Source: FDA, National Drug Code (US) Revision Year: 2021
The goal of therapy is to reduce urinary cystine concentration below its solubility limit. Tiopronin is an active reducing agent which undergoes thiol-disulfide exchange with cystine to form a mixed disulfide of tiopronin-cysteine. From this reaction, a water-soluble mixed disulfide is formed and the amount of sparingly soluble cystine is reduced.
The decrement in urinary cystine produced by tiopronin is generally proportional to the dose. A reduction in urinary cystine of 250-350 mg/day at tiopronin dosage of 1 g/day, and a decline of approximately 500 mg/day at a dosage of 2 g/day, might be expected. Tiopronin has a rapid onset and offset of action, showing a fall in cystine excretion on the first day of administration and a rise on the first day of drug withdrawal.
When THIOLA IR and THIOLA EC single doses were given to fasted healthy subjects, the median time to peak plasma levels (Tmax) was 1 (range: 0.5 to 2.1) and 3 (range: 1.0 to 6.0) hours, respectively. The peak exposure (Cmax) and total exposure (AUC0-t) of tiopronin from THIOLA EC tablets were decreased by 22% and 7% respectively compared to THIOLA IR tablets.
When THIOLA EC tablets were administered crushed in applesauce, the median time to peak plasma levels of tiopronin (Tmax) was 1 hour (range: 0.5 to 2.0) compared to 3.1 hours (range: 1.5 to 4.0) when administered as intact EC tablets.
When THIOLA EC tablets were administered crushed in applesauce, the maximum concentration (Cmax) and exposure (AUC0-t) to tiopronin were increased by 38% and 14%, respectively, compared to THIOLA EC tablets administered intact.
Administration of the THIOLA EC tablet with food decreases Cmax of tiopronin by 13% and AUC0-t by 25% compared to THIOLA EC administered in a fasted state.
Since the drug is dosed to effect, the study results support administration of THIOLA EC tablets with or without food; administer at the same time each day with a routine pattern with regard to meals.
When tiopronin is given orally, up to 48% of dose appears in urine during the first 4 hours and up to 78% by 72 hours.
An in vitro dissolution study was conducted to evaluate the impact of alcohol (5, 10, 20, and 40%) on the dose dumping of THIOLA EC tablets. The study results showed that the addition of alcohol to the dissolution media increases the dissolution rate of THIOLA EC tablets in the acidic media of 0.1N HCl [see Drug Interactions (7.1)].
Long-term carcinogenicity studies in animals have not been performed.
Tiopronin was not genotoxic in the chromosomal aberration, sister chromatid exchange, and in vivo micronucleus assays.
High doses of tiopronin in experimental animals have been shown to interfere with maintenance of pregnancy and viability of the fetus. In 2 published male fertility studies in rats, tiopronin at 20 mg/kg/day intramuscular (IM) for 60 days induced reductions in testis, epididymis, vas deferens, and accessory sex glands weights and in the count and motility of cauda epididymal sperm.
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