Acetazolamide

Uses and Indications

This drug is indicated for the adjunctive treatment of the following conditions:

• Edema:

  • Edema due to congestive heart failure

  • Drug-induced edema

• Epilepsy:

  • Centrencephalic epilepsies (petit mal, unlocalized seizures)

• Glaucoma:

  • Chronic simple (open-angle) glaucoma

  • Secondary glaucoma

  • Preoperatively in acute angle-closure glaucoma where delay of surgery is desired in order to lower intraocular pressure

Additionally, this drug is indicated for the prevention or amelioration of symptoms associated with acute mountain sickness in climbers attempting rapid ascent and in those who are very susceptible to acute mountain sickness despite gradual ascent.

Limitations of Use

No teratogenic or nonteratogenic effects have been mentioned.

Dosage and Administration

Acetazolamide is available in tablet and capsule forms, including extended-release formulations. The following dosage recommendations are provided for various indications:

Glaucoma: The dosage for glaucoma ranges from 250 mg to 1 g of acetazolamide per 24 hours, typically administered in divided doses for amounts exceeding 250 mg. The preferred dosage for secondary glaucoma and preoperative treatment of acute congestive glaucoma is 250 mg every four hours. In acute cases, an initial dose of 500 mg may be given, followed by 125 mg or 250 mg every four hours as needed. Continuous supervision by a physician is advisable, and intravenous therapy may be utilized for rapid relief of ocular tension in acute situations.

Epilepsy: For epilepsy, the suggested total daily dose is 8 to 30 mg per kg, divided into multiple doses, with an optimum range of 375 to 1,000 mg daily. When administered alongside other anticonvulsants, the starting dose should be 250 mg once daily, which can be adjusted based on clinical response.

Congestive Heart Failure: The starting dose for congestive heart failure is typically 250 to 375 mg once daily in the morning (approximately 5 mg/kg). For optimal diuretic effect, it is recommended to administer the medication on alternate days or for two days, alternating with a day of rest. If the patient does not continue to lose edema fluid after an initial response, it is advisable to skip medication for a day rather than increasing the dose.

Drug-Induced Edema: The recommended dosage for drug-induced edema is 250 to 375 mg of acetazolamide once daily for one or two days, alternating with a day of rest.

Acute Mountain Sickness: For acute mountain sickness, the dosage is 500 mg to 1,000 mg daily, administered in divided doses using tablets or extended-release capsules. A higher dose of 1,000 mg is recommended in situations of rapid ascent, such as during rescue or military operations. It is preferable to initiate dosing 24 to 48 hours before ascent and to continue for 48 hours while at high altitude, or longer as necessary to manage symptoms.

In cases where adequate control is not achieved with the standard dosing regimen, alternative administration methods may be employed, including the use of acetazolamide tablets or parenteral formulations, with dosing schedules such as 250 mg every four hours or an initial dose of 500 mg followed by 250 mg or 125 mg every four hours, depending on the clinical scenario.

Contraindications

Acetazolamide is contraindicated in patients with hypersensitivity to acetazolamide or any excipients in the formulation, as cross-sensitivity with sulfonamides and other sulfonamide derivatives may occur.

Acetazolamide therapy is also contraindicated in situations where sodium and/or potassium blood serum levels are depressed, in cases of marked kidney and liver disease or dysfunction, in suprarenal gland failure, and in hyperchloremic acidosis. Additionally, it is contraindicated in patients with cirrhosis due to the risk of developing hepatic encephalopathy.

Long-term administration of acetazolamide is contraindicated in patients with chronic non-congestive angle-closure glaucoma, as it may allow for organic closure of the angle while masking the worsening glaucoma through lowered intraocular pressure.

Warnings and Precautions

Fatal Reactions to Sulfonamides 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, as well as anaphylaxis. Sensitizations may recur when a sulfonamide is readministered, irrespective of the route of administration. If signs of hypersensitivity or other serious reactions occur, the use of this drug should be discontinued immediately.

Caution with Concomitant Medications Caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as serious adverse effects such as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported.

