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Carbonic Anhydrase Inhibitors (Systemic)

This monograph includes information on the following:

1) Acetazolamide
2) Dichlorphenamide  
3) Methazolamide


INN:
Dichlorphenamide  —Diclofenamide {42}

VA CLASSIFICATION
Acetazolamide
Primary: CV703
Secondary: OP113; CN400; MS900; GU900

Dichlorphenamide
Primary: CV703
Secondary: OP113

Methazolamide
Primary: CV703
Secondary: OP113


Commonly used brand name(s): Acetazolam1; Ak-Zol1; Apo-Acetazolamide1; Daranide2; Dazamide1; Diamox1; Diamox Sequels1; MZM3; Neptazane3; Storzolamide1.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antiglaucoma agent (systemic)—Acetazolamide; Dichlorphenamide;  Methazolamide;

Anticonvulsant—Acetazolamide (tablets and injection);

Altitude sickness (acute) prophylactic and therapeutic agent{10}—Acetazolamide;

Antiparalytic (familial periodic paralysis)—Acetazolamide;

Diuretic, urinary alkalinizing—Acetazolamide (parenteral);

Antiurolithic (uric acid calculi; cystine calculi)—Acetazolamide Tablets USP;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Glaucoma, open-angle (treatment) {37} {39} {40} {41}
Glaucoma, secondary (treatment) {37} {39} {40} {41}
Glaucoma, angle-closure (treatment) or {37} {39} {40} {41}
[Glaucoma, malignant (treatment)]—Carbonic anhydrase inhibitors are indicated primarily as adjuncts to other agents in the treatment of open-angle (chronic simple) glaucoma and secondary glaucoma, and to lower intraocular pressure prior to surgery for some types of glaucoma.
—These medications should not be used for long-term therapy in noncongestive angle-closure (closed-angle) glaucoma; organic closure of the angle may occur while the worsening condition is masked by the lowered intraocular pressure. {37} {39}
—[Acetazolamide is used to lower intraocular pressure in the treatment of malignant (ciliary block) glaucoma, which may occur after inflammation, surgery, trauma, or use of miotics.] {03} {04}

Epilepsy, {37} {39} absence seizure pattern (treatment)
Epilepsy, tonic-clonic seizure pattern (treatment)
Epilepsy, mixed seizure pattern (treatment)
Epilepsy, simple partial seizure pattern (treatment) or {14}
Epilepsy, myoclonic seizure pattern (treatment)— Acetazolamide is indicated as an adjunct to other anticonvulsants in the management of absence seizures (petit mal), generalized tonic-clonic seizures (grand mal), mixed seizure patterns, simple partial seizure patterns, {14} and myoclonic seizure patterns. It may be especially useful for intermittent therapy in females who experience increased seizure activity at the time of menstruation.

Altitude sickness (prophylaxis)1 or {37} {39}
Altitude sickness (treatment)1{37}{39}—Oral acetazolamide is indicated to decrease the incidence and/or severity of symptoms (such as headache, nausea, shortness of breath, dizziness, drowsiness, and fatigue) associated with acute altitude sickness in mountain climbers who are attempting rapid ascent and in those who are very susceptible to altitude sickness despite gradual ascent. Gradual ascent is desirable for prevention of acute altitude sickness even when acetazolamide is used. However, prompt descent may still be necessary if severe manifestations of acute altitude sickness, such as pulmonary edema or cerebral edema, occur. {01} {02}

[Paralysis, familial periodic (treatment) ]1—Acetazolamide is used to treat both the hypokalemic and hyperkalemic forms of familial periodic paralysis. It terminates the acute attacks and, with chronic use, prevents their recurrence. It may be the drug of choice in the hypokalemic form of the condition.

[Toxicity, weakly acidic medications (treatment) ]—Parenteral acetazolamide is used to produce a forced alkaline diuresis as a method of increasing the elimination of certain weakly acidic medications.

[Renal calculi, uric acid (prophylaxis) ]1or
[Renal calculi, cystine (prophylaxis) ]1—Oral acetazolamide is used to alkalinize the urine as a means of preventing the occurrence or recurrence of uric acid renal stones, especially in patients receiving uricosuric antigout agents, or of cystine renal stones.

Unaccepted
Acetazolamide has also been used to prevent or counteract metabolic alkalosis, including that which may occur following open-heart surgery; however, it is no longer used for these indications.

