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.

Acetazolamide is available in oral tablet form, with dosages of 125 mg and 250 mg of acetazolamide per tablet. The formulation includes inactive ingredients such as dibasic calcium phosphate dihydrate, corn starch, crospovidone, povidone, purified water, and magnesium stearate.

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. In acute cases, an initial dose of 500 mg may be given, followed by subsequent doses of 125 mg or 250 mg every four hours.

In the treatment of epilepsy, the suggested total daily dose is between 8 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 prescribed alongside other anticonvulsants, the starting dose should be 250 mg once daily.

For patients with congestive heart failure, the starting dose is generally 250 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 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 between 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 with sulfonamides and other sulfonamide derivatives may occur.

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 particularly 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, other blood dyscrasias, and anaphylaxis. It is crucial to recognize that sensitizations may recur upon readministration 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 doses of 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 during treatment.

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 other serious conditions like fulminant hepatic necrosis, agranulocytosis, and aplastic anemia. It is crucial to discontinue the medication immediately if any 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, and fever. Patients may also experience pain at the injection site, flushing, and gastrointestinal disturbances such as nausea, vomiting, and diarrhea. Neurological effects such as drowsiness, dizziness, paraesthesia, and confusion have also been noted, which may impair the ability to drive or operate machinery.

Other notable adverse reactions encompass hematological and lymphatic disorders, including various blood dyscrasias such as leukopenia, thrombocytopenia, and aplastic anemia. Patients may also experience abnormal liver function, cholestatic jaundice, and in some cases, hepatic insufficiency or fulminant hepatic necrosis. Metabolic and nutritional issues, including metabolic acidosis, electrolyte imbalances, and changes in appetite or taste, have been reported as well.

Skin reactions can include allergic responses such as urticaria and photosensitivity. Additionally, patients may experience disturbances in special senses, including hearing disturbances and transient myopia. Urogenital adverse reactions may involve crystalluria, hematuria, and an increased risk of nephrolithiasis with long-term therapy.

Overall, while many of these adverse reactions are manageable, early detection and appropriate intervention are essential to ensure patient safety.

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 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, which may increase its pharmacological effects.

• Lithium: Acetazolamide increases the excretion of lithium, potentially leading to decreased serum levels. 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 necessitate dosage adjustments or increased monitoring for adverse effects.

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

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

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 monitoring and potential dosage adjustments are recommended for patients receiving acetazolamide 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 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. 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 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

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 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 function tests 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 tailored to the patient's clinical presentation.

Potential Symptoms and Monitoring Patients may exhibit symptoms related to electrolyte imbalances, the development of an acidotic state, and central nervous system effects. It is essential to monitor serum electrolyte levels, with particular attention to potassium, as well as blood pH levels to assess the patient's metabolic status.

Management Procedures Supportive measures are critical in restoring electrolyte and pH balance. The acidotic state can typically be corrected through the administration of bicarbonate, which helps to neutralize excess acidity in the blood.

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 be particularly relevant in cases of acetazolamide overdosage, especially when complicated by renal failure, as dialysis can 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 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 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, other blood dyscrasias, and 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.

Caution is recommended for patients receiving concomitant high-dose aspirin and acetazolamide, as reports indicate occurrences of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. Common adverse reactions associated with all 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.

Variations in blood glucose levels, both increases and decreases, have been documented in patients treated with acetazolamide. The treatment 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 to acetazolamide, such as drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery.

Growth retardation has been observed 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 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 should be informed that gradual ascent is recommended to minimize the risk of acute mountain sickness. If rapid ascent is necessary and acetazolamide tablets are used, 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 should be exercised when acetazolamide is administered to patients receiving concomitant high-dose aspirin, as serious adverse effects including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported.

Healthcare providers should discuss the potential for both increases and decreases in blood glucose levels in patients treated with acetazolamide, particularly in those with impaired glucose tolerance or diabetes mellitus. Additionally, patients should be made aware that acetazolamide treatment may lead to electrolyte imbalances, such as hyponatremia and hypokalemia, as well as metabolic acidosis. Therefore, periodic monitoring of serum electrolytes is recommended, especially in patients with conditions that predispose them to electrolyte and acid/base imbalances, including those with impaired renal function (particularly elderly patients), diabetes mellitus, and impaired alveolar ventilation.

Patients should also be cautioned that some adverse reactions to acetazolamide, 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 monitoring throughout treatment. If significant changes are detected, early discontinuation of the drug and initiation of appropriate therapy are essential. Periodic monitoring of serum electrolytes should also be conducted.

Finally, healthcare providers should discuss the potential risks of acetazolamide in nursing infants. A decision should be made regarding whether to discontinue nursing or to discontinue the drug, weighing the importance of the medication 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 accordance with the following 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 tablet therapy, clinicians are advised to obtain a baseline complete blood count (CBC) and platelet count prior to treatment initiation, as well as at regular intervals throughout the therapy. This monitoring is essential to detect hematologic reactions that are common to all sulfonamides.

In the event of significant changes in hematologic parameters, early discontinuation of the medication and the implementation of appropriate therapeutic measures are crucial. Additionally, periodic monitoring of serum electrolytes is recommended to manage potential imbalances effectively.

FDA Insert (PDF)

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

View full prescribing information (PDF)