General Precautions Increasing the dose does not enhance diuresis and may increase the incidence of drowsiness and/or paresthesia. In fact, increasing the dose often results in a decrease in diuresis. Under certain circumstances, very large doses may be administered in conjunction with other diuretics to achieve diuresis in cases of complete refractory failure. Additionally, choroidal effusion and choroidal detachment have been reported following the use of acetazolamide in the postoperative period after ophthalmic surgery. Discontinue acetazolamide if choroidal effusion and/or choroidal detachment is suspected.

Laboratory Monitoring To monitor for hematologic reactions common to all sulfonamides, it is recommended that a baseline complete blood count (CBC) and platelet count be obtained prior to initiating acetazolamide therapy and at regular intervals during treatment. If significant changes occur, early discontinuation and the institution of appropriate therapy are crucial. Periodic monitoring of serum electrolytes is also recommended.

Side Effects

Adverse Reactions

Acetazolamide is associated with a range of adverse reactions, which can be categorized by seriousness and frequency. The following outlines the reported adverse reactions based on clinical trial and postmarketing data.

Serious Adverse Reactions

• Fatal Reactions: Rare fatalities have occurred due to severe reactions to sulfonamides, including:

  • Stevens-Johnson syndrome

  • Toxic epidermal necrolysis

  • Fulminant hepatic necrosis

  • Agranulocytosis

  • Aplastic anemia

  • Other blood dyscrasias

  • Anaphylaxis

• Hypersensitivity Reactions: Sensitizations may recur upon readministration of sulfonamides, regardless of the route of administration. Discontinue use if signs of hypersensitivity or other serious reactions occur.

Common Adverse Reactions

• Body as a Whole:

  • Headache

  • Malaise

  • Fatigue

  • Fever

  • Pain at injection site

  • Flushing

  • Growth retardation in children

  • Flaccid paralysis

  • Anaphylaxis

• Digestive:

  • Gastrointestinal disturbances (nausea, vomiting, diarrhea)

• Hematological/Lymphatic:

  • Blood dyscrasias (aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, thrombocytopenic purpura, melena)

• Hepato-biliary Disorders:

  • Abnormal liver function

  • Cholestatic jaundice

  • Hepatic insufficiency

  • Fulminant hepatic necrosis

• Metabolic/Nutritional:

  • Metabolic acidosis

  • Electrolyte imbalance (hypokalemia, hyponatremia)

  • Osteomalacia with long-term phenytoin therapy

  • Loss of appetite

  • Taste alteration

  • Hyper/hypoglycemia

• Nervous:

  • Drowsiness

  • Paresthesia (numbness and tingling of extremities and face)

  • Depression

  • Excitement

  • Ataxia

  • Confusion

  • Convulsions

  • Dizziness

• Skin:

  • Allergic skin reactions (urticaria, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis)

• Special Senses:

  • Hearing disturbances

  • Tinnitus

  • Transient myopia (due to forward movement of the ciliary body leading to narrowing of the angle)

• Urogenital:

  • Crystalluria

  • Increased risk of nephrolithiasis with long-term therapy

  • Hematuria

  • Glycosuria

  • Renal failure

  • Polyuria

Additional Notes

• Caution with Concomitant Medications: Caution is advised for patients receiving high-dose aspirin and acetazolamide, as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported.

• Monitoring Recommendations: Periodic monitoring of serum electrolytes is recommended due to the potential for electrolyte imbalances and metabolic acidosis, particularly in patients with impaired renal function, diabetes mellitus, or other conditions predisposing to such imbalances.

• Driving and Machinery Operation: Some adverse reactions, such as drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery.

This summary of adverse reactions is based on data from multiple sources and reflects the potential risks associated with acetazolamide therapy.

Drug Interactions

Acetazolamide has several notable drug interactions that can affect its efficacy and safety profile.

Pharmacokinetic Interactions

• Phenytoin: Acetazolamide modifies the metabolism of phenytoin, leading to increased serum levels. This may enhance the risk of osteomalacia in patients undergoing chronic phenytoin therapy. Caution is advised for patients receiving chronic concomitant therapy.

• Primidone: Acetazolamide decreases the gastrointestinal absorption of primidone, which may result in lower serum concentrations of primidone and its metabolites, potentially diminishing its anticonvulsant effect. Caution is recommended when initiating, discontinuing, or adjusting the dose of acetazolamide in patients on primidone.