Acetazolamide has also been used as a diuretic in the treatment of edema due to congestive heart disease {02} {37} {39} and drug-induced edema. {02} {37} {39} However, it has been replaced by newer diuretics for these indications.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Acetazolamide—222.24 {42}
    Acetazolamide sodium—244.22 {42}
    Dichlorphenamide—305.15 {42}
    Methazolamide—236.26 {42}

Mechanism of action/Effect:

Nonbacteriostatic sulfonamide derivatives. {02} {37} {39} Inhibition of the enzyme carbonic anhydrase decreases formation of hydrogen and bicarbonate ions from carbon dioxide and water and reduces the availability of these ions for active transport. These agents reduce plasma bicarbonate concentration and increase plasma chloride concentration, producing systemic metabolic acidosis. Although all of these medications may produce diuresis with acute or intermittent administration, loss of diuretic effect occurs with chronic administration. Therefore, dichlorphenamide and methazolamide are not used as diuretics, and acetazolamide is now being used only to produce alkaline diuresis in certain cases of drug overdose. Methazolamide has less diuretic effect and less influence on urinary bicarbonate {18} than do other carbonic anhydrase inhibitors with doses used in glaucoma.


Antiglaucoma agent:

Lowers intraocular pressure by decreasing the production of aqueous humor by 50 to 60%. The mechanism is not completely understood but probably involves a decrease of the bicarbonate ion concentration in ocular fluids. {05} These agents have no effect on the facility of aqueous outflow. The ocular action is independent of any diuretic action.



Acetazolamide:


Anticonvulsant—

Mechanism of action has not been fully determined. Inhibition of carbonic anhydrase in the central nervous system (CNS) may increase carbon dioxide tension, resulting in a retardation of neuronal conduction. The production of systemic metabolic acidosis may also be involved. This action is independent of any diuretic action.



Altitude sickness, acute, prophylactic and therapeutic agent—

May act by producing metabolic acidosis resulting in increased respiratory drive and arterial oxygen tension and/or by causing diuresis.

In clinical trials, pulmonary function, such as minute ventilation, expired vital capacity, and peak flow, was greater in climbers treated with acetazolamide, whether they had acute altitude sickness or were asymptomatic. Acetazolamide-treated climbers also had less difficulty sleeping. {01} {02}



Antiparalytic (for familial periodic paralysis)—

May stabilize muscle membranes against abnormal fluxes of potassium ions. Alternatively, may produce metabolic acidosis resulting in prevention of the intracellular shift of potassium. {05}



Diuretic, urinary alkalinizing—

Induces alkaline diuresis by lowering hydrogen ion concentration in the renal tubule and increasing excretion of bicarbonate, sodium, potassium, and water. This increases the solubility in urine of weakly acidic drugs and promotes their excretion.



Antiurolithic—

Alkalinization of the urine increases the solubility in urine of uric acid and cystine, thereby reducing the formation of uric acid- or cystine-containing renal stones.



Absorption:

Well absorbed; methazolamide absorbed more slowly than acetazolamide or dichlorphenamide.

Protein binding:

Acetazolamide—Very high (90%). {14}

Methazolamide—Moderate.

Half-life:

Acetazolamide (tablets)—10 to 15 hours. {14}

Methazolamide—14 hours.

Time to peak concentration:

Acetazolamide tablets—2 to 4 hours after a 500-mg dose.

Acetazolamide extended-release capsules—8 to 12 hours after a 500-mg dose.

Peak serum concentration:

Acetazolamide tablets—12 to 27 mcg per mL with a 500-mg dose.

Acetazolamide extended-release capsules—6 mcg per mL with a 500-mg dose.

Elimination:
    Acetazolamide—Renal; as unchanged drug; 90 to 100% of a dose is excreted within 24 hours after administration of oral tablets or intravenous injection; 47% of a dose is excreted within 24 hours after administration of extended-release capsules.
    Dichlorphenamide—Unknown.
    Methazolamide—Renal; 15 to 30% excreted unchanged. Remainder unknown.



Effects on intraocular pressure


Drug
Onset of
Action
Peak Effect
Duration of
Action (hr)
Acetazolamide
Extended-release
capsules
2 hr
8–12 hr
18–24
Tablets
1–1.5 hr
2–4 hr
8–12
Intravenous
2 min
15 min
4–5
Dichlorphenamide
Tablets
0.5–1 hr
2–4 hr
6–12
Methazolamide
Tablets
2–4 hr
6–8 hr
10–18


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to antibacterial sulfonamides, thiazide diuretics, or other sulfonamide-derivative diuretics may be sensitive to carbonic anhydrase inhibitors also. {37} {39}

Carcinogenicity

Long-term studies in animals have not been conducted using carbonic anhydrase inhibitors. {37} {38} {39} {40} {41}

Mutagenicity

Acetazolamide—In a bacterial mutagenicity assay, acetazolamide was not mutagenic when evaluated with and without metabolic activation. {37} {38} {39}

