abnormal

Neuromuscular & skeletal: Flaccid paralysis, paresthesia

Ocular: Myopia

Otic: Hearing disturbance, tinnitus

Miscellaneous: Anaphylaxis

Overdosage/Toxicology

Symptoms of overdose include low blood sugar, tingling of lips and tongue, nausea, yawning, confusion, agitation, tachycardia, sweating, convulsions, stupor, and coma. Hypoglycemia should be managed with 50 mL I.V. dextrose 50% followed immediately with a continuous infusion of 10% dextrose in water (administer at a rate sufficient enough to approach a serum glucose level of 100 mg/dL). The use of corticosteroids to treat hypoglycemia is controversial, however, adding 100 mg of hydrocortisone to the dextrose infusion may prove helpful.

Drug Interactions

Inhibits CYP3A4 (weak)

Amphetamines: Urinary excretion of amphetamine may be decreased; magnitude and duration of effects may be enhanced.

Cyclosporine trough concentrations may be increased resulting in possible nephrotoxicity and neurotoxicity.

Digitalis toxicity may occur if hypokalemia is untreated.

Lithium: Acetazolamide increases lithium excretion; lithium serum levels may be decreased.

Methenamine: Urinary antiseptic effect may be prevented by acetazolamide.

Phenytoin: Serum concentrations of phenytoin may be increased; incidence of osteomalacia may be enhanced or increased in patients on chronic phenytoin therapy.

Primidone serum concentrations may be decreased.

Quinidine: Urinary excretion of quinidine may be decreased and effects may be enhanced.

Salicylate use may result in carbonic anhydrase inhibitor accumulation and toxicity including CNS depression and metabolic acidosis

Stability

Capsules, tablets: Store at controlled room temperature.

Injection: Store vial for injection (prior to reconstitution) at controlled room temperature. Reconstitute with at least 5 mL sterile water to provide a solution containing not more than 100 mg/mL. Reconstituted solution may be refrigerated (2°C to 8°C) for 1 week, however, use within 12 hours is recommended. Further dilute in D5W or NS for I.V. infusion. Stability of IVPB solution is 5 days at room temperature (25°C) and 44 days at refrigeration (5°C).

Compatibility

Stable in dextran 6% in D5W, dextran 6% in NS, D5LR, D5NS, D5¹ /2NS, D5¹ /4NS, D5W, D10W, LR, NS, ¹ /2NS

Y-site administration: Variable (consult detailed reference): Diltiazem, TPN

Compatibility when admixed: Compatible : Cimetidine, ranitidine. Incompatible: Multivitamins

Mechanism of Action

Reversible inhibition of the enzyme carbonic anhydrase resulting in reduction of hydrogen ion secretion at renal tubule and an increased renal excretion of sodium, potassium, bicarbonate, and water to decrease production of aqueous humor; also inhibits carbonic anhydrase in central nervous system to retard abnormal and excessive discharge from CNS neurons

Pharmacodynamics/Kinetics

Onset of action: Capsule, extended release: 2 hours; I.V.: 2 minutes

Peak effect: Capsule, extended release: 8-12 hours; I.V.: 15 minutes; Tablet: 2-4 hours

Duration: Inhibition of aqueous humor secretion: Capsule, extended release: 18-24 hours; I.V.: 4-5 hours; Tablet: 8-12 hours

Distribution: Erythrocytes, kidneys; blood-brain barrier and placenta; distributes into milk (~30% of plasma concentrations)

Excretion: Urine (70% to 100% as unchanged drug)

Dosage

Note: I.M. administration is not recommended because of pain secondary to the alkaline pH

Children:

Glaucoma:

Oral: 8-30 mg/kg/day or 300-900 mg/m² /day divided every 8 hours

I.V.: 20-40 mg/kg/24 hours divided every 6 hours, not to exceed 1 g/day

Edema: Oral, I.V.: 5 mg/kg or 150 mg/m² once every day

Epilepsy: Oral: 8-30 mg/kg/day in 1-4 divided doses, not to exceed 1 g/day; sustained release capsule is not recommended for treatment of epilepsy

Adults:

Glaucoma:

Chronic simple (open-angle): Oral: 250 mg 1-4 times/day or 500 mg sustained release capsule twice daily

Secondary, acute (closed-angle): I.V.: 250-500 mg, may repeat in 2-4 hours to a maximum of 1 g/day

Edema: Oral, I.V.: 250-375 mg once daily

Epilepsy: Oral: 8-30 mg/kg/day in 1-4 divided doses; sustained release capsule is not recommended for treatment of epilepsy

Mountain sickness: Oral: 250 mg every 8-12 hours (or 500 mg extended release capsules every 12-24 hours)

Therapy should begin 24-48 hours before and continue during ascent and for at least 48 hours after arrival at the high altitude

Urine alkalinization (unlabeled use): Oral: 5 mg/kg/dose repeated 2-3 times over 24 hours

Respiratory stimulant in COPD (unlabeled use): Oral, I.V.: 250 mg twice daily

Elderly: Oral: Initial: 250 mg twice daily; use lowest effective dose

Dosing adjustment in renal impairment:

Clcr 10-50 mL/minute: Administer every 12 hours

Clcr<10 mL/minute: Avoid use (ineffective)

Hemodialysis: Moderately dialyzable (20% to 50%)

Peritoneal dialysis: Supplemental dose is not necessary

Administration

Oral: May cause an alteration in taste, especially carbonated beverages; short-acting tablets may be crushed and suspended in cherry or chocolate syrup to disguise the bitter taste of the drug, do not use fruit juices, alternatively submerge tablet in 10 mL of hot water and add 10 mL honey or syrup

Monitoring Parameters

Intraocular pressure, potassium, serum bicarbonate; serum electrolytes, periodic CBC with differential

Test Interactions

May cause false-positive results for urinary protein with Albustix®, Labstix®, Albutest®, Bumintest®; interferes with HPLC theophylline assay

Dietary Considerations

May be taken with food to decrease GI upset. Sodium content of 500 mg injection: 47.2 mg (2.05 mEq).

