THIOLA

THIOLA (tiopronin) immediate-release tablets are a reducing and cystine-binding thiol drug (CBTD) for oral use. Tiopronin is N-(2-Mercaptopropionyl) glycine and has the following structure: Tiopronin has the empirical formula C 5 H 9 NO 3 S and a molecular weight of 163.20. In this drug product tiopronin exists as a dl racemic mixture. Tiopronin is a white crystalline powder, which is freely soluble in water. Each THIOLA tablet contains 100 mg of tiopronin. The inactive ingredients in THIOLA tablets include calcium carbonate, carnauba wax, ethyl cellulose, dimethylaminoethyl methacrylate: butyl methacrylate: methyl methacrylate copolymer (Eudragit E 100), hydroxy-propyl cellulose, lactose monohydrate, magnesium stearate, povidone, sugar, talc, titanium dioxide. tiopronin-struct

THIOLA is indicated, in combination with high fluid intake, alkali, and diet modification, for the prevention of cystine stone formation in adults and pediatric patients 20 kg and greater with severe homozygous cystinuria, who are not responsive to these measures alone. --------------------------------------------INDICATIONS AND USAGE----------------------------------------- THIOLA 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 20 kg and greater with severe homozygous cystinuria, who are not responsive to these measures alone. (1)

2.1 Recommended Dosage 2.2 Monitoring 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 weighing 20 kg and greater 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 THIOLA in 3 divided doses at the same times each day at least one hour before or 2 hours after meals. Consider starting THIOLA at a lower dosage in patients with history of severe toxicity to d-penicillamine. 2.2 Monitoring Measure urinary cystine 1 month after starting THIOLA and every 3 months thereafter. Adjust THIOLA 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 THIOLA in patients who develop proteinuria, and monitor urinary protein and renal function. Consider restarting THIOLA treatment at a lower dosage after resolution of proteinuria. ------------------------------------------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 20 kg and greater is 15 mg/kg/day. Avoid dosages greater than 50 mg/kg per day in pediatric patients. (2.1, 5.1, 8.4) • Administer THIOLA in 3 divided doses at the same times each day at least one hour before or 2 hours after meals. (2.1) • Measure urinary cystine 1 month after initiation of THIOLA and every 3 months thereafter. (2.2)

THIOLA is contraindicated in patients with hypersensitivity to tiopronin or any other components of THIOLA [see Warnings and Precautions (5.2)]. ----------------------------------------------CONTRAINDICATIONS------------------------------------------ • Hypersensitivity to tiopronin or any component of THIOLA (4)

6.1 Clinical Trials Experience 6.2 Postmarketing Experience The following adverse reactions are discussed in greater detail in other sections of the labeling: • Proteinuria [see Warnings and Precautions (5.1)] • Hypersensitivity [see Warnings and Precautions (5.2)] 6.1 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 THIOLA. In those without prior history of d-penicillamine treatment, 6% developed reactions of sufficient severity to require THIOLA withdrawal. Table 1 presents adverse reactions ≥5% in either treatment group occurring in this trial. 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. 6.2 Postmarketing Experience Adverse reactions have been reported from the literature, as well as during post-approval use of THIOLA. 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 THIOLA exposure. Adverse reactions reported during the postmarketing use of THIOLA are listed by body system in Table 2. ---------------------------------------------ADVERSE REACTIONS------------------------------------------- Most common adverse reactions (≥10%) are nausea, diarrhea or soft stools, oral ulcers, rash, fatigue, fever, arthralgia, proteinuria, and emesis. (6) To report SUSPECTED ADVERSE REACTIONS, contact Mission Pharmacal Company at toll-free phone # 1-800-298-1087 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Picture Image