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, USP. The tablets also contain inactive ingredients, which include colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone K30, and talc.

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 management of glaucoma, the recommended 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; however, some patients may respond adequately to 250 mg twice daily. In acute cases, an initial dose of 500 mg may be administered, followed by 125 mg or 250 mg every four hours as needed.

In the treatment of epilepsy, the suggested total daily dose of acetazolamide is between 8 to 30 mg per kg, divided into multiple doses, with an optimum range of 375 to 1000 mg daily. When used in conjunction with other anticonvulsants, the starting dose is typically 250 mg once daily, which may be increased based on clinical response.

For patients with congestive heart failure, the starting dose is generally 250 to 375 mg once daily in the morning, equivalent to approximately 5 mg/kg. To achieve optimal diuretic effects, acetazolamide tablets are best administered 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 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 500 mg to 1000 mg daily, administered in divided doses using either tablets or sustained-release capsules. A higher dose of 1000 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 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, agranulocytosis, aplastic anemia, and other blood dyscrasias, as well as anaphylaxis. It is crucial to recognize that sensitization may recur upon re-administration of a sulfonamide, regardless of the route of administration. Therefore, if any signs of hypersensitivity or other serious reactions manifest, the use of this drug must be discontinued immediately.

Caution is particularly advised for patients who are concurrently receiving high doses of aspirin and acetazolamide. Reports have indicated that such combinations may lead to severe adverse effects, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death.

In terms of general precautions, it is important to note that increasing the dosage of acetazolamide does not enhance diuresis and may, in fact, lead to an increased incidence of drowsiness and/or paresthesia. In many cases, escalating the dose can result in a decrease in diuresis. However, in specific situations, very large doses may be administered alongside other diuretics to achieve diuresis in cases of complete refractory failure.

To ensure patient safety and monitor for potential hematologic reactions associated with sulfonamides, it is recommended that a baseline complete blood count (CBC) and platelet count be obtained prior to initiating acetazolamide tablet therapy. Regular monitoring of these parameters should continue throughout the course of treatment. Should significant changes in hematologic status occur, early discontinuation of the drug and the initiation of appropriate therapeutic measures are essential. Additionally, periodic monitoring of serum electrolytes is advised to detect any imbalances that may arise during therapy.

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 anaphylaxis, agranulocytosis, aplastic anemia, and fatalities due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and fulminant hepatic necrosis. These serious reactions may occur even with the first administration of the drug, and sensitizations can recur upon re-exposure, regardless of the route of administration. If any signs of hypersensitivity or other serious reactions manifest, it is imperative to discontinue use immediately.

Common adverse reactions reported in clinical trials and postmarketing experiences encompass a variety of systems. Patients frequently report headaches, malaise, fatigue, and fever. Local reactions at the injection site, such as pain and flushing, are also noted. Gastrointestinal disturbances, including nausea, vomiting, and diarrhea, are commonly observed.

Hematological and lymphatic adverse reactions may include blood dyscrasias such as leukopenia, thrombocytopenia, and thrombocytopenic purpura. Patients may also experience abnormal liver function, cholestatic jaundice, and hepatic insufficiency, with some cases progressing to fulminant hepatic necrosis.

Metabolic and nutritional effects can manifest as metabolic acidosis, electrolyte imbalances (notably hypokalemia and hyponatremia), and loss of appetite. Long-term therapy with phenytoin has been associated with osteomalacia, while patients may also experience hyperglycemia or hypoglycemia and taste alterations.

Neurological adverse reactions include drowsiness, paraesthesia (numbness and tingling of extremities and face), depression, excitement, ataxia, confusion, dizziness, and convulsions.

Skin reactions may present as allergic responses, including urticaria, photosensitivity, and severe conditions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Patients may also report disturbances in special senses, such as 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 serious outcomes such as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported in these cases.

Drug Interactions

Acetazolamide has several notable drug interactions that may impact patient management and therapeutic outcomes.

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: Acetazolamide decreases the gastrointestinal absorption of primidone, potentially lowering serum concentrations and diminishing its anticonvulsant efficacy. 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 reduced by acetazolamide, which may lead to an increased effect of quinidine.

