VENXXIVA

Clinical summary

Indications and usage 1 INDICATIONS AND USAGE 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. VENXXIVA is a reducing and complexing thiol 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. ( 1 ) Dosage and administration 2 DOSAGE AND ADMINISTRATION The recommended initial dosage in adult patients is 800 mg/day. In clinical studies, the average dosage was about 1,000 mg/day. ( 2.1 ) 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. ( 5.1 , 8.4 ) Measure urinary cystine 1 month after initiation of VENXXIVA and every 3 months thereafter. ( 2.3 ) Administer VENXXIVA in 3 divided doses at the same times each day, without food. ( 2.1 ) 2.1 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 [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.4 )] . 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. 2.3 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 [see Warnings and Precautions ( 5.1 )] . 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. Warnings and cautions 5 WARNINGS AND PRECAUTIONS Proteinuria, including nephrotic syndrome, and membranous nephropathy, has been reported with tiopronin use. Pediatric patients receiving greater than 50 mg/kg of tiopronin per day may be at increased risk for proteinuria. ( 2.1 , 5.1 , 8.4 ) Hypersensitivity reactions have been reported during tiopronin treatment. ( 4 , 5.2 ) 5.1 Proteinuria Proteinuria, including nephrotic syndrome, and membranous nephropathy, have been reported with tiopronin use. Pediatric patients receiving greater than 50 mg/kg of tiopronin per day may be at increased risk for proteinuria. [see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.1 , 6.2 ), Use in Specific Populations ( 8.4 )] . Monitor patients for the development of proteinuria and discontinue therapy in patients who develop proteinuria [see Dosage and Administration ( 2.3 )] . 5.2 Hypersensitivity Reactions Hypersensitivity reactions (drug fever, rash, fever, arthralgia and lymphadenopathy) have been reported [see Contraindications ( 4 )] . Drug interactions 7 DRUG INTERACTIONS 7.1 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 [see Clinical Pharmacology ( 12.3 )] . Pregnancy 8.1 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 r