Acetazolamide

Description

Acetazolamide extended-release capsules are a carbonic anhydrase inhibitor formulated for oral administration. Each capsule contains 500 mg of acetazolamide, with inactive ingredients including hydroxypropyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, and talc. The capsule shell comprises D&C RED no. 28, D&C YELLOW no. 10, FD&C RED no. 40, gelatin, and titanium dioxide. The imprinting ink contains shellac (24 to 27%), dehydrated alcohol (23 to 26%), isopropyl alcohol (1 to 3%), butyl alcohol (1 to 3%), propylene glycol (3 to 7%), strong ammonia solution (1 to 2%), black iron oxide (24 to 28%), potassium hydroxide (0.05 to 0.1%), and purified water (15 to 18%).

Acetazolamide USP is a white to faintly yellowish-white, crystalline, odorless powder with a molecular weight of 222.24 and a chemical formula of C₄H₆N₄O₃S₂. It is sparingly soluble in practically boiling water, slightly soluble in alcohol, and very slightly soluble in water. The chemical name for acetazolamide is N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl) acetamide.

Uses and Indications

This drug is indicated for the adjunctive treatment of chronic simple (open-angle) glaucoma and secondary glaucoma. It is also indicated for preoperative use in acute angle-closure glaucoma when a delay in surgery is desired to lower intraocular pressure. Additionally, this drug is indicated for the prevention or amelioration of symptoms associated with acute mountain sickness, even with gradual ascent.

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

For the management of glaucoma, the recommended dosage of acetazolamide is 500 mg, administered as one capsule twice daily. The administration schedule consists of one capsule in the morning and one capsule in the evening. While dose adjustments may be necessary based on individual patient response, it is important to note that dosages exceeding 2 capsules (1 g) typically do not yield an increased therapeutic effect. Continuous supervision by a physician is advisable during treatment.

In cases where inadequate control is observed, alternative administration methods may be employed using acetazolamide in tablet or parenteral forms, adhering to more frequent dosing schedules. For example, a dosage of 250 mg may be administered every four hours. An initial dose of 500 mg can be followed by subsequent doses of either 250 mg or 125 mg every four hours, tailored to the specific clinical scenario.

For the prevention and treatment of acute mountain sickness, the recommended dosage ranges from 500 mg to 1000 mg daily, divided into appropriate doses using either tablets or extended-release capsules. In situations requiring rapid ascent, such as rescue or military operations, a higher dose of 1000 mg is recommended. Dosing should ideally commence 24 to 48 hours prior to ascent and continue for 48 hours while at high altitude, or longer as necessary to effectively manage symptoms.

Contraindications

Use of acetazolamide is contraindicated in the following situations:

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 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 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

Fatalities, although rare, have been reported due to severe reactions associated with sulfonamides, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, anaphylaxis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is crucial to recognize that sensitizations may recur upon readministration 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, metabolic acidosis, coma, and even death.

Increasing the dosage of acetazolamide does not enhance diuresis and may, in fact, lead to an increased incidence of drowsiness and/or paresthesia. In many cases, escalating the dose results in a decrease in diuresis. However, in specific situations, 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 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 further safeguard patient health.

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 severe hypersensitivity reactions such as anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which have been associated with fatalities, albeit rarely. Other serious hematological conditions such as agranulocytosis, aplastic anemia, and various blood dyscrasias have also been reported. Additionally, cases of fulminant hepatic necrosis and hepatic insufficiency have been observed. Patients should be monitored closely for signs of these serious reactions, and the medication should be discontinued immediately if such symptoms arise.

Common adverse reactions reported in clinical trials and postmarketing experiences include headache, malaise, fatigue, and fever. Local reactions such as pain at the injection site and flushing have also been noted. Gastrointestinal disturbances, including nausea, vomiting, and diarrhea, are frequently reported.

Patients may also experience neurological effects such as drowsiness, dizziness, confusion, and paresthesia, which includes numbness and tingling of the extremities and face. Psychological effects such as depression and excitement have been documented as well.

