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AcetaZOLAMIDE

Pronunciation

Pronunciation

(a set a ZOLE a mide)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Extended Release 12 Hour, Oral:

Diamox Sequels: 500 mg

Generic: 500 mg

Solution Reconstituted, Injection [preservative free]:

Generic: 500 mg (1 ea)

Tablet, Oral:

Generic: 125 mg, 250 mg

Brand Names: U.S.

  • Diamox Sequels

Pharmacologic Category

  • Anticonvulsant, Miscellaneous
  • Carbonic Anhydrase Inhibitor
  • Diuretic, Carbonic Anhydrase Inhibitor
  • Ophthalmic Agent, Antiglaucoma

Pharmacology

Reversible inhibition of the enzyme carbonic anhydrase resulting in reduction of hydrogen ion secretion at renal tubule and an increased renal excretion of sodium, potassium, bicarbonate, and water. Decreases production of aqueous humor and inhibits carbonic anhydrase in central nervous system to retard abnormal and excessive discharge from CNS neurons.

Absorption

Appears to be dose dependent; erratic with daily doses >10 mg/kg

Distribution

Erythrocytes, kidneys; blood-brain barrier and placenta; distributes into milk (~30% of plasma concentrations)

Excretion

Urine (70% to 100% [IV, tablet], 47% [extended release capsule] as unchanged drug within 24 hours)

Onset of Action

Capsule (extended release): 2 hours; Tablet (immediate release): 1 to 1.5 hours; IV: 2 to 10 minutes

Peak effect: Capsule (extended release): 8 to 18 hours; IV: 15 minutes; Tablet: 2 to 4 hours

Time to Peak

Plasma: Capsule (extended release): 3 to 6 hours; Tablet: 1 to 4 hours; IV: 15 minutes

Duration of Action

Inhibition of aqueous humor secretion: Capsule (extended release): 18 to 24 hours; IV: 4 to 5 hours; Tablet: 8 to 12 hours

Half-Life Elimination

2.4 to 5.8 hours

Protein Binding

95%

Use: Labeled Indications

Treatment of glaucoma (chronic simple open-angle, secondary glaucoma, preoperatively in acute angle-closure); drug-induced edema or edema due to congestive heart failure (adjunctive therapy; IV and immediate release dosage forms); centrencephalic epilepsies (IV and immediate release dosage forms); prevention or amelioration of symptoms associated with acute mountain sickness (immediate and extended release dosage forms)

Use: Unlabeled

Metabolic alkalosis; respiratory stimulant in stable hypercapnic COPD

Contraindications

Hypersensitivity to acetazolamide, sulfonamides, or any component of the formulation; hepatic disease or insufficiency; decreased sodium and/or potassium levels; adrenocortical insufficiency, cirrhosis; hyperchloremic acidosis, severe renal disease or dysfunction; long-term use in noncongestive angle-closure glaucoma

Note: Although the FDA approved product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged. See “Warnings/Precautions” for more detail.

Dosing: Adult

Note: IM administration is not recommended because of pain secondary to the alkaline pH.

Altitude illness: Oral: Manufacturer's labeling: 500-1000 mg/day in divided doses every 8-12 hours (immediate release tablets) or divided every 12-24 hours (extended release capsules). These doses are associated with more frequent and/or increased side effects. Alternative dosing has been recommended:

Prevention: 125 mg twice daily; beginning either the day before (preferred) or on the day of ascent; may be discontinued after staying at the same elevation for 2-3 days or if descent initiated (Basnyat, 2006; Luks, 2010). Note: In situations of rapid ascent (such as rescue or military operations), 1000 mg/day is recommended by the manufacturer. The Wilderness Medical Society recommends consideration of using dexamethasone in addition to acetazolamide in these situations (Luks, 2010).

Treatment: 250 mg twice daily. Note: With high altitude cerebral edema, dexamethasone is the primary treatment; however, acetazolamide may be used adjunctively with the same treatment dose (Luks, 2010).

Edema: Oral, IV: 250-375 mg once daily

Epilepsy: Oral: 8-30 mg/kg/day in divided doses. A lower dosing range of 4-16 mg/kg/day in 1-4 divided doses has also been recommended; maximum dose: 30 mg/kg/day or 1 g/day (Oles, 1989; Reiss, 1996). Note: Minimal additional benefit with doses >16 mg/kg/day. Extended release capsule is not recommended for treatment of epilepsy.

Glaucoma: Oral, IV:

Chronic simple (open-angle): 250 mg 1-4 times/day or 500 mg extended release capsule twice daily

Secondary or acute (closed-angle): Initial: 250-500 mg; maintenance: 125-250 mg every 4 hours (250 mg every 12 hours has been effective in short-term treatment of some patients)

Metabolic alkalosis (off-label use): IV: 500 mg as a single dose; reassess need based upon acid-base status (Marik, 1991; Mazur, 1999)

Respiratory stimulant in stable hypercapnic COPD (off-label use): Oral: 250 mg twice daily (Wagenaar, 2003)

Dosing: Geriatric

Refer to adult dosing. Oral: Initial doses should begin at the low end of the dosage range.

