Acetazolamide

Description

Acetazolamide Extended-release Capsules, USP are formulated as an inhibitor of the enzyme carbonic anhydrase. The active ingredient, acetazolamide, is a white to faintly yellowish white, crystalline, odorless powder with a molecular weight of 222.25 g/mol and a chemical formula of C₄H₆N₄O₃S₂. The chemical name for acetazolamide is N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl) acetamide. Acetazolamide is sparingly soluble in practically boiling water, slightly soluble in alcohol, and very slightly soluble in water.

Each extended-release capsule is designed for oral administration and contains 500 mg of acetazolamide. The formulation includes several inactive ingredients: gelatin, iron oxide yellow, microcrystalline cellulose, sodium lauryl sulfate, talc, and titanium dioxide. The capsules are printed with black pharmaceutical ink, which consists of black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution. The product meets the USP Dissolution Test 3 standards.

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

The recommended dosage for the management of glaucoma is 1 capsule (500 mg) administered twice daily, with one capsule taken in the morning and another in the evening. Dosage adjustments may be made based on individual patient response, particularly with respect to symptomatology and intraocular pressure. It is important to note that dosages exceeding 2 capsules (1 g) typically do not yield additional therapeutic benefits. Continuous supervision by a physician is advised to ensure optimal management.

In instances where adequate control is not achieved with the twice-daily administration of acetazolamide extended-release capsules, alternative formulations such as acetazolamide tablets or parenteral options may be utilized. These alternatives can be dosed more frequently, with regimens including 250 mg every four hours, or an initial dose of 500 mg followed by 250 mg or 125 mg every four hours, tailored to the specific clinical scenario.

For the 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 involving rapid ascent, such as during rescue or military operations, the higher dosage of 1000 mg is advised. 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 due to its sulfonamide derivative nature.

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 but not limited to 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 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 outcomes, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death.

To ensure patient safety and monitor for potential 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 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 against adverse effects.

Side Effects

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

Serious adverse reactions include anaphylaxis, which has been reported in rare cases, along with fatalities due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia. Patients may experience blood dyscrasias, including leukopenia and thrombocytopenic purpura. It is important to note that sensitization may recur upon re-administration of the drug, regardless of the route. If any signs of hypersensitivity or other serious reactions occur, the drug should be discontinued immediately.

Common adverse reactions reported in clinical trials and postmarketing experiences include headache, malaise, fatigue, fever, and pain at the injection site. Patients may also experience gastrointestinal disturbances such as nausea, vomiting, and diarrhea. Other common reactions include drowsiness, dizziness, and paresthesia, which may include numbness and tingling of the extremities and face.

Skin reactions such as urticaria, photosensitivity, and more severe conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis have also been observed. Additionally, patients may report hearing disturbances and tinnitus.

Metabolic and nutritional adverse reactions include metabolic acidosis, electrolyte imbalances (notably hypokalemia and hyponatremia), loss of appetite, and taste alterations. Long-term therapy may lead to osteomalacia and hyper/hypoglycemia.

Hepato-biliary disorders such as abnormal liver function, cholestatic jaundice, hepatic insufficiency, and fulminant hepatic necrosis have been noted. Urogenital adverse reactions include crystalluria, hematuria, glycosuria, and an increased risk of nephrolithiasis with long-term therapy.

Patients receiving concomitant high-dose aspirin and acetazolamide should be monitored closely, as severe reactions including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported.

Elderly patients with reduced renal function are particularly at risk for severe metabolic acidosis. Caution is advised for patients experiencing drowsiness, fatigue, or myopia, as these may impair the ability to drive or operate machinery.

Overall, early detection of adverse reactions is crucial, and appropriate therapy should be instituted if any serious reactions occur.

Drug Interactions

Aspirin is referenced in the WARNINGS section and should be considered in the context of potential interactions.

Acetazolamide has several notable interactions that may affect the pharmacokinetics and pharmacodynamics of concomitantly administered medications.

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 long-term treatment with both medications.

• Primidone: Acetazolamide may decrease the serum concentrations of primidone and its metabolites by reducing gastrointestinal absorption. This could result in a diminished 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, potentially enhancing both the magnitude and duration of their effects.

