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 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. 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 mg 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 administered 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 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 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 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 essential. Additionally, periodic monitoring of serum electrolytes is advised to maintain patient safety during treatment.

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 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, and aplastic anemia. Patients may experience growth retardation, flaccid paralysis, and other blood dyscrasias, necessitating immediate discontinuation of the drug and appropriate therapeutic intervention upon detection of hypersensitivity or serious reactions.

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. Patients may experience drowsiness, dizziness, and paraesthesia, which can impair the ability to drive or operate machinery.

Hematological and lymphatic reactions may manifest as blood dyscrasias, including leukopenia, thrombocytopenia, and melena. Hepato-biliary disorders such as abnormal liver function, cholestatic jaundice, and hepatic insufficiency have been noted, with some cases leading to fulminant hepatic necrosis.

Metabolic and nutritional adverse reactions include metabolic acidosis and electrolyte imbalances, particularly hypokalemia and hyponatremia. Long-term therapy with phenytoin may lead to osteomalacia, while patients may also experience loss of appetite and alterations in taste.

Skin reactions can range from allergic responses, including urticaria and photosensitivity, to more severe conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis. Special senses may be affected, with reports of hearing disturbances, tinnitus, and transient myopia.

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

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. Additionally, both increases and decreases in blood glucose levels have been observed in patients treated with acetazolamide, which should be considered in those with impaired glucose tolerance or diabetes mellitus. Periodic monitoring of serum electrolytes is recommended due to the potential for electrolyte imbalances.

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 may decrease the gastrointestinal absorption of primidone, resulting in lower serum concentrations of primidone and its metabolites. This could potentially 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, 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.

Overall, careful monitoring and dosage adjustments may be necessary when acetazolamide is used in conjunction with these 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. Long-term therapy with acetazolamide has been associated with growth retardation in children, which is believed to be secondary to chronic acidosis. Caution is advised when considering the use of this medication in the pediatric population.

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 their responses differ from those of younger patients. 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 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 evaluate the risks and benefits before prescribing this medication 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

There is no specific information 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 rare occurrence of fulminant hepatic necrosis, which can lead to fatalities. It is essential to monitor liver function closely in these patients.

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 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, 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 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. Prompt initiation of dialysis may be warranted in such cases 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.

The drug demonstrated 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 1,000 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 commonly 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. 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.

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. Additionally, healthcare providers should inform patients that gradual ascent is recommended to avoid acute mountain sickness. If rapid ascent occurs while using acetazolamide tablets, 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 also be exercised for 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. Furthermore, both increases and decreases in blood glucose levels have been reported in patients treated with acetazolamide, which should be considered for those with impaired glucose tolerance or diabetes mellitus.

Healthcare providers should recommend periodic monitoring of serum electrolytes, as acetazolamide treatment may lead to electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis. This is particularly important for 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 informed 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 common to all 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 and appropriate therapy should be considered.

For nursing women, healthcare providers should 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 risk to the child. Acetazolamide should only be used by nursing women if the potential benefits justify the risks.

Lastly, the safety and effectiveness of acetazolamide in pediatric patients have not been established, and healthcare providers should be aware that growth retardation has been reported in children receiving long-term therapy, believed to be secondary to chronic acidosis. Metabolic acidosis, which can be severe, may also 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 keep the container tightly closed to maintain the integrity of the product.

Storage conditions require the product to be maintained 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 outlined by USP Controlled Room Temperature guidelines.

Healthcare professionals are reminded to keep this and all medications out of the reach of children to ensure safety.

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, early discontinuation of the medication and implementation of appropriate therapeutic measures 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 Major Pharmaceuticals. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)