Methazolamide—In the Ames bacterial test, methazolamide was not mutagenic. {41}

Pregnancy/Reproduction
Fertility—
Acetazolamide: Acetazolamide had no effect on fertility of male and female rats administered oral daily doses of up to 4 times the recommended human dose of 1000 mg in a 50 kg individual. {37} {38} {39}

Dichlorphenamide and methazolamide: Long-term studies in animals have not been conducted. {40} {41}

Pregnancy—
Adequate and well-controlled studies have not been done using carbonic anhydrase inhibitors in humans. {37} {38} {39} {40} {41}


Acetazolamide

Acetazolamide has been shown to cause limb defects in mice, rats, hamsters, and rabbits. {19} {37} {38} {39}

FDA Pregnancy Category C. {37} {38} {39} {40} {41}



Dichlorphenamide and methazolamide

Dichlorphenamide and methazolamide, when given in large doses, have been shown to cause skeletal anomalies in rats. {40} {41}

FDA Pregnancy Category C. {37} {38} {39} {40} {41}


Breast-feeding

Because of the potential for serious adverse reactions, a decision should be made whether to discontinue nursing during therapy with carbonic anhydrase inhibitors. {37} {38} {39} {40} {41}

Acetazolamide—Acetazolamide may be distributed into breast milk. {14} {20}

Dichlorphenamide and methazolamide —It is not known whether dichlorphenamide or methazolamide is distributed into breast milk. {40} {41}

Pediatrics

Appropriate studies on the relationship of age to the effects of carbonic anhydrase inhibitors have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date.


Geriatrics


No information is available on the relationship of age to the effects of carbonic anhydrase inhibitors in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving these medications.


Dental

Acetazolamide may cause facial paresthesia, such as numbness, tingling, or burning feeling of the mouth, tongue, or lips. Other carbonic anhydrase inhibitors may cause similar side effects. {11}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Corticosteroids, glucocorticoid, especially with significant mineralocorticoid activity or
Corticosteroids, mineralocorticoid or
Amphotericin B, parenteral or
Corticotropin, especially prolonged therapeutic use    (concurrent use with carbonic anhydrase inhibitors may result in severe hypokalemia and should be undertaken with caution; serum potassium concentrations and cardiac function should be monitored during concurrent use)

    (concurrent use of corticosteroids or corticotropin with acetazolamide sodium may increase the risk of hypernatremia and/or edema because these medications cause sodium and fluid retention; the risk with corticosteroids or corticotropin may depend on the patient's sodium requirement as determined by the condition being treated)

    (the possibility should be considered that concurrent chronic use of corticosteroids or corticotropin with carbonic anhydrase inhibitors may increase the risk of hypocalcemia and osteoporosis because these medications increase calcium excretion)


» Amphetamines or
Anticholinergics, especially atropine and related compounds or
» Mecamylamine or
» Quinidine    (therapeutic and/or side effects may be enhanced or prolonged when these medications are used concurrently with carbonic anhydrase inhibitors, especially acetazolamide, as a result of decreased excretion caused by alkalinization of urine; concurrent use with mecamylamine is not recommended; dosage adjustments of the other medications may be needed when carbonic anhydrase inhibitor therapy is initiated or discontinued or if the dosage is changed)


Antidiabetic agents, oral or
Insulin    (hypoglycemic response may be decreased during concurrent use because carbonic anhydrase inhibitors may cause hyperglycemia and glycosuria in diabetic patients; dosage adjustments may be required)


Barbiturates, especially phenobarbital or
Carbamazepine or
Phenytoin or other hydantoin anticonvulsants or
Primidone    (osteopenia induced by these agents may be enhanced; it is recommended that patients receiving concurrent therapy be monitored for early signs of osteopenia and that the carbonic anhydrase inhibitor be discontinued and appropriate treatment initiated if necessary)


Ciprofloxacin    (urinary alkalizers, such as carbonic anhydrase inhibitors, may reduce the solubility of ciprofloxacin in the urine; patients should be observed for signs of crystalluria and nephrotoxicity)


Digitalis glycosides    (concurrent use with carbonic anhydrase inhibitors may enhance the possibility of digitalis toxicity associated with hypokalemia)


Diuretics, other    (diuretic effects may be enhanced during concurrent therapy; however, the hypokalemic and hyperuricemic effects of many diuretics may also be enhanced during concurrent therapy)


Ephedrine    (urine alkalinization induced by carbonic anhydrase inhibitors may increase the half-life of ephedrine and prolong its duration of action, especially if the urine remains alkaline for several days or longer; dosage adjustment of ephedrine may be necessary)


Mannitol or
Urea    (concurrent use with carbonic anhydrase inhibitors may lead to increased reduction of intraocular pressure as well as increased diuresis)