• Lithium: Acetazolamide increases the excretion of lithium, which may lead to decreased lithium levels in the body.

• Cyclosporine: Acetazolamide may elevate serum levels of cyclosporine, necessitating monitoring of cyclosporine levels during concurrent use.

Pharmacodynamic Interactions

• Folic Acid Antagonists: Acetazolamide may enhance the effects of other folic acid antagonists, which could lead to increased toxicity or adverse effects.

• Antidiabetic Agents: Acetazolamide may cause fluctuations in blood glucose levels, either increasing or decreasing them. This variability should be considered in patients receiving antidiabetic medications.

• Amphetamines: Acetazolamide decreases the urinary excretion of amphetamines, potentially enhancing their effects and prolonging their duration of action.

• Quinidine: The drug reduces the urinary excretion of quinidine, which may enhance its pharmacological effects.

• Methenamine: Acetazolamide may inhibit the urinary antiseptic effect of methenamine.

Concomitant Use Considerations

• Carbonic Anhydrase Inhibitors: Due to possible additive effects, the concurrent use of acetazolamide with other carbonic anhydrase inhibitors is not advisable.

• Sodium Bicarbonate: The combination of acetazolamide and sodium bicarbonate increases the risk of renal calculus formation.

Drug & Laboratory Test Interactions

• Sulfonamides: These may yield false negative or decreased values for urinary phenolsulfonphthalein and phenol red elimination values for urinary protein, serum non-protein, and serum uric acid.

• Crystals in Urine: Acetazolamide may lead to an increased level of crystals in the urine.

• Theophylline Assays: Acetazolamide interferes with the HPLC method of assay for theophylline, with the degree of interference depending on the solvent used in the extraction. Other assay methods for theophylline may not be affected.

Monitoring Recommendations

• For patients receiving high-dose aspirin and acetazolamide, caution is advised due to the risk of severe adverse effects, including anorexia, tachypnea, lethargy, coma, and death.

• It is recommended to obtain a baseline complete blood count (CBC) and platelet count prior to initiating acetazolamide therapy, with regular monitoring during treatment to detect hematologic reactions common to sulfonamides.

• Periodic monitoring of serum electrolytes is also advised to ensure patient safety.

Pediatric Use

The safety and effectiveness of acetazolamide in pediatric patients have not been established. This includes both the standard tablet and extended-release capsule formulations.

Growth Retardation: Long-term therapy with acetazolamide has been associated with growth retardation in children, which is believed to be secondary to chronic acidosis.

Dosing Information: For pediatric patients with epilepsy, the suggested total daily dose is 8 to 30 mg per kg, divided into multiple doses, with an optimum range appearing to be from 375 to 1000 mg daily. When acetazolamide tablets are used in combination with other anticonvulsants, a recommended starting dose is 250 mg once daily in addition to existing medications.

Caution is advised when considering the use of acetazolamide in children, particularly regarding the potential for growth-related side effects.

Geriatric Use

Elderly patients may experience severe metabolic acidosis, particularly those with reduced renal function. Clinical studies of acetazolamide have not included sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients; however, available clinical experience has not identified significant differences in responses between these groups.

In general, dose selection for elderly patients should be approached with caution, typically starting at the low end of the dosing range. This cautious approach is necessary due to the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

Elderly patients may also exhibit heightened sensitivity to side effects, including drowsiness and confusion. Regular monitoring of serum electrolytes and renal function is recommended, particularly for those with pre-existing conditions that may affect electrolyte balance. Dosage adjustments should be made with careful individual attention to symptomatology and response, especially in the context of potential interactions with other medications, such as high-dose aspirin, which may exacerbate adverse effects. Continuous supervision by a physician is advisable to ensure safety and efficacy in this population.

Pregnancy

Acetazolamide is classified as a Pregnancy Category C medication. It has been shown to be teratogenic, specifically causing defects of the limbs, in animal studies involving mice, rats, hamsters, and rabbits. There are no adequate and well-controlled studies in pregnant women to assess the safety of acetazolamide during pregnancy.

