Thiola (tiopronin) Indications and Usage

About Thiola^®

Thiola^® is indicated for the prevention of cystine (kidney) stone formation in patients with severe homozygous cystinuria with urinary cystine greater than 500 mg/day, who are resistant to treatment with conservative measures of high fluid intake, alkali and diet modification, or who have adverse reactions to d-penicillamine.

Cystine stones typically occur in approximately 10,000 persons in the United States who are homozygous for cystinuria. These persons excrete abnormal amounts of cystine in urine of over 250 mg/g creatinine, as well as excessive amounts of other dibasic amino acids (lysine, arginine and ornithine). In addition, they show varying intestinal transport defects for these same amino acids. The stone formation is the result of poor aqueous solubility of cystine.

Since there are no known inhibitors of the crystallization of cystine, the stone formation is determined primarily by the urinary supersaturation of cystine. Thus, cystine stones could theoretically form whenever urinary cystine concentration exceeds the solubility limit. Cystine solubility in urine is pH-dependent, and ranges from 170-300 mg/liter at pH 5, 190-400 mg/liter at pH 7 and 220-500 mg/liter at pH 7.5.

The goal of therapy is to reduce urinary cystine concentration below its solubility limit. It may be accomplished by dietary means aimed at reducing cystine synthesis and by a high fluid intake in order to increase urine volume and thereby lower cystine concentration.

Unfortunately, the above conservative measures alone may be ineffective in controlling cystine stone formation in some homozygous patients with severe cystinuria (urinary cystine exceeding 500 mg/day). In such patients, d-penicillamine has been used as an additional therapy. Like Thiola^®, d-penicillamine undergoes thiol-disulfide exchange with cystine, thereby lowering the amount of sparingly soluble cystine in urine.

However, d-penicillamine treatment is frequently accompanied by adverse reactions, such as dermatologic complications, hypersensitivity reactions, hematologic abnormalities and renal disturbances. Thiola^® may have a particular therapeutic role in such patients.

Important Safety Information

Warnings

Despite apparent lower toxicity of THIOLA^®, THIOLA^® may potentially cause all the serious adverse reactions reported for d-penicillamine. Thus, although no death has been reported to result directly from THIOLA^® treatment, a fatal outcome from THIOLA^® is possible, as has been reported with d-penicillamine therapy from such complications as aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture's syndrome or myasthenia gravis.

Leukopenia of the granulocytic series may develop without eosinophilia. Thrombocytopenia may be immunologic in origin or occur on an idiosyncratic basis. The reduction in peripheral blood white count to less than 3500/cubic mm or in platelet count to below 100,000 cubic mm mandates cessation of therapy. Patients should be instructed to report promptly the occurrence of any symptom or sign of these hematological abnormalities, such as fever, sore throat, chills, bleeding or easy bruisability.

Proteinuria, sometimes sufficiently severe to cause nephrotic syndrome, may develop from membranous glomerulopathy. A close observation of affected patients is mandatory.

The following complications, though rare, have been reported during d-penicillamine therapy and could occur during THIOLA^® treatment. When there are abnormal urinary findings associated with hemoptysis and pulmonary infiltrates suggestive of Goodpasture's syndrome, THIOLA^® treatment should be stopped. Appearance of myasthenic syndrome or myasthenia gravis requires cessation of treatment. When pemphigus-type reactions develop, THIOLA^® therapy should be stopped. Steroid treatment may be necessary.

Precautions

Patients should be advised of the potential development of complications and to report promptly the occurrence of any symptom or sign of them.

To help monitor potential complications, the following tests are recommended: peripheral blood counts, direct platelet count, hemoglobin, serum albumin, liver function tests, 24-hour urinary protein and routine urinalysis at 3-6 month intervals during treatment. In order to assess effect on stone disease, urinary cystine analysis should be monitored frequently during the first 6 months when the optimum dose schedule is being determined, and at 6-month intervals thereafter. Abdominal roentogenogram (KUB) is advised on a yearly basis to monitor the size and appearance/disappearance of stone(s).

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Long-term carcino-genicity studies in animals have not been performed. High doses of THIOLA^® in experimental animals have been shown to interfere with maintenance of pregnancy and viability of the fetus.

USE IN PREGNANCY: Pregnancy category C. D-penicillamine has been shown to cause skeletal defects and cleft palates in the fetus when given to pregnant rats at 10 times the dose recommended for human use. A similar teratogenicity might be expected for THIOLA^® although no such findings could be related to the drug in studies in mice and rats at doses up to 10 times the highest recommended human dose. There are no adequate and well-controlled studies in pregnant women. THIOLA^® should be used during pregnancy only if the potential benefit justifies potential risk to the fetus.

NURSING MOTHERS: Because THIOLA? may be excreted in milk and because of the potential serious adverse reactions of nursing infants from THIOLA^®, mothers taking THIOLA^® should not nurse their infants.

PEDIATRIC USE: Safety and effectiveness below the age of 9 have not been established.

This material is intended to provide basic information. Patients should discuss all medical advice, diagnosis, and treatment with their healthcare provider.

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