Acetazolamide

Description

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

Uses and Indications

This drug is indicated for the adjunctive treatment of edema due to congestive heart failure, drug-induced edema, and centrencephalic 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 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 1000 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. 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 typically between 500 mg to 1000 mg daily, divided into multiple doses. 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 reported due to severe reactions associated with 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. In the event of any signs of hypersensitivity or other serious adverse reactions, the use of this drug must be discontinued immediately.

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

To ensure patient safety and 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 the initiation of acetazolamide therapy. Regular monitoring of these parameters should continue throughout the course of treatment. Should significant changes in hematologic status be observed, it is imperative to discontinue the drug promptly and initiate appropriate therapeutic measures. Additionally, periodic monitoring of serum electrolytes is advised to further safeguard patient health during therapy.

Side Effects

Adverse reactions associated with the use of this medication can be categorized by seriousness and frequency.

Serious adverse reactions include anaphylaxis, which has been reported in rare cases, along with fatalities due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia. Patients may experience sensitization upon re-administration of sulfonamides, regardless of the route of administration. It is crucial to discontinue the drug immediately if signs of hypersensitivity or other serious reactions occur.

Common adverse reactions reported in clinical trials and postmarketing experiences include headache, malaise, fatigue, fever, and pain at the injection site. Gastrointestinal disturbances such as nausea, vomiting, and diarrhea are also frequently observed. Additionally, patients may experience drowsiness, paraesthesia (including numbness and tingling of extremities and face), depression, excitement, ataxia, confusion, and dizziness.

Skin reactions can manifest as allergic responses, including urticaria, photosensitivity, and severe conditions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Hematological and lymphatic adverse reactions may include blood dyscrasias such as aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and thrombocytopenic purpura.

Patients may also experience metabolic and nutritional issues, including metabolic acidosis, electrolyte imbalances (notably hypokalemia and hyponatremia), loss of appetite, taste alterations, and hyper/hypoglycemia. In children, growth retardation has been noted.

Hepato-biliary disorders may present as abnormal liver function, cholestatic jaundice, hepatic insufficiency, and in rare cases, fulminant hepatic necrosis. Urogenital adverse reactions include crystalluria, increased risk of nephrolithiasis with long-term therapy, hematuria, glycosuria, renal failure, and polyuria.

Eye disorders such as choroidal effusion, choroidal detachment, and transient myopia have also been reported. Otologic issues may include hearing disturbances and tinnitus.

Caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as severe reactions including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been documented.

Overall, early detection of adverse reactions is essential, and the drug should be discontinued with appropriate therapy initiated 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 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: The urinary antiseptic effect of methenamine may be inhibited by acetazolamide, which could reduce 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.

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 documented limb defects observed 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 acetazolamide therapy 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 available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

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

Dosage adjustments may be necessary based on the severity of hepatic impairment, and healthcare providers should evaluate the risks and benefits of treatment in this population. Regular assessment of liver enzymes and overall liver function is recommended to ensure patient safety and to mitigate the risk of serious 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 exhibit symptoms related to electrolyte imbalances, the development of an acidotic state, and central nervous system effects. It is crucial to monitor serum electrolyte levels, with particular attention to potassium, as well as blood pH levels to assess the patient's condition accurately.

Management Procedures Supportive measures are essential for restoring electrolyte and pH balance. The acidotic state can typically be corrected through the administration of bicarbonate, which helps to normalize blood pH.

In addition, despite acetazolamide's high intraerythrocytic distribution and significant plasma protein binding, 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 who present with renal failure, where dialysis can facilitate the removal of the drug from the system.

Nonclinical Toxicology

Acetazolamide has demonstrated teratogenic effects in animal studies, with oral or parenteral administration resulting in limb defects in mice, rats, hamsters, and rabbits. There are no adequate and well-controlled studies available in pregnant women; therefore, acetazolamide should be used during pregnancy only if the potential benefits outweigh the potential risks to the fetus.

In terms of non-teratogenic effects, acetazolamide did not affect 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 based on a 50 kg individual.

Long-term studies to assess the carcinogenic potential of acetazolamide in animals have not been conducted. Additionally, acetazolamide was found to be non-mutagenic in a bacterial mutagenicity assay, both with and without metabolic activation. No further specific details regarding animal pharmacology and toxicology are available beyond the aforementioned mutagenicity and fertility effects.

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.

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. Choroidal effusion and choroidal detachment have been documented following the use of acetazolamide in the postoperative period after ophthalmic surgery; discontinuation of acetazolamide is recommended if these conditions are suspected.

Adverse reactions common to all sulfonamide derivatives may manifest, including 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. 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; therefore, periodic monitoring of serum electrolytes is recommended. Some adverse reactions, such as 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, metabolic acidosis, which can be severe, 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 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 high-dose aspirin concurrently with acetazolamide, as this combination has been associated with serious adverse effects, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death.

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

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 monitoring throughout treatment. If significant changes are detected, early discontinuation and appropriate therapy are essential.

For nursing women, it is important to discuss the potential for serious adverse reactions in nursing infants due to acetazolamide. 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.

Finally, healthcare providers should inform patients that the safety and effectiveness of acetazolamide in pediatric patients have not been established, and growth retardation has been reported in children receiving long-term therapy, believed to be secondary to chronic acidosis. Additionally, metabolic acidosis, which can be severe, may occur in elderly patients with reduced renal function.

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), in accordance with USP Controlled Room Temperature guidelines. Additionally, it is crucial to keep this medication, along with all other medications, out of the reach of children to ensure safety.

Additional Clinical Information

To monitor for hematologic reactions associated with sulfonamides, clinicians should obtain a baseline complete blood count (CBC) and platelet count for patients prior to initiating acetazolamide tablets therapy. Regular monitoring of these parameters is advised throughout the treatment course. In the event of significant changes, early discontinuation of therapy and the implementation of appropriate interventions are crucial. Additionally, periodic monitoring of serum electrolytes is recommended to ensure patient safety.

FDA Insert (PDF)

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

View full prescribing information (PDF)