Skin reactions can vary from mild allergic responses, such as urticaria and photosensitivity, to more severe conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis.

Metabolic and nutritional adverse reactions include metabolic acidosis, electrolyte imbalances (notably hypokalemia and hyponatremia), and changes in appetite and taste. Long-term therapy with phenytoin has been associated with osteomalacia, while hyperglycemia and hypoglycemia have also been reported.

Urogenital adverse reactions may include crystalluria, hematuria, glycosuria, and an increased risk of nephrolithiasis with long-term therapy. Renal failure and polyuria have also been observed.

Patients receiving concomitant high-dose aspirin and acetazolamide should be monitored closely, as serious reactions such as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death have been reported in these cases.

Overall, while many adverse reactions are manageable, healthcare providers should remain vigilant for serious reactions and provide appropriate interventions as necessary.

Drug Interactions

Acetazolamide is associated with several significant drug interactions that may impact therapeutic outcomes and safety.

Pharmacokinetic Interactions:

• Phenytoin: 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 long-term concomitant therapy with these agents.

• Primidone: The gastrointestinal absorption of primidone is decreased by acetazolamide, potentially resulting in lower serum concentrations of primidone and its metabolites. This may 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 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 advisable.

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

• Sodium Bicarbonate: Concurrent use of acetazolamide and sodium bicarbonate may increase the risk of renal calculus formation.

Pharmacodynamic Interactions:

• Folic Acid Antagonists: Acetazolamide may enhance the effects of other folic acid antagonists, warranting caution in patients receiving these medications.

• Methenamine: Acetazolamide may inhibit the urinary antiseptic effect of methenamine, which could compromise its therapeutic efficacy.

Laboratory Test Interactions:

• Sulfonamides: The use of sulfonamides may yield false negative or decreased values for urinary phenolsulfonphthalein and phenol red elimination values, as well as for urinary protein, serum non-protein, and serum uric acid.

• Crystalluria: Acetazolamide may lead to an increased level of crystals in the urine, which should be monitored.

• Theophylline Assay: Acetazolamide interferes with the high-performance liquid chromatography (HPLC) method for the assay of theophylline. The degree of interference may depend on the solvent used in the extraction process; however, acetazolamide may not affect other assay methods for theophylline.

Healthcare professionals should exercise caution and consider appropriate monitoring when prescribing acetazolamide in conjunction with the aforementioned medications and conditions.

Packaging & NDC

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

Pediatric Use

The safety and effectiveness of acetazolamide extended-release capsules in pediatric patients below the age of 12 years have not been established. Caution is advised when considering long-term therapy in this population, as growth retardation has been reported in children, which is believed to be secondary to chronic acidosis associated with the treatment.

Geriatric Use

Elderly patients may experience metabolic acidosis, which can be severe, particularly in those with reduced renal function. Due to the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies, dose selection for geriatric patients should be approached with caution. It is generally recommended to initiate treatment at the low end of the dosing range to mitigate potential risks and ensure safety. Regular monitoring of renal function and metabolic status is advised to identify any adverse effects promptly and to adjust dosing as necessary.

Pregnancy

Acetazolamide, administered orally or parenterally, has demonstrated teratogenic effects in animal studies, specifically resulting in limb defects in mice, rats, hamsters, and rabbits. Currently, there are no adequate and well-controlled studies available in pregnant women to fully assess the risks associated with its use during pregnancy. Therefore, acetazolamide should be prescribed to pregnant patients only if the potential benefits outweigh the potential 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 risks and benefits 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. 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 when prescribing this medication to individuals 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 associated with sulfonamides, including the rare occurrence of fulminant hepatic necrosis, which can be fatal. It is particularly important to monitor patients with compromised liver function who are receiving concomitant high-dose aspirin and acetazolamide, as these combinations may increase the risk of adverse reactions.

