Acetazolamide

Description

Acetazolamide extended-release capsules are formulated as an inhibitor of the enzyme carbonic anhydrase. The active ingredient, acetazolamide, is characterized as a white to faintly yellowish white crystalline, odorless powder that is 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, and it possesses a specific chemical structure.

Each capsule, intended for oral administration, contains 500 mg of acetazolamide. The formulation includes several inactive ingredients: ammonio methacrylate copolymer dispersion types A and B, FD&C yellow #6, gelatin, microcrystalline cellulose, sodium lauryl sulfate, talc, and titanium dioxide. The capsule is printed with black pharmaceutical ink, which contains black iron oxide as a coloring agent.

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 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 in the context of 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. Typically, one capsule should be taken in the morning and one in the evening. While dosage adjustments may be made based on individual patient response, it is important to note that dosages exceeding 2 capsules (1 g) do not generally yield an increased therapeutic effect. Continuous supervision by a physician is advisable to monitor the patient's response and adjust treatment as necessary.

In the case of acute mountain sickness, the recommended dosage ranges from 500 mg to 1,000 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 1,000 mg is recommended. 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 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. These reactions include, but are not limited to, Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, anaphylaxis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is important to note that sensitization 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 should be discontinued immediately.

Healthcare professionals should exercise caution when prescribing this medication to patients who are concurrently receiving high-dose aspirin and acetazolamide. There have been reports of serious adverse effects in such cases, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death. Continuous monitoring of patients under these circumstances is recommended to ensure timely identification and management of any potential complications.

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, which have been associated with fatalities, albeit rarely. Other serious hematological conditions such as agranulocytosis, aplastic anemia, and various blood dyscrasias have also been reported. Additionally, cases of fulminant hepatic necrosis and hepatic insufficiency have been observed. Due to the potential for sensitization, it is crucial to discontinue the medication if any signs of hypersensitivity or serious reactions occur.

Common adverse reactions reported in clinical trials and postmarketing experiences include headache, malaise, fatigue, and fever. Local reactions such as pain at the injection site and flushing have also been noted. Gastrointestinal disturbances, including nausea, vomiting, and diarrhea, are frequently observed.

Patients may also experience neurological effects such as drowsiness, dizziness, confusion, and paresthesia, which includes numbness and tingling in the extremities and face. Psychological effects such as depression and excitement have been documented, along with ataxia and convulsions.

Metabolic and nutritional adverse reactions include metabolic acidosis, electrolyte imbalances (notably hypokalemia and hyponatremia), and changes in appetite and taste. Long-term therapy with phenytoin has been associated with osteomalacia.

Dermatological reactions can manifest as allergic skin responses, including urticaria and photosensitivity, as well as more severe conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis.

In terms of urogenital effects, crystalluria, hematuria, glycosuria, and renal failure have been reported, alongside an increased risk of nephrolithiasis with long-term therapy and polyuria.

Patients should be monitored closely for these adverse reactions, particularly those that are serious or potentially life-threatening. Caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as severe reactions including metabolic acidosis and lethargy have been documented.

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 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, which may result in lower serum concentrations of primidone and its metabolites. This reduction could potentially 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, potentially enhancing both the magnitude and duration of their effects.

• Quinidine: The urinary excretion of quinidine is also reduced by acetazolamide, which may amplify its pharmacological effects.

• Lithium: Acetazolamide increases the excretion of lithium, which may lead to decreased serum lithium levels. Monitoring of lithium levels is advisable when these drugs 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, warranting caution in concurrent use.

• Methenamine: The urinary antiseptic effect of methenamine may be inhibited by acetazolamide, which could compromise its therapeutic efficacy.

Combination with Other Carbonic Anhydrase Inhibitors:The concomitant use of acetazolamide with other carbonic anhydrase inhibitors is not recommended due to the potential for additive effects.

Renal Considerations:The concurrent use of acetazolamide and sodium bicarbonate may increase the risk of renal calculus formation, and patients should be monitored accordingly.

Laboratory Test Interactions:

• Urinary Tests: 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.

• Crystalluria: Acetazolamide may lead to an increased level of crystals in the urine.

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

Healthcare professionals should exercise caution and consider appropriate monitoring when prescribing acetazolamide in conjunction with the aforementioned medications and conditions.