Dosing: Pediatric

Note: IM administration is not recommended because of pain secondary to the alkaline pH.

Epilepsy: Oral: Refer to adult dosing.

Altitude illness: Oral:

Prevention: 2.5 mg/kg/dose every 12 hours started either the day before (preferred) or on the day of ascent and may be discontinued after staying at the same elevation for 2-3 days or if descent initiated; maximum dose: 125 mg/dose (Luks, 2010). Note: The International Society for Mountain Medicine does not recommend prophylaxis in children except in the rare circumstance of unavoidable rapid ascent or in children with known previous susceptibility to acute mountain sickness (Pollard, 2001).

Treatment: 2.5 mg/kg/dose every 8-12 hours; maximum dose: 250 mg/dose. Note: With high altitude cerebral edema, dexamethasone is the primary treatment; however, acetazolamide may be used adjunctively with the same treatment dose (Luks, 2010; Pollard, 2001).

Dosing: Renal Impairment

Note: Use is contraindicated in marked renal impairment; creatinine clearance cutoff not specified in manufacturer’s labeling.

CrCl 10-50 mL/minute: Administer every 12 hours.

CrCl <10 mL/minute: Avoid use.

Hemodialysis: Moderately dialyzable (20% to 50%).

Peritoneal dialysis: Supplemental dose is not necessary (Schwenk, 1994).

Dosing: Hepatic Impairment

Use contraindicated in patients with cirrhosis or marked liver disease or dysfunction.

Reconstitution

Injection: Reconstitute with at least 5 mL sterile water to provide a solution containing not more than 100 mg/mL.

Extemporaneously Prepared

A 25 mg/mL oral suspension may be made with tablets and either a 1:1 mixture of Ora-Sweet® and Ora-Plus® or a 1:1 mixture of Ora-Sweet® SF and Ora-Plus®. Crush twelve 250 mg tablets in a mortar and reduce to a fine powder. Add small portions of chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label “shake well” and “refrigerate”. Stable for 60 days (Allen, 1996). When diluted in 120 mL solution of cherry syrup concentrate diluted 1:4 with simple syrup, NF, it is stable 60 days refrigerated (preferred) or at room temperature (Nahata, 2004).

Allen LV Jr and Erickson MA 3rd, "Stability of Acetazolamide, Allopurinol, Azathioprine, Clonazepam, and Flucytosine in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53(16):1944-9.8862208Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Oral: May be administered with food. May cause an alteration in taste, especially carbonated beverages. Short-acting tablets may be crushed and suspended in cherry or chocolate syrup to disguise the bitter taste of the drug; do not use fruit juices. Alternatively, submerge tablet in 10 mL of hot water and add 10 mL honey or syrup.

IM: IM administration is painful because of the alkaline pH of the drug; use by this route is not recommended.

IV: Direct IV injection is the preferred parenteral route of administration. Specific IV push rates are not provided in the manufacturer’s labeling. However, an IV push rate of up to 500 mg over 3 minutes has been reported in a clinical trial (Mazur, 1999). Additionally, a study to assess cerebrovascular reserve used a rapid IV push of up to 1 g over ≤1 minute (Piepgras, 1990).

Dietary Considerations

May be taken with food to decrease GI upset. May have additive effects with other folic acid antagonists. Some products may contain sodium.

Compatibility

Stable in D5LR, D5NS, D51/2NS, D51/4NS, D5R, D5W, D10W, LR, NS, 1/2NS, R, SL.

Y-site administration: Incompatible with TrophAmine®.

Storage

Capsules, tablets: Store at controlled room temperature.

Injection: Store intact vials at 20°C to 25°C (68°F to 77°F). Store reconstituted solutions for 3 days under refrigeration at 2°C to 8°C (36°F to 46°F), or 12 hours at room temperature, 20°C to 25°C (68°F to 77°F).

Drug Interactions

Alpha-/Beta-Agonists (Indirect-Acting): Carbonic Anhydrase Inhibitors may increase the serum concentration of Alpha-/Beta-Agonists (Indirect-Acting). Monitor therapy

Amphetamines: Carbonic Anhydrase Inhibitors may decrease the excretion of Amphetamines. Monitor therapy

Analgesics (Opioid): May enhance the adverse/toxic effect of Diuretics. Monitor therapy

CarBAMazepine: Carbonic Anhydrase Inhibitors may increase the serum concentration of CarBAMazepine. Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of other Carbonic Anhydrase Inhibitors. The development of acid-base disorders with concurrent use of ophthalmic and oral carbonic anhydrase inhibitors has been reported. Management: Avoid concurrent use of different carbonic anhydrase inhibitors if possible. Monitor patients closely for the occurrence of kidney stones and with regards to severity of metabolic acidosis. Avoid combination

CycloSPORINE (Systemic): AcetaZOLAMIDE may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Monitor therapy

Flecainide: Carbonic Anhydrase Inhibitors may increase the serum concentration of Flecainide. Monitor therapy

