AHFS Class:

• Carbonic Anhydrase Inhibitors 52:40.12

Generic Name(s):

• acetaZOLAMIDE

• acetaZOLAMIDE Sodium

Acetazolamide is a carbonic anhydrase inhibitor.

Acetazolamide shares the uses of the carbonic anhydrase inhibitors; however, the extended-release capsules are intended for use only for the adjunctive treatment of open-angle (noncongestive, chronic simple) or secondary glaucoma, for short-term preoperative therapy in angle-closure glaucoma (obstructive, narrow-angle) when delay of surgery is desired in order to lower intraocular pressure (IOP), and for prevention or amelioration of symptoms associated with acute high-altitude sickness (mountain sickness). Long-term use of oral carbonic anhydrase inhibitors in the treatment of glaucoma is limited by systemic adverse effects.134,136 (See Uses: Glaucoma, in the Carbonic Anhydrase Inhibitors General Statement 52:40.12.)

Acetazolamide is used as an adjunct to other anticonvulsants in the management of centrencephalic epilepsies (e.g., petit mal, unlocalized seizures). Tolerance to the anticonvulsant effects of acetazolamide develop quickly, and the drug may be ineffective for prolonged therapy. Although acetazolamide may be useful in partial, myoclonic, absence, and primary generalized tonic-clonic seizures that have not responded adequately to other anticonvulsants, acetazolamide has not been evaluated in controlled clinical studies in specific seizure types.

Acetazolamide is used to increase altitude tolerance in the prevention or amelioration of symptoms (e.g., headache, lassitude, insomnia, nausea, shortness of breath, dizziness) associated with acute mountain sickness in climbers attempting rapid ascent and in those who are very susceptible to the condition despite gradual ascent. Use of acetazolamide does not obviate prompt descent in patients who develop severe forms of acute mountain sickness (e.g., high-altitude pulmonary and/or cerebral edema). The drug does not prevent acute mountain sickness, but rather shortens the time of acclimatization. Acetazolamide also is used in the treatment and prevention of high-altitude sleep disorders.

Reconstitution and Administration

Acetazolamide is administered orally. Acetazolamide sodium is preferably administered by direct IV injection; IM administration is painful because of the alkaline pH of the drug solution and therefore is not recommended.

Acetazolamide sodium sterile powder is reconstituted by adding at least 5 mL of sterile water for injection to a vial containing 500 mg of acetazolamide to provide a solution containing not more than 100 mg/mL.

When an oral liquid preparation of acetazolamide is needed, the appropriate number of commercially available tablets may be crushed and suspended in cherry, chocolate, raspberry, or any other highly flavored carbohydrate syrup. (Elixirs or other vehicles containing alcohol or glycerin will not disguise the bitter taste of the drug.) Up to 500 mg of acetazolamide can be suspended in 5 mL of syrup; however, suspensions containing 250 mg of the drug per 5 mL of syrup are more palatable. Suspensions of acetazolamide in syrup are stable for about 1 week. Alternatively, up to one tablet of acetazolamide may be softened in 2 teaspoonsful of hot water and added to 2 teaspoonsful of honey or syrup, then swallowed all at once. This liquid should be prepared just prior to administration. The drug will not dissolve in fruit juices, nor will the taste be disguised.

Dosage

Dosage of acetazolamide should be adjusted according to the patient's requirements and response. Dosage of acetazolamide sodium is expressed in terms of acetazolamide.

