acetohydroxamic acid 250 MG Oral Tablet

INDICATIONS AND USAGE Acetohydroxamic acid is indicated as adjunctive therapy in patients with chronic urea-splitting urinary infection. AHA is intended to decrease urinary ammonia and alkalinity, but it should not be used in lieu of curative surgical treatment (for patients with stones) or antimicrobial treatment. Long-term treatment with AHA may be warranted to maintain urease inhibition as long as urea-splitting infection is present. Experience with AHA does not go beyond 7 years. A patient package insert should be distributed to each patient who receives AHA.

DOSAGE AND ADMINISTRATION AHA should be administered orally, one tablet 3-4 times a day in a total daily dose of 10-15 mg/kg/day. The recommended starting dose is 12 mg/kg/day, administered at 6-8 hour intervals at a time when the stomach is empty. The maximum daily dose should be no more than 1.5 grams, regardless of body weight. The dosage should be reduced in patients with reduced renal function. Patients whose serum creatinine is greater than 1.8 mg/dl should take no more than 1.0 gm/day; such patients should be dosed at q-12-h intervals. Further reductions in dosage to prevent the accumulation of toxic concentrations in the blood may also be desirable. Insufficient data exists to accurately characterize the optimum dose and/or dose interval in patients with moderate degrees of renal insufficiency. Patients with advanced renal insufficiency (i.e., serum creatinine more than 2.5 mg/dl) should not be treated with AHA. The risk of accumulation of toxic blood levels of AHA seems to be greater than the chances for a beneficial effect in such patients. In children an initial dose of 10 mg/kg/day is recommended. Close monitoring of the patient’s clinical condition and hematologic status is recommended. Titration of the dose to higher or lower levels may be required to obtain an optimum therapeutic effect and/or to reduce the risk of side effects.

WARNINGS A Coombs negative hemolytic anemia has occurred in patients receiving AHA. Gastrointestinal upset characterized by nausea, vomiting, anorexia and generalized malaise have accompanied the most severe forms of hemolytic anemia. Approximately 15% of patients receiving AHA have had only laboratory findings of an anemia. However, most patients developed a mild reticulocytosis. The untoward reactions have reverted to normal following cessation of treatment. A complete blood count, including a reticulocyte count, is recommended after two weeks of treatment. If the reticulocyte count exceeds 6%, a reduced dosage should be entertained. A CBC and reticulocyte count are recommended at 3-month intervals for the duration of treatment.

Acetohydroxamic acid should not be used in: a. patients whose physical state and disease are amenable to definitive surgery and appropriate antimicrobial agents b. patients whose urine is infected by non-urease producing organisms c. patients whose urinary infections can be controlled by culture-specific oral antimicrobial agents d. patients whose renal function is poor (i.e., serum creatinine more than 2.5 mg/dl and/or creatinine clearance less than 20 ml/min) e. female patients who do not evidence a satisfactory method of contraception f. patients who are pregnant Acetohydroxamic acid may cause fetal harm when administered to a pregnant woman. AHA was teratogenic (retarded and/or clubbed rear leg at 750 mg/kg and above and exencephaly and encephalocele at 1,500 mg/kg) when given intraperitoneally to rats. AHA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the fetus.

CLINICAL PHARMACOLOGY AHA reversibly inhibits the bacterial enzyme urease, thereby inhibiting the hydrolysis of urea and production of ammonia in urine infected with urea-splitting organisms. The reduced ammonia levels and decreased pH enhance the effectiveness of antimicrobial agents and allow an increased cure rate of these infections. AHA is well absorbed from the gastrointestinal tract after oral administration; peak blood levels occur from 0.25 to 1 hour after dosing. The compound is distributed throughout body water, and there is no known binding to any tissue. AHA chelates with dietary iron within the gut. This reaction may interfere with absorption of AHA and with iron. Concomitant hypochromic anemia should be treated with intramuscular iron. In rodents, the metabolic fate of AHA is well known; 55% is excreted unchanged in urine, 25% is excreted as acetamide or acetate and 7% is excreted by the lungs as carbon dioxide. Less than 1% is excreted in the feces. Approximately 5% of the administered dose is unaccounted for. In rodents, AHA shows a dose-related change in pharmacokinetics; with increasing dose, there is an increase in the half-life and an increase in the percent of the administered dose recovered in urine as unchanged AHA. Pharmacokinetics in man are generally similar to rodents including the dose-related increase in half-life, but they are not as well characterized as in the rodent. Thirty-six to sixty-five percent (36-65%) of the oral dosage is excreted unchanged in the urine. It is unaltered AHA in the urine that provides the therapeutic effect, but the precise concentration of AHA in urine that is necessary to inhibit urease is incompletely delineated. Therapeutic benefit may be obtained from concentrations as low as 8 mcg/ml; higher concentrations (i.e., 30 mcg/ml) are expected to provide more complete inhibition of urease. The plasma half-life of AHA is approximately 5-10 hours in subjects with normal renal function and is prolonged in patients with reduced renal function. Acetohydroxamic acid has been evaluated clinically in patients with urea-splitting urinary infections, often accompanied by struvite stone disease, that were recalcitrant to other forms of medical and surgical management. In these clinical trials, AHA reduced the pathologically elevated urinary ammonia and pH levels that result from the hydrolysis of urea by the enzyme, urease. AHA does not acidify urine directly nor does it have a direct antibacterial effect. The usefulness of reducing ammonia levels and decreasing urinary pH is suggested by single (not yet replicated) clinical trials in which urease inhibition 1) allowed successful antibiotic treatment of urea-splitting Proteus infections after surgical removal of struvite stones in patients not cured by 3 months of antibacterial treatment alone, and 2) reduced the rate of stone growth in patients who were not candidates for surgical removal of stones.