Acetazolamide

Description

Acetazolamide, USP, is an inhibitor of the enzyme carbonic anhydrase. It appears as a white to faintly yellowish white crystalline, odorless powder that is weakly acidic. Acetazolamide is 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 222.24 and a molecular formula of C₄H₆N₄O₃S₂.

Acetazolamide is available in oral tablet form, containing 125 mg and 250 mg of acetazolamide, USP, respectively. The tablets include the following inactive ingredients: calcium stearate, lactose monohydrate, pregelatinized starch (maize), and sodium starch glycolate (type A).

Uses and Indications

This drug is indicated for the adjunctive treatment of edema due to congestive heart failure, drug-induced edema, and centrencphalic epilepsies, including 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 attempting rapid ascent, as well as in individuals who are particularly susceptible to acute mountain sickness despite gradual ascent.

No teratogenic or nonteratogenic effects have been reported.

Dosage and Administration

For the management 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; however, some patients may respond adequately to 250 mg twice daily for short-term therapy. In acute cases, an initial dose of 500 mg may be given, followed by 125 mg or 250 mg every four hours as needed. Intravenous therapy may be employed for rapid relief of ocular tension in acute situations.

In the treatment of epilepsy, the suggested total daily dose is between 8 mg per kg and 30 mg per kg, administered in divided doses, with an optimum range of 375 mg to 1000 mg daily. When acetazolamide is prescribed alongside 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 mg to 375 mg once daily in the morning, equivalent to approximately 5 mg/kg. Optimal diuretic effects are achieved when the medication is 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 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 500 mg to 1000 mg daily, divided into doses using 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 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, although rare, have been associated with severe reactions to sulfonamides, including but 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 crucial to recognize that sensitization may recur upon re-administration of a sulfonamide, regardless of the route of administration. Should any signs of hypersensitivity or other serious reactions manifest, the use of this drug must be discontinued immediately.

Caution is warranted for patients who are concurrently receiving high-dose 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.

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

Healthcare professionals should be aware that choroidal effusion and choroidal detachment have been reported following the use of acetazolamide in the postoperative period after ophthalmic surgery. If there is any suspicion of choroidal effusion or detachment, acetazolamide should be discontinued promptly.

To 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 initiating acetazolamide 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 initiation of appropriate therapy are essential. Additionally, periodic monitoring of serum electrolytes is advised to ensure patient safety.

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, which has been reported in rare cases, as well as severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Fatalities have occurred due to these severe reactions, along with fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is crucial to discontinue the medication immediately if any signs of hypersensitivity or serious reactions occur. Additionally, caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as severe outcomes including metabolic acidosis, coma, and death have been documented.

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 notable reactions include drowsiness, paraesthesia (numbness and tingling), depression, excitement, ataxia, confusion, and dizziness.

Skin reactions can manifest as allergic responses, including urticaria and photosensitivity. Eye disorders such as choroidal effusion, choroidal detachment, and transient myopia have also been observed. Urogenital effects may include crystalluria, hematuria, glycosuria, and an increased risk of nephrolithiasis with long-term therapy.

Metabolic and nutritional adverse reactions include metabolic acidosis, electrolyte imbalances (such as hypokalemia and hyponatremia), loss of appetite, taste alterations, and hyper/hypoglycemia. Hematological and lymphatic reactions may involve blood dyscrasias, including aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and thrombocytopenic purpura.

Patients should be monitored closely for these adverse reactions, particularly those that are serious or potentially life-threatening. Early detection and appropriate management are essential to mitigate risks associated with this medication.

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 of phenytoin. This interaction may enhance the risk of osteomalacia in patients undergoing chronic phenytoin therapy. Caution is advised for patients receiving chronic concomitant therapy.

• Primidone: Acetazolamide decreases the gastrointestinal absorption of primidone, potentially resulting in lower serum concentrations of primidone and its metabolites. This may diminish the anticonvulsant effect. Caution is recommended when initiating, discontinuing, or adjusting the dose of acetazolamide in patients on primidone therapy. Due to possible additive effects, concomitant use with other carbonic anhydrase inhibitors is not advisable.

• 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, potentially enhancing its pharmacological effects.

• Lithium: Acetazolamide increases the excretion of lithium, which may lead to decreased serum levels of lithium. Monitoring of lithium levels is recommended.

• 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 necessitate dosage adjustments or increased monitoring of therapeutic effects.

• Antidiabetic Agents: Acetazolamide has the potential to either increase or decrease blood glucose levels. Caution should be exercised in patients receiving antidiabetic medications, with appropriate monitoring of blood glucose levels.

• Methenamine: Acetazolamide may inhibit the urinary antiseptic effect of methenamine, which should be considered when co-administering these agents.

Combination Therapy Considerations:

• The concurrent use of acetazolamide and sodium bicarbonate increases the risk of renal calculus formation. Clinicians should evaluate the necessity of this combination and monitor for signs of renal complications.

In summary, careful monitoring and potential dosage adjustments are advised when acetazolamide is used in conjunction with the aforementioned medications to mitigate the risk of 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 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 implications of treatment with acetazolamide in women of childbearing potential and to discuss the potential risks with their patients.

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 associated with sulfonamides, including the rare occurrence of fulminant hepatic necrosis, which can be fatal. It is particularly important to monitor patients with compromised liver function who are receiving concomitant high-dose aspirin and acetazolamide, as these medications may exacerbate liver-related issues.

Healthcare providers are advised to assess liver function regularly and consider the overall clinical status of patients with hepatic impairment when determining the appropriateness of treatment and any necessary dosage adjustments.

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 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

Long-term studies in animals to evaluate the carcinogenic potential of acetazolamide have not been conducted. In a bacterial mutagenicity assay, acetazolamide was not found to be mutagenic when evaluated with and without metabolic activation. Additionally, the drug had no effect 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 in 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. 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 and/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.

Certain adverse reactions to acetazolamide, including 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. 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 sulfonamide derivatives, 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. Patients should be informed of the importance of early detection of these reactions, and that the medication should be discontinued immediately if such reactions occur, with appropriate therapy initiated.

For patients with pulmonary obstruction or emphysema, it is crucial 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 in conjunction with acetazolamide should be closely monitored, 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 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 acetazolamide therapy. 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 (particularly elderly patients), diabetes mellitus, and impaired alveolar ventilation.

Patients should also be made aware that certain adverse reactions to acetazolamide, including 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 of the drug and initiation of appropriate therapy are essential. Regular monitoring of serum electrolytes should be emphasized as part of ongoing patient care.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), in compliance with USP Controlled Room Temperature guidelines. 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 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 potential imbalances.

FDA Insert (PDF)

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

View full prescribing information (PDF)