ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactionsare discussed in greater detail in other sections of the labeling:Proteinuria [see Warnings and Precautions (5.1)] Hypersensitivity [see Warnings and Precautions (5.2)] Proteinuria [see Warnings and Precautions (5.1)] Hypersensitivity [see Warnings and Precautions (5.2)] 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.. 6.1 Clinical Trials Experience. Because clinical trials are conducted underwidely varying conditions, the adverse reaction rates observed inthe clinical trials of the drug cannot be directly compared to ratesin the clinical trials of another drug and may not reflect the ratesobserved in practice.Adverse reactions occurring at an incidence of >=5% in an uncontrolledtrial in 66 patients with cystinuria age to 68 years are shown inthe table below. Patients in group had previously been treated withd-penicillamine; those in group had not. Of those patients who hadstopped taking d-penicillamine due to toxicity (34 out of 49 patientsin group 1), 22 were able to continue treatment with THIOLA. In thosewithout prior history of d-penicillamine treatment, 6% developed reactionsof sufficient severity to require THIOLA withdrawal.Table presentsadverse reactions >=5% in either treatment group occurring in thistrial.Table 1:Adverse ReactionsOccurring in One or More Patients System Organ ClassAdverse ReactionGroup 1Previously treated withd-penicillamine(N 49)Group 2Naive to d-penicillamine(N 17)Blood and Lymphatic System Disordersanemia1 (2%)1 (6%)Gastrointestinal Disordersnausea12 (25%)2 (12%)emesis5 (10%)-diarrhea/soft stools9 (18%)1 (6%)abdominal pain-1 (6%)oral ulcers6 (12%)3 (18%)General Disorders and AdministrationSite Conditionsfever4 (8%)-weakness2 (4%)2 (12%)fatigue7 (14%)-peripheral (edema)3 (6%)1 (6%)chest pain-1 (6%)Metabolism and Nutrition Disordersanorexia4 (8%)-Musculoskeletal and Connective TissueDisordersarthralgia-2 (12%)Renal and Urinary Disordersproteinuria5 (10%)1 (6%)impotence-1 (6%)Respiratory, Thoracic and MediastinalDisorderscough-1 (6%)Skin andSubcutaneous Tissue Disordersrash7 (14%)2 (12%)ecchymosis3 (6%)-pruritus2 (4%)1 (6%)urticaria4 (8%)-skin wrinkling3 (6%)1 (6%)Taste DisturbanceA reduction in taste perception may develop. It is believedto be the result of chelation of trace metals by tiopronin. Hypogeusiais often self-limited.. 6.2 Postmarketing Experience. Adverse reactions have been reported fromthe literature, as well as during post-approval use of THIOLA. Becausethe post-approval reactions are reported voluntarily from populationof uncertain size, it is not always possible to reliably estimatetheir frequency or establish causal relationship to THIOLA exposure.Adverse reactions reportedduring the postmarketing use of THIOLA are listed by body system in Table 2.Table 2:Adverse Reactions Reportedfor THIOLA Pharmacovigilance by System Organ Class and Preferred TermSystem Organ ClassPreferred TermCardiac Disorderscongestive heart failureEar and Labyrinth DisordervertigoGastrointestinal Disordersabdominal discomfort; abdominal distension; abdominalpain; chapped lips; diarrhea; dry mouth; dyspepsia; eructation; flatulence;gastrointestinal disorder; gastroesophageal reflux disease; nausea;vomiting; jaundice; liver transaminitisGeneral Disorders and AdministrationSite Conditionsasthenia; chest pain; fatigue; malaise; pain; peripheralswelling; pyrexia; swellingInvestigationsglomerular filtration rate decreased; weight increasedMetabolism and Nutrition Disordersdecreased appetite; dehydration; hypophagiaMusculoskeletal and Connective TissueDisordersarthralgia; back pain; flank pain; joint swelling;limb discomfort; musculoskeletal discomfort; myalgia; neck pain; painin extremityNervous System Disordersageusia; burning sensation; dizziness; dysgeusia;headache; hypoesthesiaRenal and Urinary Disordersnephrotic syndrome; proteinuria; renal failureSkin and Subcutaneous Tissue Disordersdry skin; hyperhidrosis; pemphigus foliaceus; pruritus;rash; rash pruritic; skin irritation; skin texture abnormal; skinwrinkling; urticaria.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The goal of therapy is to reduce urinarycystine concentration below its solubility limit. Tiopronin is anactive reducing agent which undergoes thiol-disulfide exchange withcystine to form mixed disulfide of tiopronin-cysteine. From thisreaction, water-soluble mixed disulfide is formed and the amountof sparingly soluble cystine is reduced.. 12.2 Pharmacodynamics. The decrement in urinary cystine producedby tiopronin is generally proportional to the dose. reduction inurinary 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 administrationand rise on the first day of drug withdrawal.. 12.3 Pharmacokinetics. AbsorptionTHIOLA TabletsWhen THIOLAsingle doses were given to fasted healthy subjects (n 39), the mediantime to peak plasma level (Tmax) was (range:0.5 to 2.1) hours.EliminationExcretionWhen tiopronin is given orally, up to48% 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-bindingthiol drug (CBTD) for oral use. Tiopronin is N-(2-Mercaptopropionyl)glycine and has the following structure:Tiopronin has the empiricalformula C5H9NO3S and molecular weight of 163.20. In this drug producttiopronin 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: butylmethacrylate: methyl methacrylate copolymer (Eudragit 100), hydroxy-propylcellulose, lactose monohydrate, magnesium stearate, povidone, sugar,talc, titanium dioxide.. tiopronin-structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended initial dosage in adult patients is 800mg/day. In clinical studies, the average dosage was about 1,000 mg/day.(2.1)The recommended initial dosage in pediatric patients 20kg and greater is 15 mg/kg/day. Avoid dosages greater than 50 mg/kgper day in pediatric patients. (2.1, 5.1, 8.4)Administer THIOLA in divided doses at the same times eachday at least one hour before or hours after meals. (2.1)Measure urinary cystine month after initiation of THIOLAand every months thereafter. (2.1). The recommended initial dosage in adult patients is 800mg/day. In clinical studies, the average dosage was about 1,000 mg/day.