Acetazolamide

Description

Acetazolamide Extended-Release Capsules are formulated as an inhibitor of the enzyme carbonic anhydrase. Each capsule contains 500 mg of acetazolamide, which is characterized as a white to faintly yellowish white crystalline, odorless powder. Acetazolamide 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.

These extended-release capsules are intended for oral administration and include inactive ingredients such as microcrystalline cellulose, sodium lauryl sulfate, hydroxypropyl cellulose, and talc. The capsule shell is composed of FD&C green #3, FDA/E172 black iron oxide, FDA/E172 yellow iron oxide, titanium dioxide, and gelatin. The imprinting ink contains shellac, propylene glycol, potassium hydroxide, and black iron oxide.

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 in cases 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, typically one capsule in the morning and one in the evening. Dosage adjustments may be made; however, doses exceeding 2 capsules (1 g) generally do not yield additional therapeutic effects. Continuous supervision by a physician is advised to monitor the patient's response to treatment.

In cases where adequate control is not achieved with the standard twice-daily regimen, alternative administration of acetazolamide in tablet or parenteral form may be considered. This can be done using more frequent dosing schedules, such as 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 individual patient's needs.

For the treatment of acute mountain sickness, the recommended dosage ranges from 500 mg to 1000 mg daily, divided into appropriate doses using 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 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 with sulfonamides and other sulfonamide derivatives may occur.

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 associated with severe reactions to 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. Should any signs of hypersensitivity or other serious reactions manifest, 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.

It is important to note that increasing the dose of acetazolamide does not enhance diuresis and may, in fact, elevate the incidence of drowsiness and/or paresthesia. In many cases, escalating the dosage can lead to a reduction in diuresis. However, in specific situations, very large doses may be administered alongside other diuretics to achieve diuresis in cases of complete refractory failure.

Healthcare professionals should be aware that choroidal effusion and choroidal detachment have been reported 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 ensure patient safety and monitor for hematologic reactions commonly associated with 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 be observed, early discontinuation of the drug and initiation of appropriate therapy are imperative. 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 anaphylaxis, which can be life-threatening, and fatalities have been reported, albeit rarely, due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia. Other blood dyscrasias, including leukopenia and thrombocytopenic purpura, have also been observed. Patients should be monitored for signs of hypersensitivity or other serious reactions, and the medication should be discontinued immediately if such symptoms arise. Caution is particularly advised for patients receiving concomitant high-dose aspirin and acetazolamide, as severe outcomes including metabolic acidosis, coma, and death have been documented.

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, dizziness, confusion, and paresthesia (numbness and tingling of extremities and face) have been noted, along with mood alterations including depression and excitement.

Dermatological reactions can manifest as allergic skin responses, including urticaria, photosensitivity, and severe conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis. Patients may also report hearing disturbances and tinnitus.

Metabolic and nutritional adverse reactions include metabolic acidosis, electrolyte imbalances (notably hypokalemia and hyponatremia), loss of appetite, and alterations in taste. Long-term therapy with phenytoin has been associated with osteomalacia, while hyperglycemia and hypoglycemia have also been reported.

Hepatic adverse reactions may present as abnormal liver function, cholestatic jaundice, hepatic insufficiency, and in severe cases, fulminant hepatic necrosis. Urogenital effects include crystalluria, increased risk of nephrolithiasis, hematuria, glycosuria, renal failure, and polyuria.

In pediatric populations, growth retardation has been observed, and there is a risk of flaccid paralysis. Eye disorders such as choroidal effusion, choroidal detachment, and transient myopia have also been reported.

Overall, healthcare providers should remain vigilant for these adverse reactions and manage them appropriately to ensure patient safety.

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, potentially resulting in lower 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 reduces the urinary excretion of amphetamines, which may enhance both the magnitude and duration of their effects.

• Quinidine: The urinary excretion of quinidine is also decreased by acetazolamide, potentially increasing its pharmacological effects.

• Lithium: Acetazolamide increases the excretion of lithium, which may lead to decreased serum levels. Monitoring of lithium levels is advised, especially when initiating or adjusting acetazolamide therapy.

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

• Sodium Bicarbonate: Concurrent use of acetazolamide and sodium bicarbonate may increase the risk of renal calculus formation.

Pharmacodynamic Interactions

• Folic Acid Antagonists: Acetazolamide may enhance the effects of other folic acid antagonists, warranting caution in patients receiving these agents.

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

Laboratory Test Interactions

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

• 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 for the assay of theophylline. The degree of interference is dependent on the solvent used in the extraction process; however, acetazolamide may not affect other assay methods for theophylline.

In summary, careful consideration and monitoring are advised when acetazolamide is used in conjunction with the aforementioned medications and laboratory tests to mitigate potential 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 breastfed infant.

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.

Hepatic Impairment

Patients with hepatic impairment should be treated with caution due to the potential for severe reactions, including fulminant hepatic necrosis, which can be fatal, although such occurrences are rare. It is essential to monitor liver function closely in these patients to detect any adverse effects promptly.

Dosage adjustments may be necessary based on the severity of liver impairment, and healthcare providers should evaluate the risks versus benefits of treatment in this population. Regular assessment of liver enzymes and overall liver function is recommended to ensure patient safety and to guide therapeutic decisions.

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 of overdosage may include 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. Supportive measures should be implemented to restore both electrolyte and pH balance. The acidotic state can typically be corrected through the administration of bicarbonate.

Additionally, despite Acetazolamide's high intraerythrocytic distribution and significant plasma protein binding properties, it may be dialyzable. This characteristic is particularly relevant in the management of acetazolamide overdosage, especially when complicated by renal failure. Healthcare professionals should consider dialysis as a potential intervention in such cases to facilitate the removal of the drug from the system.

Nonclinical Toxicology

Acetazolamide has demonstrated teratogenic effects in animal 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 based on a 50 kg individual.

Long-term studies to assess the carcinogenic potential of acetazolamide have not been conducted in animals. However, in a bacterial mutagenicity assay, acetazolamide was found to be non-mutagenic, both with and without metabolic activation.

No additional specific details regarding animal pharmacology and toxicology are provided beyond the information included in this section.

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.

Adverse reactions commonly associated with all sulfonamide derivatives 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.

Caution is recommended for patients concurrently receiving high-dose aspirin and acetazolamide, as reports have indicated occurrences of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. Acetazolamide treatment may also lead to electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis; therefore, periodic monitoring of serum electrolytes is suggested.

Some adverse reactions related 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 Westminster Pharmaceuticals, LLC at 1-844-221-7294 or the FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

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. It is advisable to discuss the potential risks associated with this medication in such patients.

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 there have been reports of serious adverse effects including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death.

Patients with impaired glucose tolerance or diabetes mellitus should be informed that both increases and decreases in blood glucose levels have been reported with acetazolamide treatment. This information is crucial for managing their condition effectively.

Electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis, may occur with acetazolamide treatment. Therefore, periodic monitoring of serum electrolytes is recommended, particularly for patients with conditions that predispose them to such imbalances, including those with impaired renal function (especially 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, healthcare providers should recommend obtaining a baseline complete blood count (CBC) and platelet count prior to initiating acetazolamide therapy, as well as at regular intervals during treatment. If significant changes are detected, early discontinuation of the drug and initiation of appropriate therapy are essential.

Finally, periodic monitoring of serum electrolytes should be emphasized as a standard practice during acetazolamide therapy.

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 20°C to 25°C (68°F to 77°F), as defined by the United States Pharmacopeia (USP) 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 any potential imbalances.

FDA Insert (PDF)

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

View full prescribing information (PDF)