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 222.24 and a molecular formula of C₄H₆N₄O₃S₂.

Acetazolamide is available in oral tablet form, with dosages of 125 mg and 250 mg of acetazolamide per tablet. The formulation includes the following inactive ingredients: povidone, croscarmellose sodium, purified water, lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide, talc, and magnesium stearate.

Uses and Indications

This drug is indicated for the adjunctive treatment of edema due to congestive heart failure, drug-induced edema, and centrencephalic epilepsies, including 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 attempting rapid ascent, as well as in individuals who are particularly susceptible to acute mountain sickness despite gradual ascent.

No teratogenic or nonteratogenic effects have been reported.

Dosage and Administration

For the management of glaucoma, the recommended dosage of acetazolamide ranges from 250 mg to 1 g per 24 hours, typically administered in divided doses for amounts exceeding 250 mg. Dosages above 1 g per 24 hours do not yield additional therapeutic effects. It is essential to adjust the dosage based on individual patient response, taking into account symptomatology and ocular tension.

In cases of secondary glaucoma and for preoperative treatment of acute congestive glaucoma, the preferred dosage is 250 mg every four hours. Some patients may respond adequately to a regimen of 250 mg twice daily for short-term therapy. For acute cases, an initial dose of 500 mg may be given, followed by subsequent doses of 125 mg or 250 mg every four hours, tailored to the patient's specific needs.

For the treatment of epilepsy, the suggested total daily dose is between 8 to 30 mg per kg, divided into multiple doses. The optimum dosage range appears to be from 375 mg to 1000 mg daily. When acetazolamide is administered alongside other anticonvulsants, the starting dose should be 250 mg once daily, with the possibility of increasing the dose as clinically indicated.

In the management of congestive heart failure, the typical starting dose is 250 to 375 mg once daily in the morning, which corresponds to approximately 5 mg/kg. If the patient does not continue to lose edema fluid, it is advisable to skip a dose for one day rather than increasing the dosage. Optimal diuretic effects are often achieved when the medication is administered on alternate days or for two consecutive days followed by a day of rest.

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

In the prevention and treatment of acute mountain sickness, the dosage is typically between 500 mg to 1000 mg daily, administered in divided doses using either tablets or sustained-release capsules. A higher dosage of 1000 mg is recommended for patients ascending rapidly. 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 as necessary to manage symptoms effectively.

Contraindications

Use of acetazolamide is contraindicated in the following conditions:

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 blood serum levels due to the potential for exacerbating electrolyte imbalances.

The drug is also contraindicated in individuals with marked kidney and liver disease or dysfunction, as well as in cases of suprarenal gland failure, due to the risk of further compromising renal and hepatic function.

Patients with hyperchloremic acidosis should not use acetazolamide, as it may worsen the acid-base imbalance.

In patients with cirrhosis, acetazolamide is contraindicated 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 mask the worsening of glaucoma while allowing for organic closure of the angle.

Warnings and Precautions

Fatalities have been reported, albeit infrequently, as a result of severe reactions to sulfonamides. These reactions include, but are not limited to, Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias, as well as anaphylaxis. It is important to note that sensitization may recur upon re-administration of a sulfonamide, regardless of the route of administration. Should any signs of hypersensitivity or other serious adverse reactions manifest, the use of this drug must be discontinued immediately.

Caution is particularly warranted for patients who are concurrently receiving high doses of aspirin along with acetazolamide. Reports have indicated that such combinations may lead to severe adverse effects, including anorexia, tachypnea, lethargy, metabolic acidosis, coma, and even death. Continuous monitoring of these patients is recommended to mitigate potential risks associated with this combination therapy.

Side Effects

Adverse reactions associated with the use of this medication have been observed in clinical trials and postmarketing experiences. These reactions can be categorized by seriousness and frequency.

Serious adverse reactions include anaphylaxis, which may occur upon re-administration of the drug, 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. Patients should be monitored closely for signs of hypersensitivity or other serious reactions, and the drug should be discontinued immediately if such reactions occur.

Common adverse reactions reported include headache, malaise, fatigue, fever, and pain at the injection site. Patients may also experience gastrointestinal disturbances, such as nausea, vomiting, and diarrhea. Other frequently noted reactions include drowsiness, dizziness, and paraesthesia, which encompasses numbness and tingling of the extremities and face.

Hematological and lymphatic reactions may manifest as blood dyscrasias, including aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and thrombocytopenic purpura. Additionally, metabolic and nutritional issues such as metabolic acidosis, electrolyte imbalances (including hypokalemia and hyponatremia), and alterations in appetite and taste have been documented. Long-term therapy may lead to growth retardation in children, believed to be secondary to chronic acidosis.

Hepato-biliary disorders may present as abnormal liver function, cholestatic jaundice, hepatic insufficiency, and in severe cases, fulminant hepatic necrosis. Skin reactions can include allergic responses such as urticaria, photosensitivity, and severe conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis.

Ocular adverse reactions have been noted, including choroidal effusion, choroidal detachment, and transient myopia. Otologic issues may involve hearing disturbances and tinnitus. Urogenital reactions can include crystalluria, hematuria, glycosuria, renal failure, and an increased risk of nephrolithiasis with long-term therapy.