Glaucoma

In the adjunctive treatment of open-angle glaucoma in adults, 250 mg of acetazolamide is usually administered orally 1-4 times daily.100 Adult dosage of the extended-release capsules is 500 mg twice daily, usually in the morning and evening.101 Acetazolamide dosage in excess of 1 g daily in adults usually does not produce an increased effect.100,101 Patients whose glaucoma is not adequately controlled by twice-daily administration of the extended-release capsules may respond to therapy with the tablet or parenteral preparations of acetazolamide.101 In adults with secondary glaucoma and preoperatively in adults with acute angle-closure glaucoma, 250 mg of acetazolamide in tablet formulation may be administered orally every 4 hours.100 Some adults have responded to short-term therapy with 250 mg twice daily.100 In some acute glaucomas, an initial oral dose of 500 mg followed by 125-250 mg every 4 hours in adults may be preferable.100

When IV therapy is used in adults with secondary glaucoma and preoperatively in adults with acute angle-closure glaucoma, the recommended dosage of acetazolamide is 250 mg every 4 hours.102 Some adults have responded to short-term therapy with 250 mg twice daily.102 In some acute glaucomas, an initial IV dose of 500 mg followed by 125-250 mg every 4 hours in adults may be preferable.102

In children with glaucoma, the oral dosage of acetazolamide is 8-30 mg/kg or 300-900 mg/m² daily, in 3 divided doses. In acute glaucoma in children, 5-10 mg/kg may be administered IV every 6 hours.

Seizure Disorders

As an adjunct to other anticonvulsants in the prophylactic management of seizure disorders, the usual oral or IV dosage of acetazolamide for adults and children is 8-30 mg/kg daily, in divided doses.100,102 When acetazolamide is given concurrently with other anticonvulsants, the usual initial dosage is 250 mg daily.100,102 The optimum dosage appears to be 375 mg to 1 g daily, although some patients may respond to lower dosage.100,102 Some clinicians suggest that dosage in excess of 1 g daily does not result in increased effectiveness.100,102 In the prophylactic management of seizure disorders, the addition, withdrawal, or replacement of one anticonvulsant drug with another should be accomplished gradually.

Edema

In edema secondary to congestive heart failure or drug therapy, the usual initial adult oral or IV dosage of acetazolamide is 250-375 mg daily (5 mg/kg) in the morning.100,102 Although some patients have received very large doses of acetazolamide in conjunction with other diuretics in order to achieve diuresis, increasing the dose may not increase diuresis and may increase the incidence of adverse effects such as drowsiness or paresthesia. Failures in diuretic therapy with acetazolamide may result from overdoses or too frequent dosage.100,102 If the patient fails to continue to lose edema fluid after an initial response, acetazolamide should be withheld for one day to allow for kidney recovery.100,102 To avoid loss of diuretic effect, the drug should be given intermittently (on alternate days or for 2 consecutive days followed by a drug-free day).100,102

As a diuretic in children, an acetazolamide dosage of 5 mg/kg or 150 mg/m² may be administered orally or IV once daily in the morning.

Acute Mountain Sickness

For the prevention or amelioration of symptoms associated with acute mountain sickness in adult expeditioners or tourist-trekkers, the usual oral dosage of acetazolamide is 0.5-1 g daily in divided doses as appropriate using conventional tablets or extended-release capsules, beginning 24-48 hours before and continued during ascent and for at least 48 hours after arrival at the high altitude; therapy with the drug may be continued at high altitude as necessary to control symptoms.100,102 Some clinicians state that acetazolamide 125-250 mg (as conventional tablets) twice daily beginning 24 hours before ascent has been effective in preventing acute mountain sickness; acetazolamide 500 mg (as extended-release capsules) given once every 24 hours also has been effective.103 For the management of high-altitude sleep disorders, acetazolamide 125 mg at bedtime has been used.103 For the treatment of acute mountain sickness, some experts recommend an acetazolamide dose of 250 mg given within 24 hours of the onset of symptoms and a second 250-mg dose given 8 hours later.103

Other Uses

In the treatment of periodic paralysis†, 250 mg of acetazolamide has usually been administered orally 2 to 3 times daily; however, a few patients have responded to 250-375 mg daily, and a few patients have required up to 1.5 g daily.

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, drug interactions, laboratory test interferences, and dosage and administration of acetazolamide, see the Carbonic Anhydrase Inhibitors General Statement 52:40.12.

