ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS6.1 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 ExperienceBecause 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 to 68 years are shown in the table below. Patients in group had previously been treated with d-penicillamine; those in group 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 presents adverse reactions >=5% in either treatment group occurring in this trial. Taste DisturbanceA 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 ExperienceAdverse 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics. 12.1 Mechanism of ActionThe 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 mixed disulfide of tiopronincysteine. From this reaction, water-soluble mixed disulfide is formed and the amount of sparingly soluble cystine is reduced. 12.2 Pharmacodynamics The decrement in urinary cystine produced by tiopronin is generally proportional to the dose. reduction in urinary cystine of 250-350 mg/day at tiopronin dosage of g/day, and decline of approximately 500 mg/day at dosage of g/day, might be expected. Tiopronin has rapid onset and offset of action, showing fall in cystine excretion on the first day of administration and rise on the first day of drug withdrawal. 12.3 Pharmacokinetics Absorption THIOLA Tablets When THIOLA single doses were given to fasted healthy subjects (n 39), the median time to peak plasma level (T max) was (range: 0.5 to 2.1) hours. Elimination ExcretionWhen tiopronin is given orally, up to 48% of dose appears in urine during the first hours and up to 78% by 72 hours.

DESCRIPTION SECTION.

11 DESCRIPTION. THIOLA (tiopronin) immediate-release tablets are 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 5H 9NO 3S and molecular weight of 163.20. In this drug product tiopronin exists as dl racemic mixture. Tiopronin is 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 100), hydroxy-propyl cellulose, lactose monohydrate, magnesium stearate, povidone, sugar, talc, titanium dioxide. tiopronin-struct.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION2.1 Recommended Dosage 2.2 Monitoring. 2.1 Recommended DosageAdults: 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 divided doses at the same times each day at least one hour before or hours after meals. Consider starting THIOLA at lower dosage in patients with history of severe toxicity to d-penicillamine.2.2 MonitoringMeasure urinary cystine month after starting THIOLA and every months thereafter. Adjust THIOLA dosage to maintain urinary cystine concentration less than 250 mg/L. Assess for proteinuria before treatment and every to 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 lower dosage after resolution of proteinuria. ------------------------------------------DOSAGE AND ADMINISTRATION-------------------------------------o 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 divided doses at the same times each day at least one hour before or hours after meals. (2.1) Measure urinary cystine month after initiation of THIOLA and every months thereafter. (2.2).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. 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 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).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisLong-term carcinogenicity studies in animals have not been performed. Mutagenesis Tiopronin was not genotoxic in the chromosomal aberration, sister chromatid exchange, and in vivo micronucleus assays. Impairment of Fertility High doses of tiopronin in experimental animals have been shown to interfere with maintenance of pregnancy and viability of the fetus. In 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use. 8.1 PregnancyRisk SummaryAvailable published case report data with tiopronin have not identified 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 times 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 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 2% to 4% and 15% to 20%, respectively. Clinical ConsiderationsDisease-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 times the highest recommended human dose of grams/day (based on mg/m 2). 8.2 Lactation Risk Summary There are no data on the presence of tiopronin in either human or animal milk or on the effects of the breastfed child. published study suggests that tiopronin may suppress milk production. Because of the potential for serious adverse reactions, including nephrotic syndrome, advise patients that breastfeeding is not recommended during treatment with THIOLA. 8.4 Pediatric Use THIOLA is indicated in pediatric patients weighing 20 kg or more 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 trial in patients 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 [see Dosage and Administration (2.1, 2.2), Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. THIOLA tablets are not approved for use in pediatric patients weighing less than 20 kg or in pediatric patients unable to swallow tablets [see Recommended Dosage (2.1)]. 8.5 Geriatric Use This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. -----------------------------------------USE IN SPECIFIC POPULATIONS--------------------------------------o Lactation: Breastfeeding is not recommended. (8.2) Geriatric: Choose dose carefully and monitor renal function in the elderly. (8.5) See 17 for PATIENT COUNSELING INFORMATION.Revised: 01/2021.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS5.1 Proteinuria 5.2 Hypersensitivity Reactions. 5.1 ProteinuriaProteinuria, 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 (2.2), 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 (2.2)]. 5.2 Hypersensitivity ReactionsHypersensitivity reactions (drug fever, rash, fever, arthralgia and lymphadenopathy) have been reported [see Contraindications (4)]. ------------------------------------------WARNINGS AND PRECAUTIONS-------------------------------------o 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).