Acetazolamide

Description

Acetazolamide is an inhibitor of the enzyme carbonic anhydrase, presented as a white to faintly yellowish white crystalline, odorless powder. It is characterized as 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, with a molecular weight of 222.25 and a molecular formula of C₄H₆N₄O₃S₂.

Acetazolamide tablets, USP, are formulated for oral administration, available in dosages of 125 mg and 250 mg of acetazolamide. Each tablet contains inactive ingredients, including lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, sodium lauryl sulfate, and sodium starch glycolate.

Uses and Indications

This drug is indicated for the adjunctive treatment of various conditions, including edema due to congestive heart failure, drug-induced edema, and centrencephalic epilepsies, specifically petit mal and unlocalized seizures. It is also indicated for the management of chronic simple (open-angle) glaucoma and secondary glaucoma. Additionally, this drug may be used preoperatively in cases of acute angle-closure glaucoma when a delay in surgery is desired to lower intraocular pressure.

Furthermore, this drug is indicated for the prevention or amelioration of symptoms associated with acute mountain sickness in climbers who are attempting rapid ascent, as well as in individuals who are particularly susceptible to acute mountain sickness, even with gradual ascent.

No teratogenic or nonteratogenic effects have been reported.

Dosage and Administration

For the management of glaucoma, acetazolamide is administered at a dosage range of 250 mg to 1 g per 24 hours, typically in divided doses for amounts exceeding 250 mg. The preferred dosage for secondary glaucoma is 250 mg every four hours; however, some patients may respond adequately to 250 mg administered twice daily. In acute cases, an initial dose of 500 mg is recommended, followed by 125 mg to 250 mg every four hours.

In the treatment of epilepsy, the suggested total daily dose of acetazolamide is between 8 to 30 mg per kg, divided into multiple doses. The optimum daily dosage range is 375 mg to 1000 mg; some patients may achieve therapeutic effects with lower doses. When used in conjunction with other anticonvulsants, the starting dose should be 250 mg once daily.

For patients with congestive heart failure, the starting dose is 250 mg to 375 mg once daily in the morning, which corresponds to approximately 5 mg/kg. Optimal results are often observed when the medication is administered on alternate days or for two consecutive days followed by a day of rest.

In cases of drug-induced edema, the recommended dosage is 250 mg to 375 mg of acetazolamide once daily for one or two days, alternating with a day of rest.

For the prevention and treatment of acute mountain sickness, the dosage is set at 500 mg to 1000 mg daily, divided into multiple doses. A higher dose of 1000 mg is advised for situations involving rapid ascent. 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.

Contraindications

Acetazolamide therapy is contraindicated in patients with depressed sodium and/or potassium blood serum levels due to the risk of exacerbating electrolyte imbalances. It is also contraindicated in individuals with marked kidney and liver disease or dysfunction, as well as in cases of suprarenal gland failure, which may impair drug metabolism and excretion.

Additionally, the use of acetazolamide is contraindicated in patients with hyperchloremic acidosis, as it may worsen acid-base imbalances. In patients with cirrhosis, the risk of developing hepatic encephalopathy necessitates avoidance of this medication. Long-term administration is also contraindicated in patients with chronic noncongestive angle-closure glaucoma, as it may mask worsening glaucoma while allowing for organic closure of the angle.

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, 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. In the event of hypersensitivity signs or other serious reactions, the use of this drug must be discontinued immediately.

Caution is warranted for patients who are concurrently receiving high doses of aspirin and acetazolamide. Reports have indicated that such combinations may lead to severe adverse effects, including anorexia, tachypnea, lethargy, 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 alongside 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 acetazolamide therapy, with regular monitoring throughout treatment. This is essential for detecting hematologic reactions that are common to all sulfonamides. Should significant changes in laboratory values occur, early discontinuation of the drug and initiation of appropriate therapy are critical. Additionally, periodic monitoring of serum electrolytes is advised to maintain patient safety during treatment.

Side Effects

Patients may experience a range of adverse reactions while using this medication, which can be categorized by frequency and seriousness.

Common adverse reactions include paresthesias, particularly a tingling sensation in the extremities, hearing dysfunction or tinnitus, loss of appetite, taste alteration, and gastrointestinal disturbances such as nausea, vomiting, and diarrhea. Additionally, patients may experience polyuria, along with occasional instances of drowsiness and confusion.

