Acetazolamide

Description

Acetazolamide 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. Each tablet contains 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 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 regimen for secondary glaucoma and preoperative treatment of acute congestive glaucoma is 250 mg every four hours, or alternatively, 250 mg twice daily for short-term therapy. In acute cases, an initial dose of 500 mg may be administered, followed by subsequent doses of 125 mg or 250 mg every four hours. 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 to 30 mg per kg, divided into multiple doses, with an optimum range of 375 to 1,000 mg daily. When acetazolamide is prescribed alongside other anticonvulsants, the starting dose should be 250 mg once daily.

For patients with congestive heart failure, the typical starting dose is 250 to 375 mg once daily in the morning, which corresponds 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 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 1,000 mg daily, administered in divided doses using either tablets or sustained-release capsules. A higher dose 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, 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. In the event of any signs of hypersensitivity or other serious reactions, the use of this drug must be discontinued immediately.

Caution is advised for patients who are concurrently receiving high-dose aspirin and acetazolamide. Serious adverse effects such as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death have been documented in these cases.

Increasing the dosage of acetazolamide does not enhance diuresis and may lead to an increased incidence of drowsiness and/or paresthesia. In fact, higher doses can often result in decreased 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, 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 treatment course to detect any hematologic reactions common to sulfonamides. Should significant changes in laboratory results occur, early discontinuation of the drug and initiation of appropriate therapy are imperative. Additionally, periodic monitoring of serum electrolytes is advised to maintain 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 signs of hypersensitivity or other serious reactions occur. Additionally, caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as severe outcomes including metabolic acidosis and coma 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. Neurological effects such as drowsiness, dizziness, confusion, and paraesthesia (numbness and tingling) have been noted, along with mood changes including depression and excitement.

Skin reactions may manifest as allergic responses, including urticaria and photosensitivity. Patients have also reported disturbances in hearing and transient myopia.

Metabolic and nutritional adverse reactions include electrolyte imbalances, such as hypokalemia and hyponatremia, as well as metabolic acidosis. Long-term therapy with phenytoin has been associated with osteomalacia, and fluctuations in blood glucose levels have been observed in patients with diabetes mellitus or impaired glucose tolerance.

Urogenital adverse reactions may include crystalluria, hematuria, glycosuria, and an increased risk of nephrolithiasis with long-term therapy. Renal failure and polyuria have also been reported.

Monitoring of serum electrolytes is recommended, particularly in patients predisposed to electrolyte and acid/base imbalances, such as those with impaired renal function or diabetes mellitus. Some adverse reactions, including drowsiness and fatigue, may impair the ability to drive or operate machinery, necessitating caution in these activities.

Overall, early detection of adverse reactions is essential, and appropriate therapeutic measures should be instituted as necessary.

Drug Interactions

Acetazolamide is associated with several significant drug interactions that may impact therapeutic outcomes and safety.

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 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.

• 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 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, warranting caution when these agents are used together.

• 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: The urinary antiseptic effect of methenamine may be inhibited by acetazolamide, which could compromise its therapeutic 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 recommended.

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 consideration of dosage adjustments 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 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 evidence of limb defects observed in mice, rats, hamsters, and rabbits. There are 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 benefit justifies the potential risk to the fetus. Healthcare professionals are advised to carefully consider the risks and benefits before prescribing acetazolamide 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 to sulfonamides, including the rare occurrence of fulminant hepatic necrosis, which can be fatal. It is essential to monitor liver function closely in these patients, particularly when initiating therapy or adjusting dosages.

Additionally, patients receiving concomitant high-dose aspirin and acetazolamide may require further evaluation and monitoring, as the combination of these medications could exacerbate hepatic concerns. Adjustments to the treatment regimen should be considered based on the patient's liver function status and overall clinical condition. 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 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.

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 patients with concurrent renal failure.

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 1,000 mg based on 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 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 have indicated 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.

Growth retardation has been noted in children undergoing long-term therapy, believed to be secondary to chronic acidosis. Severe metabolic acidosis may occur in elderly patients with diminished renal function. Both increases and decreases in blood glucose levels have been documented in patients treated with acetazolamide. Treatment with 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 associated with acetazolamide, such as drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery. To report 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 that adverse reactions common to all sulfonamide derivatives may occur, including but not limited to 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 immediately if any adverse effects are observed, with appropriate therapy instituted.

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.

When discussing the prevention of acute mountain sickness, healthcare providers should recommend gradual ascent to avoid complications. If rapid ascent is necessary and acetazolamide tablets are used, it is important to inform patients 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.

Healthcare providers should also caution patients receiving concomitant high-dose aspirin and acetazolamide, as there have been reports of serious adverse effects including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death.

Patients should be informed that both increases and decreases in blood glucose levels have been observed in those treated with acetazolamide. This is particularly relevant for patients with impaired glucose tolerance or diabetes mellitus, and they should be monitored accordingly.

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 (particularly 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 safely.

To monitor for hematologic reactions associated with sulfonamides, healthcare providers should recommend obtaining a baseline complete blood count (CBC) and platelet count prior to initiating acetazolamide therapy, with regular intervals for monitoring during treatment. If significant changes are detected, early discontinuation and appropriate therapy should be considered.

Finally, healthcare providers should discuss the potential risks of acetazolamide in nursing infants. A 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. Acetazolamide should only be used by nursing women if the potential benefits justify the risks.

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 store the product 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 defined by USP Controlled Room Temperature guidelines.

To ensure the integrity of the product, the container must be kept tightly closed when not in use. Additionally, it is crucial to keep this and all medications out of the reach of children.

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 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 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)