» Methenamine    (efficacy may be reduced because alkaline urine produced by carbonic anhydrase inhibitors inhibits methenamine conversion to formaldehyde, which is the active bacteriostatic derivative of methenamine; {18} concurrent use is not recommended)


Mexiletine    (marked alkalinization of urine by carbonic anhydrase inhibitors may retard renal excretion of mexiletine)


Neuromuscular blocking agents, nondepolarizing    (hypokalemia induced by carbonic anhydrase inhibitors may enhance the blockade of nondepolarizing neuromuscular blocking agents, possibly leading to increased or prolonged respiratory depression or paralysis [apnea]; serum potassium concentration determinations may be necessary prior to administration of a nondepolarizing neuromuscular blocking agent)


Salicylates    (the risk of salicylate intoxication in patients receiving large doses of salicylates may be increased during concurrent therapy because metabolic acidosis induced by carbonic anhydrase inhibitors may increase penetration of salicylate into the brain. Anorexia, tachypnea, lethargy, coma, and death have been reported with concurrent use of high-dose aspirin and carbonic anhydrase inhibitors. {37} {38} {39} {40} {41} In addition, the increased risk of severe metabolic acidosis and salicylate toxicity should be considered if acetazolamide is used to produce forced alkaline diuresis in the treatment of salicylate overdose. With average doses of salicylates, alkalinization of the urine results in increased salicylate excretion and decreased salicylate plasma concentrations {02} {18} {21} {37} {38} {39} {40} {41})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Urine 17-hydroxysteroid (17-OHCS) determinations    (may produce false-positive results by interfering with absorbance in the modified Glenn-Nelson technique)


Urine protein determinations    (may produce false-positive results with bromophenol blue test reagent and with sulfosalicylic acid, heat and acetic acid, and nitric acid ring test methods because of alkalinization of urine)

With physiology/laboratory test values
Ammonia concentrations, blood and
Bilirubin concentrations, serum and
Urobilinogen concentrations, urine    (may be increased)


Bicarbonate concentrations, plasma    (usually are decreased)


Calcium concentrations, urine    (may be increased or unchanged)


Chloride concentrations, plasma    (may be increased, especially with acetazolamide)


Citrate concentrations, urine    (may be decreased; in combination with increased or unchanged urine calcium concentrations may result in renal calculi and ureteral colic)


Glucose concentrations, blood and
Glucose concentrations, urine    (may be increased, especially in diabetic or prediabetic patients receiving acetazolamide; patients not predisposed to diabetes are not significantly affected)


Iodine uptake by the thyroid gland    (may be decreased in hyperthyroid patients or those with normal thyroid function but not in hypothyroid patients)


Potassium concentrations, serum    (may be decreased, especially when therapy is initiated or with intermittent dosage; with continuous therapy, serum potassium concentrations usually return to normal)


Uric acid concentrations, serum    (may be increased; rarely, gout may be exacerbated)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Adrenal gland failure or adrenocortical insufficiency (Addison's disease){37}{39}    (patients more susceptible to electrolyte imbalances)


Diabetes mellitus    (may increase blood and urine sugar concentrations)


Gout, except when used to prevent uric acid calculi in patients receiving uricosuric antigout agents or
» Hyperchloremic acidosis or{37}{39}
» Hypokalemia, hyponatremia, or other electrolyte imbalance or{37}{39}
Respiratory acidosis    (may be exacerbated)


» Hepatic disease, including cirrhosis, or impairment{37}{39}    (patients more susceptible to electrolyte imbalances; increased risk of hepatic coma and hepatotoxicity)


Impaired alveolar ventilation due to pulmonary disease, edema, infection, or obstruction    (respiratory acidosis may be induced or increased {02})


» Renal failure, disease, or impairment{37}{39}    (excessively high plasma concentrations may result and the acidosis of renal failure may be aggravated {18})


» Renal calculi, calcium-containing, or history of    (may be exacerbated or induced during therapy)


Sensitivity to carbonic anhydrase inhibitors{37}{39}{40}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Complete blood cell (CBC) count{02}
Platelet count{02}    (baseline CBC and platelet counts recommended prior to initiating therapy and at regular intervals during therapy. If significant changes occur, medication should be promptly discontinued and appropriate therapy instituted {02} {07} {08})


» Electrolyte concentrations, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy, especially in patients for whom hypokalemia or other electrolyte imbalances would be detrimental, such as those with hepatic cirrhosis or those receiving potassium-wasting medications or digitalis)


Urologic examinations    (may be necessary to detect possible renal problems, especially crystalluria or renal calculi)




Side/Adverse Effects

Note: Serious side/adverse effects occur infrequently; many of the serious adverse effects are those that are common to all sulfonamide derivatives, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. {37} {38} {39} {41} Rarely, these serious adverse effects have caused fatalities. {37} {38} {39} {41} Many side effects are dose-related and may respond to a reduction of dosage.
Hypokalemia may occur if diuresis is brisk and may be especially likely to occur if hepatic cirrhosis is present, if potassium intake is inadequate, or if other potassium-wasting drugs are used concurrently. Potassium supplementation may be necessary in some patients.
Severe metabolic acidosis or acidotic coma may occur rarely during long-term carbonic anhydrase inhibitor therapy and may be corrected by administration of bicarbonate.



