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 is characterized by a molecular weight of 222.25 and a chemical formula of C₄H₆N₄O₃S₂. The chemical name for acetazolamide is N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide, and it exhibits sparing solubility in practically boiling water, very slight solubility in water, and slight solubility in alcohol.

The extended-release capsules include inactive ingredients such as microcrystalline cellulose, sodium lauryl sulfate, and talc. The capsule shell is composed of D&C Red No. 28, D&C Yellow No. 10, FD&C Red No. 40, gelatin, and titanium dioxide. The imprinting ink contains shellac, propylene glycol, potassium hydroxide, and iron oxide black.

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 preoperative use in acute angle-closure glaucoma when a delay in 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 with gradual ascent.

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

Dosage and Administration

The recommended dosage for the management of glaucoma is 500 mg, administered as one capsule twice daily. Typically, one capsule should be taken in the morning and one in the evening. While dosage adjustments 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 any dosage modifications. Continuous supervision by a physician is advised to ensure optimal management.

In cases where adequate control is not achieved with the twice-daily administration of acetazolamide extended-release capsules, alternative formulations such as acetazolamide tablets or parenteral forms may be utilized. These should be administered according to more frequent dosing schedules, which may include 250 mg every four hours or an initial dose of 500 mg followed by 250 mg or 125 mg every four hours, tailored to the specific clinical scenario.

For the treatment of acute mountain sickness, the recommended 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 advised. 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 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 individuals 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 extended-release capsules 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 sensitizations may recur upon re-administration of a sulfonamide, regardless of the route of administration. Should any signs of hypersensitivity or other serious reactions manifest, the use of this drug must be discontinued immediately.

Caution is warranted for patients concurrently receiving high-dose aspirin alongside acetazolamide extended-release capsules. 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 in conjunction with 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 therapy with acetazolamide extended-release capsules. Regular monitoring of these parameters should continue throughout the treatment course to detect any hematologic reactions common to sulfonamides. 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 maintain 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, flaccid paralysis, and fatalities due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia. These serious reactions have been reported in clinical settings, and sensitization may recur upon readministration of sulfonamides, regardless of the route of administration. It is imperative to discontinue use immediately if signs of hypersensitivity or other serious reactions occur.

Common adverse reactions reported by patients include headache, malaise, fatigue, fever, and pain at the injection site. Additionally, gastrointestinal disturbances such as nausea, vomiting, and diarrhea have been frequently observed. Patients may also experience various nervous system effects, including drowsiness, dizziness, confusion, and paresthesia, which encompasses numbness and tingling in the extremities and face.

Hematological and lymphatic reactions may manifest as blood dyscrasias, including aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenic purpura. Abnormal liver function, cholestatic jaundice, and hepatic insufficiency are notable hepatobiliary disorders that may arise. Furthermore, metabolic and nutritional issues such as metabolic acidosis, electrolyte imbalances (including hypokalemia and hyponatremia), and changes in appetite or taste have been documented.

Skin reactions can include allergic responses such as urticaria, photosensitivity, and severe 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.

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

Caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide extended-release capsules, as serious outcomes such as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported in these cases.

Drug Interactions

Acetazolamide extended-release capsules exhibit several significant drug interactions that warrant careful consideration in clinical practice.

Pharmacokinetic Interactions

• Phenytoin: Acetazolamide modifies the metabolism of phenytoin, leading to increased serum levels. This elevation may enhance the risk of osteomalacia in patients undergoing chronic phenytoin therapy. Caution is advised for patients receiving concomitant therapy with phenytoin, and monitoring of phenytoin serum levels may be necessary.

• Primidone: The use of acetazolamide may decrease serum concentrations of primidone and its metabolites by reducing gastrointestinal absorption. This interaction could potentially diminish the anticonvulsant effect of primidone. Caution is recommended when initiating, discontinuing, or adjusting the dose of acetazolamide in patients on primidone therapy.

• Amphetamines: Acetazolamide decreases the urinary excretion of amphetamines, which may enhance both the magnitude and duration of their effects. Monitoring for increased effects of amphetamines is advisable.

• Quinidine: The urinary excretion of quinidine is reduced by acetazolamide, potentially enhancing its pharmacological effects. Clinicians should monitor patients for increased quinidine effects.

• Lithium: Acetazolamide increases the excretion of lithium, which may result in decreased serum lithium levels. Regular monitoring of lithium levels is recommended to avoid subtherapeutic effects.

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

Pharmacodynamic Interactions

• Folic Acid Antagonists: Acetazolamide may enhance the effects of other folic acid antagonists. Caution is advised when these agents are used concurrently.

• Carbonic Anhydrase Inhibitors: Due to the potential for additive effects, concomitant use of acetazolamide with other carbonic anhydrase inhibitors is not recommended.

• Methenamine: Acetazolamide may interfere with the urinary antiseptic effect of methenamine, which should be considered when prescribing these medications together.

Laboratory Test Interactions

• Sulfonamides: The use of sulfonamides may yield false negative or decreased values for urinary phenolsulfonphthalein and phenol red elimination values for urinary protein, serum non-protein, and serum uric acid.

• Theophylline Assays: Acetazolamide can interfere with the high-performance liquid chromatography (HPLC) method for theophylline assay, with the extent of interference depending on the solvent used in the extraction. Alternative assay methods for theophylline may not be affected.

• Urinary Crystals: Acetazolamide may lead to an increased level of crystals in the urine, which should be monitored in patients receiving this medication.

Clinicians are advised to consider these interactions when prescribing acetazolamide extended-release capsules and to implement appropriate monitoring strategies to mitigate potential adverse effects.

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 this population, as growth retardation has been reported in children, which is believed to be secondary to chronic acidosis associated with the treatment.

