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.

Acetazolamide is available in oral tablet form, with each tablet containing either 125 mg or 250 mg of acetazolamide. The tablets include the following inactive ingredients: corn starch, dibasic calcium phosphate dihydrate, magnesium stearate, purified water, sodium starch glycolate, and povidone.

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 of 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 administered, 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 mg per kg 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 mg 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 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 typically 500 mg to 1000 mg daily, divided into multiple doses. A higher dosage 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 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 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 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.

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 choroidal 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 tablet therapy. Regular monitoring of these parameters should continue throughout the course of therapy. Should significant changes be observed, 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 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. 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 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 manifest as metabolic acidosis, electrolyte imbalances (including hypokalemia and hyponatremia), loss of appetite, and alterations in taste.

Skin reactions may include allergic responses such as urticaria and photosensitivity. Eye disorders reported include choroidal effusion and transient myopia, while otologic reactions may involve hearing disturbances and tinnitus. Urogenital adverse reactions can include crystalluria, hematuria, glycosuria, and an increased risk of nephrolithiasis with long-term therapy.

Growth retardation has been noted in children, and there is a potential risk of flaccid paralysis. It is important for healthcare providers to monitor patients closely for these adverse reactions and to take appropriate action if they occur.

Drug Interactions

Concomitant use of acetazolamide with other medications may lead to significant drug interactions, necessitating careful monitoring and potential dosage adjustments.

Pharmacokinetic Interactions:

• Phenytoin: Acetazolamide modifies the metabolism of phenytoin, resulting in increased serum levels. 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 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 potentiate its effects.

• Lithium: Acetazolamide increases the excretion of lithium, potentially leading to decreased serum levels. Monitoring of lithium levels is advised.

• 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 in concurrent use.

• Antidiabetic Agents: Acetazolamide has the potential to either increase or decrease blood glucose levels. Patients on 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 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 advisable.

Renal Considerations:

The concurrent use of acetazolamide and sodium bicarbonate may increase the risk of renal calculus formation, and patients should be monitored for signs of renal complications.

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 and consider individual patient factors when prescribing to patients with reduced kidney function, as the absence of specific guidance necessitates careful clinical judgment.

Hepatic Impairment

Patients with hepatic impairment should be treated with caution due to the potential for severe reactions, including rare but serious outcomes such as fulminant hepatic necrosis associated with sulfonamide use. It is essential to monitor liver function closely in these patients, as compromised liver function may increase the risk of adverse effects.

While specific dosage adjustments for patients with hepatic impairment are not provided, healthcare professionals are advised to evaluate the individual patient's liver function and consider the severity of impairment when determining treatment plans. Regular monitoring of liver enzymes and overall liver function is recommended to ensure patient safety and to mitigate the risk of severe hepatic reactions.

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, particularly 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 levels.

In instances of acetazolamide overdosage, it is noteworthy that despite its significant intraerythrocytic distribution and high plasma protein binding, the drug may be dialyzable. This characteristic is particularly relevant in cases complicated by renal failure, where dialysis may aid in the management of the overdosage.

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 1000 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, 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.

Common adverse reactions associated with 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.

In patients treated with acetazolamide, both increases and decreases in blood glucose levels have been observed. Acetazolamide may also lead to electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis; therefore, periodic monitoring of serum electrolytes is recommended. Adverse reactions such as drowsiness, fatigue, and myopia may impair the ability to drive and operate machinery.

Growth retardation has been noted in children undergoing long-term therapy, likely 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 concomitant high-dose aspirin and acetazolamide about the potential for serious adverse effects, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death.

Patients with impaired glucose tolerance or diabetes mellitus should be informed that both increases and decreases in blood glucose levels have been reported with acetazolamide treatment, necessitating careful monitoring of their glucose levels.

Electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis, may occur with acetazolamide treatment. Therefore, periodic monitoring of serum electrolytes is recommended, particularly in patients with conditions that predispose them to such imbalances, including those with impaired renal function (especially 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 risk 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 various package configurations, with specific NDC numbers available upon request. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F). Temporary excursions are permitted between 15°C to 30°C (59°F to 86°F). Proper storage conditions are essential to maintain the integrity 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. 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 initiation of appropriate therapy are crucial. Additionally, periodic monitoring of serum electrolytes is recommended to manage potential imbalances.

FDA Insert (PDF)

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

View full prescribing information (PDF)