Acetazolamide

Description

Acetazolamide extended-release capsules are a carbonic anhydrase inhibitor formulated for oral administration. Each capsule contains 500 mg of acetazolamide, which is chemically designated as N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide. The molecular weight of acetazolamide is 222.24, and its chemical formula is C₄H₆N₄O₃S₂.

Acetazolamide USP appears as a white to faintly yellowish-white, crystalline, odorless powder. It is sparingly soluble in practically boiling water, slightly soluble in alcohol, and very slightly soluble in water. The capsules include inactive ingredients such as hydroxypropyl cellulose, 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 (24 to 27%), dehydrated alcohol (23 to 26%), isopropyl alcohol (1 to 3%), butyl alcohol (1 to 3%), propylene glycol (3 to 7%), strong ammonia solution (1 to 2%), black iron oxide (24 to 28%), potassium hydroxide (0.05 to 0.1%), and purified water (15 to 18%).

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

For the management of glaucoma, the recommended dosage is 1 capsule (500 mg) administered twice daily, with one capsule taken in the morning and one in the evening. It is important to note that dose adjustments may be necessary, as dosages exceeding 2 capsules (1 g) typically do not yield an increased therapeutic effect. Continuous supervision by a physician is advisable to monitor the patient's response and adjust the treatment as needed.

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 administration may be utilized. The recommended dosage for these alternatives is 250 mg every four hours. An initial dose of 500 mg may be administered, followed by subsequent doses of either 250 mg or 125 mg every four hours, depending on the 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. A higher dosage of 1000 mg is recommended in situations involving rapid ascent, such as during rescue or military operations. It is preferable to initiate dosing 24 to 48 hours prior to ascent and to continue treatment for 48 hours while at high altitude, or longer if necessary to effectively control 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. 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 and acetazolamide, as there have been reports of adverse effects including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death.

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 circumstances, 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 course of treatment. Should significant changes in hematologic status occur, 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, along with severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Fatalities have occurred due to these severe reactions, as well as fulminant hepatic necrosis, agranulocytosis, and aplastic anemia. Blood dyscrasias, including leukopenia and thrombocytopenic purpura, have also been noted. It is crucial to discontinue the medication 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, and fever. Patients may also experience pain at the injection site, flushing, and gastrointestinal disturbances such as nausea, vomiting, and diarrhea. Additionally, growth retardation has been observed in children, along with flaccid paralysis.

Hematological and lymphatic reactions may manifest as blood dyscrasias, including aplastic anemia, agranulocytosis, and melena. Hepato-biliary disorders may present 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 hyper/hypoglycemia. Long-term therapy with phenytoin has been associated with osteomalacia.

Nervous system reactions can include drowsiness, paresthesia (numbness and tingling of extremities and face), depression, excitement, ataxia, confusion, convulsions, and dizziness. Patients may also report hearing disturbances and tinnitus.

Skin reactions may involve allergic responses such as urticaria, photosensitivity, and severe skin conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis. Eye disorders may include choroidal effusion, choroidal detachment, and transient myopia due to ciliary body movement.

Urogenital adverse reactions can manifest as 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 serious reactions such as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported. Additionally, some adverse reactions, including drowsiness and fatigue, may impair the ability to drive or operate machinery. Early detection of adverse reactions is essential, and appropriate therapy should be instituted if necessary.

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: The gastrointestinal absorption of primidone is decreased by acetazolamide, potentially resulting in lower serum concentrations of primidone and its metabolites. This 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 lead to decreased serum lithium levels. Monitoring of lithium levels is advised.

• 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, warranting caution when these agents are used together.

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

• Methenamine: Acetazolamide may inhibit the urinary antiseptic effect of methenamine, which could compromise its therapeutic efficacy.

Laboratory Test Interactions

• Urinary Assays: Sulfonamides may produce false negative or decreased values for urinary phenolsulfonphthalein and phenol red elimination values for urinary protein, serum non-protein, and serum uric acid.

• Crystalluria: Acetazolamide may lead to an increased level of crystals in the urine, which should be monitored.

• Theophylline Assay: Acetazolamide interferes with the high-performance liquid chromatography (HPLC) method of assay for theophylline. The degree of interference may depend on the solvent used in the extraction process, although it may not affect other assay methods for theophylline.

Risk of Renal Calculi

The concurrent use of acetazolamide and sodium bicarbonate increases the risk of renal calculus formation, and this combination should be approached with caution.

In summary, careful consideration and monitoring are essential when acetazolamide is used in conjunction with the aforementioned medications and conditions to mitigate potential adverse effects and ensure therapeutic efficacy.

Packaging & NDC

The table below lists all NDC Code configurations of Acetazolamide Extended-Release, 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 documented 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 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 be fatal.

It is particularly important to monitor patients with compromised liver function who are receiving concomitant high-dose aspirin and acetazolamide, as these combinations may increase the risk of severe adverse reactions. Regular assessment of liver function is recommended to ensure patient safety and to guide any necessary adjustments in therapy.

Overdosage

In the event of an overdosage, no specific antidote is available. Management should focus on symptomatic and supportive care to address the patient's needs effectively.

Potential Symptoms and Effects Patients may experience various complications, including 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.

In cases 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 important in managing overdosage, especially when renal failure is present, as dialysis may aid in the removal of the drug from the system.

Healthcare professionals should remain vigilant and implement these management strategies promptly to mitigate the effects of overdosage.

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. Additionally, the drug had 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. 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 is warranted 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 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; 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 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. Patients should be informed of the importance of early detection of such reactions, and that the drug should be discontinued immediately if any adverse effects are observed, with appropriate therapy instituted.

For patients with pulmonary obstruction or emphysema, healthcare providers should exercise caution when prescribing acetazolamide, as it may precipitate or exacerbate acidosis in individuals with impaired alveolar ventilation.

Patients should be counseled on the importance of gradual ascent to avoid acute mountain sickness. If rapid ascent is necessary and acetazolamide is used, it should be emphasized 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.

Healthcare providers should also caution patients receiving concomitant high-dose aspirin and acetazolamide, as serious adverse effects including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported.

Patients with impaired glucose tolerance or diabetes mellitus should be informed that both increases and decreases in blood glucose levels have been observed in those treated with acetazolamide, necessitating careful monitoring of their condition.

Acetazolamide treatment may lead to electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis. Therefore, healthcare providers should recommend periodic monitoring of serum electrolytes, 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.

Patients should be made aware 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 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 monitoring throughout treatment. If significant changes are detected, early discontinuation of the drug and initiation of appropriate therapy are crucial. Periodic monitoring of serum electrolytes should also be emphasized.

Storage and Handling

The product is supplied in well-closed containers to ensure integrity and stability. It should be stored at a temperature range of 20° to 25° C (68° to 77° F), in accordance with USP Controlled Room Temperature guidelines. Proper storage conditions are essential to maintain the quality 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, as well as at regular intervals throughout the therapy. This monitoring is crucial for detecting hematologic reactions that are common to all sulfonamides. In the event of significant changes in these parameters, early discontinuation of the medication and the implementation of appropriate therapeutic measures are essential. Additionally, periodic monitoring of serum electrolytes is recommended to further safeguard patient health.

FDA Insert (PDF)

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

View full prescribing information (PDF)