Acetazolamide

Description

Acetazolamide extended-release capsules are formulated as an inhibitor of the enzyme carbonic anhydrase. The active ingredient, acetazolamide, is characterized as a white to faintly yellowish white crystalline, odorless powder that is 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 222.24 and a chemical formula of C₄H₆N₄O₃S₂.

Each extended-release capsule is designed for oral administration and contains 500 mg of acetazolamide. The formulation includes inactive ingredients such as ethyl acrylate and methacrylate copolymer, microcrystalline cellulose, purified talc, and sodium lauryl sulfate. The capsule shell is composed of FD&C Blue 1, FD&C Yellow 6, gelatin, iron oxide yellow, and titanium dioxide. The imprinting ink contains shellac, iron oxide black, and potassium hydroxide.

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 use preoperatively in acute angle-closure glaucoma when a delay of 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 in the context of gradual ascent.

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

Dosage and Administration

For the management of glaucoma, the recommended dosage is 1 capsule (500 mg) administered twice daily. Typically, one capsule should be taken in the morning and another in the evening. While dosage adjustments may be necessary, it is generally observed that doses exceeding 2 capsules (1 g) do not yield additional therapeutic effects. Careful individual assessment of symptomatology and intraocular pressure is essential for any dosage modifications. Continuous supervision by a physician is advised to ensure optimal treatment outcomes.

In the case of acute mountain sickness, the dosage ranges from 500 mg to 1000 mg daily, divided into appropriate doses using either tablets or extended-release capsules. For situations involving rapid ascent, such as rescue or military operations, the higher dosage of 1000 mg is recommended. It is preferable to initiate treatment 24 to 48 hours prior to ascent and to continue for 48 hours while at high altitude, or longer if 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 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 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 advised for patients who are concurrently receiving high-dose aspirin and acetazolamide. Serious adverse effects such as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death have been documented in these cases.

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 can often result in decreased diuresis. However, in specific situations, very large doses may be administered alongside other diuretics to achieve diuresis in cases of complete refractory failure.

Choroidal effusion and choroidal detachment have been reported following the use of acetazolamide in the postoperative period after ophthalmic surgery. If there is any suspicion of choroidal effusion or detachment, acetazolamide should be discontinued promptly.

To 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 initiating acetazolamide therapy. Regular monitoring of these parameters during therapy is essential. Should significant changes be observed, early discontinuation of the drug and initiation of appropriate therapy are critical. Additionally, periodic monitoring of serum electrolytes is advised to ensure patient safety.

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 other blood dyscrasias have also been reported. Additionally, cases of fulminant hepatic necrosis and severe liver dysfunction, including cholestatic jaundice 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 any symptoms of hypersensitivity or other serious reactions occur.

Common adverse reactions reported in clinical trials and postmarketing experiences include headache, malaise, fatigue, fever, and pain at the injection site. Gastrointestinal disturbances such as nausea, vomiting, and diarrhea are also frequently noted. Patients may experience various nervous system effects, including drowsiness, dizziness, confusion, and paresthesia, which may manifest as numbness and tingling in the extremities and face.

Skin reactions, including allergic responses such as urticaria and photosensitivity, have been documented. Long-term therapy may lead to growth retardation in children and an increased risk of nephrolithiasis. Metabolic and nutritional effects, such as metabolic acidosis, electrolyte imbalances (including hypokalemia and hyponatremia), and alterations in appetite and taste, have also been reported.

Patients receiving concomitant high-dose aspirin and acetazolamide should be approached with caution, as there have been reports of severe reactions including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death.

Overall, while many adverse reactions are manageable, the potential for serious outcomes necessitates careful monitoring and patient education regarding the signs and symptoms of these reactions.

Drug Interactions

Acetazolamide exhibits several significant drug interactions that may impact therapeutic outcomes and patient safety. These interactions can be categorized into pharmacokinetic and pharmacodynamic effects.

Pharmacokinetic Interactions

• Phenytoin: Acetazolamide modifies the metabolism of phenytoin, leading to increased serum levels. This elevation 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, potentially resulting in lower serum concentrations of primidone and its metabolites. This interaction may diminish the anticonvulsant effect. Careful monitoring is recommended when initiating, discontinuing, or adjusting the dose of acetazolamide in patients on primidone.