Given the potential risks to fetal outcomes, acetazolamide should only be used in pregnant patients if the potential benefits justify the potential risks to the fetus. Healthcare providers are advised to carefully consider the necessity of treatment with acetazolamide in this population and to discuss the associated risks with their patients.

Lactation

Acetazolamide is excreted in breast milk, and there is a potential for serious adverse reactions in breastfed infants. Therefore, lactating mothers should carefully consider whether to discontinue breastfeeding or to discontinue the medication, weighing the importance of the drug to the mother against the potential risks to the child.

Acetazolamide should only be used by nursing women if the potential benefits justify the potential risks to the infant. Caution is advised when administering this medication to nursing mothers, as the effects on breastfed infants are not fully known.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available labeling for Acetazolamide, which is provided in both tablet and capsule forms, including extended-release formulations. The labeling does not include any information regarding necessary dosage adjustments, special monitoring, or safety considerations for individuals with reduced kidney function.

As such, healthcare professionals should exercise caution when prescribing Acetazolamide to patients with renal impairment, given the absence of guidance on how to manage dosing or monitoring in this population. It is advisable to consider the overall clinical context and to monitor renal function closely in these patients, as the lack of specific recommendations may necessitate individualized assessment and management strategies.

Hepatic Impairment

Patients with hepatic impairment should be treated with caution when using acetazolamide, as fatalities have occurred, albeit rarely, due to severe reactions to sulfonamides, including fulminant hepatic necrosis.

It is particularly important to monitor patients with liver problems closely, as severe reactions may occur. Special caution is advised for those receiving concomitant high-dose aspirin and acetazolamide, as this combination may increase the risk of adverse effects.

No specific dosage adjustments have been provided for patients with hepatic impairment; however, careful monitoring of liver function and clinical status is recommended to mitigate potential risks.

Overdosage

In cases of acetazolamide overdosage, no specific antidote is known, and treatment should be symptomatic and supportive. Potential symptoms may include electrolyte imbalance, development of an acidotic state, and central nervous system effects. It is essential to monitor serum electrolyte levels, particularly potassium, as well as blood pH levels.

Supportive measures are required to restore electrolyte and pH balance. The acidotic state can typically be corrected through the administration of bicarbonate. Additionally, acetazolamide is dialyzable, which may be particularly important in managing overdosage, especially when complicated by renal failure.

While no data are available regarding acetazolamide overdose in humans, as no cases of acute poisoning have been reported, animal studies suggest that acetazolamide is remarkably nontoxic. Nonetheless, vigilance in monitoring and supportive care remains crucial in the event of an overdose.

Nonclinical Toxicology

Teratogenic Effects

Acetazolamide, administered orally or parenterally, has been shown to be teratogenic, resulting in defects of the limbs in various animal species, including mice, rats, hamsters, and rabbits. There are no adequate and well-controlled studies in pregnant women. Therefore, acetazolamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Carcinogenesis and Mutagenesis

Long-term studies in animals to evaluate the carcinogenic potential of acetazolamide have not been conducted. In a bacterial mutagenicity assay, acetazolamide was not found to be mutagenic when evaluated with and without metabolic activation.

Impairment of Fertility

The drug had no effect on fertility when administered in the diet to male and female rats at a daily intake of up to four times the recommended human dose of 1,000 mg in a 50 kg individual.

Animal Pharmacology and Toxicology

No specific details regarding animal pharmacology and toxicology beyond the mutagenicity and fertility effects have been provided. However, it has been noted that acetazolamide may lead to adverse developmental outcomes and metabolic disturbances, including metabolic acidosis and electrolyte imbalances, in animal studies. Additionally, growth retardation has been reported in children receiving long-term therapy, believed to be secondary to chronic acidosis.

Storage and Handling

Acetazolamide is supplied in the following forms:

• Tablets: Available in bottles of 100 tablets with a child-resistant closure.

• Capsules: Available in extended-release formulations.

The storage conditions for Acetazolamide are as follows:

• Store at 20° to 25°C (68° to 77°F); excursions are permitted between 15° to 30°C (59° to 86°F) See USP Controlled Room Temperature.

• Keep the container tightly closed and dispense in a tight, light-resistant container as defined in the USP, using a child-resistant closure where applicable.

• It is essential to keep this and all medications out of the reach of children.