General Articles

Acetazolamide

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
AcetaZOLAMIDE may be confused with acetoHEXAMIDE
Diamox® Sequels® may be confused with Diabinese®, Dobutrex®, Trimox®

U.S. BRAND NAMES — Diamox® Sequels®

PHARMACOLOGIC CATEGORY
Anticonvulsant, Miscellaneous
Carbonic Anhydrase Inhibitor
Diuretic, Carbonic Anhydrase Inhibitor
Ophthalmic Agent, Antiglaucoma

DOSING: ADULTS — Note: I.M. administration is not recommended.

Glaucoma:
Chronic simple (open-angle): Oral: 250 mg 1-4 times/day or 500 mg extended 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, not to exceed 1 g/day. Note: Extended release capsule is not recommended for treatment of epilepsy.

Metabolic alkalosis (unlabeled use): I.V. 250 mg every 6 hours for 4 doses or 500 mg single dose; reassess need based upon acid-base status

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.
Note: In situations of rapid ascent (such as rescue or military operations), 1000 mg/day is recommended.

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

DOSING: PEDIATRIC — Note: I.M. administration is not recommended.

(For additional information see “Acetazolamide: Pediatric drug information”)

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: Refer to adult dosing.

DOSING: ELDERLY — Oral: Initial: 250 mg once or twice daily; use lowest effective dose possible.

DOSING: RENAL IMPAIRMENT
Clcr 10-50 mL/minute: Administer every 12 hours.

Clcr <10 mL/minute: Avoid use (ineffective). Moderately dialyzable (20% to 50%) DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. Capsule, extended release: 500 mg
Diamox® Sequels®: 500 mg

Injection, powder for reconstitution: 500 mg

Tablet: 125 mg, 250 mg

DOSAGE FORMS: CONCISE
Capsule, extended release: 500 mg
Diamox® Sequels®: 500 mg

Injection, powder for reconstitution: 500 mg

Tablet: 125 mg, 250 mg

GENERIC EQUIVALENT AVAILABLE — Yes

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.

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

I.V.: No specific guidance given by manufacturer, but I.V. push at a rate of up to 500 mg over 3 minutes has been reported in a clinical trial (Mazur, 1999); a study to assess cerebrovascular reserve has used rapid I.V. push of up to 1 g over ≤ 1 minute (Piepgras, 1990)

SEE MORE:  SILLIVER Abbott

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.

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 — Metabolic alkalosis; respiratory stimulant in COPD; urine alkalinization

ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.

Cardiovascular: Flushing

Central nervous system: Ataxia, confusion, convulsions, depression, dizziness, drowsiness, excitement, fatigue, fever, 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 alteration, 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

Local: Pain at injection site

Neuromuscular & skeletal: Flaccid paralysis, paresthesia

Ocular: Myopia

Otic: Hearing disturbance, tinnitus

Miscellaneous: Anaphylaxis

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
Concerns related to adverse effects: CNS effects: Impairment of mental alertness and/or physical coordination may occur. Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonylurea 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. Discontinue if signs of hypersensitivity are noted.

Disease-related concerns: Diabetes: Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control. Hepatic impairment: Use with caution in patients with hepatic dysfunction; in cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Respiratory acidosis: Use with caution in patients with respiratory acidosis.

Special populations: Elderly: Use with caution in the elderly; may be more sensitive to side effects.

Other warnings/precautions: I.M. administration: Painful because of the alkaline pH of the drug; use by this route is not recommended.

METABOLISM / TRANSPORT EFFECTS — Inhibits CYP3A4 (weak)

DRUG INTERACTIONS
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alpha-/Beta-Agonists: Carbonic Anhydrase Inhibitors may decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Dipivefrin. Risk C: Monitor therapy

SEE MORE:  COTRI Unexolabs

Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Amphetamines:
Carbonic Anhydrase Inhibitors may decrease the excretion of Amphetamines. Risk C: Monitor therapy

Anticonvulsants (Barbiturate): Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Anticonvulsants (Barbiturate). Specifically, osteomalacia and rickets. Risk C: Monitor therapy

Anticonvulsants (Hydantoin): Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Anticonvulsants (Hydantoin). Specifically, osteomalacia and rickets. Risk C: Monitor therapy

Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy

CarBAMazepine: Carbonic Anhydrase Inhibitors may increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Flecainide: Carbonic Anhydrase Inhibitors may decrease the excretion of Flecainide. Risk C: Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification

Memantine: Carbonic Anhydrase Inhibitors may decrease the excretion of Memantine. Risk C: Monitor therapy

Methenamine: Carbonic Anhydrase Inhibitors may diminish the therapeutic effect of Methenamine. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce dosage of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Primidone: Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Primidone. Specifically, osteomalacia and rickets. Carbonic Anhydrase Inhibitors may decrease the serum concentration of Primidone. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

QuiNIDine: Carbonic Anhydrase Inhibitors may decrease the excretion of QuiNIDine. Risk C: Monitor therapy

RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification

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Salicylates: May enhance the adverse/toxic effect of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. Risk D: Consider therapy modification

Trientine: Carbonic Anhydrase Inhibitor Diuretics may decrease the serum concentration of Trientine. Risk C: Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

PREGNANCY RISK FACTOR — C (show table)

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”)

DIETARY CONSIDERATIONS — May be taken with food to decrease GI upset. May have additive effects with other folic acid antagonists. Sodium content of 500 mg injection: 47.2 mg (2.05 mEq).

PRICING — (data from drugstore.com)
Capsule, 12-hour (AcetaZOLAMIDE)
500 mg (100): $299.97

Capsule, 12-hour (Diamox Sequels)
500 mg (60): $314.98

Tablets (AcetaZOLAMIDE)
125 mg (90): $29.99
250 mg (60): $29.99

MONITORING PARAMETERS — Intraocular pressure, potassium, serum bicarbonate; serum electrolytes, periodic CBC with differential; monitor growth in pediatric patients

CANADIAN BRAND NAMES — Apo-Acetazolamide®; Diamox®

INTERNATIONAL BRAND NAMES — Acetadiazol (MX); Acetak (PE); Albox (JP); Apo-Acetazolamide (MY); Azol (TW); Carbinib (PT); Cetamid (PH); Diamox (AE, AR, AT, AU, BD, BE, BG, BH, BR, CH, CL, CO, CY, CZ, DE, DK, EG, ES, FI, FR, GB, GR, HK, HN, HR, ID, IE, IL, IN, IQ, IR, IT, JO, JP, KP, KW, LB, LU, LY, MY, NL, NO, OM, PH, PK, PT, QA, RU, SA, SE, SG, SY, TH, TR, TW, VE, YE, ZA); Diamox Sustets (CO); Diluran (CZ); Diural (UY); Diuramid (PL); Evamox (PK); Fonurit (HU); Glaupax (CH, DE, HR, JP, TH); Huma-Zolamide (HN, HU); Ledamox (JP); Lediamox (PT); Medene (TH); Optamide (PH); Renamid (HR); Stazol (PY); Synomax (IN); Uramox (IL); Zolmide (PH)

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)

PATIENT INFORMATION — Report numbness or tingling of extremities. Do not crush, chew, or swallow contents of long-acting capsule; may be opened and sprinkled on soft food. Ability to perform tasks requiring mental alertness and/or physical coordination may be impaired. Take with food; drug may cause substantial increase in blood glucose in some patients with diabetes.