(2.1). The recommended initial dosage in pediatric patients 20kg and greater is 15 mg/kg/day. Avoid dosages greater than 50 mg/kgper day in pediatric patients. (2.1, 5.1, 8.4). Administer THIOLA in divided doses at the same times eachday at least one hour before or hours after meals. (2.1). Measure urinary cystine month after initiation of THIOLAand every months thereafter. (2.1). 2.1 Recommended Dosage. Adults: The recommendedinitial dosage in adult patients is 800 mg/day. In clinical studies,the average dosage was about 1,000 mg/day.Pediatrics: The recommendedinitial dosage in pediatric patients weighing 20 kg and greater is15 mg/kg/day. Avoid dosages greater than 50 mg/kg per day in pediatricpatients [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)].Administer THIOLA in divided doses at the same times each day atleast one hour before or hours after meals.Consider starting THIOLA at lower dosagein patients with history of severe toxicity to d-penicillamine.. 2.2 Monitoring. Measure urinary cystine month after starting THIOLA and every 3months thereafter. Adjust THIOLA dosage to maintain urinary cystineconcentration less than 250 mg/L.Assess for proteinuria before treatmentand every to months during treatment [see Warnings andPrecautions (5.1)].Discontinue THIOLA in patientswho develop proteinuria, and monitor urinary protein and renal function.Consider restarting THIOLA treatment at lower dosage after resolutionof proteinuria.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding is not recommended. (8.2)Geriatric: Choose dose carefully and monitor renal functionin the elderly. (8.5). Lactation: Breastfeeding is not recommended. (8.2). Geriatric: Choose dose carefully and monitor renal functionin the elderly. (8.5). 8.1 Pregnancy. Risk SummaryAvailable publishedcase report data with tiopronin have not identified drug-associatedrisk for major birth defects, miscarriage, or adverse maternal orfetal outcomes. Renal stones in pregnancy may result in adverse pregnancyoutcomes (see ClinicalConsiderations ). In animal reproduction studies, therewere no adverse developmental outcomes with oral administration oftiopronin to pregnant mice and rats during organogenesis at dosesup to times 2 grams/day human dose (based on mg/m2). The estimated background risk of major birth defectsand miscarriage for the indicated population is unknown. All pregnancieshave background risk of birth defect, loss, or other adverse outcomes.In the U.S. general population, the estimated background risk of majorbirth defects and miscarriage in clinically recognized pregnanciesare 2% to 4% and 15% to 20%, respectively. Clinical ConsiderationsDisease-associated maternal and/or embryo/fetalriskRenal stones in pregnancy may increase therisk of adverse pregnancy outcomes, such as preterm birth and lowbirth weight.DataAnimal DataNo findings of fetal malformations could be attributed to the drugin reproduction studies in mice and rats at doses up to times thehighest recommended human dose of grams/day (based on mg/m2).. 8.2 Lactation. Risk SummaryThere are no dataon the presence of tiopronin in either human or animal milk or onthe effects of the breastfed child. published study suggests thattiopronin may suppress milk production. Because of the potential forserious adverse reactions, including nephrotic syndrome, advise patientsthat breastfeeding is not recommended during treatment with THIOLA.. 8.4 Pediatric Use. THIOLA is indicated in pediatric patientsweighing 20 kg or more with severe homozygous cystinuria, in combinationwith high fluid intake, alkali, and diet modification, for the preventionof cystine stone formation who are not responsive to these measuresalone. This indication is based on safety and efficacy data froma trial in patients years to 68 years of age and clinical experience.Proteinuria, including nephrotic syndrome, has been reported in pediatricpatients. Pediatric patients receiving greater than 50 mg/kg tioproninper day may be at greater risk [see Dosage and Administration(2.1, 2.2), Warnings and Precautions (5.1)[see Adverse Reactions (6.1)].THIOLA tabletsare not approved for use in pediatric patients weighing less than20 kg or in pediatric patients unable to swallow tablets [seeDosage and Administration (2.1)].. 8.5 Geriatric Use. This drug is known to be substantially excretedby the kidney, and the risk of adverse reactions to this drug maybe greater in patients with impaired renal function. Because elderlypatients are more likely to have decreased renal function, care shouldbe taken in dose selection, and it may be useful to monitor renalfunction.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Proteinuria, including nephrotic syndrome, and membranousnephropathy, has been reported with tiopronin use. Pediatric patientsreceiving greater than 50 mg/kg of tiopronin per day may be at increasedrisk for proteinuria. (2.1, 5.1, 8.4)Hypersensitivity reactions have been reported during tiopronintreatment. (4, 5.2). Proteinuria, including nephrotic syndrome, and membranousnephropathy, has been reported with tiopronin use. Pediatric patientsreceiving greater than 50 mg/kg of tiopronin per day may be at increasedrisk for proteinuria. (2.1, 5.1, 8.4). Hypersensitivity reactions have been reported during tiopronintreatment. (4, 5.2). 5.1 Proteinuria. Proteinuria, including nephrotic syndrome, and membranous nephropathy,have been reported with tiopronin use. Pediatric patients receivinggreater than 50 mg/kg of tiopronin per day may be at increased riskfor 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 proteinuriaand 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)].