• Lithium: Acetazolamide increases the excretion of lithium, potentially resulting in decreased serum levels of lithium.

• Cyclosporine: Acetazolamide may elevate serum levels of cyclosporine, necessitating monitoring of cyclosporine concentrations.

Pharmacodynamic Interactions:

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

• Antidiabetic Agents: Acetazolamide may cause fluctuations in blood glucose levels, warranting careful monitoring in patients receiving antidiabetic medications.

• Methenamine: The urinary antiseptic effect of methenamine may be inhibited by acetazolamide, which should be considered when co-administering these agents.

Combination with Other Carbonic Anhydrase Inhibitors:

Due to the potential for 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 consideration and monitoring are advised 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 in pediatric patients have not been established. Caution is advised when considering long-term therapy, 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. 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, 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.

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

There is no specific information regarding renal impairment, dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider individual patient factors when prescribing to patients with renal impairment, as the absence of detailed guidance necessitates careful clinical judgment.

Hepatic Impairment

Patients with hepatic impairment should be treated with caution due to the potential for severe reactions associated with sulfonamides, including the rare occurrence of fulminant hepatic necrosis, which can lead to fatalities. It is essential to monitor liver function closely in these patients to detect any deterioration in their condition.

No specific dosage adjustments are provided for patients with compromised liver function; however, clinicians should consider the overall clinical status of the patient and the severity of hepatic impairment when prescribing this medication. Regular assessment of liver enzymes and other relevant laboratory values is recommended to ensure patient safety and to mitigate the risk of adverse effects.

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.

Additionally, despite acetazolamide's high intraerythrocytic distribution and significant plasma protein binding properties, it is important to note that acetazolamide 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 to facilitate the removal of the drug from the system.

Nonclinical Toxicology

Long-term studies in animals to evaluate the carcinogenic potential of acetazolamide have not been conducted. In a bacterial mutagenicity assay, acetazolamide was found to be non-mutagenic when evaluated both with and without metabolic activation. Additionally, the drug demonstrated no adverse effects 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 for 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, agranulocytosis, aplastic anemia, and other blood dyscrasias, as well as anaphylaxis. It is noted that sensitizations may recur upon re-administration 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 warranted 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. Early detection of these reactions is crucial, and the drug should be discontinued with appropriate therapy initiated.

Both increases and decreases in blood glucose levels have been observed in patients treated with acetazolamide, necessitating consideration in individuals with impaired glucose tolerance or diabetes mellitus.

Acetazolamide treatment may lead to electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis. Periodic monitoring of serum electrolytes is recommended, particularly for patients with conditions that predispose them to electrolyte and acid/base imbalances, such as those with impaired renal function (including elderly patients), diabetes mellitus, and impaired alveolar ventilation.

Some adverse reactions associated with acetazolamide, including 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, severe metabolic acidosis may occur in elderly patients with reduced renal function.

Patient Counseling

Healthcare providers should advise patients that the use of acetazolamide may lead to adverse reactions common to all sulfonamide derivatives, including but not limited to anaphylaxis, fever, and various skin rashes such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Patients should be informed about the potential for 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 any adverse effects 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, emphasizing 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 warned about the potential for serious adverse effects, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death. Additionally, healthcare providers should inform patients that both increases and decreases in blood glucose levels have been reported with acetazolamide treatment, which is particularly relevant for those with impaired glucose tolerance or diabetes mellitus.

Electrolyte imbalances, such as hyponatremia and hypokalemia, as well as metabolic acidosis, may occur during treatment with acetazolamide. 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 also be made aware that some adverse reactions, including drowsiness, fatigue, and myopia, may impair their ability to drive or operate machinery safely. To monitor for hematologic reactions associated with 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 observed, early discontinuation and appropriate management should be implemented. Regular monitoring of serum electrolytes is also recommended throughout the course of therapy.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permissible between 15° to 30°C (59° to 86°F), in accordance with USP Controlled Room Temperature guidelines. Proper container requirements must be adhered to, and special handling needs should be followed to ensure product integrity.

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. 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 further safeguard patient health.

FDA Insert (PDF)

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

View full prescribing information (PDF)