NEODOSE

INDICATIONS

• Metabolic alkalosis, chronic: Serum bicarbonate was reduced in 89 infants and neonatesmwith metabolic alkalosis associated with chronic respiratory insufficiency treated with 129 acetaZOLAMIDE courses in a retrospective review. The regimen was a single-course of 3 to 5mg/kg/dose IV every 6 hours up to a maximum 4 doses/24-hour period. The mean measured serum bicarbonate was reduced from 29.5+/-3.7 mEq/L to 26.9+/-3.8 mEq/L, base excess was reduced from 10+/-3.4 mEq/L to 4.8+/-4 mEq/L, and serum chloride was increased from 98.9+/-5.3 mEq/L to 101.2+/-5.5mEq/L after 24 hours of acetaZOLAMIDE administration (p less than 0.001 for all measures). A significant reduction in pH (7.41 to 7.37) and pCo2 (58.5 to 55.6 mmHg) and an increase in serum creatinine (0.38 to 0.43 mg/dL) was observed. Uncompensated respiratory acidosis occurred in 4 patients. Neonatal outcome was not assessed.
• Posthemorrhagic ventricular dilation (PHVD), adjunct; Prevention of shunt placement: Use of acetaZOLAMIDE and furosemide in preterm infants with PHVD was associated with a higher rate of shunt placement, death, and increased neurological morbidity as compared to standard therapy alone, in a multicenter, randomized, controlled trial (n=177). Infants less than 3 months beyond the expected date of delivery and with a ventricular width more than 4 mm above the 97th percentile after intraventricular hemorrhage received either standard therapy plus acetaZOLAMIDE 100 mg/kg daily and furosemide 1 mg/kg daily (n=88) or standard therapy alone (n=89). Mean gestation age was 28.5 weeks and median postnatal age was 23.5 days in the drug therapy group. Median treatment duration of acetaZOLAMIDE was 35 days. Assessments at 1 year showed that death or shunt placement had occurred in 56 infants (63.3%) in the drug therapy group and in 46 (52.2%) allocated to standard therapy (11.1% (CI, -3.2% to 25.2%; p=0.15). Adverse effects were reported in 38 infants, 23 of whom required permanent discontinuation of drug therapy. In a small cohort study, 9 of 10 preterm infants with raised intracranial hypertension secondary to PVHD treated with acetaZOLAMIDE and furosemide avoid placement of a ventriculoperitoneal shunt; in comparison, 3 of 6 patients who received serial lumbar puncture avoided shunt placement. acetaZOLAMIDE was started at 20 mg/kg/day and increased by 10 mg/kg up to 100 mg/kg/day in 3 divided doses administered orally or if necessary, IV; dose of furosemide was 1 mg/kg daily orally or IV. Mean gestational age was 28.4 weeks. Limited use of acetaZOLAMIDE may be warranted in infants with PVHD and raised intracranial hypertension based on the findings of Kennedy et al, 2001.

FDA APPROVED INDICATION

• Oral extended-release capsules: Indicated in patients 12 years or older for the prevention or amelioration of symptoms associated with acute mountain sickness despite gradual ascent. Also indicated in patients 12 years or older as adjunctive treatment of open-angle glaucoma, secondary glaucoma, and preoperatively in acute closed-angle glaucoma when delay of surgery is indicated in order to lower intraocular pressure. Safety and efficacy of oral extended-release capsules not established in pediatric patients younger than 12 years.
• IV and oral immediate-release: Safety and efficacy of IV injection and oral immediate-release tablets not established in pediatric patients.

CONTRAINDICATIONS/PRECAUTIONS

Contraindicated with depressed sodium and/or potassium blood serum levels, marked renal or hepatic disease or dysfunction (including cirrhosis), suprarenal gland failure, hyperchloremic acidosis, and long-term administration in patients with chronic noncongestive angle-closure glaucoma. Sulfonamide derivative; cross sensitivity possible. Increasing dose does not increase effect; it may decrease diuresis and increase risk of drowsiness and paresthesia. May precipitate or aggravate acidosis in patients with pulmonary obstruction or emphysema where alveolar ventilation may be impaired. Gradual ascent recommended when used for acute mountain sickness. Long-term therapy in pediatric patients has resulted in growth retardation secondary to chronic acidosis. Blood glucose increases and decreases have been reported in patients with diabetes mellitus or impaired glucose tolerance. May cause electrolyte imbalances (eg, hyperkalemia, hyponatremia, and metabolic acidosis); caution recommended with current, or predisposition to, electrolyte and acid/base imbalances (eg, impaired renal function, diabetes mellitus, and impaired alveolar ventilation).

ADVERSE EFFECTS

Nephrocalcinosis, per renal ultrasound, occurred more frequently in the acetaZOLAMIDE/furosemide group than standard therapy group (24% vs 4% (difference 19%, CI 9% to 30%), in a randomized, controlled trial (n=177) of preterm infants (mean gestation age 28.5 weeks and median postnatal age was 23.5 days) with post-hemorrhagic ventricular dilation. Median treatment duration of acetaZOLAMIDE was 35 days. Hypercalciuria occurred in 7 of 12 infants exposed to furosemide and acetaZOLAMIDE; nephrocalcinosis developed in 5 of the 7 patients with hypercalciuria. A transient increase in intracranial pressure was demonstrated in 6 of 8 infants (25 to 37 weeks gestation, 16 to 121 postnatal days) with post-hemorrhagic hydrocephalus administered IV acetaZOLAMIDE 50 mg/kg. No increase was observed with oral administration. In all 4 preterm infants with chronic lung disease, discontinuation of acetaZOLAMIDE (IV and oral) was necessary due to the inability to compensate for the rise in pCo2.

BLACK BOX WARNING

Severe reactions to sulfonamides (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias) have occurred, rarely resulting in fatality. Sensitizations may recur. Discontinue use if hypersensitivity or other serious reactions occur. Anorexia, tachypnea, lethargy, coma, and death have been reported with concomitant high-dose aspirin and acetaZOLAMIDE.

ADMINISTRATION

IV route preferred; IM use not recommended . Recommended concentrations for intermittent IV are 50 mg/mL or 100 mg/mL.

MONITORING

Obtain a CBC and platelet count at baseline and regularly during treatment. Monitor serum electrolytes periodically. Consider monitoring urinary pH in patients on acetaZOLAMIDE concomitantly with other antiepileptic drugs, particularly valproate.