Metabolic effects have also been observed, including metabolic acidosis and electrolyte imbalance. Other occasional adverse reactions reported include transient myopia, which invariably subsides upon reduction or discontinuation of the medication, as well as urticaria, melena, hematuria, glycosuria, hepatic insufficiency, flaccid paralysis, photosensitivity, and convulsions.

Serious adverse reactions, although rare, can be life-threatening. Fatalities have occurred due to severe reactions to sulfonamides, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is important to note that sensitizations may recur upon readministration of a sulfonamide, regardless of the route of administration. If any signs of hypersensitivity or other serious reactions occur, the use of this drug should be discontinued immediately.

Caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as reports have indicated that such combinations may lead to anorexia, tachypnea, lethargy, coma, and even death.

Drug Interactions

Caution is advised when acetazolamide is administered concurrently with high-dose aspirin. The combination may lead to severe adverse effects, including anorexia, tachypnea, lethargy, coma, and potentially fatal outcomes.

For patients receiving acetazolamide, it is recommended to obtain a baseline complete blood count (CBC) and platelet count prior to the initiation of therapy. Regular monitoring of these parameters should continue throughout the treatment course to identify any hematologic reactions associated with sulfonamides. In the event of significant changes in blood counts, early discontinuation of acetazolamide and the implementation of appropriate therapeutic measures are essential.

Additionally, periodic monitoring of serum electrolytes is advised to ensure patient safety and to manage any potential imbalances that may arise during treatment with acetazolamide.

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 in pediatric patients have not been established. Therefore, caution should be exercised when considering its use in this population. Further studies are needed to determine appropriate dosing and potential outcomes in children and adolescents.

Geriatric Use

Caution is advised when administering acetazolamide to elderly patients, particularly those receiving concomitant high-dose aspirin. Reports have indicated that such combinations may lead to serious adverse effects, including anorexia, tachypnea, lethargy, coma, and even death.

In geriatric patients, increasing the dosage of acetazolamide does not enhance diuresis and may instead elevate the risk of drowsiness and/or paresthesia. It is important to note that higher doses can often result in a decrease in diuresis, necessitating careful consideration of dosage adjustments.

Elderly patients with pulmonary obstruction or emphysema, conditions that may impair alveolar ventilation, should use acetazolamide with caution due to the potential for precipitating or exacerbating acidosis.

Prior to initiating acetazolamide tablet therapy, it is recommended that a baseline complete blood count (CBC) and platelet count be obtained for geriatric patients, with regular monitoring throughout the treatment course. Should significant changes in these parameters occur, early discontinuation of therapy and the implementation of appropriate interventions are crucial. Additionally, periodic monitoring of serum electrolytes is advised to ensure patient safety.

The safety and effectiveness of acetazolamide have not been established in pediatric patients, and this information may be relevant when considering treatment options for elderly patients with comorbid conditions.

Pregnancy

Acetazolamide is classified as a Pregnancy Category C medication. Animal studies have demonstrated teratogenic effects, including limb defects, in mice, rats, hamsters, and rabbits following oral or parenteral administration. However, there are no adequate and well-controlled studies in pregnant women to fully assess the risks associated with its use during pregnancy.

Given the potential for fetal harm, acetazolamide should only be administered to pregnant patients if the potential benefits outweigh the risks to the fetus. Healthcare professionals are advised to carefully evaluate the necessity of acetazolamide in this population and consider alternative therapies when appropriate.

Lactation

Lactating mothers should be aware of the potential for serious adverse reactions in breastfed infants due to the excretion of acetazolamide in breast milk. A careful decision must be made regarding whether to discontinue nursing or to discontinue the drug, weighing the importance of the medication to the mother against the potential risks to the nursing 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 of these patients.

Hepatic Impairment

Patients with hepatic impairment may experience an increased risk of severe reactions to sulfonamides, including fulminant hepatic necrosis, which can lead to fatalities, albeit rarely. It is essential to monitor liver function closely in these patients. Due to the potential for serious adverse effects, caution is advised when prescribing this medication to individuals with compromised liver function. Dosage adjustments may be necessary based on the severity of hepatic impairment, and ongoing assessment of liver enzymes and overall liver function is recommended throughout the treatment course.