The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive: *
Legend:
I=Acetazolamide
II=Dichlorphenamide
III =Methazolamide

I
 
II
 
III
 
Medical attention needed
 
     
Acidosis (shortness of breath, troubled breathing) #
R
R
R
Blood dyscrasias (fever and sore throat, unusual bruising or bleeding) {02}
R
R
R
Bloody or black, tarry stools {02}
 
R
R
R
Cholestatic jaundice (darkening of urine, pale stools, yellow eyes or skin)
R
U
U
Clumsiness or unsteadiness
 
R
R
R
Confusion
 
R
R
R
Convulsions
 
R
R
R
Crystalluria, renal calculus, or sulfonamide-like nephrotoxicity (blood in urine, difficult urination, pain in lower back, pain or burning while urinating, sudden decrease in amount of urine) {02}
L
L
L
Hypersensitivity(fever, hives, itching, skin rash or sores) {02} {37} {39}
R
R
R
Hypokalemia (dryness of mouth, increased thirst, irregular heartbeats, mood or mental changes, muscle cramps or pain, nausea or vomiting, unusual tiredness or weakness, weak pulse)
R
R
R
Mental depression
 
L
L
L
Nearsightedness §
 
R
R
R
Ringing or buzzing in ears
 
R
R
R
Severe muscle weakness or trembling
 
R
R
R
Unusual tiredness or weakness **
 
M
M
M
Medical attention needed only if continuing or bothersome
 
     
Constipation
 
U
R
U
Diarrhea
 
M
M
M
Dizziness or lightheadedness
 
U
L
L
Drowsiness
 
L
L
L
Feeling of choking or lump in throat
 
U
R
U
General feeling of discomfort or illness
 
M
M
M
Headache {18}
 
R
R
R
Increase in frequency of urination or amount of urine
 
M
M
R
Increased sensitivity of eyes to sunlight {02} {08}
 
R
U
R
Loss of appetite
 
M
M
M
Loss of taste and smell
 
R
R
R
Metallic taste in mouth
 
M
M
M
Nausea or vomiting
 
M
M
M
Nervousness or irritability
 
U
R
U
Numbness, tingling, or burning in hands, fingers, feet, toes, mouth, tongue, lips, or anus
 
M
M
M
Weight loss
 
M
M
M
* Acetazolamide is the most widely used carbonic anhydrase inhibitor; most of the data concerning side effects have been reported for that medication. The comparatively infrequent reports of side effects with other agents of this group may reflect their less frequent usage rather than actual reduced incidence. The pharmacologic similarity of these medications suggests that side effects occurring with one may potentially occur with the others. However, many side effects may not occur with the same severity or frequency with all carbonic anhydrase inhibitors, and patients unable to tolerate one of these medications may be able to tolerate another. Frequency of side effects (generalized): M = more frequent; L = less frequent; R = rare; U = unknown.
 May be more likely to occur with acetazolamide and least likely to occur with methazolamide.
 May be more likely to occur with dichlorphenamide.
§ Transient myopia may occur when therapy is initiated and usually responds to a reduction in dosage or withdrawal of therapy. {37} {39} Transient myopia may not recur if therapy is restarted.
# May be less likely to occur with dichlorphenamide.
** Usually part of a general feeling of malaise induced by these agents but should be evaluated because rarely may indicate acidosis, blood dyscrasias, or hypokalemia.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Carbonic Anhydrase Inhibitors (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to carbonic anhydrase inhibitors, antibacterial sulfonamides, thiazide diuretics, or other sulfonamide-derivative diuretics

Pregnancy—Studies in animals have shown teratogenic (skeletal anomalies) and embryocidal effects





Breast-feeding—Use is not recommended, because these medicines may be distributed into breast milk and have the potential for serious adverse reactions
Other medications, especially amphetamines, mecamylamine, methenamine, or quinidine
Other medical problems, especially adrenal gland failure or adrenocortical insufficiency; hepatic disease, including cirrhosis or impairment; hyperchloremic acidosis; hypokalemia, hyponatremia, or other electrolyte imbalance; renal calculi, calcium-containing, or history of; or renal failure, disease, or impairment