It is important to note that both increases and decreases in blood glucose levels have been reported in patients treated with this medication, necessitating careful monitoring in those with impaired glucose tolerance or diabetes mellitus. Furthermore, caution is advised for patients receiving concomitant high-dose aspirin and acetazolamide, as severe reactions such as metabolic acidosis and lethargy have been documented.

Periodic monitoring of serum electrolytes is recommended due to the potential for electrolyte imbalances and metabolic acidosis, particularly in elderly patients with reduced renal function.

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 of phenytoin. This interaction may enhance the risk of osteomalacia in patients undergoing chronic phenytoin therapy. Caution is advised for patients receiving long-term concomitant therapy.

• Primidone: Acetazolamide may decrease the gastrointestinal absorption of primidone, resulting in lower serum concentrations of primidone and its metabolites. This 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, which may enhance both the magnitude and duration of their effects.

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

• Lithium: Acetazolamide increases the excretion of lithium, which may lead to decreased serum levels of lithium. Monitoring of lithium levels is advisable.

• 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.

• Antidiabetic Agents: Acetazolamide has the potential to either increase or decrease blood glucose levels. Patients receiving antidiabetic medications should be monitored closely for changes in glycemic control.

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

Combination Therapy Considerations:

• The concurrent use of acetazolamide with other carbonic anhydrase inhibitors is not advisable due to the potential for additive effects.

• When used together, acetazolamide and sodium bicarbonate may increase the risk of renal calculus formation, necessitating caution and monitoring for patients at risk.

In summary, careful consideration and monitoring are essential when acetazolamide is prescribed alongside other medications, particularly those listed above, 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 in pediatric patients 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. Clinical studies involving acetazolamide did not include a sufficient number of subjects aged 65 and older to ascertain whether this population responds differently compared to younger individuals. However, other clinical experiences have not indicated any significant differences in responses between elderly and younger patients.

In general, dose selection for geriatric patients should be approached with caution. It is advisable to initiate treatment at the lower end of the dosing range, taking into account the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Regular monitoring of these patients is recommended to ensure safety and efficacy.

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 child.

Renal Impairment

Patients with renal impairment have no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular assessment of renal function may be warranted to ensure safe and effective use of the medication in patients with reduced kidney function.

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 to detect any adverse effects promptly.

While specific dosage adjustments for patients with compromised liver function are not provided, the risk of severe reactions necessitates careful consideration of the benefits and risks of treatment in this population. Regular assessment of liver enzymes and overall liver function is recommended to ensure patient safety.

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 Monitoring Patients may experience 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.

Additionally, despite acetazolamide's high intraerythrocytic distribution and significant plasma protein binding properties, it is important to note that acetazolamide is dialyzable. This characteristic may play a critical role in the management of acetazolamide overdosage, especially in cases complicated by renal failure. Healthcare professionals should consider dialysis as a potential intervention in such scenarios 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 risks to the fetus.

In terms of non-teratogenic effects, growth retardation has been observed in children undergoing long-term therapy, which is believed to be secondary to chronic acidosis.

Long-term studies assessing the carcinogenic potential of acetazolamide in animals have not been conducted. In a bacterial mutagenicity assay, acetazolamide was found to be non-mutagenic, both with and without metabolic activation. Furthermore, the drug 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 1000 mg for a 50 kg individual.

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

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, as well as anaphylaxis. 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.

Common adverse reactions associated with 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.

In patients treated with acetazolamide, both increases and decreases in blood glucose levels have been observed. Acetazolamide may also 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 noted 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 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 arise, 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 tablets are 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 with acetazolamide treatment. This is particularly important for those managing their blood sugar levels.

Electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis, may occur with acetazolamide treatment. Therefore, healthcare providers should recommend periodic monitoring of serum electrolytes, especially in 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 common to all sulfonamides, healthcare providers should recommend obtaining a baseline complete blood count (CBC) and platelet count prior to initiating acetazolamide therapy, with regular monitoring during treatment. If significant changes are detected, early discontinuation and appropriate therapy should be considered. Periodic monitoring of serum electrolytes is also advised.

Finally, healthcare providers should discuss the potential for serious adverse reactions in nursing infants due to acetazolamide. A decision should be made regarding whether to discontinue nursing or the medication, weighing the importance of the drug to the mother against the potential risk to the child. Acetazolamide should only be used by nursing women if the potential benefits justify the risks.

Storage and Handling

The product is supplied in well-closed containers as defined by the United States Pharmacopeia (USP). It should be stored 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) in accordance with USP Controlled Room Temperature guidelines.

Additional Clinical Information

To ensure patient safety during acetazolamide tablet 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, as acetazolamide may cause electrolyte imbalances, including hyponatremia and hypokalemia, as well as metabolic acidosis.

Patients should be counseled on the potential adverse reactions associated with sulfonamide derivatives, which include severe conditions such as anaphylaxis, various skin rashes, and hematologic disorders. Caution is particularly important for patients with pulmonary obstruction or emphysema, as acetazolamide may exacerbate acidosis. When considering ascent to high altitudes, gradual ascent is preferred to mitigate the risk of acute mountain sickness, and the use of acetazolamide does not replace the need for immediate descent in severe cases. Clinicians should also be aware of the potential for altered blood glucose levels in patients with diabetes and the risk of adverse reactions that may impair the ability to drive or operate machinery. Special caution is warranted for patients on high-dose aspirin concurrently with acetazolamide due to reported severe adverse effects.

FDA Insert (PDF)

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

View full prescribing information (PDF)