Acetazolamide

Description

Acetazolamide extended-release capsules, USP, are formulated as an inhibitor of the enzyme carbonic anhydrase. Each capsule contains 500 mg of acetazolamide, which is characterized as a white to faintly yellowish white crystalline, odorless powder. Acetazolamide 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, and it possesses a specific chemical structure.

In addition to acetazolamide, the capsules include several inactive ingredients: ammonio methacrylate copolymer dispersion types A and B, FD&C yellow #6, gelatin, microcrystalline cellulose, sodium lauryl sulfate, talc, and titanium dioxide. The capsules are printed with black pharmaceutical ink, which contains black iron oxide as a coloring agent. Acetazolamide extended-release capsules meet the USP Dissolution Test 3, ensuring appropriate release characteristics for oral administration.

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

The recommended dosage for the management of glaucoma is 1 capsule (500 mg) administered twice daily, typically one capsule in the morning and one in the evening. Dosage adjustments may be necessary, but 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 dosage adjustments. Continuous supervision by a physician is advised to ensure optimal management.

In cases 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 alternatives, the recommended dosing schedule includes 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 prevention and treatment of acute mountain sickness, the dosage ranges from 500 mg to 1,000 mg daily, divided into appropriate doses using either tablets or extended-release capsules. In situations involving rapid ascent, such as rescue or military operations, a higher dosage of 1,000 mg is recommended. It is advisable 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 infrequent, have been associated with severe reactions to sulfonamides, including but not limited to Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, anaphylaxis, agranulocytosis, aplastic anemia, and various other blood dyscrasias. It is critical to note 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 medication must be discontinued immediately.

Caution is particularly warranted for patients who are concurrently receiving high doses of aspirin alongside acetazolamide. Reports have indicated that such combinations may lead to severe adverse effects, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death. Healthcare professionals should closely monitor these patients for any signs of these serious reactions and consider appropriate laboratory tests to assess metabolic status and overall health.

Side Effects

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

Serious adverse reactions include anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Fatalities have occurred, albeit rarely, due to these severe reactions. Patients should be monitored for signs of hypersensitivity or other serious reactions, and the medication should be discontinued immediately if such symptoms arise. Additionally, caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as severe outcomes including metabolic acidosis, coma, and death have been reported.

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 observed. Patients may experience drowsiness, paresthesia (including numbness and tingling of the extremities and face), depression, excitement, ataxia, confusion, and dizziness.

Skin reactions, including allergic responses such as urticaria, photosensitivity, and more severe conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis, have been noted. Additionally, disturbances in special senses, such as hearing disturbances, tinnitus, and transient myopia, have been reported.

Metabolic and nutritional adverse reactions include metabolic acidosis, electrolyte imbalances (notably hypokalemia and hyponatremia), loss of appetite, taste alterations, and hyper/hypoglycemia. Urogenital effects such as crystalluria, increased risk of nephrolithiasis with long-term therapy, hematuria, glycosuria, renal failure, and polyuria have also been documented.

Patients should be aware that growth retardation in children and flaccid paralysis have been observed, and long-term phenytoin therapy may lead to osteomalacia. It is essential for healthcare providers to remain vigilant for these adverse reactions and to take appropriate action when necessary.

Drug Interactions

Acetazolamide has several notable drug interactions that may impact its efficacy and safety profile.

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, 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 lithium levels. Monitoring of lithium levels is advisable 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 in concurrent use.

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

• Carbonic Anhydrase Inhibitors: The concomitant use of acetazolamide with other carbonic anhydrase inhibitors is not recommended due to the potential for additive effects.

Laboratory Test Interactions:

• 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 levels.

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

• Theophylline Assays: 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 and may not affect other assay methods for theophylline.

Renal Considerations:

• The concurrent use of acetazolamide and sodium bicarbonate may increase the risk of renal calculus formation, necessitating caution in patients with a history of kidney stones.

Overall, careful monitoring and consideration of dosage adjustments are recommended when acetazolamide is used in conjunction with the aforementioned medications and conditions.

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 no adequate and well-controlled studies available in pregnant women to assess the safety of acetazolamide during pregnancy. Therefore, acetazolamide should be used in pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Healthcare professionals are advised to carefully consider the risks and benefits before prescribing acetazolamide to pregnant patients or 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 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 to detect any signs of hepatic deterioration.

Additionally, caution is advised for patients with compromised liver function who are receiving concomitant high-dose aspirin and acetazolamide. The interaction between these medications may exacerbate hepatic impairment, necessitating careful evaluation and monitoring of liver-related parameters throughout the treatment course. Adjustments to dosage or treatment regimens may be required based on the patient's liver function status and overall clinical condition.

Overdosage

In the event of an overdosage, no specific antidote is available. Management should focus on symptomatic and supportive care to address the patient's needs effectively.

Potential Symptoms and Effects 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 cases of acetazolamide overdosage, it is noteworthy that despite its high intraerythrocytic distribution and significant plasma protein binding properties, acetazolamide may be dialyzable. This characteristic is particularly relevant in managing overdosage when renal failure is present, as 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 1,000 mg for a 50 kg individual.

Long-term studies to assess the carcinogenic potential of acetazolamide in animals have not been conducted. 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 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 indicate occurrences of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. Adverse reactions commonly associated with 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 linked to 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 suspected adverse reactions, individuals are encouraged to contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) 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. 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 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, noting 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 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, healthcare providers should inform patients that both increases and decreases in blood glucose levels have been observed in those treated with acetazolamide, which is particularly relevant for individuals with impaired glucose tolerance or diabetes mellitus.

Electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis, may occur during acetazolamide treatment. 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, diabetes mellitus, or 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 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 therapy and to conduct regular follow-up assessments. If significant changes are detected, early discontinuation and appropriate management should be implemented.

For nursing mothers, healthcare providers should discuss the potential risks to nursing infants associated with 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 providers should be aware of reports of growth retardation in children receiving long-term therapy, likely due to chronic acidosis.

Finally, when prescribing acetazolamide to elderly patients, healthcare providers should exercise caution in dose selection, 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 medications.

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, with regular monitoring throughout therapy to detect hematologic reactions common to sulfonamides. Significant changes in these parameters warrant early discontinuation of the drug and appropriate intervention. Additionally, 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 counseled on the risk of adverse reactions associated with sulfonamide derivatives, such as anaphylaxis, fever, and various skin reactions, and the importance of early detection and discontinuation of the drug if these occur. Caution is particularly advised for patients with pulmonary conditions, those on high-dose aspirin, and individuals with diabetes or renal impairment, as these factors may exacerbate the risk of adverse effects. Furthermore, patients should be informed that acetazolamide may affect blood glucose levels and that side effects like drowsiness and fatigue could impair their ability to drive or operate machinery. Gradual ascent is recommended to prevent acute mountain sickness, and the use of acetazolamide does not eliminate the need for prompt descent in severe cases of high altitude sickness.

FDA Insert (PDF)

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

View full prescribing information (PDF)