Proper use of this medication
» Importance of not taking more medication than the amount prescribed

Taking medication with meals to lessen gastrointestinal upset

How to minimize inconvenience of unwanted diuresis

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Caution if drowsiness, dizziness, lightheadedness, or tiredness occurs

Regular visits to physician to check progress during therapy

» Possibility of hypokalemia

Diabetics: May increase blood and urine glucose concentrations

Importance of adequate {18} fluid intake during therapy to help prevent kidney stones

Checking with physician before discontinuing acetazolamide (when used as anticonvulsant); gradual dosage reduction may be desirable


Side/adverse effects
Signs of potential side effects, especially acidosis; blood dyscrasias; bloody or black, tarry stools; cholestatic jaundice; clumsiness or unsteadiness; confusion; convulsions; crystalluria, renal calculus, sulfonamide-like nephrotoxicity; hypersensitivity; hypokalemia; mental depression; nearsightedness; ringing or buzzing in ears; severe muscle weakness or trembling; or unusual tiredness or weakness


General Dosing Information
Carbonic anhydrase inhibitors are usually used concurrently with other antiglaucoma agents including miotics, mydriatics, and osmotic agents. {37} {39} {40} {41}

Dosage should be adjusted according to the requirements and response of the individual patient as indicated by measurement of ocular tension and symptomatology. {37} {39}

Carbonic anhydrase inhibitors may be given with meals to minimize gastrointestinal upset.

Maintenance of a high fluid intake may be advisable, especially in patients with hypercalciuria or gout, to reduce the risk of renal calculi.

Patients unable to tolerate one carbonic anhydrase inhibitor because of side effects may be able to tolerate another.

If a satisfactory lowering of intraocular pressure is not achieved or maintained with one carbonic anhydrase inhibitor, one of the other agents in this group may provide a beneficial effect.

It is recommended that various brands of acetazolamide marketed by different manufacturers not be used interchangeably unless data indicating therapeutic equivalence are available; bioequivalence problems have been reported.

It is recommended that carbonic anhydrase inhibitor therapy be discontinued if hematopoietic reactions, fever, skin rash, or renal problems occur.

If potassium supplementation is needed in a patient receiving a carbonic anhydrase inhibitor, the fact that plasma chloride concentration may be elevated should be kept in mind and a potassium preparation chosen that does not contain chloride. {18}

ACETAZOLAMIDE

Summary of Differences
Indications: Also indicated as an anticonvulsant, to prevent or reduce severity of symptoms of acute altitude sickness, to treat toxicity caused by weakly acidic medications, to treat familial periodic paralysis, and to prevent uric acid or cystine renal calculi.

Side effects: See Side/Adverse Effects .


Additional Dosing Information
See also General Dosing Information.

When acetazolamide is added to existing anticonvulsant therapy, {22} an initial daily dose of 4 to 5 mg per kg of body weight per day {14} in addition to existing medication is recommended. Dosage may be increased as necessary. Changes from other anticonvulsants to acetazolamide or withdrawal of acetazolamide therapy should be gradual to prevent increased seizure activity and possible status epilepticus. {37} {39}

Tolerance to the anticonvulsant effect of acetazolamide develops rapidly, over weeks or months in some patients. {14}



For oral dosage forms only:
   • Both the acetazolamide tablets and extended-release capsules are indicated for use in glaucoma and for prophylaxis and treatment of acute altitude sickness. Although the extended release capsules may be better tolerated than the acetazolamide tablets or the tablets of the other carbonic anhydrase inhibitors, they may be less effective in some patients. {38}


For parenteral dosage forms only:
   • Direct intravenous administration is preferred; intramuscular injection is not recommended, {39} because it is painful due to the alkaline pH of the solution. {02}
   • Parenteral administration is usually used when the patient cannot take oral medication or when a rapid initial intraocular pressure-lowering action is necessary. Therapy is usually continued with oral acetazolamide, depending on the patient's condition and response.


Oral Dosage Forms

Note:  Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ACETAZOLAMIDE EXTENDED-RELEASE CAPSULES

Usual adult and adolescent dose
Antiglaucoma agent
Oral, 500 mg two times a day, in the morning and evening. {38}

Note: In the treatment of glaucoma, dosage greater than 1 gram per day usually does not produce an increased effect. {38}


Altitude sickness, acute, prophylactic and therapeutic agent1
Oral, 500 mg one or two times a day. {01} {02} {37} {38}

