Acetazolamide

Description

Acetazolamide is an inhibitor of the enzyme carbonic anhydrase, presented as a white to faintly yellowish white crystalline, odorless powder. It is characterized as weakly acidic, very slightly soluble in water, and slightly soluble in alcohol. The chemical name for acetazolamide is N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)-acetamide, with a molecular weight of 222.25 and a molecular formula of C₄H₆N₄O₃S₂.

Acetazolamide is available in oral tablet form, with dosages of 125 mg and 250 mg of acetazolamide per tablet. The tablets contain the following inactive ingredients: corn starch, gelatin, glycerin, lactose monohydrate, magnesium stearate, purified water, sodium starch glycolate, and talc.

Uses and Indications

This drug is indicated for the adjunctive treatment of various conditions, including edema due to congestive heart failure, drug-induced edema, and centrencephalic epilepsies, specifically petit mal and unlocalized seizures. It is also indicated for the management of chronic simple (open-angle) glaucoma and secondary glaucoma. Additionally, this drug may be used preoperatively in cases of acute angle-closure glaucoma when a delay in surgery is desired to lower intraocular pressure.

Furthermore, this drug is indicated for the prevention or amelioration of symptoms associated with acute mountain sickness in climbers who are attempting rapid ascent, as well as in individuals who are particularly susceptible to acute mountain sickness, even with gradual ascent.

No teratogenic or nonteratogenic effects have been reported.

Dosage and Administration

For the management of glaucoma, the recommended dosage of acetazolamide ranges from 250 mg to 1 g 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 administered, followed by subsequent doses of 125 mg or 250 mg every four hours.

In the treatment of epilepsy, the suggested total daily dose is between 8 to 30 mg per kg, divided into multiple doses, with an optimum range of 375 to 1000 mg daily. When acetazolamide is prescribed alongside other anticonvulsants, the starting dose is 250 mg once daily.

For patients with congestive heart failure, the starting dose is generally 250 to 375 mg once daily in the morning, which corresponds to approximately 5 mg/kg. Optimal diuretic effects are achieved when the medication is administered on alternate days or for two consecutive days, followed by a day of rest.

In cases of drug-induced edema, the recommended dosage is 250 to 375 mg of acetazolamide once daily for one or two days, alternating with a day of rest.

For the prevention and treatment of acute mountain sickness, the dosage is typically 500 mg to 1000 mg daily, divided into multiple doses. A higher dose of 1000 mg is advised in situations involving rapid ascent. It is preferable to initiate dosing 24 to 48 hours prior to ascent and to continue for 48 hours while at high altitude, or longer as necessary to manage symptoms effectively.

Contraindications

Acetazolamide therapy is contraindicated in patients with depressed sodium and/or potassium blood serum levels due to the risk of exacerbating electrolyte imbalances. It is also contraindicated in individuals with marked kidney and liver disease or dysfunction, as well as in cases of suprarenal gland failure, which may impair drug metabolism and excretion.

Additionally, the use of acetazolamide is contraindicated in patients with hyperchloremic acidosis, as it may worsen acid-base imbalances. In patients with cirrhosis, the risk of developing hepatic encephalopathy necessitates avoidance of this medication. Long-term administration is also contraindicated in patients with chronic non-congestive angle-closure glaucoma, as it may mask the worsening of glaucoma while allowing for organic closure of the angle.

Warnings and Precautions

Fatalities have been reported, albeit infrequently, due to severe adverse reactions associated with sulfonamides. These reactions include, but are not limited to, Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and various other blood dyscrasias. It is crucial to note that sensitization may recur upon re-administration of a sulfonamide, regardless of the route of administration. Should any signs of hypersensitivity or other serious reactions manifest, the use of this drug must be discontinued immediately.

Caution is particularly warranted for patients who are concurrently receiving high doses of aspirin alongside acetazolamide. Reports have indicated that such combinations may lead to severe outcomes, including anorexia, tachypnea, lethargy, coma, and even death.

To ensure patient safety and monitor for hematologic reactions that are common to all sulfonamides, it is recommended that a baseline complete blood count (CBC) and platelet count be obtained prior to the initiation of acetazolamide tablet therapy. Regular monitoring of these parameters should continue throughout the course of treatment. In the event of significant changes in hematologic status, prompt discontinuation of the drug and initiation of appropriate therapeutic measures are essential. Additionally, periodic monitoring of serum electrolytes is advised to further safeguard patient health during therapy.

Side Effects

Patients may experience a range of adverse reactions while using this medication. Common adverse reactions include paresthesias, particularly a tingling sensation in the extremities, hearing dysfunction or tinnitus, loss of appetite, taste alteration, and gastrointestinal disturbances such as nausea, vomiting, and diarrhea. Additionally, polyuria, occasional drowsiness, and confusion have been reported.

