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 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 administered, 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 is between 8 to 30 mg per kg, divided into multiple doses. The optimum dosage range appears to be from 375 mg to 1000 mg daily. When acetazolamide is used in conjunction with other anticonvulsants, a starting dose of 250 mg once daily is recommended.

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. For optimal diuretic effects, it is advisable to administer the medication 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 between 500 mg to 1000 mg daily, divided into multiple doses. A higher dosage of 1000 mg is recommended for individuals ascending rapidly. 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

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 doses of 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 duration of therapy. Should significant changes in hematologic status be observed, it is imperative to discontinue the medication promptly and initiate appropriate therapeutic measures. Additionally, periodic monitoring of serum electrolytes is advised to further safeguard against potential complications.

Side Effects

Patients may experience a range of adverse reactions associated with the use of this medication, which can be categorized by seriousness and frequency.

Serious adverse reactions include anaphylaxis, which has been reported in rare cases, as well as severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Other serious hematological conditions, including agranulocytosis, aplastic anemia, and various blood dyscrasias, have also been observed. Fatalities have occurred due to these severe reactions, and sensitization may recur upon re-administration of the drug, regardless of the route. If any signs of hypersensitivity or other serious reactions occur, discontinuation of the drug is advised.

Common adverse reactions reported in clinical trials and postmarketing experiences include headache, malaise, fatigue, and fever. Patients may also experience pain at the injection site, flushing, and gastrointestinal disturbances such as nausea, vomiting, and diarrhea. Neurological effects such as drowsiness, dizziness, confusion, and paraesthesia (including numbness and tingling) have been noted, along with mood changes like depression and excitement.

Metabolic and nutritional adverse reactions may manifest as metabolic acidosis, electrolyte imbalances (including hypokalemia and hyponatremia), loss of appetite, and alterations in taste. Patients undergoing long-term therapy with phenytoin may experience osteomalacia.

Hepato-biliary disorders, including abnormal liver function, cholestatic jaundice, hepatic insufficiency, and fulminant hepatic necrosis, have been reported. Additionally, patients may experience urogenital issues such as crystalluria, hematuria, glycosuria, and an increased risk of nephrolithiasis with long-term therapy, potentially leading to renal failure and polyuria.

Skin reactions can include allergic responses such as urticaria and photosensitivity, as well as more severe conditions like erythema multiforme. Disturbances in special senses, including hearing disturbances and transient myopia, have also been documented.

Caution is particularly advised for patients receiving concomitant high-dose aspirin and acetazolamide, as serious reactions such as metabolic acidosis and lethargy have been reported. Furthermore, both increases and decreases in blood glucose levels have been observed in patients treated with acetazolamide, necessitating careful monitoring in those with impaired glucose tolerance or diabetes mellitus. Periodic monitoring of serum electrolytes is recommended due to the potential for electrolyte imbalances and metabolic acidosis, especially in patients with conditions that predispose them to such imbalances.

Some adverse reactions, including drowsiness, fatigue, and myopia, may impair the ability to drive or operate machinery, and patients should be advised accordingly.

Drug Interactions

Acetazolamide has several notable drug interactions that warrant careful consideration in clinical practice.

Pharmacokinetic Interactions:

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

• 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.

• Acetazolamide decreases the urinary excretion of amphetamine, which may enhance both the magnitude and duration of its effects.

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

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

• Concurrent use of acetazolamide and sodium bicarbonate may increase the risk of renal calculus formation, and caution should be exercised in patients taking both agents.

• Acetazolamide increases lithium excretion, which may lead to decreased lithium levels. Monitoring of lithium levels is advisable in patients receiving both medications.

Pharmacodynamic Interactions:

• Acetazolamide may enhance the effects of other folic acid antagonists, necessitating careful monitoring of patients receiving these combinations.

• The use of acetazolamide may lead to fluctuations in blood glucose levels, which should be considered in patients who are being treated with antidiabetic agents.

• Acetazolamide may prevent the urinary antiseptic effect of methenamine, which should be taken into account when prescribing these medications together.

Due to the potential for significant interactions, it is essential for healthcare providers to monitor patients closely and consider dosage adjustments as necessary when acetazolamide is used in conjunction with these medications.

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 their responses differ from those of younger patients. 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 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 breastfed infant.

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 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 this patient population.

While specific dosage adjustments are not provided, healthcare professionals are advised to evaluate the risks versus benefits of treatment in patients with compromised liver function. Regular assessment of liver enzymes and overall liver health is recommended to ensure patient safety and to mitigate the risk of adverse reactions.

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 for restoring 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 re-administration 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 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.

In patients treated with acetazolamide, both increases and decreases in blood glucose levels have been observed. Acetazolamide may also lead to electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis; therefore, periodic monitoring of serum electrolytes is recommended.

Adverse reactions to acetazolamide, such as drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery. Additionally, growth retardation has been reported in children undergoing long-term therapy, believed to be secondary to chronic acidosis. Severe metabolic acidosis may occur in elderly patients with reduced renal function.

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 with appropriate therapy initiated as necessary.

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 occurs while using acetazolamide tablets, it is important to note 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.

Caution should also be exercised for patients receiving concomitant high-dose aspirin and acetazolamide, as serious adverse effects including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported.

Healthcare providers should inform patients 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.

Acetazolamide treatment may lead to electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis. Therefore, periodic monitoring of serum electrolytes is recommended, especially for patients with conditions that predispose them to electrolyte and acid/base imbalances, such as impaired renal function (including 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 common to all sulfonamides, healthcare providers should recommend obtaining a baseline complete blood count (CBC) and platelet count prior to initiating acetazolamide therapy, with regular monitoring during treatment. If significant changes are detected, early discontinuation and appropriate therapy should be instituted. Periodic monitoring of serum electrolytes is also advised.

For nursing women, it is important to discuss the potential for serious adverse reactions in nursing infants due to acetazolamide. A decision should be made regarding whether to discontinue nursing or the drug, weighing the importance of the medication 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.

Finally, healthcare providers should inform patients that the safety and effectiveness of acetazolamide in pediatric patients have not been established, and growth retardation has been reported in children receiving long-term therapy, believed to be secondary to chronic acidosis. Additionally, metabolic acidosis, which can be severe, may occur in elderly patients with reduced renal function.

Storage and Handling

The product is supplied in bottles containing 100 tablets, each equipped with a child-resistant closure. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance 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 implementation of appropriate therapeutic measures are crucial. Additionally, periodic assessment of serum electrolytes is recommended to monitor for any potential imbalances.

FDA Insert (PDF)

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

View full prescribing information (PDF)