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, containing 125 mg and 250 mg of acetazolamide, respectively. The tablets include the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, povidone, and sodium starch glycolate.

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; however, some patients may respond adequately to 250 mg twice daily for short-term therapy. In acute cases, an initial dose of 500 mg may be given, followed by subsequent doses of 125 mg or 250 mg every four hours as needed.

In the treatment of epilepsy, the suggested total daily dose of acetazolamide is between 8 to 30 mg per kg, divided into multiple doses, with an optimum range of 375 to 1000 mg daily. When administered alongside other anticonvulsants, the starting dose should be 250 mg once daily, with adjustments made based on clinical response.

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 500 mg to 1000 mg daily, administered in divided doses using either tablets or sustained-release capsules. A higher dose of 1000 mg is advised in situations involving rapid ascent, ideally initiated 24 to 48 hours prior to ascent and continued for 48 hours at high altitude or longer as clinically necessary.

Contraindications

Use of acetazolamide is contraindicated in the following situations:

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

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

Long-term administration of acetazolamide is contraindicated in patients with chronic noncongestive 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

Fatalities, although rare, have been reported due to severe reactions associated with sulfonamides, including but not limited to Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias, as well as anaphylaxis. 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 any signs of hypersensitivity or other serious adverse reactions, the use of this drug must be discontinued immediately.

Caution is particularly warranted for patients who are concurrently receiving high-dose aspirin along with acetazolamide. Reports have indicated that such combinations may lead to severe adverse effects, including anorexia, tachypnea, lethargy, metabolic acidosis, 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. Should significant changes in hematologic status be observed, it is imperative to discontinue the drug promptly and initiate appropriate therapeutic measures. Additionally, periodic monitoring of serum electrolytes is advised to further safeguard patient health during therapy.

Side Effects

Adverse reactions associated with the use of this medication can be categorized by seriousness and frequency.

Serious adverse reactions include anaphylaxis, which may occur in susceptible patients, and fatalities have been reported, albeit rarely, due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia. Patients may experience hypersensitivity reactions upon readministration of sulfonamides, regardless of the route of administration. It is crucial to discontinue the drug immediately if any signs of hypersensitivity or other serious reactions arise.

Common adverse reactions encompass a range of symptoms affecting various body systems. Patients may report headaches, malaise, fatigue, fever, and pain at the injection site. Gastrointestinal disturbances, including nausea, vomiting, and diarrhea, are also frequently observed. Hematological and lymphatic issues may manifest as blood dyscrasias, including aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and thrombocytopenic purpura.

Hepato-biliary disorders may present as abnormal liver function, cholestatic jaundice, hepatic insufficiency, or even fulminant hepatic necrosis. Metabolic and nutritional adverse reactions can include metabolic acidosis, electrolyte imbalances (such as hypokalemia and hyponatremia), loss of appetite, taste alterations, and hyperglycemia or hypoglycemia.

Neurological effects may involve drowsiness, paraesthesia (numbness and tingling of extremities and face), depression, excitement, ataxia, confusion, convulsions, and dizziness. Skin reactions can range from allergic responses, such as urticaria and photosensitivity, to severe conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis.

Patients may also experience disturbances in special senses, including hearing disturbances, tinnitus, and transient myopia. Urogenital adverse reactions may include crystalluria, an increased risk of nephrolithiasis with long-term therapy, hematuria, glycosuria, renal failure, and polyuria.

Caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as severe reactions such as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported. Additionally, some adverse reactions, such as drowsiness, fatigue, and myopia, may impair the ability to drive or operate machinery. Metabolic acidosis, which can be severe, may occur particularly in elderly patients with reduced renal function.

Overall, early detection of adverse reactions is essential, and the drug should be discontinued with appropriate therapy instituted as necessary.

Drug Interactions

Acetazolamide has several notable drug interactions that may impact patient management and therapeutic outcomes.

Pharmacokinetic Interactions:

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

• Primidone: The gastrointestinal absorption of primidone is decreased by acetazolamide, which may result in lower serum concentrations of primidone and its metabolites. This reduction could potentially diminish the anticonvulsant effect. Caution is recommended when initiating, discontinuing, or adjusting the dose of acetazolamide in patients on primidone.

• Amphetamines: Acetazolamide decreases the urinary excretion of amphetamines, which may enhance both the magnitude and duration of their effects.

• Quinidine: The urinary excretion of quinidine is also reduced by acetazolamide, potentially increasing its pharmacological effects.

• Lithium: Acetazolamide increases the excretion of lithium, which may lead to decreased serum lithium levels. Monitoring of lithium levels is advised when these drugs are used together.

• Cyclosporine: Acetazolamide may elevate serum levels of cyclosporine, necessitating careful monitoring of cyclosporine concentrations.

Pharmacodynamic Interactions:

• Folic Acid Antagonists: Acetazolamide may enhance the effects of other folic acid antagonists, which could necessitate dosage adjustments or increased monitoring for adverse effects.

• Antidiabetic Agents: Acetazolamide has the potential to either increase or decrease blood glucose levels. Patients receiving antidiabetic medications should be monitored closely for changes in glycemic control.

• Methenamine: The urinary antiseptic effect of methenamine may be inhibited by acetazolamide, which could reduce its therapeutic efficacy.

Other Considerations:

• Sodium Bicarbonate: Concurrent use of acetazolamide with sodium bicarbonate may increase the risk of renal calculus formation, warranting caution in patients with a history of kidney stones.

