Acetazolamide Sodium (acetazolamide sodium)

Dosage of acetazolamide should be adjusted according to the patient's requirements and response. Dosage of acetazolamide sodium is expressed in terms of acetazolamide.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Potassium Wasting Diuretics/Cisapride

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent administration may result in additive effects on the QT interval.(1)

CLINICAL EFFECTS: Concurrent administration may result in prolongation of the QT interval, which may result in potentially life-threatening arrhythmias.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of cisapride states that cisapride should not be used in patients with uncorrected hypokalemia or who might experience a rapid reduction of plasma potassium, such as those patients taking potassium-wasting diuretics in the acute setting.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The manufacturer of cisapride states that QT prolongation, torsades de pointes (sometimes with syncope), cardiac arrest, and sudden death have been reported in patients who were not taking agents known to increase cisapride levels. Some of these patients had uncorrected electrolyte disorders such as hypokalemia. Therefore, the manufacturer of cisapride states that cisapride should not be used in patients with uncorrected hypokalemia or who might experience a rapid reduction of plasma potassium, such as those patients taking potassium-wasting diuretics in the acute setting.(1) There is no published documentation to support this interaction.

Sulfonamides/Methenamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Methenamine is hydrolyzed to formaldehyde in acidic urine. Sulfonamides may form an insoluble precipitate with formaldehyde in the urine.(1,2)

CLINICAL EFFECTS: The concurrent administration of methenamine and sulfamethizole or sulfathiazole is likely to form a precipitate in the urine.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Methenamine should not be administered to patients receiving sulfonamides.(1-3)

DISCUSSION: Methenamine is hydrolyzed to formaldehyde in acidic urine. An in vitro study showed that addition of methenamine and mandelic acid to saturated solutions of sulfamethizole at pH 5.0 and 6.0 produced a precipitate in one hour.(4)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Carbonic Anhydrase Inhibitors/Topiramate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Topiramate is a weak carbonic anhydrase inhibitor and can induce renal bicarbonate loss, resulting in metabolic acidosis. It can also reduce urinary citrate excretion and increase urinary pH, posing a risk for nephrolithiasis. As well, carbonic anhydrase inhibitors can cause decreased sweating and elevated body temperature, predisposing patients to heat-related disorders.(1)

CLINICAL EFFECTS: The concurrent use of topiramate with another carbonic anhydrase inhibitor may increase the risk of metabolic acidosis and kidney stone formation.(1) Concurrent use of topiramate with other carbonic anhydrase inhibitors may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Patients with conditions that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, and being on a ketogenic diet) may be at increased risk of experiencing adverse effects from concurrent carbonic anhydrase inhibitors.(1) Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The US manufacturer of topiramate states that the concurrent use of topiramate with other carbonic anhydrase inhibitors should be avoided. Patients receiving concurrent therapy should be monitored for the appearance of or worsening of metabolic acidosis, nephrolithiasis, and hyperthermia.(1) Check serum bicarbonate at baseline and periodically during treatment. Monitor for signs and symptoms of metabolic acidosis: hyperventilation, fatigue, anorexia, arrhythmias, stupor. Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of metabolic acidosis, dehydration, oligohidrosis, or elevated body temperature occur, a decreased dose or discontinuation of zonisamide should be considered.

DISCUSSION: Topiramate is a weak carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors increase urinary bicarbonate excretion, reduce urinary citrate excretion and increase urinary pH. Concurrent use of topiramate with other carbonic anhydrase inhibitors may increase the risk of metabolic acidosis and kidney stone formation and should therefore be avoided.(1) Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment.(1)

Carbonic Anhydrase Inhibitors/Zonisamide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Zonisamide is a carbonic anhydrase inhibitor and can induce renal bicarbonate loss, resulting in metabolic acidosis. It can also reduce urinary citrate excretion and increase urinary pH, posing a risk for nephrolithiasis. As well, carbonic anhydrase inhibitors can cause decreased sweating and elevated body temperature, predisposing patients to heat-related disorders. Concurrent use of zonisamide with other carbonic anhydrase inhibitors may result in an additive risk of all these effects.(1-2)

CLINICAL EFFECTS: The concurrent use of zonisamide with another carbonic anhydrase inhibitor may increase the risk of metabolic acidosis and kidney stone formation.(1) Concurrent use of zonisamide with other carbonic anhydrase inhibitors may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Patients with conditions that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, and being on a ketogenic diet) may be at increased risk of experiencing adverse effects from concurrent carbonic anhydrase inhibitors.(1) Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The UK and US manufacturers of zonisamide state that caution should be used in adults when zonisamide is prescribed with other carbonic anhydrase inhibitors.(1-2) Pediatric and adolescent patients must not take carbonic anhydrase inhibitors concurrently with zonisamide.(1) Check serum bicarbonate at baseline and periodically during treatment. Monitor for signs and symptoms of metabolic acidosis: hyperventilation, fatigue, anorexia, arrhythmias, stupor. Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of metabolic acidosis, dehydration, oligohidrosis, or elevated body temperature occur, a decreased dose or discontinuation of zonisamide should be considered.

