Acetazolamide

Description

Acetazolamide is an inhibitor of the enzyme carbonic anhydrase, presented as a white to faintly yellowish white crystalline powder. It exhibits very slight solubility in water, sparing solubility in practically boiling water, and slight solubility 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 is available in oral tablet form, containing 125 mg and 250 mg of acetazolamide, respectively. The tablets include the following inactive ingredients: lactose monohydrate, maize starch, magnesium stearate, microcrystalline cellulose, povidone, 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

Acetazolamide is indicated for various conditions, and its administration should be tailored to the specific clinical scenario while ensuring continuous physician supervision.

For glaucoma, acetazolamide is utilized as an adjunct to standard therapy. The recommended dosage ranges from 250 mg to 1 g per 24 hours, typically administered in divided doses for amounts exceeding 250 mg. Doses above 1 g per 24 hours do not enhance efficacy. Dosage adjustments should be made with careful consideration of individual symptomatology and ocular tension. For secondary glaucoma and preoperative treatment of acute congestive glaucoma, the preferred regimen is 250 mg every four hours. In some instances, a short-term therapy of 250 mg twice daily may suffice. In acute cases, an initial dose of 500 mg may be followed by 125 or 250 mg every four hours. Intravenous administration may be employed for rapid relief of ocular tension.

In the management of epilepsy, the suggested total daily dose of acetazolamide is between 8 to 30 mg per kg, divided into multiple doses. The optimum daily dosage appears to range from 375 to 1000 mg. While some patients may respond to lower doses, amounts exceeding 1 g do not yield superior results compared to a 1 g dose. When used in conjunction with other anticonvulsants, the initial dose should be 250 mg once daily, in addition to the existing medications.

For congestive heart failure, the starting dose is generally 250 to 375 mg once daily in the morning, equating to approximately 5 mg/kg. If the patient does not continue to lose edema fluid after an initial response, it is advisable to skip the medication for one day. Optimal diuretic effects are achieved when acetazolamide 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 once daily for one or two days, alternating with a day of rest.

For acute mountain sickness, the dosage ranges from 500 mg to 1000 mg daily, administered in divided doses using either tablets or sustained-release capsules. A higher dose of 1000 mg is recommended for rapid ascent scenarios. 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 due to its sulfonamide derivative nature.

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. 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 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 essential. 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 some patients, as well as severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Fatalities, although rare, 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 are observed.

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 common reactions include drowsiness, dizziness, and paraesthesia, which may manifest as numbness and tingling in the extremities and face.

Hematological and lymphatic reactions may include blood dyscrasias such as leukopenia, thrombocytopenia, and thrombocytopenic purpura. Patients may also experience abnormal liver function, cholestatic jaundice, and hepatic insufficiency. Metabolic and nutritional adverse reactions can include metabolic acidosis, electrolyte imbalances (such as hypokalemia and hyponatremia), loss of appetite, and alterations in taste.

Skin reactions may present as allergic responses, including urticaria and photosensitivity. Additionally, patients may report hearing disturbances, tinnitus, and transient myopia. Urogenital adverse reactions can include crystalluria, hematuria, glycosuria, and an increased risk of nephrolithiasis with long-term therapy.

Caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as serious reactions such as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported. Regular monitoring for early detection of adverse reactions is recommended, and the medication should be discontinued if significant adverse effects occur.

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 long-term concomitant therapy with these agents.

• 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 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, potentially reducing 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.

In summary, careful consideration and monitoring are essential 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, 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. 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 implications of treatment with acetazolamide in women of childbearing potential and to discuss the risks and benefits 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 prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to this patient population.

Hepatic Impairment

Patients with hepatic impairment should be treated with caution due to the potential for severe reactions, including fulminant hepatic necrosis, which can be fatal, although such occurrences are rare. It is essential to monitor liver function closely in these patients to detect any adverse effects promptly.

No specific dosage adjustments are recommended 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 advised to ensure patient safety and to manage any emerging complications effectively.

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 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.

Adverse reactions common to all sulfonamide derivatives have been observed, including anaphylaxis, fever, rash (notably 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 documented. Acetazolamide may also lead to electrolyte imbalances, such as hyponatremia and hypokalemia, as well as metabolic acidosis; therefore, periodic monitoring of serum electrolytes is recommended. Some adverse reactions associated with 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.

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 if such reactions occur, with appropriate therapy initiated.

For patients with pulmonary obstruction or emphysema, healthcare providers should exercise caution when prescribing acetazolamide, as it may precipitate or exacerbate acidosis. It is advisable to discuss the importance of gradual ascent to avoid acute mountain sickness. If rapid ascent is necessary and acetazolamide is used, patients should be made aware that this does not eliminate the need for immediate descent in the event 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 cautioned 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, 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 also be made aware that some adverse reactions, such as 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 recommended that a baseline complete blood count (CBC) and platelet count be obtained prior to initiating acetazolamide therapy, with regular monitoring throughout treatment. If significant changes are observed, early discontinuation of the drug and initiation of appropriate therapy are crucial. Regular monitoring of serum electrolytes should also be emphasized.

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), adhering to the guidelines set forth by the United States Pharmacopeia (USP) for Controlled Room Temperature. 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 any potential imbalances.

FDA Insert (PDF)

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

View full prescribing information (PDF)