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, administered orally or parenterally, has demonstrated teratogenic effects in animal studies, specifically resulting in limb defects in mice, rats, hamsters, and rabbits. There are currently no adequate and well-controlled studies available in pregnant women to assess the safety and efficacy of acetazolamide during pregnancy.

Given the potential risks identified in animal studies, acetazolamide should be used in pregnant patients only if the potential benefits outweigh the risks to the fetus. Healthcare professionals are advised to carefully consider the necessity of acetazolamide therapy in this population and to discuss the potential risks with women of childbearing potential who may become pregnant while on treatment.

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

Patients with renal impairment have not been specifically addressed in terms of dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to individuals with reduced kidney function, as the lack of data necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in these patients to ensure safety and efficacy.

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 to detect any signs of hepatic deterioration.

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, necessitating careful evaluation and monitoring of liver-related parameters. Adjustments to dosing or treatment regimens may be required based on the severity of hepatic impairment and the patient's overall clinical status.

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 be dialyzable. This characteristic is particularly relevant in the management of acetazolamide overdosage, especially when renal failure is present. 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

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 risks to the fetus.

In terms of non-teratogenic effects, acetazolamide 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 1,000 mg for a 50 kg individual.

Long-term studies assessing the carcinogenic potential of acetazolamide have not been conducted in animals. However, results from a bacterial mutagenicity assay indicate that acetazolamide is not mutagenic, both with and without metabolic activation.

No additional specific details regarding animal pharmacology and toxicology are available beyond the aforementioned mutagenicity and fertility effects.

Postmarketing Experience

Fatalities have been reported, albeit rarely, 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 noted that sensitizations may recur upon readministration of a sulfonamide, regardless of the route of administration. In cases where signs of hypersensitivity or other serious reactions manifest, discontinuation of the drug is advised.

Caution is recommended for patients concurrently receiving high-dose aspirin and acetazolamide, as reports indicate occurrences of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. Adverse reactions that are 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.

Acetazolamide treatment has been associated with electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis; therefore, periodic monitoring of serum electrolytes is recommended. Additionally, some adverse reactions to acetazolamide, such as drowsiness, fatigue, and myopia, may impair the ability to drive and operate machinery.

For reporting suspected adverse reactions, individuals are encouraged to contact Chartwell RX, LLC at 1-845-232-1683 or the FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

Patient Counseling

Healthcare providers should advise patients about the potential for adverse reactions associated with sulfonamide derivatives, 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. Patients should be informed of the importance of early detection of these reactions, and that the medication should be discontinued if such reactions occur, with appropriate therapy initiated.

For patients with pulmonary obstruction or emphysema, healthcare providers should exercise caution when prescribing acetazolamide, as it may precipitate or exacerbate acidosis. It is also important to counsel patients on the benefits of gradual ascent to avoid acute mountain sickness. If rapid ascent is necessary and acetazolamide is used, patients should be made aware that this does not eliminate the need 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, 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, such as hyponatremia and hypokalemia, as well as metabolic acidosis, may occur during acetazolamide treatment. 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 (particularly elderly patients), diabetes mellitus, and impaired alveolar ventilation.

Patients should also be cautioned that some adverse reactions to acetazolamide, including 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 acetazolamide therapy, with regular follow-up assessments during treatment. If significant changes are detected, early discontinuation of the drug and initiation of appropriate therapy are crucial. Regular monitoring of serum electrolytes should be emphasized as part of ongoing patient care.

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, with regular monitoring throughout therapy to detect hematologic reactions common to sulfonamides. Significant changes in these parameters warrant early discontinuation of the drug and appropriate intervention. Additionally, periodic monitoring of serum electrolytes is recommended due to the potential for electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis.

Patients should be counseled on the risk of adverse reactions associated with sulfonamide derivatives, such as anaphylaxis, fever, and various skin reactions, and the importance of early detection and discontinuation of the drug if these occur. Caution is particularly advised for patients with pulmonary conditions, those receiving high-dose aspirin, and individuals with diabetes or impaired renal function, as these factors may exacerbate the risk of adverse effects. Furthermore, patients should be informed that acetazolamide may affect blood glucose levels and that side effects like drowsiness and fatigue could impair their ability to drive or operate machinery. Gradual ascent is recommended to prevent acute mountain sickness, and the use of acetazolamide does not eliminate the need for prompt descent in severe cases of high altitude sickness.

FDA Insert (PDF)

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

View full prescribing information (PDF)