Tiopronin Drug Information

VENXXIVA is indicated, in combination with high fluid intake, alkali, and diet modification, for the prevention of cystine stone formation in adults and pediatric patients 9 years of age and older with severe homozygous cystinuria, who are not responsive to these measures alone. Additional pediatric use information is approved for Mission Pharmacal Company’s Thiola EC (tiopronin delayed-release) tablets. However, due to Mission Pharmacal Company’s marketing exclusivity rights, this drug product is not labeled with that information.

Recommended Dosage Adults

The recommended initial dosage in adult patients is 800 mg/day. In clinical studies, the average dosage was about 1,000 mg/day. Pediatrics: The recommended initial dosage in pediatric patients 9 years of age and older is 15 mg/kg/day.

Avoid dosages greater than 50 mg/kg per day in pediatric patients. Administer VENXXIVA in 3 divided doses at the same times each day, without food. Consider starting VENXXIVA at a lower dosage in patients with history of severe toxicity to d-penicillamine.

Additional pediatric use information is approved for Mission Pharmacal Company’s Thiola EC (tiopronin delayed-release) tablets. However, due to Mission Pharmacal Company’s marketing exclusivity rights, this drug product is not labeled with that information.

Monitoring

Measure urinary cystine 1 month after starting VENXXIVA and every 3 months thereafter. Adjust VENXXIVA dosage to maintain urinary cystine concentration less than 250 mg/L. Assess for proteinuria before treatment and every 3 to 6 months during treatment.

Discontinue VENXXIVA in patients who develop proteinuria, and monitor urinary protein and renal function. Consider restarting VENXXIVA treatment at a lower dosage after resolution of proteinuria.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of the drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patients in group 1 had previously been treated with d-penicillamine; those in group 2 had not. In those without prior history of d-penicillamine treatment, 6% developed reactions of sufficient severity to require tiopronin withdrawal.

Table 1 presents adverse reactions ≥5% in either treatment group occurring in this trial. Table 1: Taste Disturbance A reduction in taste perception may develop. It is believed to be the result of chelation of trace metals by tiopronin.

Hypogeusia is often self-limited.

Postmarketing Experience

Adverse reactions have been reported from the literature, as well as during post-approval use of tiopronin. Because the post-approval reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to tiopronin exposure. Adverse reactions reported during the postmarketing use of tiopronin are listed by body system in Table 2.

Table 2: Adverse Reactions Reported for Tiopronin Pharmacovigilance by

Alcohol Tiopronin is released faster from VENXXIVA in the presence of alcohol and the risk for adverse events associated with VENXXIVA when taken with alcohol is unknown. Avoid alcohol consumption 2 hours before and 3 hours after taking VENXXIVA.

Pregnancy Risk Summary Available published case report data with tiopronin have not identified a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Renal stones in pregnancy may result in adverse pregnancy outcomes (see Clinical Considerations ). In animal reproduction studies, there were no adverse developmental outcomes with oral administration of tiopronin to pregnant mice and rats during organogenesis at doses up to 2 times a 2 grams/day human dose (based on mg/m 2 ).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are respectively.

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Renal stones in pregnancy may increase the risk of adverse pregnancy outcomes, such as preterm birth and low birth weight. Data Animal Data No findings of fetal malformations could be attributed to the drug in reproduction studies in mice and rats at doses up to 2 times the highest recommended human dose of 2 grams/day (based on mg/m 2 ).

Pediatric Use VENXXIVA is indicated in pediatric patients 9 years of age and older with severe homozygous cystinuria, in combination with high fluid intake, alkali, and diet modification, for the prevention of cystine stone formation who are not responsive to these measures alone. This indication is based on safety and efficacy data from a trial in patients 9 years to 68 years of age and clinical experience. Proteinuria, including nephrotic syndrome, has been reported in pediatric patients.

Pediatric patients receiving greater than 50 mg/kg tiopronin per day may be at greater risk. VENXXIVA tablets are not approved for use in pediatric patients weighing less than 20 kg or in pediatric patients unable to swallow tablets. Additional pediatric use information is approved for Mission Pharmacal Company’s Thiola EC (tiopronin delayed-release) tablets.

However, due to Mission Pharmacal Company’s marketing exclusivity rights, this drug product is not labeled with that information.

VENXXIVA is contraindicated in patients with hypersensitivity to tiopronin or any other components of VENXXIVA. Hypersensitivity to tiopronin or any component of VENXXIVA

There is no information on overdosage with tiopronin.