Acetazolamide

Description

Acetazolamide extended-release capsules are a carbonic anhydrase inhibitor formulated for oral administration. Each capsule contains 500 mg of acetazolamide, which is a white to faintly yellowish white crystalline, odorless powder. Acetazolamide, USP, 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 222.24 and a chemical formula of C₄H₆N₄O₃S₂.

The extended-release capsules include inactive ingredients such as silicified microcrystalline cellulose, hypromellose, oleic acid, ethylcellulose, medium chain triglycerides, ammonium hydroxide, and talc. The capsule shell is composed of yellow iron oxide, gelatin, and titanium dioxide. The imprinting ink contains black iron oxide, D&C yellow #10 aluminum lake, FD&C blue #1/brilliant blue FCF aluminum lake, FD&C blue #2/indigo carmine aluminum lake, FD&C red #40/allura red AC aluminum lake, propylene glycol, and shellac glaze.

Uses and Indications

This drug is indicated for the adjunctive treatment of chronic simple (open-angle) glaucoma and secondary glaucoma. It is also indicated for use preoperatively in acute angle-closure glaucoma when a delay of surgery is desired to lower intraocular pressure.

Additionally, this drug is indicated for the prevention or amelioration of symptoms associated with acute mountain sickness, even when gradual ascent is undertaken.

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

For the management of glaucoma, the recommended dosage is 1 capsule (500 mg) administered twice daily. Typically, one capsule should be taken in the morning and another in the evening. While adjustments to the dosage may be necessary, it is generally observed that doses exceeding 2 capsules (1 g) do not yield additional therapeutic effects. Careful individual assessment of symptomatology and intraocular pressure is essential for dosage adjustments. Continuous supervision by a physician is advised to ensure optimal management.

In the case of acute mountain sickness, the dosage ranges from 500 mg to 1000 mg daily, divided into appropriate doses using either tablets or extended-release capsules. In situations involving rapid ascent, such as during rescue or military operations, the higher dosage of 1000 mg is recommended. It is preferable to initiate treatment 24 to 48 hours prior to ascent and to continue for 48 hours while at high altitude, or longer if necessary to effectively manage symptoms.

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, anaphylaxis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is crucial to recognize that sensitization may recur upon readministration 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 warranted 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.

In terms of general precautions, it is important to note that 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, escalating the dose results in a decrease in diuresis. However, under specific circumstances, 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 further safeguard patient health.

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 severe hypersensitivity reactions such as anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Fatalities, although rare, have been reported due to these severe reactions, as well as fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is important to note that sensitization may recur upon readministration of the drug, regardless of the route of administration. If any signs of hypersensitivity or other serious reactions occur, the use of this medication 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. Neurological effects such as drowsiness, paresthesia (including numbness and tingling of the extremities and face), depression, excitement, ataxia, confusion, convulsions, and dizziness have also been observed.

Hematological and lymphatic reactions may manifest as blood dyscrasias, including aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenic purpura. Patients may also experience melena. Hepato-biliary disorders can include abnormal liver function, cholestatic jaundice, hepatic insufficiency, and in severe cases, fulminant hepatic necrosis.

Metabolic and nutritional adverse reactions may involve metabolic acidosis, electrolyte imbalances (including hypokalemia and hyponatremia), loss of appetite, taste alterations, and hyperglycemia or hypoglycemia. Long-term therapy with phenytoin has been associated with osteomalacia.

Skin reactions can include allergic responses such as urticaria, photosensitivity, and severe skin conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis.

Patients may also report disturbances in special senses, including hearing disturbances and tinnitus, as well as transient myopia due to the forward movement of the ciliary body.

Urogenital adverse reactions may include crystalluria, an increased risk of nephrolithiasis with long-term therapy, hematuria, glycosuria, renal failure, and polyuria.

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 in these cases.

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, resulting in increased serum levels. This elevation may enhance the risk of osteomalacia in patients undergoing chronic phenytoin therapy. Caution is advised for patients receiving both medications concurrently.

• Primidone: The gastrointestinal absorption of primidone is decreased by acetazolamide, potentially leading to reduced serum concentrations of primidone and its metabolites. This interaction 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 urinary excretion of quinidine is also reduced by acetazolamide, potentially increasing its pharmacological effects.

• Lithium: Acetazolamide increases the excretion of lithium, which may result in decreased serum lithium levels. Monitoring of lithium levels is advised.

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

• Sodium Bicarbonate: Concurrent use with sodium bicarbonate raises the risk of renal calculus formation, warranting caution.

Pharmacodynamic Interactions:

• Folic Acid Antagonists: Acetazolamide may enhance the effects of other folic acid antagonists, which could necessitate dosage adjustments or increased monitoring for adverse effects.

