Acetazolamide

Description

Acetazolamide extended-release capsules are a carbonic anhydrase inhibitor formulated for oral administration. Each capsule contains 500 mg of acetazolamide, which is a white to faintly yellowish white crystalline, odorless powder. Acetazolamide is characterized by a molecular weight of 222.25 and a chemical formula of C₄H₆N₄O₃S₂. The chemical name for acetazolamide is N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl) acetamide, and it is sparingly soluble in practically boiling water, very slightly soluble in water, and slightly soluble in alcohol.

The extended-release capsules include inactive ingredients such as microcrystalline cellulose, sodium lauryl sulfate, and talc. The capsule shell is composed of D&C Red No. 28, D&C Yellow No. 10, FD&C Red No. 40, gelatin, and titanium dioxide. The imprinting ink contains iron oxide black, potassium hydroxide, propylene glycol, and shellac.

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, with one capsule taken in the morning and one in the evening. The maximum dosage should not exceed 2 capsules (1 g) per day, as dosages beyond this threshold do not yield an increased therapeutic effect. Dosage adjustments should be made with careful consideration of the patient's symptomatology and intraocular pressure, and continuous supervision by a physician is advisable to ensure optimal management.

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. A higher dose of 1000 mg is recommended for situations involving rapid ascent, such as rescue or military operations. 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 if necessary to effectively control 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 extended-release capsules 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 sensitization may recur upon readministration of a sulfonamide, regardless of the route of administration. Should any signs of hypersensitivity or other serious reactions manifest, the use of this drug must be discontinued immediately.

Caution is warranted for patients concurrently receiving high-dose aspirin alongside acetazolamide extended-release capsules. 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, elevate the incidence of drowsiness and/or paresthesia. In many cases, escalating the dose results in a reduction of diuresis. However, in specific situations, very large doses may be administered in conjunction with other diuretics to achieve diuresis in cases of complete refractory failure.

Healthcare professionals should be aware that choroidal effusion and choroidal detachment have been documented following the use of acetazolamide in the postoperative period after ophthalmic surgery. If there is any suspicion of choroidal effusion or detachment, the administration of acetazolamide extended-release capsules should be discontinued.

To ensure patient safety, it is recommended that a baseline complete blood count (CBC) and platelet count be obtained prior to initiating therapy with acetazolamide extended-release capsules. Regular monitoring of these parameters should continue throughout the treatment course to detect any hematologic reactions common to sulfonamides. Should significant changes in laboratory results occur, early discontinuation of the drug and initiation of appropriate therapy are imperative. Additionally, periodic monitoring of serum electrolytes is advised to maintain 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 reactions include agranulocytosis, aplastic anemia, and other blood dyscrasias. Additionally, cases of fulminant hepatic necrosis have been reported. It is important to note that sensitization may recur upon readministration of the drug, regardless of the route of administration. If any signs of hypersensitivity or other serious reactions occur, the use of this medication should be discontinued immediately.

Common adverse reactions reported by patients include headache, malaise, fatigue, fever, and pain at the injection site. Gastrointestinal disturbances such as nausea, vomiting, and diarrhea are also frequently observed. Patients may experience various nervous system effects, including drowsiness, dizziness, paresthesia (numbness and tingling of extremities and face), confusion, and convulsions.

Skin reactions can manifest as allergic responses, including urticaria, photosensitivity, and in severe cases, Stevens-Johnson syndrome and toxic epidermal necrolysis. Otologic effects such as hearing disturbances and tinnitus have also been noted.

Metabolic and nutritional adverse reactions may include metabolic acidosis, electrolyte imbalances (such as hypokalemia and hyponatremia), loss of appetite, taste alterations, and fluctuations in blood glucose levels (hyperglycemia or hypoglycemia). Long-term therapy may lead to osteomalacia and growth retardation in children.

Hepato-biliary disorders may present as abnormal liver function, cholestatic jaundice, hepatic insufficiency, and fulminant hepatic necrosis. Urogenital effects include crystalluria, increased risk of nephrolithiasis with long-term therapy, hematuria, glycosuria, renal failure, and polyuria.

Patients receiving concomitant high-dose aspirin and acetazolamide extended-release capsules should be monitored closely, as reports have indicated the potential for serious outcomes, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death.

Drug Interactions

Acetazolamide extended-release capsules exhibit several significant 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 when administering acetazolamide to patients receiving long-term phenytoin.

Additionally, acetazolamide may decrease serum concentrations of primidone and its metabolites by reducing gastrointestinal absorption, potentially diminishing its anticonvulsant efficacy. It is recommended to exercise caution when initiating, discontinuing, or adjusting the dosage of acetazolamide in patients on primidone.

The use of acetazolamide in conjunction with other carbonic anhydrase inhibitors is not advisable due to the potential for additive effects. Furthermore, acetazolamide may elevate the serum levels of cyclosporine, necessitating monitoring of cyclosporine concentrations.

Acetazolamide also affects the urinary excretion of several substances. It decreases the urinary excretion of amphetamine and quinidine, which may enhance their effects. Conversely, it increases lithium excretion, potentially leading to decreased lithium levels. The concurrent use of acetazolamide and sodium bicarbonate raises the risk of renal calculus formation.

Pharmacodynamic Interactions

Acetazolamide may increase the effects of other folic acid antagonists, which could necessitate dosage adjustments or increased monitoring for adverse effects.