Note: During rapid ascent, such as in rescue or military operations, 1,000 mg a day is recommended. Therapy should preferably be initiated 24 to 48 hours before ascent and, while at high altitude, continued for 48 hours or longer as necessary to control symptoms. {01} {02} {37} {38}
The use of acetazolamide for rapid ascent does not obviate the need for prompt descent if severe forms of high altitude sickness, such as high altitude pulmonary edema (HAPE) or high altitude cerebral edema, occur. {02} {37} {38}



Usual pediatric dose
Safety and efficacy have not been established. {38}

Strength(s) usually available
U.S.—


500 mg (Rx) [Diamox Sequels{01}{38}]

Canada—


500 mg (Rx) [Diamox Sequels]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), {38} in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness. {38}


ACETAZOLAMIDE TABLETS USP

Usual adult and adolescent dose
Antiglaucoma agent


Open-angle glaucoma:
Initial—Oral, 250 mg one to four times a day. {37}

Maintenance—To be titrated according to patient response; lower doses may be sufficient.



Secondary glaucoma and preoperative lowering of intraocular pressure :
Oral, 250 mg every four hours. {37} Some patients may respond to 250 mg two times a day. {37} In some acute cases, an initial dose of 500 mg followed by 125 or 250 mg every four hours may be preferable. {37}



Malignant (ciliary block) glaucoma:
Oral, 250 mg four times a day to reduce intraocular pressure. {04}


Anticonvulsant
Oral, 4 {14} to 30 mg {37} (usually 10 mg initially) per kg of body weight a day in up to 4 divided doses; usually 375 mg to 1 gram a day. {02} {37}

Altitude sickness, acute, prophylactic and therapeutic agent1
Oral, 250 mg two to four times a day. {01} {02} {37} {38}

Note: During rapid ascent, such as in rescue or military operations, 1,000 mg a day is recommended. Therapy should preferably be initiated 24 to 48 hours before ascent and, while at high altitude, continued for 48 hours or longer as necessary to control symptoms. {01} {02} {37} {38}
The use of acetazolamide for rapid ascent does not obviate the need for prompt descent if severe forms of high altitude sickness, such as high altitude pulmonary edema (HAPE) or high altitude cerebral edema, occur. {02} {37} {38}


[Antiparalytic ]1
Oral, 250 mg to 1.5 grams a day in divided doses.

[Antiurolithic ]1
Oral, 250 mg daily at bedtime.


Note: For use as an anticonvulsant or in open-angle glaucoma, dosage greater than 1 gram per day usually does not produce an increased effect. {37}


Usual pediatric dose
Glaucoma
Oral, 8 to 30 mg per kg of body weight, usually 10 to 15 mg per kg, or 300 to 900 mg per square meter of body surface area a day in divided doses.

Anticonvulsant
See Usual adult and adolescent dose.


Strength(s) usually available
U.S.—


125 mg (Rx) [Diamox (scored)][Generic]{02}{37}


250 mg (Rx) [Ak-Zol] [Dazamide] [Diamox (scored )] [Storzolamide][Generic]{02}{06}{09}{36}{37}

Canada—


250 mg (Rx) [Acetazolam] [Apo-Acetazolamide] [Diamox]{27}{28}

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), {37} in a well-closed container, unless otherwise specified by manufacturer.

Preparation of dosage form:
For pediatric patients or adults unable to swallow tablets—An acetazolamide oral suspension may be prepared by crushing acetazolamide tablets and suspending the resultant powder in a highly flavored syrup (cherry, raspberry, chocolate, etc.). Up to 500 mg may be suspended in 5 mL of syrup, but a suspension containing 250 mg per 5 mL is more palatable. Such a suspension is stable for 1 week. Refrigeration may improve the taste but does not increase or lengthen stability. Elixirs or other vehicles containing alcohol or glycerin will not provide a palatable suspension.

Auxiliary labeling:
   • May cause drowsiness. {01} {02}



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ACETAZOLAMIDE SODIUM STERILE USP

Usual adult and adolescent dose
Antiglaucoma agent
For rapid initial lowering of intraocular pressure: Intravenous, the equivalent of acetazolamide—500 mg. {39}

Note: Parenteral administration may be repeated in two to four hours in some acute cases, but therapy is usually continued with oral acetazolamide, depending on the patient's response.


[Diuretic (urinary alkalinizing) ]
Intravenous, 5 mg per kg of body weight or as required to achieve and maintain a forced alkaline diuresis.


Note: For other uses or when the patient is unable to take oral medication, acetazolamide may be given parenterally in dosages equivalent to those recommended for the oral tablets. (See Acetazolamide Tablets USP. )


Usual pediatric dose
Antiglaucoma agent
Acute glaucoma: Intravenous, the equivalent of acetazolamide—5 to 10 mg per kg of body weight every six hours.