• Methenamine: The urinary antiseptic effect of methenamine may be inhibited by acetazolamide, potentially compromising its therapeutic efficacy.

Laboratory Test Interactions:

• Sulfonamides: The use of sulfonamides may lead to false negative or decreased values in urinary phenolsulfonphthalein and phenol red elimination tests, as well as in serum non-protein and serum uric acid measurements.

• Crystalluria: Acetazolamide may increase the level of crystals in urine, which should be monitored.

• Theophylline Assays: Acetazolamide interferes with the high-performance liquid chromatography (HPLC) method for theophylline assay, with the degree of interference depending on the solvent used. Other assay methods for theophylline may not be affected.

In summary, careful consideration of these interactions is essential for optimizing therapeutic regimens and ensuring patient safety. Monitoring and dosage adjustments may be necessary based on the specific interactions noted.

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 extended-release capsules in pediatric patients below the age of 12 years 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. Due to the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies, dose selection for geriatric patients should be approached with caution. It is generally recommended to initiate treatment at the low end of the dosing range to mitigate potential risks and ensure safety. Regular monitoring of renal function and metabolic status is advised to identify any adverse effects promptly and to adjust dosing as necessary.

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 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 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 to sulfonamides, including the rare occurrence of fulminant hepatic necrosis, which can be fatal. It is recommended that healthcare providers closely monitor liver function in these patients, particularly when prescribing this medication.

Additionally, caution is advised for patients with compromised liver function who are receiving concomitant high-dose aspirin and acetazolamide. The interaction between these medications may exacerbate hepatic impairment and increase the risk of adverse effects. Regular assessment of liver function tests is recommended to ensure patient safety and to guide any necessary adjustments in therapy.

Overdosage

In cases of overdosage, no specific antidote is available; therefore, treatment should focus on symptomatic and supportive care. Healthcare professionals should be vigilant for potential complications, including electrolyte imbalances, the development of an acidotic state, and central nervous system effects.

Monitoring and Management

It is essential to monitor serum electrolyte levels, with particular attention to potassium, as well as blood pH levels. Supportive measures should be implemented to restore both electrolyte and pH balance. The acidotic state that may arise can typically be corrected through the administration of bicarbonate.

Dialysis Considerations

Despite the high intraerythrocytic distribution and significant plasma protein binding properties of acetazolamide, it may still be dialyzable. This characteristic is particularly relevant in the management of acetazolamide overdosage, especially when complicated by renal failure. In such cases, dialysis may be a critical component of the treatment strategy to facilitate the removal of the drug and mitigate its effects.

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 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 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, anaphylaxis, agranulocytosis, aplastic anemia, and other blood dyscrasias. 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 recommended for patients receiving concomitant high-dose aspirin and acetazolamide, as reports have indicated occurrences of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. Adverse reactions common to all sulfonamide derivatives 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.

Variations in blood glucose levels, both increases and decreases, have been documented in patients treated with acetazolamide. The treatment 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 associated with acetazolamide, such as drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery.

Growth retardation has been observed 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

Patients should be informed about the potential for adverse reactions common to all sulfonamide derivatives, including anaphylaxis, fever, and rash, which may manifest as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Other possible reactions include crystalluria, renal calculus, bone marrow depression, thrombocytopenic purpura, hemolytic anemia, leukopenia, pancytopenia, and agranulocytosis. Early detection of such reactions is crucial, and patients should be advised to discontinue the drug immediately if any of these reactions occur.

Caution is advised for patients with pulmonary obstruction or emphysema, as acetazolamide may precipitate or aggravate acidosis. Patients should be counseled on the importance of gradual ascent to avoid acute mountain sickness. It should be noted that while acetazolamide may be used during rapid ascent, it does not eliminate the need for prompt descent if severe forms of high altitude sickness, such as high altitude pulmonary edema (HAPE) or high altitude cerebral edema, occur.

Patients should also be cautioned about the potential for fluctuations in blood glucose levels while on acetazolamide, which is particularly important for those 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, especially in patients predisposed to these imbalances.

Additionally, patients should be informed that some adverse reactions to acetazolamide, such as drowsiness, fatigue, and myopia, may impair their ability to drive and operate machinery. It is recommended that a baseline complete blood count (CBC) and platelet count be obtained prior to initiating acetazolamide therapy and at regular intervals during treatment to monitor for hematologic reactions common to all sulfonamides. If significant changes occur, early discontinuance and appropriate therapy are important. Periodic monitoring of serum electrolytes should also be conducted throughout the treatment.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It should be stored at a controlled room temperature of 20°C to 25°C (68°F to 77°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 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 potential imbalances.

FDA Insert (PDF)

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

View full prescribing information (PDF)