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: maize starch, gelatin, glycerin, lactose monohydrate, magnesium stearate, 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 treatment 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, tailored to the individual patient's needs.

In the management of epilepsy, the suggested total daily dose is between 8 to 30 mg per kg, divided into multiple doses, with an optimal range of 375 to 1000 mg daily. When acetazolamide is used in conjunction with other anticonvulsants, the starting dose is typically 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. The most effective diuretic results are observed 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 ranges from 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 these conditions may impair drug metabolism and excretion. Additionally, the use of acetazolamide is contraindicated in cases of suprarenal gland failure and hyperchloremic acidosis, which may lead to further metabolic disturbances.

Patients with cirrhosis should not use acetazolamide due to the potential risk of developing hepatic encephalopathy. Furthermore, 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 of glaucoma symptoms through lowered intraocular pressure.

Warnings and Precautions

Fatalities, although rare, have been reported due to severe reactions associated with sulfonamides, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is crucial to recognize that sensitization may recur upon re-administration of a sulfonamide, regardless of the route of administration. In the event of hypersensitivity signs or other serious reactions, the use of this drug must be discontinued immediately.

Caution is warranted for patients who are concurrently receiving high-dose aspirin and acetazolamide. Reports have indicated that such combinations may lead to severe adverse effects, including anorexia, tachypnea, lethargy, coma, and even death.

In terms of general precautions, it is important to note that increasing the dosage of acetazolamide does not enhance diuresis and may, in fact, lead to an increased incidence of drowsiness and/or paresthesia. In some cases, higher doses may result in decreased diuresis. However, under specific circumstances, very large doses may be administered alongside other diuretics to achieve diuresis in cases of complete refractory failure.

To ensure patient safety, it is recommended that a baseline complete blood count (CBC) and platelet count be obtained prior to initiating acetazolamide tablet therapy. Regular monitoring of these parameters should continue throughout the treatment course to detect any hematologic reactions common to sulfonamides. Should significant changes in laboratory values occur, early discontinuation of the drug and initiation of appropriate therapy are essential. Additionally, periodic monitoring of serum electrolytes is advised to maintain patient safety during treatment.

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.

Metabolic effects associated with the medication include metabolic acidosis and electrolyte imbalance. Other occasional adverse reactions may occur, such as transient myopia, which typically resolves upon reduction or discontinuation of the medication. Other reported reactions include urticaria, melena, hematuria, glycosuria, hepatic insufficiency, flaccid paralysis, photosensitivity, and convulsions.

Serious adverse reactions, although rare, can be life-threatening. Fatalities have been reported due to severe reactions to sulfonamides, including 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 readministration of a sulfonamide, regardless of the route of administration. If any signs of hypersensitivity or other serious reactions occur, the use of this drug should be discontinued immediately.

Caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as there have been reports of anorexia, tachypnea, lethargy, coma, and death in such cases.

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 the treatment course 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. There are currently no specific age ranges or dosage recommendations provided for children, infants, or adolescents. Healthcare professionals should exercise caution when considering the use of acetazolamide in this population due to the lack of clinical data supporting its use.

Geriatric Use

Elderly patients may exhibit increased sensitivity to side effects and a potential for reduced kidney function, necessitating caution when prescribing this medication. Although no specific dosage adjustments are recommended for geriatric patients, healthcare providers should remain vigilant regarding the unique physiological changes that may affect this population.

Regular monitoring of serum electrolytes is advised, particularly in elderly patients who may have pre-existing conditions that influence electrolyte balance. This monitoring is crucial, as the risk of adverse reactions, including metabolic acidosis and electrolyte imbalances, may be heightened in this demographic.

It is important to note that the overall safety and effectiveness of acetazolamide in geriatric patients have not been specifically established. Therefore, healthcare providers should carefully consider the individual health status and potential risks when treating elderly patients with this medication.

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 pregnant patients only if the potential benefits outweigh the risks to the fetus. Healthcare professionals are advised to carefully consider the implications of treatment with acetazolamide in women of childbearing potential and to discuss the potential risks with their patients.

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 of these patients.

Hepatic Impairment

Patients with hepatic impairment may experience an increased risk of severe reactions to sulfonamides, including fulminant hepatic necrosis, which can lead to fatalities, albeit rarely. It is essential to monitor liver function closely in these patients. Due to the potential for serious adverse effects, caution is advised when prescribing this medication to individuals with compromised liver function. Dosage adjustments may be necessary based on the severity of hepatic impairment, and ongoing assessment of liver enzymes and overall liver function is recommended throughout the treatment course.

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 removal of the drug from the system.

In summary, while acetazolamide overdosage is not commonly reported and is considered nontoxic, appropriate monitoring and supportive treatment are essential to manage any potential complications effectively.

Nonclinical Toxicology

Long-term studies in animals to evaluate the carcinogenic potential of acetazolamide have not been conducted. In a bacterial mutagenicity assay, acetazolamide was found to be non-mutagenic when assessed both with and without metabolic activation. Additionally, the drug did not adversely 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 based on a 50 kg individual.

Postmarketing Experience

Fatalities have been reported, albeit rarely, in association 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. Sensitization 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 recommended.

Adverse reactions commonly associated with all sulfonamide derivatives may 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. Precautionary measures are advised for the early detection of such reactions, and the drug should be discontinued with appropriate therapy initiated as necessary.

Other occasional adverse reactions reported include urticaria, melena, hematuria, glycosuria, hepatic insufficiency, flaccid paralysis, photosensitivity, and convulsions.

Patient Counseling

Healthcare providers should advise patients that the use of acetazolamide may lead to adverse reactions common to all sulfonamide derivatives. These reactions include, but are not limited to, 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 that the drug should be discontinued immediately if any significant adverse effects occur, with appropriate therapy instituted.

For patients with pulmonary obstruction or emphysema, healthcare providers should exercise caution when prescribing acetazolamide, as it may precipitate or exacerbate acidosis. It is recommended that patients be counseled on the importance of gradual ascent to avoid acute mountain sickness. If rapid ascent is necessary and acetazolamide is used, patients should be made aware that this does not eliminate the need for prompt 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 advisable to obtain a baseline complete blood count (CBC) and platelet count prior to initiating therapy with acetazolamide, as well as at regular intervals during treatment. Patients should be informed that if significant changes in blood counts occur, early discontinuation of the drug and appropriate therapy are crucial. Additionally, periodic monitoring of serum electrolytes is recommended.

Patients should be made aware that acetazolamide has been shown to be teratogenic in animal studies, leading to limb defects. Due to the lack of adequate and well-controlled studies in pregnant women, acetazolamide should only be used during pregnancy if the potential benefits outweigh the risks to the fetus. Furthermore, healthcare providers should discuss the potential for serious adverse reactions in nursing infants and help patients make an informed decision about whether to discontinue nursing or the medication, considering the importance of the drug to the mother.

Finally, it is important to inform patients that the safety and effectiveness of acetazolamide in pediatric patients have not been established, and caution should be exercised when considering its use in this population.

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 in blood counts, early discontinuation of the medication and appropriate therapeutic interventions 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 Advagen Pharma Ltd. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)