Drug Interaction Report

GENERALLY AVOID: Concomitant use of carbonic anhydrase inhibitors such as acetazolamide, topiramate, and zonisamide with each other or with other carbonic anhydrase inhibitors may increase the risk and severity of metabolic acidosis as well as the risk of kidney stone formation due to possible additive pharmacologic effects. Carbonic anhydrase inhibitors can decrease serum bicarbonate in a dose-related manner and induce non-anion gap, hyperchloremic metabolic acidosis. In addition, they can promote stone formation by reducing urinary citrate excretion and increasing urinary pH. Because they alter electrolyte and fluid balance, carbonic anhydrase inhibitors may also predispose patients to heat-related disorders. Oligohidrosis and hyperthermia have specifically been reported with the use of topiramate or zonisamide, particularly in pediatric patients, and coadministration with other carbonic anhydrase inhibitors may potentiate the risk according to the manufacturers. Oligohidrosis and hyperthermia are sometimes associated with serious sequelae, but may be preventable by prompt recognition of symptoms and appropriate treatment.

MANAGEMENT: The use of more than one carbonic anhydrase inhibitor at a time is generally not recommended. Patients receiving treatment with a carbonic anhydrase inhibitor should have baseline and periodic measurements of serum bicarbonate. If metabolic acidosis develops and persists, consideration should be given to reducing the dosage or discontinuing treatment. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae like cardiac arrhythmias or stupor. If left untreated, metabolic acidosis can also lead to nephrolithiasis or nephrocalcinosis, osteomalacia (or rickets in children), osteoporosis, and reduced growth rates in pediatric patients. Increased fluid intake is recommended during therapy with carbonic anhydrase inhibitors to increase urinary output, which lowers the concentration of substances involved in stone formation. Patients, particularly pediatric patients, should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. Proper hydration before and during vigorous activities or exposure to warm temperatures is recommended. Patients (or their guardians or caregivers) should contact their doctor immediately if they develop signs or symptoms of kidney stones such as sudden back pain, abdominal pain and/or blood in the urine, of if they are not sweating as usual, with or without a fever. Carbonic anhydrase inhibitors should be used cautiously in the presence of predisposing factors to acidosis, such as renal impairment, severe respiratory disorders, status epilepticus, prolonged or severe diarrhea, a ketogenic diet (i.e., high protein/low carbohydrate), or surgery.