Lithostat (acetohydroxamic acid) Adverse Reactions

About Lithostat^®

Experience with AHA is limited. About 150 patients have been treated, most for periods of more than a year.

Adverse reactions have occurred in up to thirty percent (30%) of the patients receiving AHA. In some instances the reactions were symptomatic; in others only changes in laboratory parameters were noted. Adverse reactions seem to be more prevalent in patients with preexisting thrombophlebitis or phlebothrombosis and/or in patients with advanced degrees of renal insufficiency. The risk of adverse reactions is highest during the first year of treatment. Chronic treatment does not seem to increase the risk nor the severity of adverse reactions.

The following reactions have been reported:

Neurological

Mild headaches are commonly reported (about 30%) during the first 48 hours of treatment. These headaches are mild, responsive to oral salicylate-type analgesics, and usually disappear spontaneously. The headaches have not been associated with vertigo, tinnitus, or visual or auditory abnormalities. Tremulousness and nervousness have also been reported.

Gastrointestinal

Gastrointestinal symptoms, nausea, vomiting, anorexia, and malaise have occurred in 20-25% of patients. In most patients the symptoms were mild, transitory, and did not result in interruption of treatment. Approximately 3% of patients developed a hemolytic anemia of sufficient magnitude to warrant interruption in treatment; several of these patients also had symptoms of gastrointestinal upset.

Hematological

Approximately 15% of patients have had laboratory findings characteristic of a hemolytic anemia. A mild reticulocytosis (5-6%) without anemia, is even more prevalent. The laboratory findings are occasionally accompanied by systemic symptoms such as malaise, lethargy and fatigue, and gastrointestinal symptoms. Symptoms and laboratory findings have invariably improved following cessation of treatment with AHA. The hematological abnormalities are more prevalent in patients with advanced renal failure.

Dermatological

A nonpruritic, macular skin rash has occurred in the upper extremities and on the face of several patients taking AHA on a long-term basis, usually when AHA has been taken concomitantly with alcoholic beverages, but in a few patients in the absence of alcohol consumption. The rash commonly appears 30-45 minutes after ingestion of alcoholic beverages; it characteristically disappears spontaneously in 30-60 minutes. The rash may be associated with a general sensation of warmth. In some patients the rash is sufficiently severe to warrant discontinuation of treatment, but most patients have continued treatment, avoiding alcohol or using smaller quantities of it. Alopecia has also been reported in patients taking AHA.

Cardiovascular

Superficial phlebitis involving the lower extremities has occurred in several patients on AHA during the early (Phase II) clinical trials. Several of the affected patients had had phlebitic episodes prior to treatment. One patient developed deep vein thrombosis of the lower extremities. The patient with phlebothrombosis had an associated traumatic injury to the groin. It is unclear whether the phlebitis was related to or exacerbated by treatment with AHA. No patient in the three (3) year controlled (Phase III) clinical trial developed phlebitis. In all instances these vascular abnormalities returned to normal following appropriate medical therapy. Embolic phenomena have been reported in three patients taking AHA in the Phase II trial. The phlebitis and emboli resolved following discontinuation of AHA and implementation of appropriate medical therapy. Several patients have resumed treatment with AHA without ill effect. Palpitations have also been reported in patients taking AHA.

Respiratory

No symptoms have been reported. Radiographic evidence of small pulmonary emboli has been seen in three patients with phlebitis in their lower legs.

Psychiatric

Depression, anxiety, nervousness, and tremulousness have been observed in approximately 20% of patients taking AHA. In most patients the symptoms were mild and transitory, but in about 6% of patients the symptoms were sufficiently distressing to warrant interruption or discontinuation of treatment.

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.

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Adverse Reactions