Acetazolamide shares the pharmacologic actions and toxic potentials of the carbonic anhydrase inhibitors, and the usual precautions of carbonic anhydrase inhibitor therapy should be observed. (See Cautions in the Carbonic Anhydrase Inhibitors General Statement 52:40.12.) The manufacturers state that long-term use of acetazolamide is contraindicated in patients with chronic noncongestive angle-closure glaucoma since further closure of the angle may occur while worsening of glaucoma is masked by lower intraocular pressure (IOP).100,101,102

Pharmacokinetics

Absorption

Acetazolamide is well absorbed from the GI tract. Following oral administration of 500 mg of acetazolamide as tablets, peak plasma concentrations of about 12-27 mcg/mL are achieved within 1-3 hours. Low concentrations of acetazolamide are present in plasma 24 hours after the drug is given.

Distribution

Acetazolamide is distributed throughout body tissues; it concentrates principally in erythrocytes, plasma, and kidneys and, to a lesser extent, in liver, muscles, eyes, and CNS. Acetazolamide does not accumulate in tissues. The drug crosses the placenta in unknown quantities. It is not known whether acetazolamide distributes into human milk, but the drug has been detected in the milk of lactating dogs.

Elimination

Acetazolamide is excreted unchanged by the kidneys via tubular secretion and passive reabsorption. After administration of the oral tablets or after IV injection, 70-100% (average 90%) of the dose is excreted in urine within 24 hours; 47% of the dose is excreted within 24 hours following administration of the extended-release capsules.

Chemistry and Stability

Chemistry

Acetazolamide is a carbonic anhydrase inhibitor. Acetazolamide occurs as a white to faintly yellowish-white, odorless, crystalline powder. The drug is very slightly soluble in water, sparingly soluble in nearly boiling water, and slightly soluble in alcohol and has pK_as of 7.4 and 9.1. Acetazolamide sodium sterile powder is prepared from acetazolamide with the aid of sodium hydroxide and occurs as a white solid having the characteristic appearance of lyophilization. Acetazolamide sodium is freely soluble in water.

Stability

Acetazolamide tablets should be stored in a tight, light-resistant container at 20-25°C but may be exposed to temperatures ranging from 15-30°C.100 Acetazolamide extended-release capsules should be stored in a tight container at 20-25°C.101

Acetazolamide sodium sterile powder for injection should be stored at 20-25°C.102 After reconstitution with sterile water for injection, the acetazolamide sodium solution is stable for 3 days at 2-8°C or 12 hours at 20-25°C.102 However, because the product contains no preservatives, the manufacturer recommends that the solution be stored at 2-8°C and used within 12 hours after reconstitution.102

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

100. Heritage Pharmaceuticals Inc. Acetazolamide tablets prescribing information. East Brunswick, NJ; 2017 Sep.

101. Zydus Pharmaceuticals Inc. Acetazolamide extended-release capsules prescribing information. Pennington, NJ; 2018 Nov.

102. West-Ward Pharmaceuticals. Acetazolamide injection powder, lyophilized, for solution prescribing information. Eatontown, NJ; 2015 Nov.

103. Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on high-altitude illnesses: an advisory committee statement (ACS). Can Commun Dis Rep . 2007; 33:1-20.

134. Inoue K. Managing adverse effects of glaucoma medications. Clin Ophthalmol . 2014; 8:903-13. [PubMed 24872675]

135. Prum BE Jr, Herndon LW, Moroi SE et al. Primary open angle closure preferred practice pattern^® guideline. San Francisco, CA: American Academy of Ophthalmology; 2015. From the American Academy of Ophthalmology website. [Web]

136. Canadian Ophthalmological Society Glaucoma Clinical Practice Guideline Expert Committee, Canadian Ophthalmological Society. Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of glaucoma in the adult eye. Can J Ophthalmol . 2009; 44 Suppl 1:S7-93. [PubMed 19492005]

137. Jackson J, Carr LW III, Fisch BM et al. Care of the patient with primary angle closure glaucoma. St. Louis, MO: American Optometric Association; Reviewed 2001. From American Optometric Association website. [Web]