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.

Each capsule, intended for oral administration, contains 500 mg of acetazolamide along with several inactive ingredients, including microcrystalline cellulose, hydroxypropyl cellulose, pregelatinized starch, and talc. The capsule shell is composed of gelatin, sodium lauryl sulfate, and titanium dioxide. The imprinting ink used on the capsules contains shellac, potassium hydroxide, and black iron oxide.

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, acetazolamide 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 one in the evening. Dosage adjustments may be made based on individual patient response, particularly with respect to symptomatology and intraocular pressure; however, doses exceeding 2 capsules (1 g) are generally not associated with increased efficacy. 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 forms may be utilized. For these dosage forms, a more frequent dosing schedule is recommended, which may include 250 mg every four hours or an initial dose of 500 mg followed by 250 mg or 125 mg every four hours, depending on the 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 involving rapid ascent, such as during rescue or military operations, the higher dosage of 1000 mg is advised. 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 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 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 sensitizations 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 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 potential complications.

Side Effects

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

Serious adverse reactions, although rare, include fatalities due to severe hypersensitivity reactions such as anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia. Patients may experience sensitization upon re-administration of sulfonamides, regardless of the route of administration. It is crucial to discontinue the drug immediately if any signs 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 have also been frequently observed.

Patients may experience a range of hematological and lymphatic reactions, including blood dyscrasias such as aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenic purpura. Additionally, abnormal liver function, cholestatic jaundice, hepatic insufficiency, and fulminant hepatic necrosis have been noted under hepatobiliary disorders.

Metabolic and nutritional adverse reactions include metabolic acidosis, electrolyte imbalances (notably hypokalemia and hyponatremia), loss of appetite, taste alterations, and hyperglycemia or hypoglycemia. Long-term therapy with phenytoin has been associated with osteomalacia.

Neurological adverse reactions encompass drowsiness, paresthesia (including numbness and tingling of the extremities and face), depression, excitement, ataxia, confusion, convulsions, and dizziness.

Skin reactions can include allergic responses such as urticaria, photosensitivity, and severe conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis.

In terms of special senses, patients may report hearing disturbances, tinnitus, and transient myopia. Urogenital adverse reactions include crystalluria, an increased risk of nephrolithiasis with long-term therapy, hematuria, glycosuria, renal failure, and polyuria.

Caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as severe reactions including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported. Additionally, some adverse reactions, such as drowsiness, fatigue, and myopia, may impair the ability to drive or operate machinery.

Overall, early detection of adverse reactions is essential, and appropriate therapy should be instituted if necessary.

Drug Interactions

Acetazolamide exhibits several significant drug interactions that warrant careful consideration in clinical practice.

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 both medications concurrently.

• Primidone: 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.

• 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 also reduced by acetazolamide, potentially increasing its pharmacological effects.

• Lithium: Acetazolamide increases the excretion of lithium, which may lead to decreased serum levels of lithium. Monitoring of lithium levels is advisable when these drugs are used together.

• Cyclosporine: There is a potential for acetazolamide to elevate cyclosporine levels, necessitating careful monitoring of cyclosporine concentrations.

Pharmacodynamic Interactions:

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

• Methenamine: The urinary antiseptic effect of methenamine may be prevented by acetazolamide, which could compromise the therapeutic efficacy of methenamine.

Combination with Other Carbonic Anhydrase Inhibitors:

Due to the possibility of additive effects, the concomitant use of acetazolamide with other carbonic anhydrase inhibitors is not advisable.

Renal Considerations:

The concurrent use of acetazolamide and sodium bicarbonate may increase the risk of renal calculus formation, and this combination should be approached with caution.

In summary, careful monitoring and dosage adjustments may be necessary when acetazolamide is used in conjunction with the aforementioned medications 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 receiving such treatment, 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 is classified as a Pregnancy Category C medication. Animal studies have demonstrated teratogenic effects, including limb defects, in mice, rats, hamsters, and rabbits following oral or parenteral administration. However, there are no adequate and well-controlled studies in pregnant women to fully assess the risks associated with its use during pregnancy.

Given the potential for fetal harm, acetazolamide should be prescribed to pregnant patients only if the potential benefits outweigh the risks to the fetus. Healthcare professionals are advised to carefully consider the necessity of 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 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. Due to the potential for serious adverse effects in this population, careful consideration should be given to the use of this medication in patients with compromised liver function.

Monitoring of liver function is recommended for patients with hepatic impairment who are prescribed this medication. Regular assessment of liver enzymes and other relevant laboratory values should be conducted to detect any signs of hepatic toxicity early.

Dosage adjustments may be necessary based on the severity of hepatic impairment, and it is advised that clinicians exercise caution when prescribing this medication to patients with liver dysfunction.

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 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.

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 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. Additionally, acetazolamide was found to be non-mutagenic in a bacterial mutagenicity assay, both with and without metabolic activation.

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.

Caution is recommended for patients receiving concomitant 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. Some 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 also 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 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. Gradual ascent is recommended to avoid acute mountain sickness. If rapid ascent occurs while using acetazolamide, it is important to note that this does not eliminate the need for prompt descent in cases of severe high altitude sickness, such as high altitude pulmonary edema (HAPE) or high altitude cerebral edema.

Healthcare providers should also inform patients receiving concomitant high-dose aspirin and acetazolamide of the potential risks, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. Both increases and decreases in blood glucose levels have been reported 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 with acetazolamide treatment. Therefore, periodic monitoring of serum electrolytes is recommended, particularly 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, such as drowsiness, fatigue, and myopia, may impair their ability to drive or operate machinery. 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 and to conduct regular monitoring during treatment. If significant changes are observed, early discontinuation and appropriate therapy should be instituted.

For nursing mothers, healthcare providers should discuss the potential for serious adverse reactions in nursing infants from 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 benefit justifies the potential risk.

In pediatric patients under the age of 12, the safety and effectiveness of acetazolamide extended-release capsules have not been established, and growth retardation has been reported in children receiving long-term therapy, believed to be secondary to chronic acidosis.

For geriatric patients, healthcare providers should exercise caution in dose selection, typically starting at the low end of the dosing range due to the greater frequency of decreased hepatic, renal, or cardiac function, as well as concomitant disease or other drug therapy. Metabolic acidosis, which can be severe, may occur in the elderly with reduced renal function.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20° to 25°C (68° to 77°F), as defined by the United States Pharmacopeia (USP). Proper storage conditions are 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, early discontinuation of the medication and implementation of appropriate therapeutic measures 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 Ingenus Pharmaceuticals, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)