Overdosage

In the event of acetazolamide overdosage, it is important to note that there are currently no reported cases of acute poisoning in humans, and available data suggest that acetazolamide is remarkably nontoxic in animal studies. As such, no specific antidote exists for acetazolamide overdosage. Management should focus on symptomatic and supportive care.

Potential Symptoms and Monitoring Healthcare professionals should be vigilant for potential symptoms associated with overdosage, which may include 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 critical in restoring electrolyte and pH balance. The acidotic state that may arise from overdosage can typically be corrected through the administration of bicarbonate. Additionally, despite acetazolamide's high intraerythrocytic distribution and plasma protein binding properties, it may be dialyzable. This characteristic is particularly relevant in cases of overdosage complicated by renal failure, where dialysis may assist in the management of the condition.

In summary, while acetazolamide overdosage is not commonly reported, healthcare professionals should remain prepared to implement supportive care and monitor for specific symptoms to ensure patient safety and recovery.

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 found to be non-mutagenic when evaluated both with and without metabolic activation. Additionally, the drug 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.

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, agranulocytosis, aplastic anemia, and other blood dyscrasias. It is noted that sensitizations may recur upon re-administration 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, coma, and death.

Adverse reactions have been observed, particularly early in therapy, and include paresthesias, notably a "tingling" sensation in the extremities, hearing dysfunction or tinnitus, loss of appetite, taste alterations, and gastrointestinal disturbances such as nausea, vomiting, and diarrhea. Additionally, polyuria, drowsiness, and confusion have been reported.

Metabolic acidosis and electrolyte imbalances may also occur. Transient myopia has been documented, which typically resolves with a reduction or cessation of the medication.

Other occasional adverse reactions include urticaria, melena, hematuria, glycosuria, hepatic insufficiency, flaccid paralysis, photosensitivity, and convulsions.

For reporting suspected adverse reactions, individuals are encouraged to contact AvKARE, Inc. at 1-855-361-3993, via email at drugsafety@avkare.com, or the FDA at 1-800-FDA-1088 or 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. It is important to emphasize the need for early detection of these reactions, and patients should be instructed to discontinue the drug and seek appropriate therapy if such reactions occur.

For patients with pulmonary obstruction or emphysema, caution should be exercised when prescribing acetazolamide, as it may precipitate or exacerbate acidosis. Providers should discuss the importance of gradual ascent to avoid acute mountain sickness, noting that while acetazolamide may be used during rapid ascent, it does not eliminate the necessity for prompt 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 in conjunction with acetazolamide should be monitored closely, as serious adverse effects including anorexia, tachypnea, lethargy, coma, and even death have been reported. It is recommended that a baseline complete blood count (CBC) and platelet count be obtained prior to initiating acetazolamide therapy, with regular monitoring throughout treatment. If significant changes in hematologic parameters are observed, early discontinuation of the drug and appropriate intervention should be considered. Additionally, periodic monitoring of serum electrolytes is advised.

Healthcare providers should discuss the potential risks to nursing infants associated with acetazolamide, prompting a decision on whether to discontinue nursing or the medication, based on the drug's importance to the mother. The safety and effectiveness of acetazolamide in pediatric patients have not been established, and this should be communicated to patients and caregivers.

Finally, it is crucial to inform patients about the rare but serious risks of fatalities due to severe reactions to sulfonamides, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Patients should be made aware that sensitization may recur upon re-administration of a sulfonamide, regardless of the route of administration. They should be instructed to discontinue the drug and seek medical attention if any signs of hypersensitivity or other serious reactions occur.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature guidelines.

To ensure the integrity of the product, the container must be kept tightly closed at all times. Additionally, it is crucial to keep this and all medications out of the reach of children.

Additional Clinical Information

To monitor for hematologic reactions associated with sulfonamides, clinicians should obtain a baseline complete blood count (CBC) and platelet count for patients prior to starting acetazolamide tablet therapy. Regular intervals for monitoring these parameters during therapy are also recommended. In the event of significant changes, early discontinuation of the medication and initiation of appropriate therapy are crucial. Additionally, periodic monitoring of serum electrolytes is advised to ensure patient safety.

FDA Insert (PDF)

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

View full prescribing information (PDF)