Acetazolamide

Description

Acetazolamide, USP, is an inhibitor of the enzyme carbonic anhydrase, presented as a white to faintly yellowish white crystalline, odorless powder. It is characterized as 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 222.25 and a molecular formula of C₄H₆N₄O₃S₂.

Acetazolamide Tablets, USP, are formulated for oral administration, available in dosages of 125 mg and 250 mg of acetazolamide per tablet. The tablets also contain inactive ingredients, including lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, sodium lauryl sulfate, and sodium starch glycolate.

Uses and Indications

This drug is indicated for the adjunctive treatment of various conditions, including edema due to congestive heart failure, drug-induced edema, and centrencephalic epilepsies, specifically petit mal and unlocalized seizures. It is also indicated for the management of chronic simple (open-angle) glaucoma and secondary glaucoma. Additionally, this drug may be used preoperatively in cases of acute angle-closure glaucoma when a delay in surgery is desired to lower intraocular pressure.

Furthermore, this drug is indicated for the prevention or amelioration of symptoms associated with acute mountain sickness in climbers who are attempting rapid ascent, as well as in individuals who are particularly susceptible to acute mountain sickness, even with gradual ascent.

No teratogenic or nonteratogenic effects have been reported.

Dosage and Administration

For the treatment of glaucoma, the dosage of acetazolamide ranges from 250 mg to 1 g per 24 hours, typically administered in divided doses for amounts exceeding 250 mg. The preferred dosage for secondary glaucoma and preoperative treatment of acute congestive glaucoma is 250 mg every four hours. In acute cases, an initial dose of 500 mg may be given, followed by 125 mg to 250 mg every four hours as needed. Intravenous therapy may be employed for rapid relief of ocular tension in acute situations.

In the management of epilepsy, the suggested total daily dose is between 8 mg to 30 mg per kg, divided into multiple doses. The optimum dosage range appears to be from 375 mg to 1,000 mg daily. When acetazolamide is administered alongside other anticonvulsants, the starting dose should be 250 mg once daily.

For patients with congestive heart failure, the starting dose is generally 250 mg to 375 mg once daily in the morning, which corresponds to approximately 5 mg/kg. For optimal diuretic effects, it is recommended to administer the medication on alternate days or for two consecutive days, followed by a day of rest.

In cases of drug-induced edema, the recommended dosage is 250 mg to 375 mg of acetazolamide once daily for one or two days, alternating with a day of rest.

For the prevention and treatment of acute mountain sickness, the dosage is typically 500 mg to 1,000 mg daily, divided into multiple doses. A higher dosage of 1,000 mg is advised in situations involving rapid ascent. 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 as necessary to manage symptoms effectively.

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 noncongestive 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 have been reported, albeit infrequently, as a result of severe reactions to sulfonamides. These reactions include, but are not limited to, Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias, as well as anaphylaxis. It is critical to note that sensitization may recur upon re-administration of a sulfonamide, regardless of the route of administration. Should any signs of hypersensitivity or other serious adverse reactions manifest, the use of this drug must be discontinued immediately.

Caution is particularly warranted for patients who are concurrently receiving high-dose 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, which may occur upon re-administration of the drug, and fatalities have been reported, albeit rarely, due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia. Patients should be monitored for signs of hypersensitivity or other serious reactions, and the drug should be discontinued immediately if such symptoms arise.

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.

Hematological and lymphatic reactions may manifest as blood dyscrasias, including aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and thrombocytopenic purpura. Abnormal liver function, cholestatic jaundice, hepatic insufficiency, and fulminant hepatic necrosis are notable hepatobiliary disorders that may occur.

Metabolic and nutritional adverse reactions include metabolic acidosis, electrolyte imbalances (notably hypokalemia and hyponatremia), loss of appetite, taste alterations, and hyperglycemia or hypoglycemia.

Neurological effects may present as drowsiness, paraesthesia (numbness and tingling of 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.

Patients may experience disturbances in special senses, including hearing disturbances, tinnitus, and transient myopia.

Urogenital adverse reactions may involve crystalluria, increased risk of nephrolithiasis with long-term therapy, hematuria, glycosuria, renal failure, and polyuria.

It is important to note that growth retardation has been reported in children receiving long-term therapy, likely due to chronic acidosis. Additionally, metabolic acidosis can be severe in elderly patients with reduced renal function, necessitating careful monitoring. Periodic assessment of serum electrolytes is recommended to detect potential imbalances, particularly in patients receiving concomitant high-dose aspirin and acetazolamide, where severe reactions such as anorexia, tachypnea, lethargy, and even death have been documented.

Drug Interactions

Acetazolamide is associated with several significant drug interactions that may necessitate careful monitoring and dosage adjustments.

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 concomitant therapy with these agents.

• Primidone: Acetazolamide may decrease the gastrointestinal absorption of primidone, resulting in lower serum concentrations of primidone and its metabolites. This 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 use of acetazolamide reduces the urinary excretion of quinidine, 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.