Other adverse reactions, though less common, may include metabolic acidosis, electrolyte imbalance, transient myopia—which typically resolves upon reduction or discontinuation of the medication—urticaria, melena, hematuria, glycosuria, hepatic insufficiency, flaccid paralysis, photosensitivity, and convulsions.

Serious adverse reactions have been noted, including fatalities, albeit rarely, due to severe reactions to sulfonamides. These serious reactions encompass Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is important to note that sensitizations may recur upon re-administration of a sulfonamide, regardless of the route of administration. Therefore, if signs of hypersensitivity or other serious reactions occur, discontinuation of the drug is advised.

Caution is particularly warranted for patients receiving concomitant high-dose aspirin and acetazolamide, as reports have indicated the potential for severe outcomes, including anorexia, tachypnea, lethargy, coma, and death.

Drug Interactions

Caution is advised when acetazolamide is administered concurrently with high-dose aspirin. The combination may lead to severe adverse effects, including anorexia, tachypnea, lethargy, coma, and potentially fatal outcomes.

For patients receiving acetazolamide, it is recommended to obtain a baseline complete blood count (CBC) and platelet count prior to the initiation of therapy. Regular monitoring of these parameters should continue throughout treatment to identify any hematologic reactions associated with sulfonamides. In the event of significant changes in blood counts, early discontinuation of acetazolamide and the implementation of appropriate therapeutic measures are essential.

Additionally, periodic monitoring of serum electrolytes is advised to ensure patient safety and to manage any potential imbalances that may arise during treatment with acetazolamide.

Packaging & NDC

The table below lists all NDC Code configurations of Acetazolamide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of acetazolamide in pediatric patients have not been established. Therefore, caution is advised when considering its use in this population. Further studies are needed to determine appropriate dosing and outcomes in children and adolescents.

Geriatric Use

Caution is advised when administering acetazolamide to elderly patients, particularly those receiving concomitant high-dose aspirin, as serious adverse effects such as anorexia, tachypnea, lethargy, coma, and death have been reported.

In geriatric patients, increasing the dosage of acetazolamide does not enhance diuresis and may lead to an increased incidence of drowsiness and/or paresthesia. In fact, higher doses often result in a decrease in diuresis, necessitating careful consideration of dosage adjustments.

Elderly patients with pulmonary obstruction or emphysema, conditions that may impair alveolar ventilation, should use acetazolamide with caution due to the potential for precipitating or aggravating acidosis.

It is recommended that a baseline complete blood count (CBC) and platelet count be obtained prior to initiating acetazolamide therapy in geriatric patients, with regular monitoring throughout the treatment course. Should significant changes in these parameters occur, early discontinuation of the medication and the initiation of appropriate therapy are crucial. Additionally, periodic monitoring of serum electrolytes is advised to ensure patient safety.

Pregnancy

Acetazolamide, administered orally or parenterally, has demonstrated teratogenic effects in animal studies, specifically resulting in limb defects in mice, rats, hamsters, and rabbits. There are currently no adequate and well-controlled studies available in pregnant women to assess the safety and efficacy of acetazolamide during pregnancy.

Given the potential risks identified in animal studies, acetazolamide should be used in pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. It is classified as Pregnancy Category C, indicating that risk cannot be ruled out. Healthcare professionals are advised to carefully consider the risks and benefits before prescribing acetazolamide to pregnant patients or women of childbearing potential.

Lactation

Because of the potential for serious adverse reactions in nursing infants from acetazolamide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

Hepatic Impairment

Patients with hepatic impairment should be treated with caution due to the potential for severe reactions, including rare but serious outcomes such as fulminant hepatic necrosis associated with sulfonamide use. It is essential to monitor liver function closely in these patients, as compromised liver function may increase the risk of adverse effects.

While specific dosage adjustments are not provided, healthcare professionals are advised to evaluate the individual patient's liver status and consider the potential need for dose modifications or increased monitoring based on the severity of hepatic impairment. Regular assessment of liver function tests is recommended to ensure patient safety and to mitigate the risk of severe hepatic reactions.

Overdosage

In the event of acetazolamide overdosage, it is important to note that there are currently no reported cases of acute poisoning in humans, and available data suggest that acetazolamide is remarkably nontoxic based on animal studies. As such, no specific antidote exists for acetazolamide overdosage. Management should focus on symptomatic and supportive care.

Potential Symptoms and Monitoring Healthcare professionals should be vigilant for potential symptoms associated with overdosage, which may include electrolyte imbalances, the 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 to assess the patient's condition accurately.

