VENXXIVA

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. 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. 4 ) Measure urinary cystine 1 month after initiation of VENXXIVA and every 3 months thereafter. 3 ) Administer VENXXIVA in 3 divided doses at the same times each day, without food.

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. 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.

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. 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.

2 )] Most common adverse reactions (≥10%) are nausea, diarrhea or soft stools, oral ulcers, rash, fatigue, fever, arthralgia, proteinuria, and emesis. gov/medwatch. 1 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.

Adverse reactions occurring at an incidence of ≥5% in an uncontrolled trial in 66 patients with cystinuria age 9 to 68 years are shown in the table below. Patients in group 1 had previously been treated with d-penicillamine; those in group 2 had not.

Of those patients who had stopped taking d-penicillamine due to toxicity (34 out of 49 patients in group 1), 22 were able to continue treatment with tiopronin. 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:

Adverse Reactions Occurring in One or More Patients System Organ Class Adverse Reaction Group 1 Previously treated with d-penicillamine (N = 49) Group 2 Naïve to d-penicillamine (N = 17) Blood and Lymphatic System Disorders anemia 1 (2%) 1 (6%) Gastrointestinal Disorders nausea 12 (25%) 2 (12%) emesis 5 (10%) – diarrhea/soft stools 9 (18%) 1 (6%) abdominal pain – 1 (6%) oral ulcers 6 (12%) 3 (18%) General Disorders and Administration Site Conditions fever 4 (8%) – weakness 2 (4%) 2 (12%) fatigue 7 (14%) – peripheral (edema) 3 (6%) 1 (6%) chest pain – 1 (6%) Metabolism and Nutrition Disorders anorexia 4 (8%) – Musculoskeletal and Connective Tissue Disorders arthralgia – 2 (12%) Renal and Urinary Disorders proteinuria 5 (10%) 1 (6%) impotence – 1 (6%) Respiratory, Thoracic and Mediastinal Disorders cough – 1 (6%) Skin and Subcutaneous Tissue Disorders rash 7 (14%) 2 (12%) ecchymosis 3 (6%) – pruritus 2 (4%) 1 (6%) urticaria 4 (8%) – skin wrinkling 3 (6%) 1 (6%) Taste Disturbance A reduction in taste perception may develop.

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.

4 ) Hypersensitivity reactions have been reported during tiopronin treatment. 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.

4 )] . 3 )] . 2 Hypersensitivity Reactions Hypersensitivity reactions (drug fever, rash, fever, arthralgia and lymphadenopathy) have been reported [see Contraindications ( 4 )] .

2 )] . Hypersensitivity to tiopronin or any component of VENXXIVA ( 4 )