• 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, which could lead to increased toxicity or adverse effects.

• Antidiabetic Agents: Acetazolamide has the potential to either increase or decrease blood glucose levels. Patients receiving antidiabetic medications should be monitored closely for changes in glycemic control.

• Methenamine: Acetazolamide may interfere with the urinary antiseptic effect of methenamine, which could reduce its efficacy.

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, warranting caution in patients with a history of kidney stones.

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 in pediatric patients have not been established. Caution is advised when considering long-term therapy in children, as growth retardation has been reported. This condition is believed to be secondary to chronic acidosis associated with the medication.

Geriatric Use

Elderly patients may experience metabolic acidosis, which can be severe, particularly in those with reduced renal function. Clinical studies involving acetazolamide did not include a sufficient number of subjects aged 65 and older to ascertain whether this population responds differently compared to younger individuals. However, other clinical experiences have not indicated any significant differences in responses between elderly and younger patients.

In general, dose selection for geriatric patients should be approached with caution. It is advisable to initiate treatment at the lower end of the dosing range, taking into account the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Regular monitoring of these patients is recommended to ensure safety and efficacy.

Pregnancy

Acetazolamide has been shown to be teratogenic in animal studies, with documented limb defects observed in mice, rats, hamsters, and rabbits. There are currently no adequate and well-controlled studies 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 benefits outweigh the potential risks to the fetus. Healthcare professionals are advised to carefully consider the risk-benefit profile when prescribing this medication to 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 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, including rare but serious outcomes such as fulminant hepatic necrosis associated with sulfonamide use. It is essential to monitor liver function closely in this patient population.

While specific dosage adjustments are not provided, healthcare professionals are advised to evaluate the risks versus benefits of treatment in patients with compromised liver function. Regular assessment of liver enzymes and overall liver health is recommended to ensure patient safety and to mitigate the risk of adverse reactions.

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 Monitoring Patients may experience electrolyte imbalances, the development of an acidotic state, and 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.

Dialysis Considerations Despite the high intraerythrocytic distribution and significant plasma protein binding of acetazolamide, it is important to note that the drug is dialyzable. This characteristic may play a critical role in the management of acetazolamide overdosage, especially in cases complicated by renal failure. Healthcare professionals should consider dialysis as a potential intervention in such scenarios.

Nonclinical Toxicology

Acetazolamide has demonstrated teratogenic effects in nonclinical 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 1,000 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, agranulocytosis, aplastic anemia, and other blood dyscrasias, as well as anaphylaxis. 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.

Adverse reactions commonly associated with sulfonamide derivatives 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.

In patients treated with acetazolamide, both increases and decreases in blood glucose levels have been observed. Acetazolamide may also lead to electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis; therefore, periodic monitoring of serum electrolytes is recommended. Some adverse reactions, 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. Additionally, metabolic acidosis, which can be severe, may occur in elderly patients with reduced renal function.

To report suspected adverse reactions, individuals are encouraged to contact Chartwell RX, LLC at 1-845-232-1683 or the FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

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 in these populations. Additionally, healthcare providers should inform patients that gradual ascent is advisable to avoid acute mountain sickness. If rapid ascent occurs while using acetazolamide tablets, it is important to note that this does not eliminate the need for prompt descent in the event of severe high altitude sickness, such as high altitude pulmonary edema (HAPE) or high altitude cerebral edema.

Caution is also warranted for patients receiving concomitant high-dose aspirin and acetazolamide, as serious adverse effects including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported. 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.

Healthcare providers should inform patients that acetazolamide treatment may lead to electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis. 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 to acetazolamide, 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 recommended that a baseline complete blood count (CBC) and platelet count be obtained prior to initiating acetazolamide therapy and at regular intervals during treatment. If significant changes occur, 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, considering the importance of the medication to the mother. Acetazolamide should only be used by nursing women if the potential benefit justifies the potential risk to the child.

In pediatric patients, the safety and effectiveness of acetazolamide 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 be cautious with 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 a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It is essential to keep the container tightly closed to maintain product integrity.

Storage conditions require the product to be maintained at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as outlined by USP Controlled Room Temperature guidelines.

Healthcare professionals are reminded to keep this and all medications out of the reach of children to ensure safety.

Additional Clinical Information

To ensure patient safety during acetazolamide tablet 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 any hematologic reactions common to sulfonamides. Significant changes in these parameters may necessitate early discontinuation of the medication 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.

Patient counseling should emphasize the importance of gradual ascent to prevent acute mountain sickness, noting that while acetazolamide may assist, it does not replace the need for immediate descent in severe cases of high altitude sickness. Caution is warranted for patients taking high-dose aspirin concurrently, as serious adverse effects have been reported. Clinicians should also be aware of the potential for fluctuations in blood glucose levels in patients with diabetes or impaired glucose tolerance. Adverse reactions such as drowsiness, fatigue, and myopia may impair the ability to drive or operate machinery, necessitating patient awareness and caution.

FDA Insert (PDF)

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

View full prescribing information (PDF)