Patient Education

Take as directed; do not chew or crush long-acting capsule (contents may be sprinkled on soft food). May be administered with food to decrease GI upset. You will need periodic ophthalmic examinations while taking this medication. You may experience drowsiness, dizziness, or weakness (use caution when driving or engaging in tasks that require alertness until response to drug is known); or nausea, loss of appetite, or altered taste (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Monitor serum glucose closely (may cause altered blood glucose in some patients with diabetes, or unusual response to some forms of glucose testing). You may experience increased sensitivity to sunlight (use sunblock, protective clothing, and avoid exposure to direct sunlight). Report unusual and persistent tiredness; numbness, burning, or tingling of extremities or around mouth, lips, or anus; muscle weakness; black stool; or excessive depression. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Metallic taste (resolves upon discontinuation).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Drowsiness is common, may produce depression less commonly

Mental Health: Effects on Psychiatric Treatment

Can rarely cause bone marrow suppression use cautiously with clozapine and carbamazepine; may increase the excretion of lithium

Dosage Forms

Capsule, sustained release (Diamox® Sequels®): 500 mg

Injection, powder for reconstitution: 500 mg

Tablet: 125 mg, 250 mg

Extemporaneously Prepared

Tablets may be crushed and suspended in cherry, chocolate, raspberry, or other highly flavored carbohydrate syrup in concentrations of 25-100 mg/mL; simple suspensions are stable for 7 days. For solutions with longer stability, see References Parastampuria and Alexander.

Alexander KS, Haribhakti RP, and Parker GA, "Stability of Acetazolamide in Suspension Compounded From Tablets," Am J Hosp Pharm , 1991, 48(6):1241-4.

McEvoy G, ed, AHFS Drug Information 96, Bethesda, MD: American Society of Health System Pharmacists, 1996.

Parastampuria J and Gupta VD, "Development of Oral Liquid Dosage Forms of Acetazolamide," J Pharm Sci , 1990, 79:385-6.

References

"American Academy of Pediatrics Committee on Drugs: The Transfer of drugs and Other Chemicals Into Human Milk," Pediatrics , 1994, 93(1):137-150.

Chapron DJ, Gomolin IH, and Sweeney KR, "Acetazolamide Blood Concentrations Are Excessive in the Elderly: Propensity for Acidosis and Relationship to Renal Function," J Clin Pharmacol , 1989, 29(4):348-53.

Chapron DJ, Sweeney KR, Feig PU, et al, "Influence of Advanced Age on the Disposition of Acetazolamide," Br J Clin Pharmacol , 1985, 19:363-71.

Corbett JT, "Acetazolamide and Purpura," Br Med J , 1985, 1:1122-3.

Heller I, Halevy J, Cohen S, et al, "Significant Metabolic Acidosis Induced by Acetazolamide," Arch Intern Med , 1985, 145(10):1815-7.

Parikh JR, Nolan RL, Bannerjee A, et al, "Acetazolamide-Associated Nephrocalcinosis in a Transplant Kidney," Transplantation , 1995, 59(12):1742-3.

Reiss WG and Oles KS, "Acetazolamide in the Treatment of Seizures," Ann Pharmacother , 1996, 30(5):514-9.

Rousseau P and Fuentevilla-Clifton A, "Acetazolamide and Salicylate Interaction in the Elderly: A Case Report," J Am Geriatr Soc , 1993, 41(8):868-9.

Schwenk MH, St. Peter WL, Meese MG, et al, "Acetazolamide Toxicity and Pharmacokinetics in Patients Receiving Hemodialysis," Pharmacotherapy , 1995, 15(4):522-7.

Shinnar S, Gammon K, Bergman EW Jr, et al, "Management of Hydrocephalus in Infancy: Use of Acetazolamide and Furosemide to Avoid Cerebrospinal Fluid Shunts," J Pediatr , 1985, 107(1):31-7.

Vaziri ND, Saiki J, Barton CH, et al, "Hemodialyzability of Acetazolamide," South Med J , 1980, 73(4):422-3.

Wandstrat TL and Phillips J, "Pseudotumor Cerebri Responsive to Acetazolamide," Ann Pharmacother , 1995, 29(3):318.

Weiss IS, "Hirsutism After Chronic Administration of Acetazolamide," Am J Ophthalmol , 1974, 78(2):327-8.

International Brand Names

Acemox® (BD); Acetadiazol® (MX); Acetazolamida L.CH.® (CL); Acetazolamid® (AT, CY); Acetazolamide® (RO); Acetazolamide Tablets® (AT); Apo-Acetazolamide® (CA, SG); Azomid® (ZA); Défiltran® (FR); Diacarb® (RU); Diamox® (AR, AT, AU, BE, BR, CA, CH, CO, CZ, DE, DK, ES, FR, GB, HK, HR, ID, IE, IL, IN, IT, LU, NL, NO, NZ, RO, SI, TH, YU, ZA); Diamox® Depot (FI, NO); Diamox® [inj.] (AT, BE, CH, DE, FI, FR, GB, NL, RO, SI); Diazomid® (TR); Diluran® (CZ); Diuramid® (DE, PL); Edemox® (ES); Ederen® (RO); Gemphamide® (RO); Glaucomed® (CO); Glaupax® (CH, DE, EG, HK, JO, KW, LB, NL); Huma-Zolamide® (HU); ödemin® (FI); Remox® (BD); Theramox® (BD); Uramox® (IL)

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