Acetazolamide

Description

Acetazolamide Extended-release Capsules USP are a carbonic anhydrase inhibitor. The active ingredient, acetazolamide, is a white to faintly yellowish white, crystalline, odorless powder with a molecular weight of 222.25 g/mol and a chemical formula of C₄H₆N₄O₃S₂. Acetazolamide is sparingly soluble in practically boiling water, slightly soluble in alcohol, and very slightly soluble in water. The chemical name for acetazolamide is N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl) acetamide.

Each extended-release capsule intended for oral administration contains 500 mg of acetazolamide. The capsules also include inactive ingredients such as gelatin, iron oxide yellow, microcrystalline cellulose, sodium lauryl sulfate, talc, and titanium dioxide. The capsules are printed with black pharmaceutical ink, which consists of black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution. Acetazolamide Extended-release Capsules USP meet the USP Dissolution Test 3.

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 in the context of 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 1 capsule (500 mg) administered twice daily, with one capsule taken in the morning and one in the evening. While the standard dosage is effective, adjustments may be necessary based on individual patient response, particularly in relation to symptomatology and intraocular pressure. It is important to note that dosages exceeding 2 capsules (1 g) per day have not been shown to provide additional therapeutic benefit. 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 options may be utilized. For these forms, the recommended dosing schedule includes 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 prevention and treatment 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 advisable 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 due to its sulfonamide derivative nature.

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 but not limited to 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. In the event of any signs of hypersensitivity or other serious adverse reactions, the use of this drug must be discontinued immediately.

Caution is particularly warranted for patients who are concurrently receiving high-dose aspirin alongside acetazolamide. Reports have indicated that such combinations may lead to severe adverse effects, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death.

To ensure patient safety and 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 the initiation of acetazolamide therapy. Regular monitoring of these parameters should continue throughout the course of treatment. Should significant changes in hematologic status be observed, it is imperative to discontinue the drug promptly and initiate appropriate therapeutic measures. Additionally, periodic monitoring of serum electrolytes is advised to further safeguard against potential complications.

Side Effects

Adverse reactions associated with the use of this medication can be categorized by seriousness and frequency.

Serious adverse reactions, although rare, include fatalities due to severe hypersensitivity reactions such as anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia. Patients may experience recurrent sensitization upon re-administration of sulfonamides, regardless of the route of administration. It is crucial to discontinue the drug immediately if any signs of hypersensitivity or other serious reactions occur.

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 flushing, gastrointestinal disturbances (nausea, vomiting, diarrhea), and various hematological issues such as blood dyscrasias, including aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenic purpura.

Hepato-biliary disorders may manifest as abnormal liver function, cholestatic jaundice, hepatic insufficiency, and in severe cases, fulminant hepatic necrosis. Metabolic and nutritional adverse reactions include metabolic acidosis, electrolyte imbalances (notably hypokalemia and hyponatremia), loss of appetite, taste alterations, and fluctuations in blood glucose levels, which may be particularly concerning for patients with diabetes mellitus or impaired glucose tolerance.

Neurological effects such as drowsiness, paresthesia (numbness and tingling), depression, excitement, ataxia, confusion, convulsions, and dizziness have also been reported. Dermatological reactions can include allergic skin responses like urticaria, photosensitivity, and severe conditions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Ocular adverse reactions may involve choroidal effusion, choroidal detachment, and transient myopia. Urogenital issues include crystalluria, 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 severe reactions including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported. Periodic monitoring of serum electrolytes is recommended due to the potential for electrolyte imbalances and metabolic acidosis, particularly in patients with conditions that predispose them to such imbalances. Additionally, some adverse reactions, such as drowsiness and fatigue, may impair the ability to drive or operate machinery safely.

Drug Interactions

Acetazolamide has several notable drug interactions that warrant careful consideration in clinical practice.

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 long-term concomitant therapy with these agents.

• Primidone: Acetazolamide may decrease the serum concentrations of primidone and its metabolites by reducing gastrointestinal absorption. This could potentially diminish the anticonvulsant effect of primidone. 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 use of acetazolamide may reduce the urinary excretion of quinidine, potentially increasing its pharmacological effects.

• Lithium: Acetazolamide increases the excretion of lithium, which may result in decreased serum levels of lithium. Monitoring of lithium levels is advisable when these medications are used together.

