Acetohydroxamic Acid (0093)
[ a-seat'-oh-hye-drox-am'-ic as'-id ]
| Ingredients: |
Acetohydroxamic Acid |
| Indications: |
Infection, urinary tract, adjunct |
| Pregnancy Category: |
X |
| FDA Approved: |
1983- 05- 01 |
| Classes: |
Antiseptics, urinary tract |
| Brand Names: |
Lithostat
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US
;
Uronefrex
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France, Portugal, Spain
;
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| DEA schedules: |
(none)
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DESCRIPTION
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Acetohydroxamic acid is a stable, synthetic compound derived from hydroxylamine and ethyl acetate. Its molecular structure
is similar to urea.
Acetohydroxamic acid is weakly acidic, highly soluble in water, and chelates metals — notably iron. The molecular weight is
75.068. Acetohydroxamic acid has a pKa of 9.32 and a melting point of 89- 91°C. Acetohydroxamic acid is a urease inhibitor.
Lithostat is available as 250 mg tablets.
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CLINICAL PHARMACOLOGY
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Acetohydroxamic acid reversibly inhibits the bacterial enzyme urease, thereby inhibiting the hydrolysis of urea & 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.
Acetohydroxamic acid 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.
Acetohydroxamic acid chelates with dietary iron without the gut. This reaction may interfere with absorption of acetohydroxamic
acid and with iron. Concomitant hypochromic anemia should be treated with intramuscular iron.
In rodents, the metabolic fate of acetohydroxamic acid 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, acetohydroxamic acid 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 acetohydroxamic acid.
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 acetohydroxamic acid in the urine that provides the therapeutic effect, but the precise concentration
of acetohydroxamic acid in urine that is necessary to inhibit urease is incompletely delineated. Therapeutic benefit may be
obtained from concentrations as low as 8 μg/ ml; higher concentrations ( i.e., 30 μg/ ml) are expected to provide more complete inhibition of urease. The plasma half- life of acetohydroxamic acid 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,
acetohydroxamic acid reduced the pathologically elevated urinary ammonia and pH levels that result from the hydrolysis of
urea by the enzyme, urease.
Acetohydroxamic acid does not acidify urine directly nor does it have a direct anti- bacterial 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.
- 2. Reduced the rate of stone growth in patients who were not candidates for surgical removal of stones.
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INDICATIONS AND USAGE
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Acetohydroxamic acid is indicated as adjunctive therapy in patients with chronic urea- splitting urinary infection. Acetohydroxamic
acid 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 acetohydroxamic acid may be warranted to
maintain urease inhibition as long as urea- splitting infection is present. Experience with acetohydroxamic acid does not
go beyond 7 years. A Patient Package Insert should be distributed to each patient who receives acetohydroxamic acid.
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CONTRAINDICATIONS
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Acetohydroxamic acid should not be used in:
| • |
Patients whose physical state and disease are amenable to definitive surgery and appropriate antimicrobial agents.
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Patients whose urine is infected by non- urease producing organisms.
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Patients whose urinary infections can be controlled by culture- specific oral antimicrobial agents.
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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).
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Female patients who do not evidence a satisfactory method of contraception.
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| • |
Patients who are pregnant.
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Acetohydroxamic acid may cause fetal harm when administered to a pregnant woman. Acetohydroxamic acid was teratogenic (retarded
and/ or clubbed rear leg at 750 mg/ kg and above and exencephaly and encephalocele at 1500 mg/ kg) when given intraperitoneally
to rats. Acetohydroxamic acid 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.
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WARNINGS
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A Coombs negative hemolytic anemia has occurred in patients receiving acetohydroxamic acid. Gastrointestinal upset characterized
by nausea, vomiting, anorexia and generalized malaise have accompanied the most severe forms of hemolytic anemia. Approximately
15% of patients receiving acetohydroxamic acid 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 2 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.
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PRECAUTIONS
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General
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Hematologic Effects
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Bone marrow depression (leukopenia, anemia, and thrombocytopenia) has occurred in experimental animals receiving large doses
of acetohydroxamic acid, but has not been seen in man to date. Acetohydroxamic acid is a known inhibitor of DNA synthesis
and also chelates metals - notably iron. Its bone marrow suppressant effect is probably related to its ability to inhibit
DNA synthesis, but anemia could also be related to depletion of iron stores. To date, the only clinical effect noted has been
hemolysis, with a decrease in the circulating red blood cells, hemoglobin and hematocrit. Abnormalities in platelet or white
blood cell count have not been noted. However, clinical monitoring of the platelet and white cell count is recommended.
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Monitoring Liver Function
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Abnormalities of liver function have not been reported to date. However, a chloro- benzene derivative of acetohydroxamic acid
caused significant liver dysfunction in an unrelated study. Therefore, close monitoring of liver function is recommended.
(See Carcinogenesis, Mutagenesis, and Impairment of Fertility for discussion of possible hepatic carcinogenesis.)