Geriatric Use

Elderly patients may experience metabolic acidosis, which can be severe, particularly in those with reduced renal function. Therefore, careful consideration of renal status is essential when treating this population.

In general, dose selection for geriatric patients should be approached with caution. It is recommended to initiate therapy at the lower end of the dosing range. This recommendation is based on the increased likelihood of diminished hepatic, renal, or cardiac function in elderly individuals, as well as the potential for concomitant diseases or interactions with other drug therapies. Regular monitoring of renal function and overall health status is advised to ensure safety and efficacy in this demographic.

Pregnancy

Acetazolamide, administered orally or parenterally, has been shown to be teratogenic in animal studies, with evidence of limb defects observed in mice, rats, hamsters, and rabbits. There are no adequate and well-controlled studies in pregnant women to assess the safety and efficacy of acetazolamide during pregnancy.

Due to the potential risks identified in animal studies, acetazolamide should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. It is classified as Pregnancy Category C, indicating that risk cannot be ruled out. Healthcare professionals are advised to carefully consider the risks and benefits when prescribing acetazolamide to pregnant patients or women of childbearing potential.

Lactation

Because of the potential for serious adverse reactions in nursing infants from acetazolamide extended-release capsules, 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 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 associated with sulfonamides, including the rare occurrence of fulminant hepatic necrosis, which can be fatal. It is particularly important to monitor patients with compromised liver function who are receiving concomitant high-dose aspirin and acetazolamide extended-release capsules.

Healthcare providers should assess liver function prior to initiating treatment and consider regular monitoring throughout the course of therapy to detect any signs of hepatic deterioration. Adjustments to dosage may be necessary based on the severity of liver impairment and the patient's overall clinical status.

Overdosage

In cases of overdosage with acetazolamide extended-release capsules, no specific antidote is available. Management should focus on symptomatic and supportive care.

Potential Symptoms and Monitoring Patients may experience electrolyte imbalances, the development of an acidotic state, and central nervous system effects. It is essential 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 crucial for restoring electrolyte and pH balance. The acidotic state can typically be corrected through the administration of bicarbonate. Additionally, despite the high intraerythrocytic distribution and significant plasma protein binding of acetazolamide, the drug may be dialyzable. This characteristic is particularly relevant in cases of overdosage complicated by renal failure, where dialysis may aid in the removal of the drug from the system.

Nonclinical Toxicology

Long-term studies in animals to evaluate the carcinogenic potential of acetazolamide extended-release capsules have not been conducted. In a bacterial mutagenicity assay, acetazolamide extended-release capsules were 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 1000 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, anaphylaxis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is noted that sensitizations 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 extended-release capsules, as reports indicate occurrences of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death.

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. Early detection of such reactions is crucial, and the drug should be discontinued with appropriate therapy initiated.

Both increases and decreases in blood glucose levels have been documented 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. Periodic monitoring of serum electrolytes is recommended, particularly for patients with conditions that predispose them to electrolyte and acid/base imbalances, such as impaired renal function (including elderly patients), diabetes mellitus, and impaired alveolar ventilation.

Some adverse reactions associated with acetazolamide, including 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, severe metabolic acidosis may occur in elderly patients with reduced renal function.

Patient Counseling

Healthcare providers should advise patients about the potential adverse reactions associated with acetazolamide extended-release capsules, which 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. Early detection of these reactions is crucial, and patients should be instructed to discontinue the medication and seek appropriate therapy if such reactions occur.

For patients with pulmonary obstruction or emphysema, it is important to use acetazolamide with caution, as it may precipitate or worsen acidosis. Providers should recommend gradual ascent to avoid acute mountain sickness and clarify that while acetazolamide may be used during rapid ascent, it does not eliminate the need for immediate descent in cases of severe high altitude sickness, such as high altitude pulmonary edema (HAPE) or high altitude cerebral edema.

Patients receiving high-dose aspirin concurrently with acetazolamide should be monitored closely, as there have been reports of serious adverse effects, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. Additionally, healthcare providers should inform patients that both increases and decreases in blood glucose levels have been observed with acetazolamide treatment, which is particularly relevant for those with impaired glucose tolerance or diabetes mellitus.

Electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis, may occur during treatment with acetazolamide. 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, diabetes mellitus, or impaired alveolar ventilation.

Patients should also be made aware 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 common to all sulfonamides, it is advisable to obtain a baseline complete blood count (CBC) and platelet count prior to initiating therapy and to conduct regular monitoring throughout treatment. If significant changes are detected, early discontinuation and appropriate management should be implemented.

For nursing mothers, healthcare providers should discuss the potential risks to nursing infants associated with 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.

The safety and effectiveness of acetazolamide extended-release capsules in pediatric patients under 12 years of age have not been established, and providers should inform parents that growth retardation has been reported in children receiving long-term therapy, likely due to chronic acidosis.

In elderly patients, there is a risk of severe metabolic acidosis, particularly in those with reduced renal function. Therefore, dose selection should be cautious, typically starting at the lower end of the dosing range to account for the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as outlined by the United States Pharmacopeia (USP) guidelines for controlled room temperature.

Care should be taken to ensure that the product is kept in its original container to maintain stability and integrity. Special handling requirements should be observed to prevent exposure to extreme temperatures outside the specified range.

Additional Clinical Information

To ensure patient safety during acetazolamide extended-release capsules therapy, clinicians should obtain a baseline complete blood count (CBC) and platelet count prior to initiation and continue monitoring at regular intervals. This is crucial for detecting hematologic reactions commonly associated with sulfonamides. In the event of significant changes in these parameters, early discontinuation of the medication and implementation of appropriate therapeutic measures are advised.

Additionally, periodic monitoring of serum electrolytes is recommended to manage potential imbalances during treatment.

FDA Insert (PDF)

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

View full prescribing information (PDF)