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

• Quinidine: The urinary excretion of quinidine is also decreased 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 recommended to avoid subtherapeutic dosing.

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

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

Pharmacodynamic Interactions

• Folic Acid Antagonists: Acetazolamide may enhance the effects of other folic acid antagonists, which could lead to increased toxicity or adverse effects.

• Methenamine: The urinary antiseptic effect of methenamine may be inhibited by acetazolamide, potentially reducing its therapeutic efficacy.

Laboratory Test Interactions

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

• Theophylline Assays: Acetazolamide can interfere with the high-performance liquid chromatography (HPLC) method for the assay of theophylline, with the degree of interference depending on the solvent used in the extraction. Other assay methods for theophylline may not be affected.

In summary, careful consideration and monitoring are advised when acetazolamide is used in conjunction with the aforementioned medications and laboratory tests to mitigate potential adverse effects and ensure therapeutic efficacy.

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 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.

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 lower end of the dosing range to mitigate potential risks and ensure safety. Regular monitoring of renal function and metabolic status is advised to adjust dosing as necessary and to prevent adverse effects in this population.

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 only be prescribed to pregnant patients 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 patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 adverse effects, dosage adjustments may be necessary for individuals with compromised liver function. Healthcare providers should evaluate the severity of hepatic impairment and consider the need for more frequent monitoring of liver enzymes and overall liver function during treatment.

Patients with significant hepatic impairment should be treated with caution, and the risks versus benefits of therapy should be carefully assessed before initiation.

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 various 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.

In instances of acetazolamide overdosage, it is noteworthy that despite its high intraerythrocytic distribution and significant plasma protein binding properties, acetazolamide may be dialyzable. This characteristic can be particularly relevant in managing overdosage cases complicated by renal failure, where dialysis may aid in the removal of the drug from the system.

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 evaluated both with and without metabolic activation. Additionally, the drug demonstrated no adverse effects 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 for a 50 kg individual.

Postmarketing Experience

Fatalities have been reported, albeit rarely, due to severe reactions associated with sulfonamides, including but not limited to Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, anaphylaxis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is 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 warranted for patients concurrently receiving high-dose aspirin and acetazolamide, as reports have indicated occurrences of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. Adverse reactions that are common to all sulfonamide derivatives may include anaphylaxis, fever, rash (encompassing 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, such as hyponatremia and hypokalemia, as well as metabolic acidosis; therefore, periodic monitoring of serum electrolytes is recommended. Additionally, some adverse reactions to acetazolamide, including drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery.

Patient Counseling

Patients should be advised to monitor for signs of hypersensitivity or serious reactions, including anaphylaxis, fever, rash, and blood dyscrasias. They should be instructed to discontinue use immediately if any of these reactions occur. Caution is advised for patients with pulmonary obstruction or emphysema, as acetazolamide may precipitate or aggravate acidosis.

Healthcare providers should recommend gradual ascent to avoid acute mountain sickness. It is important to inform patients that if rapid ascent occurs, acetazolamide does not eliminate the need for prompt descent in the event of severe high altitude sickness. Additionally, patients receiving high-dose aspirin in conjunction with acetazolamide should be monitored closely due to the risk of serious adverse effects.

Patients should be informed that both increases and decreases in blood glucose levels have been reported, which is particularly important for those with diabetes or impaired glucose tolerance. Periodic monitoring of serum electrolytes is recommended due to the potential for electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis.

Patients should be cautioned that adverse reactions such as drowsiness, fatigue, and myopia may impair their ability to drive or operate machinery. It is recommended that a baseline complete blood count (CBC) and platelet count be obtained prior to initiating therapy and monitored regularly during treatment.

Patients should also be informed that acetazolamide may cause crystalluria and increase the risk of nephrolithiasis with long-term therapy. Nursing mothers should consider the potential risks to infants when deciding whether to continue nursing or discontinue the drug. Furthermore, pediatric patients may experience growth retardation with long-term therapy, which is believed to be secondary to chronic acidosis.

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°C to 25°C (68°F 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 essential to detect 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 crucial. 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 as submitted by Accord Healthcare Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)