DISCUSSION: Zonisamide is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors increase urinary bicarbonate excretion, reduce urinary citrate excretion and increase urinary pH. Concurrent use of zonisamide with other carbonic anhydrase inhibitors may increase the risk of metabolic acidosis and kidney stone formation and should therefore be avoided.(1) Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment and resulted in death.(1)

Urinary Alkalinizers/Dextroamphetamine Transdermal

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Urinary alkalinizers decrease the renal elimination of dextroamphetamine.(1)

CLINICAL EFFECTS: Concurrent use of dextroamphetamine and urinary alkalinizers may result in increased dextroamphetamine levels and side effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of dextroamphetamine with urinary alkalinizing agents should be avoided.(1)

DISCUSSION: Concurrent use of alkalinizing agents with dextroamphetamine decreases the renal elimination of dextroamphetamine. Co-administration of these should be avoided because of the potential of increased actions of dextroamphetamine.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Acetazolamide; Methazolamide/Aspirin (> 100 Mg); Salicylates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Acetazolamide and methazolamide may reduce blood pH, causing a shift of salicylates from plasma into tissues (eg, central nervous system). Alternatively, toxicity may be due to salicylate-induced displacement of the carbonic anhydrase inhibitor from its protein binding sites and inhibition of renal tubular secretion.

CLINICAL EFFECTS: An increase in the pharmacologic effects of salicylates with possible toxicity may occur.

PREDISPOSING FACTORS: High doses of salicylates, low body weight.

PATIENT MANAGEMENT: Avoid the combination if possible. If it is necessary to administer these drugs concurrently, monitor salicylate levels and monitor the patient for symptoms of toxicity. Adjust the dose as needed.

DISCUSSION: Two young patients with unimpaired renal and hepatic function were found to have developed metabolic acidosis after treatment for glaucoma and joint pain with a combination of salicylates and carbonic anhydrase inhibitors in normal doses.(1) A 67-year old woman and a 75-year old woman taking carbonic anhydrase inhibitors for therapy of glaucoma and high doses of aspirin for arthritis developed severe acid-base imbalance and salicylate intoxication.(2) Neither patient exhibited ill effects when taking high aspirin doses without a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitor-induced acidemia increases the risk of developing salicylate intoxication in patients receiving high aspirin doses. Two elderly patients, who were chronically receiving aspirin developed lethargy, incontinence, and confusion after dosing with acetazolamide.(3) These effects could have been due to either drug (see mechanism).

Carbonic Anhydrase Inhibitors/Lithium

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbonic anhydrase inhibitors may increase the renal excretion of lithium, either by alkalinization of the urine or by impairing the proximal tubular reabsorption of lithium.

CLINICAL EFFECTS: Concurrent use of a carbonic anhydrase inhibitor may result in decreased levels and clinical effectiveness of lithium.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lithium levels should be monitored in patients receiving concurrent therapy or if the carbonic anhydrase inhibitor is withdrawn from concurrent therapy. The dose of lithium may need to be adjusted.

DISCUSSION: One study involving six subjects showed that the concurrent use of a single dose of both lithium carbonate and acetazolamide caused a 27% to 31% increase in the urinary excretion of lithium.(1) Acetazolamide has been used in combination with other agents to treat lithium toxicity.(2)

Carbonic Anhydrase Inhibitors/Metformin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbonic anhydrase inhibitors increase bicarbonate excretion which may cause metabolic acidosis.(1) High systemic concentrations of metformin may result in lactic acidosis.(2,3) Topiramate, a mild carbonic anhydrase inhibitor, may also increase systemic exposure to metformin.(1)

CLINICAL EFFECTS: Carbonic anhydrase inhibitors may increase the risk for metformin associated lactic acidosis.(1-3) Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low blood pH, increased anion gap and elevated blood lactate.(2) Carbonic anhydrase inhibitors linked to this monograph are acetazolamide, dichlorphenamide, methazolamide, sulthiame, topiramate, and zonisamide.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent.