[Diuretic (urinary alkalinizing) ]
Intravenous, the equivalent of acetazolamide: 5 mg per kg of body weight or 150 mg per square meter of body surface area once a day in the morning for one or two days alternated with a drug-free day.


Strength(s) usually available
U.S.—


500 mg (Rx) [Diamox][Generic]{02}{39}

Canada—


500 mg (Rx) [Diamox]

Packaging and storage:
Prior to reconstitution, store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), {39} unless otherwise specified by manufacturer.

Preparation of dosage form:
Sterile Acetazolamide Sodium USP is reconstituted for parenteral use by adding at least 5 mL of Sterile Water for Injection USP {39} to the vial and shaking to dissolve. A solution prepared using 5 mL of diluent contains the equivalent of 100 mg of acetazolamide per mL.

Stability:
After reconstitution, solutions retain their potency for 1 week if refrigerated. {39} However, because they contain no preservative, use within 24 hours is strongly recommended. {39}


DICHLORPHENAMIDE

Summary of Differences
Side effects: See Side/Adverse Effects .


Oral Dosage Forms

DICHLORPHENAMIDE TABLETS USP

Usual adult and adolescent dose
Antiglaucoma agent
Initial: 100 to 200 mg for the first dose followed by 100 mg every twelve hours until the desired response is obtained. {40}

Maintenance: 25 to 50 mg one to three times a day. {40}


Usual pediatric dose
Safety and efficacy have not been established. {40}

Strength(s) usually available
U.S.—


50 mg (Rx) [Daranide (scored)]{07}{40}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness. {07}


METHAZOLAMIDE

Summary of Differences
Side effects: See Side/Adverse Effects .


Oral Dosage Forms

METHAZOLAMIDE TABLETS USP

Usual adult and adolescent dose
Antiglaucoma agent
Oral, 50 {41} to 100 mg two or three times a day. {41}


Usual pediatric dose
Safety and efficacy have not been established. {41}

Strength(s) usually available
U.S.—


25 mg (Rx) [MZM{10}] [Neptazane{08}{41}][Generic]


50 mg (Rx) [MZM{10}] [Neptazane{08}{41} ( scored)][Generic]

Canada—


50 mg (Rx) [Neptazane]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness. {08}



Revised: 01/24/1995



References
  1. Acetazolamide package insert (Diamox Sequels, Lederle—US), Rev 4/87, Rec 5/88.
  1. Acetazolamide package insert (Diamox Tablets, Diamox for Injection, Lederle—US), Rev 3/87, Rec 5/88.
  1. Reviewer's comment on Indications Index, 1986.
  1. Reviewer's responses to Ophthalmics Ballot, 9/86.
  1. Panel comments, 7/24/86.
  1. Acetazolamide tablets package insert (Dazamide, Major—US), Rev 4/86, Rec 5/87.
  1. Dichlorphenamide tablets package insert (Daranide, MSD—US), Rev 11/86, Rec 5/88.
  1. Methazolamide tablets package insert (Neptazane, Lederle—US), Rev 3/86, Rec 5/88.
  1. Acetazolamide tablets package insert (Ak-Zol, Akorn—US), Rev 2/81, Rec 5/88.
  1. Methazolamide package insert (MZM, CIBA Vision—US).
  1. Dental panel meeting, 8/6/86.
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  1. Additional panel comments from revision dated 7/24/86.
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  1. Worsham, et al. Sacrococcygeal teratoma in a neonate. Association with maternal use of acetazolamide. JAMA 1978 Jul 21; 240(3): 251-2.
  1. Acetazolamide excretion into human breast milk. [Letter]. Br J Clin Pharmacol 1984; 17: 599-600.
  1. Sweeney, et al. Toxic interaction between acetazolamide and salicylate: case reports and a pharmacokinetic explanation. Clin Pharmacol Ther; 1986 Nov: 518-24.
  1. AES Society Proceedings. Effect of adjunctive acetazolamide in uncontrolled seizures. Epilepsia 1985; 26(5): 545.
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  1. Acetazolamide tablets package insert (Acetazolam, ICN—Canada), Rev 1/84, Rec 5/88.
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  1. Acetazolamide (Storzolamide, Storz). In: Olin BR, editor. Drug facts and comparisons. St. Louis: Facts and Comparisons Inc, 1992.
  1. Acetazolamide tablets (Diamox, Lederle). In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994: 1156.
  1. Acetazolamide extended-release capsules (Diamox Sequels, Lederle). In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994: 1157.
  1. Acetazolamide parenteral (Diamox, Lederle). In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994: 1156.
  1. Dichlorphenamide tablets (Daranide, MSD). In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994: 1427.
  1. Methazolamide tablets (Neptazane, Lederle). In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994: 1175.
  1. Fleeger CA, editor. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1993.
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