Fosphenytoin-Phenytoin: Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Fosphenytoin-Phenytoin. Specifically, the risk for osteomalacia or rickets may be increased. Monitor therapy

Lithium: Carbonic Anhydrase Inhibitors may decrease the serum concentration of Lithium. Monitor therapy

Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification

Memantine: Carbonic Anhydrase Inhibitors may increase the serum concentration of Memantine. Monitor therapy

MetFORMIN: Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Monitor therapy

Methenamine: Carbonic Anhydrase Inhibitors may diminish the therapeutic effect of Methenamine. Management: Consider avoiding this combination. Monitor for decreased therapeutic effects of methenamine if used concomitant with a carbonic anhydrase inhibitor. Consider therapy modification

Mianserin: May diminish the therapeutic effect of Anticonvulsants. Monitor therapy

Orlistat: May decrease the serum concentration of Anticonvulsants. Monitor therapy

Primidone: Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Primidone. Specifically, osteomalacia and rickets. Carbonic Anhydrase Inhibitors may decrease the serum concentration of Primidone. Monitor therapy

QuiNIDine: Carbonic Anhydrase Inhibitors may decrease the excretion of QuiNIDine. Monitor therapy

Salicylates: May enhance the adverse/toxic effect of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. Management: Avoid these combinations when possible.Dichlorphenamide use with high-dose aspirin as contraindicated. If another combination is used, monitor patients closely for adverse effects. Tachypnea, anorexia, lethargy, and coma have been reported. Consider therapy modification

Sodium Bicarbonate: AcetaZOLAMIDE may enhance the adverse/toxic effect of Sodium Bicarbonate. Specifically, the risk of renal calculus formation may be increased. Monitor therapy

Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Consider therapy modification

Trientine: Carbonic Anhydrase Inhibitor Diuretics may decrease the serum concentration of Trientine. Monitor therapy

Test Interactions

May cause false-positive results for urinary protein with Albustix®, Labstix®, Albutest®, Bumintest®; interferes with HPLC theophylline assay and serum uric acid levels

Adverse Reactions

Frequency not defined.

Cardiovascular: Flushing

Central nervous system: Ataxia, confusion, convulsions, depression, dizziness, drowsiness, excitement, fatigue, flaccid paralysis, headache, malaise, paresthesia

Dermatologic: Allergic skin reaction, skin photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Electrolyte imbalance, growth retardation (children), hyperglycemia, hypoglycemia, hypokalemia, hyponatremia, metabolic acidosis

Gastrointestinal: Decreased appetite, diarrhea, dysgeusia, glycosuria, melena, nausea, vomiting

Genitourinary: Crystalluria, hematuria

Hematologic and oncologic: Agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia, thrombocytopenic purpura

Hepatic: Abnormal hepatic function tests, cholestatic jaundice, fulminant hepatic necrosis, hepatic insufficiency

Hypersensitivity: Anaphylaxis

Local: Pain at injection site

Ophthalmic: Myopia

Otic: Auditory disturbance, tinnitus

Renal: Polyuria, renal failure

Miscellaneous: Fever

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Impairment of mental alertness and/or physical coordination may occur.

• Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.

Disease-related concerns:

• Diabetes: Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control.

• Hepatic impairment: Use with caution in patients with hepatic dysfunction; in cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy.

• Respiratory acidosis: Use with caution in patients with respiratory acidosis; may worsen acidosis.

Concurrent drug therapy issues:

• Aspirin (high dose): Use with caution or avoid in patients taking high-dose aspirin concurrently; may lead to severe adverse effects including tachypnea, anorexia, lethargy, coma, and death.

Special populations:

• Elderly: Use with caution in the elderly; may be more sensitive to side effects.

Other warnings/precautions:

• Appropriate use: Increasing the dose does not increase diuresis and may increase the incidence of drowsiness and/or paresthesia; often results in a reduction of diuresis.

• IM administration: Painful because of the alkaline pH of the drug; use by this route is not recommended.

Monitoring Parameters

Intraocular pressure; serum electrolytes, periodic CBC with differential; monitor growth in pediatric patients

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Limited data is available following the use of acetazolamide in pregnant women for the treatment of idiopathic intracranial hypertension (Falardeau, 2013; Kesler, 2013).

Pregnant women exposed to acetazolamide during pregnancy for the treatment of seizure disorders are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at aedpregnancyregistry.org

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, change in taste, diarrhea, lack of appetite, blurred vision, fatigue, loss of strength and energy, or headache. Have patient report immediately to prescriber signs of lactic acidosis (fast breathing, fast heartbeat, abnormal heartbeat, vomiting, drowsiness, shortness of breath, feeling very tired or weak, severe dizziness, feeling cold, or muscle pain or cramps), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), vision changes, hearing impairment, tinnitus, burning or numbness feeling, hematuria, urinary retention, change in amount of urine passed, signs of a severe sulfonamide reaction (rash; red, swollen, blistered, or peeling skin; red or irritated eyes; sores in your mouth, throat, nose, or eyes; fever, chills, or sore throat; cough that is new or worse; loss of strength and energy; any bruising or bleeding; or signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes), or injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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