Acetazolamide

Description

Acetazolamide, USP 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 specific chemical structure.

Acetazolamide Tablets, USP are formulated for oral administration, available in dosages of 125 mg and 250 mg of acetazolamide, USP, respectively. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone K30, and talc. The formulation meets the USP Dissolution Test 2 standards.

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; however, some patients may respond adequately to 250 mg twice daily for short-term therapy. 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 as needed.

In the treatment of epilepsy, the suggested total daily dose is between 8 to 30 mg per kg, divided into multiple doses, with an optimum range of 375 to 1000 mg daily. When acetazolamide is prescribed alongside other anticonvulsants, the starting dose should be 250 mg once daily, with the possibility of increasing the dosage based on clinical response.

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. To achieve optimal diuretic effects, acetazolamide tablets are best 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, administered in divided doses using either tablets or sustained-release capsules. 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 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 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 hypersensitivity signs 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. Reports have indicated that such combinations may lead to severe adverse effects, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death.

Increasing the dosage of acetazolamide does not enhance diuresis and may, in fact, lead to an increased incidence of drowsiness and/or paresthesia. In many cases, higher doses can 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 documented following the use of acetazolamide in the postoperative period after ophthalmic surgery. If there is any suspicion of choroidal effusion or 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 therapy. Regular monitoring of these parameters should continue throughout the treatment. 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 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 fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is important to note that sensitization may recur upon re-administration of the drug, regardless of the route. If any signs of hypersensitivity or other serious reactions occur, the drug should be discontinued immediately.

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, paraesthesia (numbness and tingling of extremities and face), and dizziness. Additionally, patients may report alterations in taste, loss of appetite, and metabolic changes such as hyperglycemia or hypoglycemia.

Hematological and lymphatic reactions may manifest as blood dyscrasias, including leukopenia, thrombocytopenia, and thrombocytopenic purpura. Hepatic adverse reactions can include abnormal liver function, cholestatic jaundice, and hepatic insufficiency. Metabolic and nutritional issues may arise, such as metabolic acidosis and electrolyte imbalances, particularly hypokalemia and hyponatremia, especially with long-term therapy.

Skin reactions can range from allergic responses, including urticaria and photosensitivity, to more severe conditions like Stevens-Johnson syndrome. Otologic effects may include hearing disturbances and tinnitus, while eye disorders can present as choroidal effusion, choroidal detachment, and transient myopia.

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

Caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as serious reactions such as metabolic acidosis, lethargy, and even death have been documented. Additionally, some adverse reactions, including drowsiness and fatigue, may impair the ability to drive or operate machinery. Early detection of adverse reactions is crucial, and appropriate therapy should be instituted if necessary.

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 efficacy. 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 lead to an increased effect of quinidine.

• Lithium: Acetazolamide increases the excretion of lithium, potentially resulting in decreased serum levels of lithium.

• Cyclosporine: Acetazolamide may elevate serum levels of cyclosporine, necessitating monitoring of cyclosporine concentrations.

Pharmacodynamic Interactions:

• Folic Acid Antagonists: Acetazolamide may enhance the effects of other folic acid antagonists, warranting careful monitoring of therapeutic outcomes.

• Antidiabetic Agents: Acetazolamide may cause fluctuations in blood glucose levels, which should be considered in patients receiving antidiabetic medications.

• Methenamine: The urinary antiseptic effect of methenamine may be inhibited by acetazolamide, which could compromise 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 should be taken into account when considering treatment options.

In summary, careful monitoring and dosage adjustments may be necessary 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. Due to the absence of adequate and well-controlled studies in pregnant women, the safety of acetazolamide during pregnancy remains unclear. 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 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 are not provided, healthcare professionals should consider the overall clinical status of patients with liver problems and adjust treatment accordingly. Regular assessment of liver function tests 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 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 patients who present with renal failure.

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 assessed both with and without metabolic activation. Additionally, the drug did not adversely 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 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.

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.

Patient Counseling

Healthcare providers should advise patients that the use of acetazolamide may lead to adverse reactions common to all sulfonamide derivatives, including but not limited to anaphylaxis, fever, and various skin rashes such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Patients should be informed about the potential for crystalluria, renal calculus, bone marrow depression, thrombocytopenic purpura, hemolytic anemia, leukopenia, pancytopenia, and agranulocytosis. Early detection of these reactions is crucial, and patients should be instructed to discontinue the medication and seek appropriate therapy if they experience any concerning symptoms.

For patients with pulmonary obstruction or emphysema, healthcare providers should emphasize the need for caution when using acetazolamide, as it may precipitate or worsen acidosis in individuals with impaired alveolar ventilation.

Patients planning to ascend to high altitudes should be counseled on the importance of gradual ascent to minimize the risk of acute mountain sickness. If rapid ascent occurs while using acetazolamide, it should be clearly communicated that this does not eliminate the necessity for immediate 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 with impaired glucose tolerance or diabetes mellitus should be made aware that both increases and decreases in blood glucose levels have been reported with acetazolamide treatment. This information is vital for managing their condition effectively.

Electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis, may occur during acetazolamide therapy. Therefore, healthcare providers should recommend periodic monitoring of serum electrolytes, particularly for patients with conditions that predispose them to such imbalances, including those with impaired renal function, elderly patients, and individuals with diabetes mellitus or impaired alveolar ventilation.

Patients should be informed 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 associated with sulfonamides, it is advisable for healthcare providers to obtain a baseline complete blood count (CBC) and platelet count prior to initiating acetazolamide therapy, with regular follow-up assessments during treatment. If significant changes are detected, early discontinuation of the medication and appropriate therapeutic interventions should be implemented. Regular monitoring of serum electrolytes is also recommended throughout the course of therapy.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It should be stored at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permitted between 15° to 30°C (59° to 86°F), in accordance 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. 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 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 ANI Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)