No specific dosage adjustments are provided for patients with hepatic impairment; however, careful monitoring of liver function is recommended to ensure patient safety. Regular assessment of liver enzymes and overall liver health should be conducted to detect any signs of deterioration in liver function promptly.

Overdosage

In cases of overdosage, no specific antidote is available; therefore, treatment should focus on symptomatic and supportive care. Healthcare professionals should be vigilant for potential complications, including electrolyte imbalances, the development of an acidotic state, and central nervous system effects.

Monitoring of serum electrolyte levels, particularly potassium, as well as blood pH levels, is essential in managing overdosage. Supportive measures should be implemented to restore both electrolyte and pH balance. The acidotic state that may arise can typically be corrected through the administration of bicarbonate.

Despite acetazolamide's high intraerythrocytic distribution and significant plasma protein binding properties, it may still be dialyzable. This characteristic is particularly relevant in the management of acetazolamide overdosage, especially when complicated by renal failure. Therefore, healthcare providers should consider dialysis as a potential intervention in such cases.

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 not found to be mutagenic when evaluated with and without metabolic activation.

The drug demonstrated 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 1000 mg in a 50 kg individual.

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, anaphylaxis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It has been noted that sensitizations may recur upon readministration 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.

Caution is recommended for patients concurrently receiving high-dose aspirin and acetazolamide, as reports indicate occurrences of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. Adverse reactions common to 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.

Acetazolamide treatment has been associated with electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis; therefore, periodic monitoring of serum electrolytes is recommended. Additionally, some adverse reactions to acetazolamide, such as drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery.

For reporting of suspected adverse reactions, individuals are encouraged to contact AvKARE at 1-855-361-3993 or the FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

Patient Counseling

Healthcare providers should advise patients about the potential for adverse reactions associated with acetazolamide, which 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. Patients should be informed of the importance of early detection of these reactions, and that the medication should be discontinued if any significant adverse effects occur, with appropriate therapy initiated.

For patients with pulmonary obstruction or emphysema, it is crucial to exercise caution when prescribing acetazolamide, as it may precipitate or exacerbate acidosis. Providers should discuss the importance of gradual ascent to avoid acute mountain sickness, emphasizing that while acetazolamide may be used during rapid ascent, it does not eliminate the need for immediate descent in cases of severe high altitude sickness, such as high altitude pulmonary edema (HAPE) or high altitude cerebral edema.

Patients receiving high-dose aspirin in conjunction with acetazolamide should be closely monitored, as serious adverse effects including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported. Additionally, healthcare providers should inform patients that both increases and decreases in blood glucose levels have been observed with acetazolamide treatment, which is particularly relevant for those with impaired glucose tolerance or diabetes mellitus.

Electrolyte imbalances, such as hyponatremia and hypokalemia, as well as metabolic acidosis, may occur during treatment with acetazolamide. 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 also be made aware that certain adverse reactions, including drowsiness, fatigue, and myopia, may impair their ability to drive or operate machinery safely. To monitor for hematologic reactions common to all sulfonamides, it is advisable to obtain a baseline complete blood count (CBC) and platelet count prior to initiating acetazolamide therapy, with regular follow-up assessments during treatment. If significant changes in blood counts are detected, early discontinuation of the drug and initiation of appropriate therapy are essential. Regular monitoring of serum electrolytes should also be emphasized.

Storage and Handling

The product is supplied in well-closed containers to ensure integrity and stability. 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 quality and efficacy of the product.

Additional Clinical Information

To ensure patient safety during acetazolamide therapy, clinicians are advised to obtain a baseline complete blood count (CBC) and platelet count prior to treatment initiation, as well as at regular intervals throughout the therapy. This monitoring is crucial for detecting hematologic reactions that are common to all sulfonamides. In the event of significant changes in these parameters, early discontinuation of the medication and the implementation of appropriate therapeutic measures are essential. Additionally, periodic monitoring of serum electrolytes is recommended to further safeguard patient health.

FDA Insert (PDF)

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

View full prescribing information (PDF)