Management Procedures Supportive measures are critical in restoring electrolyte and pH balance. The acidotic state that may arise from overdosage can typically be corrected through the administration of bicarbonate. Additionally, despite acetazolamide's high intraerythrocytic distribution and plasma protein binding properties, it may be dialyzable. This characteristic is particularly relevant in cases of overdosage complicated by renal failure, where dialysis may aid in the management of the condition.

In summary, while acetazolamide overdosage is not commonly associated with severe toxicity, appropriate monitoring and supportive care are essential to address any potential complications that may arise.

Nonclinical Toxicology

Acetazolamide has demonstrated teratogenic effects in animal studies, with oral or parenteral administration resulting in limb defects in mice, rats, hamsters, and rabbits. There are no adequate and well-controlled studies available in pregnant women. Therefore, acetazolamide should be used during pregnancy only if the potential benefits outweigh the potential risks to the fetus.

In terms of non-teratogenic effects, acetazolamide did not affect 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 1000 mg for a 50 kg individual.

Long-term studies to assess the carcinogenic potential of acetazolamide have not been conducted in animals. However, in a bacterial mutagenicity assay, acetazolamide was found to be non-mutagenic, both with and without metabolic activation.

No additional specific details regarding animal pharmacology and toxicology are provided beyond the information already mentioned in the non-teratogenic effects and nonclinical toxicology sections.

Postmarketing Experience

Fatalities have been reported, albeit infrequently, associated with severe reactions to sulfonamides, including but not limited to Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is noted that sensitizations may recur upon re-administration of a sulfonamide, regardless of the route of administration. In cases where signs of hypersensitivity or other serious reactions manifest, discontinuation of the drug is advised.

Common adverse reactions associated with sulfonamide derivatives include anaphylaxis, fever, rash (which may encompass erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), crystalluria, renal calculus, bone marrow depression, thrombocytopenic purpura, hemolytic anemia, leukopenia, pancytopenia, and agranulocytosis. Early detection of such reactions is crucial, and the drug should be discontinued with appropriate therapy initiated as necessary.

Occasional adverse reactions that have been reported include urticaria, melena, hematuria, glycosuria, hepatic insufficiency, flaccid paralysis, photosensitivity, and convulsions. For further information regarding possible reactions common to sulfonamide derivatives, please refer to the PRECAUTIONS: Information for Patients section.

Patient Counseling

Healthcare providers should advise patients that the use of acetazolamide may lead to adverse reactions common to all sulfonamide derivatives. These reactions can include anaphylaxis, fever, rash (such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), crystalluria, renal calculus, bone marrow depression, thrombocytopenic purpura, hemolytic anemia, leukopenia, pancytopenia, and agranulocytosis. Patients should be informed of the importance of early detection of these reactions, and they should be instructed to discontinue the medication and seek appropriate therapy if any of these symptoms occur.

For patients with pulmonary obstruction or emphysema, healthcare providers should emphasize the need for caution when using acetazolamide, as it may precipitate or worsen acidosis in individuals with impaired alveolar ventilation.

Patients should be counseled on the importance of gradual ascent to avoid acute mountain sickness. If rapid ascent is necessary and acetazolamide is used, it should be clearly communicated that this does not eliminate the need for immediate descent in the event of severe high altitude sickness, such as high altitude pulmonary edema (HAPE) or high altitude cerebral edema.

Healthcare providers should also caution patients receiving high-dose aspirin concurrently with acetazolamide, as this combination has been associated with serious adverse effects, including anorexia, tachypnea, lethargy, coma, and even death.

To monitor for hematologic reactions associated with sulfonamides, it is recommended that a baseline complete blood count (CBC) and platelet count be obtained prior to initiating acetazolamide therapy, with regular monitoring throughout treatment. Patients should be informed that significant changes in these parameters may necessitate early discontinuation of the drug and the initiation of appropriate therapy. Additionally, periodic monitoring of serum electrolytes is advised.

Finally, healthcare providers should discuss the potential for serious adverse reactions in nursing infants due to acetazolamide. A careful decision should be made regarding whether to discontinue nursing or to stop the medication, taking into account the importance of the drug for the mother’s health.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in compliance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

To ensure patient safety during acetazolamide tablet therapy, clinicians are advised to obtain a baseline complete blood count (CBC) and platelet count prior to treatment initiation. Regular monitoring of these parameters should continue throughout the therapy to detect any hematologic reactions commonly associated with sulfonamides. In the event of significant changes, early discontinuation of the medication and implementation of appropriate therapeutic measures are crucial. Additionally, periodic monitoring of serum electrolytes is recommended to manage potential imbalances.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Acetazolamide as submitted by Sun Pharmaceutical Industries, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)