• Carbonic Anhydrase Inhibitors: The concomitant use of acetazolamide with other carbonic anhydrase inhibitors is not recommended due to the potential for additive effects.

Healthcare providers should consider these interactions when prescribing acetazolamide and monitor patients accordingly to ensure safe and effective therapy.

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. Caution is advised when considering long-term therapy in children, as growth retardation has been reported, which is believed to be secondary to chronic acidosis.

Geriatric Use

Elderly patients may experience metabolic acidosis, which can be severe, particularly in those with reduced renal function. Clinical studies involving acetazolamide did not include a sufficient number of subjects aged 65 and older to ascertain whether this population responds differently compared to younger individuals. However, other clinical experiences have not indicated any significant differences in responses between elderly and younger patients.

In general, dose selection for geriatric patients should be approached with caution. It is advisable to initiate treatment at the lower end of the dosing range, taking into account the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Regular monitoring of these patients is recommended to ensure safety and efficacy.

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 necessity of treatment with acetazolamide in this population and to discuss the potential risks with 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. Acetazolamide should only be used by lactating mothers if the potential benefit justifies the potential risk to the child.

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 and consider individual patient factors when prescribing to patients with reduced kidney function, as the absence of specific guidance necessitates careful clinical judgment.

Hepatic Impairment

Patients with hepatic impairment should be treated with caution due to the potential for severe reactions, including fulminant hepatic necrosis, which can lead to fatalities, albeit rarely. It is essential to monitor liver function closely in these patients to detect any adverse effects promptly.

No specific dosage adjustments are recommended for patients with compromised liver function; however, clinicians should consider the overall clinical status of the patient and the severity of hepatic impairment when prescribing this medication. Regular assessment of liver function tests is advised to ensure patient safety and to manage any emerging complications effectively.

Overdosage

In cases of overdosage, no specific antidote is available. Management should focus on symptomatic and supportive care to address the patient's needs effectively.

Potential Symptoms and Monitoring Patients may experience electrolyte imbalances, the development of an acidotic state, and central nervous system effects. It is crucial 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 essential to restore electrolyte and pH balance. The acidotic state can typically be corrected through the administration of bicarbonate, which helps to normalize blood pH levels.

Additionally, despite acetazolamide's high intraerythrocytic distribution and significant plasma protein binding properties, it is important to note that acetazolamide is dialyzable. This characteristic may play a critical role in the management of acetazolamide overdosage, especially in patients who present with renal failure.

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 in animals have not been conducted. 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 available beyond the aforementioned mutagenicity and fertility effects.

Postmarketing Experience

Fatalities have been reported, albeit rarely, due to severe reactions associated with sulfonamides, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias, as well as anaphylaxis. Sensitization may recur upon readministration of a sulfonamide, regardless of the route of administration. In cases of hypersensitivity or other serious reactions, discontinuation of the drug is advised.

Common adverse reactions associated with all sulfonamide derivatives 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.

Adverse reactions to acetazolamide have been noted, including drowsiness, fatigue, and myopia, which may impair the ability to drive and operate machinery. Growth retardation has been observed in children undergoing long-term therapy, likely secondary to chronic acidosis.

Severe metabolic acidosis may occur in elderly patients with reduced renal function. Additionally, both increases and decreases in blood glucose levels have been documented in patients treated with acetazolamide, necessitating caution in individuals with impaired glucose tolerance or diabetes mellitus. Acetazolamide treatment may also lead to electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis; therefore, periodic monitoring of serum electrolytes is recommended.

Patient Counseling

Healthcare providers should advise patients that adverse reactions common to all sulfonamide derivatives may occur, including but 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. Early detection of such reactions is crucial, and the drug should be discontinued immediately if any adverse effects are observed, with appropriate therapy instituted.

Patients with pulmonary obstruction or emphysema should be cautioned that acetazolamide may precipitate or aggravate acidosis, and its use should be approached with caution in these populations.

When discussing the prevention of acute mountain sickness, healthcare providers should recommend gradual ascent to avoid complications. If rapid ascent is necessary and acetazolamide tablets are used, it is important to inform patients 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 concomitant high-dose aspirin and acetazolamide, as there have been reports of serious adverse effects, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death.

Patients should be informed that both increases and decreases in blood glucose levels have been observed in those treated with acetazolamide. This is particularly relevant for patients with impaired glucose tolerance or diabetes mellitus, and monitoring of blood glucose levels may be warranted.

Electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis, may occur during acetazolamide treatment. Therefore, periodic monitoring of serum electrolytes is recommended, especially for patients with conditions that predispose them to such imbalances, including those with impaired renal function (particularly elderly patients), diabetes mellitus, and impaired alveolar ventilation.

Patients should be made aware that some adverse reactions to acetazolamide, such as drowsiness, fatigue, and myopia, may impair their ability to drive or operate machinery safely.

To monitor for hematologic reactions associated with sulfonamides, healthcare providers should recommend obtaining a baseline complete blood count (CBC) and platelet count prior to initiating acetazolamide therapy, with regular monitoring throughout treatment. If significant changes are detected, early discontinuation and appropriate therapy are essential.

Finally, healthcare providers should discuss the potential risks of acetazolamide in nursing infants. A decision should be made regarding whether to discontinue nursing or the medication, weighing the importance of the drug to the mother against the potential risk to the child. Acetazolamide should only be used by nursing women if the potential benefits justify the risks.

Storage and Handling

The product is supplied in bottles containing 100 tablets, each equipped with a child-resistant closure. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions must be maintained to ensure 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 initiation 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 Zydus Lifesciences Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)