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Use in Patients With Renal Impairment
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Since acetohydroxamic acid is eliminated primarily by the kidneys, patients with significantly impaired renal function should
be closely monitored, and a reduction of daily dose may be needed to avoid excessive drug accumulation. (See DOSAGE AND ADMINISTRATION .)
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Carcinogenesis, Mutagenesis, and Impairment of Fertility
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Well controlled, long- term animal studies that identify the carcinogenic potential of acetohydroxamic acid treatment have
not been conducted. Acetamide, a metabolite of acetohydroxamic acid, has been shown to cause hepatocellular carcinoma in rats
at oral doses 1500 times the human dose. Acetohydroxamic acid is cytotoxic and was positive for mutagenicity in the Ames test.
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Nursing Mothers
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It is not known whether acetohydroxamic acid is secreted in human milk. Because many drugs are excreted in human milk, and
because of the potential for serious adverse reactions in nursing infants from acetohydroxamic acid, a decision should be
made to discontinue nursing or the drug, taking into account the significance of the drug to the mother's well being.
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Pediatric Use
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Children with chronic, recalcitrant, urea- splitting urinary infection may benefit from treatment with acetohydroxamic acid.
However, detailed studies involving dosage and dose intervals in children have not been established. Children have tolerated
a dose of 10 mg/ kg/ day, taken in 2 or 3 divided doses, satisfactorily for periods up to 1 year. Close monitoring of such
patients is mandatory.
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DRUG INTERACTIONS
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Acetohydroxamic acid has been used concomitantly with insulin, oral and parenteral antibiotics, and progestational agents.
No clinically significant interactions have been noted, but until wider clinical experience is obtained, acetohydroxamic acid
should be used with caution in patients receiving other therapeutic agents.
Acetohydroxamic acid taken in association with alcoholic beverages has resulted in a rash. (See ADVERSE REACTIONS .)
Acetohydroxamic acid chelates heavy metals — notably iron. The absorption of iron and acetohydroxamic acid from the intestinal
lumen may be reduced when both drugs are taken concomitantly. When iron administration is indicated, intramuscular iron is
probably the product of choice.
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ADVERSE REACTIONS
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Experience with acetohydroxamic acid is limited. About 150 patients have been treated, most for periods of more than a year.
Adverse reactions have occurred in up to 30% of the patients receiving acetohydroxamic acid. 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 acetohydroxamic acid. 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 acetohydroxamic
acid on a long- term basis, usually when acetohydroxamic acid 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
acetohydroxamic acid.
- Cardiovascular: Superficial phlebitis involving the lower extremities has occurred in several patients on acetohydroxamic acid during the
early (Phase 2) 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 acetohydroxamic acid. No
patient in the 3 year controlled (Phase 3) clinical trial developed phlebitis. In all instances these vascular abnormalities
returned to normal following appropriate medical therapy. Embolic phenomena have been reported in 3 patients taking acetohydroxamic
acid in the Phase 2 trial. The phlebitis and emboli resolved following discontinuation of acetohydroxamic acid and implementation
of appropriate medical therapy. Several patients have resumed treatment with acetohydroxamic acid without ill effect. Palpitations
have also been reported in patients taking acetohydroxamic acid.
- Respiratory: No symptoms have been reported. Radiographic evidence of small pulmonary emboli has been seen in 3 patients with phlebitis
in their lower legs.
- Psychiatric: Depression, anxiety, nervousness, and tremulousness have been observed in approximately 20% of patients taking acetohydroxamic
acid. 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.
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OVERDOSAGE
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Acute deliberate overdosage in man has not occurred, but would be expected to induce the following symptoms: anorexia, malaise,
lethargy, diminished sense of well being, tremulousness, anxiety, nausea and vomiting. Laboratory findings are likely to include
an elevated reticulocyte count and a severe hemolytic reaction requiring hospitalization, symptomatic treatment, and possibly
blood transfusions. Concomitant reduction in platelets and/ or white blood cells should be anticipated.
Milder overdosages resulting in hemolysis have occurred in an occasional patient with reduced renal function after several
weeks or months of continuous treatment.
The acute LD50 of acetohydroxamic acid in animals (rats) is 4.8 g/ kg.
Recommended treatment for an overdosage reaction consists of (1) cessation of treatment, (2) close monitoring of hematologic
status, (3) symptomatic treatment, and (4) blood transfusions as required by the clinical circumstances. The drug is probably
dialyzable, but this property has not been tested clinically.
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DOSAGE AND ADMINISTRATION
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Acetohydroxamic acid 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 g, 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 g/ day; such patients should be dosed at q12h 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 acetohydroxamic acid. The risk of accumulation of toxic
blood levels of acetohydroxamic acid 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.
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HOW SUPPLIED
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Lithostat is available for oral administration as 250 mg white colored, round tablets.
Storage: Lithostat should be stored in a dry place at room temperature, 15- 30°C (59- 86°F). Container should be closed tightly.
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PRODUCT IDENTIFICATION
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None Available |
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
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| tablet - oral - 250 mg -
|
| 100.0's |
$103.13 |
Lithostat
Mission Pharmacal Company
|
00178050001 |
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