• Quinidine: The urinary excretion of quinidine is reduced by acetazolamide, which may lead to an increased effect of quinidine.

• Lithium: Acetazolamide increases the excretion of lithium, which may result in decreased serum levels of lithium. 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, warranting caution when these agents are used concurrently.

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

Combination Therapy Considerations:

• The concurrent use of acetazolamide with other carbonic anhydrase inhibitors is not advisable due to the potential for additive effects.

• When acetazolamide is used alongside sodium bicarbonate, there is an increased risk of renal calculus formation, and this combination should be approached with caution.

Healthcare professionals should consider these interactions when prescribing acetazolamide and monitor patients accordingly to mitigate potential adverse effects.

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 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. 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 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 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 breastfed infant.

Renal Impairment

Patients with renal impairment may not have specific information regarding dosage adjustments, special monitoring, or safety considerations outlined in the prescribing information. Therefore, healthcare professionals should exercise caution when prescribing to this population, as the absence of detailed guidance necessitates careful clinical judgment and individualized patient assessment. Regular monitoring of renal function is advisable to ensure patient safety and therapeutic efficacy.

Hepatic Impairment

Patients with hepatic impairment should be treated with caution due to the potential for severe reactions to sulfonamides, which may include rare but fatal outcomes such as fulminant hepatic necrosis. It is particularly important to monitor these patients closely, especially if they are receiving concomitant high-dose aspirin and acetazolamide.

Healthcare providers are advised to assess liver function regularly and consider the implications of hepatic impairment when determining the appropriateness of treatment. Adjustments to dosage may be necessary based on the severity of liver dysfunction, and ongoing evaluation of liver function tests is recommended to ensure patient safety.

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 levels.

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

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 adversely 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 have not been conducted in animals. 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, anaphylaxis, agranulocytosis, aplastic anemia, and other blood dyscrasias. 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.

Choroidal effusion and choroidal detachment have been documented following the use of acetazolamide in the postoperative period after ophthalmic surgery. If choroidal effusion or choroidal detachment is suspected, acetazolamide should be discontinued.

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.

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

Some adverse reactions associated with acetazolamide, such as drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery. Growth retardation has been reported in children undergoing long-term therapy, believed to be secondary to chronic acidosis. Furthermore, metabolic acidosis, which can be severe, may occur in elderly patients with reduced renal function.

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. Early detection of these reactions is crucial, and patients should be instructed to discontinue the medication and seek appropriate therapy if such reactions occur.

For patients with pulmonary obstruction or emphysema, it is important to use acetazolamide with caution, as it may precipitate or worsen acidosis. Healthcare providers should recommend gradual ascent to avoid acute mountain sickness and inform patients that rapid ascent while using acetazolamide 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 concurrently with acetazolamide should be monitored closely, as there have been reports of serious adverse effects, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. Additionally, both increases and decreases in blood glucose levels have been observed in patients treated with acetazolamide, which should be considered for those with impaired glucose tolerance or diabetes mellitus.

Electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis, may occur during acetazolamide treatment. Therefore, healthcare providers should recommend periodic monitoring of serum electrolytes, particularly for patients with conditions that predispose them to such imbalances, including those with impaired renal function, diabetes mellitus, or impaired alveolar ventilation.

Patients should be informed that some adverse reactions, 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, 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 are detected, early discontinuation and appropriate management should be implemented.

For nursing women, healthcare providers should discuss the potential for serious adverse reactions in nursing infants due to acetazolamide. A careful decision should be made regarding whether to discontinue nursing or the medication, weighing the importance of the drug to the mother against the potential risks to the child.

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 reports of growth retardation in children receiving long-term therapy, likely due to chronic acidosis.

In elderly patients with reduced renal function, there is a risk of severe metabolic acidosis. Therefore, dose selection should be approached with caution, 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 a tight container, in accordance with USP guidelines. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), as defined by USP Controlled Room Temperature. Proper adherence to these storage conditions is essential to maintain the integrity 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. 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 Zydus Lifesciences Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)