Thiola

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

6 ADVERSE REACTIONS 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