Laboratory Test Interactions

Acetazolamide can interfere with laboratory assays, notably the HPLC method for theophylline, with the degree of interference depending on the solvent used in the extraction process. It is important to note that acetazolamide may produce an increased level of crystals in the urine, which could affect the interpretation of urinary tests.

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. Clinicians should be aware of these potential laboratory test interactions when interpreting results in patients receiving 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 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 diminished 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. There are no adequate and well-controlled studies available in pregnant women to assess the safety and efficacy of acetazolamide during pregnancy. Therefore, acetazolamide should be used in pregnant patients only if the potential benefit justifies the potential risk to the fetus. Healthcare professionals are advised to carefully consider the risks and benefits before prescribing acetazolamide to women of childbearing potential.

Lactation

Because of the potential for serious adverse reactions in nursing infants from acetazolamide extended-release capsules, 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

There is no specific information regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment should be treated with caution due to the potential for severe reactions to sulfonamides, including the rare occurrence of fulminant hepatic necrosis, which can be fatal. It is recommended that healthcare providers closely monitor liver function in these patients.

Additionally, caution is advised for patients who are receiving concomitant high-dose aspirin and acetazolamide extended-release capsules, as the combination may exacerbate the risk of adverse hepatic reactions. Regular assessment of liver function tests is recommended to ensure patient safety and to guide any necessary adjustments in therapy.

Overdosage

In cases of overdosage with acetazolamide extended-release capsules, no specific antidote is available. Management should focus on symptomatic and supportive care to address the potential complications that may arise.

Potential Symptoms and Complications 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 where renal failure complicates the overdosage, it is noteworthy that acetazolamide extended-release capsules, despite their high intraerythrocytic distribution and significant plasma protein binding, may be dialyzable. This aspect should be considered in the overall management strategy for affected patients.

Nonclinical Toxicology

Long-term studies in animals to evaluate the carcinogenic potential of acetazolamide extended-release capsules have not been conducted. In a bacterial mutagenicity assay, acetazolamide extended-release capsules were 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. Sensitization 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 extended-release capsules, as reports have indicated occurrences of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. Additionally, choroidal effusion and choroidal detachment have been documented following the use of acetazolamide in the postoperative period after ophthalmic surgery; acetazolamide extended-release capsules should be discontinued if these conditions are suspected.

Common adverse reactions associated with 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. Furthermore, certain adverse reactions to acetazolamide, including drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery.

Patient Counseling

Healthcare providers should advise patients about the potential for adverse reactions associated with acetazolamide extended-release capsules, 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. Early detection of these reactions is crucial, and patients should be instructed to discontinue the medication and seek appropriate therapy if such reactions occur.

Patients with pulmonary obstruction or emphysema should be cautioned that acetazolamide may precipitate or worsen acidosis, necessitating careful monitoring. Additionally, when discussing high-altitude travel, healthcare providers should emphasize the importance of gradual ascent to minimize the risk of acute mountain sickness. If rapid ascent is necessary, patients should be informed that the use of acetazolamide does not eliminate the need for immediate 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 inform patients receiving high-dose aspirin concurrently with acetazolamide of the potential risks, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death. Patients with impaired glucose tolerance or diabetes mellitus should be made aware that both increases and decreases in blood glucose levels have been reported with acetazolamide treatment.

Periodic monitoring of serum electrolytes is recommended, as acetazolamide can cause electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis. Special caution should be exercised in patients predisposed to these imbalances, such as those with impaired renal function, diabetes mellitus, or impaired alveolar ventilation.

Patients should be informed that some adverse reactions, including drowsiness, fatigue, and myopia, may impair their ability to drive or operate machinery safely. To monitor for hematologic reactions common to sulfonamides, healthcare providers should recommend obtaining a baseline complete blood count (CBC) and platelet count prior to initiating therapy, with regular follow-up assessments. If significant changes are observed, early discontinuation and appropriate management are essential.

For nursing mothers, a careful decision should be made regarding the continuation of acetazolamide therapy, weighing the importance of the medication against the potential risks to the nursing infant. Acetazolamide should only be used by nursing women if the benefits justify the risks.

The safety and effectiveness of acetazolamide extended-release capsules in pediatric patients under 12 years of age have not been established, and healthcare providers should be aware of the potential for growth retardation in children receiving long-term therapy due to chronic acidosis.

Finally, in elderly patients with reduced renal function, there is a risk of severe metabolic acidosis. Therefore, dose selection should be cautious, typically starting at the lower end of the dosing range to account for the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It should be stored at a controlled room temperature of 25°C (77°F). Temporary excursions are permitted within the range of 15°C to 30°C (59°F to 86°F), in accordance with USP guidelines for controlled room temperature.

Care should be taken to ensure that the product is kept in its original container to maintain its integrity and efficacy. Special handling requirements should be observed to prevent exposure to extreme temperatures or conditions that may compromise the product's quality.

Additional Clinical Information

To ensure patient safety during acetazolamide extended-release capsules 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 associated with sulfonamides. In the event of significant changes, early discontinuation of the medication and appropriate therapeutic interventions are crucial. Additionally, periodic assessment of serum electrolytes is recommended to monitor for potential imbalances.

FDA Insert (PDF)

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

View full prescribing information (PDF)