• 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.

• Methenamine: The concurrent use of acetazolamide may prevent the urinary antiseptic effect of methenamine, potentially compromising 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 combination of acetazolamide and sodium bicarbonate may increase the risk of renal calculus formation, and caution should be exercised when these agents are used together.

In summary, careful monitoring and dosage adjustments may be necessary when acetazolamide is used in conjunction with the aforementioned medications to mitigate the risk of 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 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 lower end of the dosing range to mitigate potential risks and ensure safety. Regular monitoring of renal function and metabolic status is advised to adjust dosing as necessary and to prevent adverse effects in this population.

Pregnancy

Acetazolamide 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. 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 consider the risks and benefits before prescribing acetazolamide 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 child.

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 when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring of these patients.

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 are advised to evaluate the individual patient's liver status and consider the potential need for dose modifications or increased monitoring based on the severity of hepatic impairment. 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 various 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.

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

Nonclinical Toxicology

Acetazolamide has demonstrated teratogenic effects in nonclinical studies, with oral or parenteral administration resulting in limb defects in mice, rats, hamsters, and rabbits. There are no adequate and well-controlled studies available in pregnant women; therefore, acetazolamide should be used during pregnancy only if the potential benefits outweigh the potential risks to the fetus.

In terms of non-teratogenic effects, acetazolamide 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.

Long-term studies to assess the carcinogenic potential of acetazolamide have not been conducted in animals. Additionally, acetazolamide was evaluated in a bacterial mutagenicity assay and was found to be non-mutagenic, both with and without metabolic activation. No further specific details regarding animal pharmacology and toxicology are available beyond the studies on mutagenicity and carcinogenic potential.

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 indicate occurrences of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. Choroidal effusion and choroidal detachment have been documented following the use of acetazolamide in the postoperative period after ophthalmic surgery; discontinuation of acetazolamide should be considered if these conditions are suspected.

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. Both increases and decreases in blood glucose levels have been observed in patients treated with acetazolamide, necessitating caution 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; 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

Patients should be informed about the potential for adverse reactions associated with sulfonamide derivatives, including anaphylaxis, fever, and various skin rashes such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Other serious reactions may include crystalluria, renal calculus, bone marrow depression, thrombocytopenic purpura, hemolytic anemia, leukopenia, pancytopenia, and agranulocytosis. Early detection of these reactions is essential, and patients should be advised to discontinue the medication if any of these adverse effects occur.

Healthcare providers should exercise caution when prescribing acetazolamide to patients with pulmonary obstruction or emphysema, as the medication may precipitate or worsen acidosis. Patients should be counseled on the importance of gradual ascent to prevent acute mountain sickness. It should be emphasized that while acetazolamide may be used during rapid ascent, it does not negate 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.

Patients receiving high-dose aspirin in conjunction with acetazolamide should be closely monitored for serious adverse effects, which may include anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death. Additionally, both increases and decreases in blood glucose levels have been reported in patients treated with acetazolamide, necessitating careful consideration in those with impaired glucose tolerance or diabetes mellitus.

Electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis, may occur during acetazolamide treatment. Periodic monitoring of serum electrolytes is recommended, particularly for patients with conditions that predispose them to such imbalances. 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.

Prior to initiating acetazolamide therapy, it is advisable to obtain a baseline complete blood count (CBC) and platelet count, with regular monitoring during treatment to detect any hematologic reactions. Patients should be informed that acetazolamide may lead to an increased level of crystals in the urine.

Nursing mothers should consider the potential for serious adverse reactions in nursing infants and make an informed decision regarding the continuation of breastfeeding or the medication based on the importance of the drug to the mother. The safety and effectiveness of acetazolamide extended-release capsules in pediatric patients under the age of 12 have not been established, and there have been reports of growth retardation in children receiving long-term therapy, likely due to chronic acidosis.

In elderly patients, there is a risk of severe metabolic acidosis, particularly with reduced renal function. Caution is advised in dose selection, typically starting at the lower end of the dosing range.

Storage and Handling

The product is supplied in a tight container, in accordance with USP standards. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), as defined by 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, early discontinuation of the medication and implementation of appropriate therapeutic measures are crucial. Additionally, periodic assessment of serum electrolytes is recommended to further safeguard patient health.

FDA Insert (PDF)

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

View full prescribing information (PDF)