PATIENT MANAGEMENT: For patients receiving concurrent therapy, monitor renal function and assure that patient does not have risk factors for metformin associated lactic acidosis. Discontinue metformin when risk factors are present. If both drugs are given, monitor renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio. Manufacturer recommendations: the manufacturer of metformin recommends caution with concomitant use of carbonic anhydrase inhibitors due to an increased risk for metformin associated lactic acidosis.(2) The manufacturer of topiramate notes that topiramate can frequently cause metabolic acidosis and that metformin should not be used in patients with metabolic acidosis.(1)

DISCUSSION: A literature search for lactic acidosis due solely to the combination of metformin and carbonic anhydrase inhibitors or topiramate did not reveal any case reports of symptomatic metabolic acidosis due to this combination. Never-the-less, since carbonic anhydrase inhibitors act by inhibiting the reabsorption of bicarbonate in the renal tubule, some lowering of systemic bicarbonate and pH is common and supports the plausibility of this interaction. In addition, a pharmacokinetic interaction has been described with topiramate. A study in healthy volunteers evaluated the effect of topiramate 100 mg every 12 hours on the kinetics of metformin 500 mg every 12 hours. Mean metformin exposure (area-under-curve or AUC) was increased 25%.(1)

Urinary Alkalinizers/Memantine; Amantadine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Memantine and amantadine elimination is impaired by urinary alkalinization.(1,2)

CLINICAL EFFECTS: Potentiation of memantine or amantadine effects may be observed.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patient for adverse reactions such as dizziness, headache, or confusion if a urinary alkalinizer is required. The memantine or amantadine dose may need to be adjusted when a urinary alkalinizer is started or stopped.(1,2)

DISCUSSION: The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Urine alkalinization may lead to an accumulation of memantine with a possible increase in adverse effects. Urine pH is also altered by diet and clinical state of the patient (e.g., renal tubular acidosis or severe infections of the urinary tract). Hence, memantine should be used with caution under these conditions.(1) A study in rats showed that concomitant administration of sodium bicarbonate with amantadine caused a decrease in amantadine renal clearance (1.16 vs. 0.76). Amantadine's area-under-the-curve (AUC) was increased approximately 78%.(3) A study in 12 healthy subjects showed that plasma concentrations of memantine are dependent on urine pH. Alkaline urine pH caused a 79% reduction in renal clearance.(4)

Urinary Alkalinizers/Sympathomimetics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unionized sympathomimetic amines will be reabsorbed into systemic circulation from the distal tubules of the kidneys.

CLINICAL EFFECTS: Enhanced sympathomimetic activity and increased risk of sympathomimetic toxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Watch patient for enhanced sympathomimetic side effects when urinary alkalinizers are concomitantly used. A lower dose of certain sympathomimetics may be required.

DISCUSSION: Signs and symptoms of sympathomimetic toxicity include euphoria, confusion, delirium, hallucinations and nervousness.

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• Adrenocortical insufficiency
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Hepatic cirrhosis
• Hyperchloremic acidosis
• Hypokalemia
• Hyponatremia

• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Disease of liver
• Recurrent calcium renal calculi

• Diabetes mellitus
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Suicidal ideation

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Less Frequent

• Crystalluria
• Depression
• Kidney stone

Rare or Very Rare

• Abnormal hepatic function tests
• Acidosis
• Acute pulmonary edema
• Agranulocytosis
• Anaphylaxis
• Aplastic anemia
• Black tarry stools
• Blood dyscrasias
• Choroidal detachment
• Choroidal effusion
• Flaccid paralysis
• Glycosuria
• Hemolytic anemia
• Hepatic necrosis
• Hyperglycemia
• Hypoglycemic disorder
• Hypokalemia
• Idiopathic thrombocytopenic purpura
• Jaundice
• Leukopenia
• Obstructive hyperbilirubinemia
• Pancytopenia
• Renal failure
• Secondary angle-closure glaucoma
• Seizure disorder
• Stevens-johnson syndrome
• Toxic epidermal necrolysis

More Frequent

• Anorexia
• Diarrhea
• Dysgeusia
• Fatigue
• Malaise
• Nausea
• Vomiting

Less Frequent

• Drowsy
• Hematuria
• Hyponatremia

Rare or Very Rare

• Acute cognitive impairment
• Ataxia
• Dizziness
• Erythema
• Fever
• Headache disorder
• Hearing disorder
• Injection site sequelae
• Myopia
• Paresthesia
• Parosmia
• Polyuria
• Skin photosensitivity
• Tinnitus
• Urticaria

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