Lithostat (acetohydroxamic acid) Drug Facts and Product Info

About Lithostat^®

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.

Lithostat® is a prescription drug that prevents the excessive build-up of ammonia in your urine to control its acidity and alkalinity (pH). It may improve the effectiveness of antibiotics and help increase the cure rate in patients treated for chronic urea-splitting urinary infection.

Important Safety Information

Lithostat® should not be used in place of surgery. Surgical removal of all kidney stones, combined with antibiotics that eliminate the infection causing the stones, will provide the best chance for a cure. Lithostat® is more effective after removal of large struvite stones or stones that become lodged in the urinary tract.

Lithostat® is not for everyone. You should not take Lithostat® if your health and physical condition are a good fit for surgery and appropriate antibiotics.

Do not take Lithostat® if you are pregnant, may become pregnant, or are breastfeeding. Lithostat® contains acetohydroxamic acid (AHA), which has been linked to birth defects in laboratory animals and may cause harm to your unborn child. Some drugs can pass to infants through breast milk, and there may be serious side effects from AHA, so you should stop nursing if you are taking Lithostat®.

Do not take Lithostat® if you have poor kidney function, if your urine is infected by organisms that do not produce the enzyme urease, or if your infection can be controlled by culture-specific antimicrobial agents (antibiotics that prevent the specific type of bacteria causing your infection).

Do not take other prescription drugs or over the counter medications while you are taking Lithostat®, unless you are directed to do so by your doctor. In particular, do not take any medications that contain iron, because Lithostat® reacts with iron and both the iron and the Lithostat® may become ineffective.

AHA is eliminated primarily by the kidneys, so if you have reduced kidney function, your doctor will closely monitor you and may decrease your dosage of Lithostat® to avoid excessive build up of AHA in your system.

Liver problems have not been reported with Lithostat®. However, a compound related to AHA caused significant problems in an unrelated study, so your doctor will need to monitor your liver function.

For best results, you must take Lithostat® plus antibiotic therapy exactly as your physician prescribes it. If you don't follow your daily dosage schedule, your treatment will be less effective, and you will be likely to form new stones.

Patients that drank alcohol while taking Lithostat® have reported a flushing skin reaction (redness, warmth, and tingling), which lasted approximately 30 minutes. The reaction disappeared without treatment, however, its cause and significance are unknown, so you should not drink alcohol while taking Lithostat®.

Lithostat® may cause unknown side effects. Some reported side effects include headaches, abdominal discomfort, nausea, hair loss, shakiness, and anemia (a reduction in red blood cells). In early research, life-threatening problems (blood clot in the legs) occurred in several patients with advanced disease.

However, in more extensive, later research, these problems have not occurred. No patient has died because of taking Lithostat®. The most serious side effects seem to occur in patients with poor kidney function or those with a previous history of these conditions.

An abnormal breakdown of red blood cells (called a Coombs negative hemolytic anemia) has occurred in some patients taking AHA. The most severe forms of this condition were accompanied by gastrointestinal symptoms, such as nausea, vomiting, loss of appetite, and a general feeling of discomfort. Some patients had only laboratory findings of an anemia; however, most developed a mild reticulocytosis (an increase in immature red blood cells). The negative effects of Lithostat® disappeared after patients stopped taking the drug and began appropriate medical treatment.

Bone marrow depression (a decrease in white blood cells, red blood cells, or platelets) has occurred in laboratory animals receiving large doses of AHA; however, this has not yet been seen in humans.

There have not been acceptable long-term studies of the cancer-causing potential of Lithostat®. However, Lithostat® alters genetic material and kills tissue cells grown in lab tests. High doses of acetamide, a compound related to Lithostat®, are associated with liver cancer in laboratory rats. Therefore, Lithostat® may have the potential to cause cancer in humans.

Always report any unusual side effects to your doctor immediately. Mild symptoms usually do not call for stopping treatment. Severe symptoms may require that you stop treatment temporarily and/or change your dosage.

To report negative side effects, contact Mission Pharmacal Company at 1-800-298-1087 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.