MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The goal of therapy is to reduce urinary cystine concentrationbelow its solubility limit. Tiopronin is an active reducing agentwhich undergoes thiol-disulfide exchange with cystine to form mixeddisulfide of tiopronin-cysteine. From this reaction, water-solublemixed disulfide is formed and the amount of sparingly soluble cystineis reduced.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-term carcinogenicity studies in animals have not been performed.MutagenesisTiopronin was not genotoxic in the chromosomal aberration,sister chromatid exchange, and in vivo micronucleusassays.Impairment of FertilityHigh doses of tioproninin experimental animals have been shown to interfere with maintenanceof pregnancy and viability of the fetus. In published male fertilitystudies in rats, tiopronin at 20 mg/kg/day intramuscular (IM) for60 days induced reductions in testis, epididymis, vas deferens, andaccessory sex glands weights and in the count and motility of caudaepididymal sperm.

LABOR & DELIVERY SECTION.

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 THIOLAEC.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Thefollowing adverse reactions are discussed in greater detail in othersections 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 1-800-298-1087or 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 1Previouslytreated withd-penicillamine(N 49)Group 2Naiveto 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 reported duringthe 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 urinary cystine concentrationbelow its solubility limit. Tiopronin is an active reducing agentwhich undergoes thiol-disulfide exchange with cystine to form mixeddisulfide of tiopronin-cysteine. From this reaction, water-solublemixed disulfide is formed and the amount of sparingly soluble cystineis reduced. 12.2 Pharmacodynamics. The decrement in urinary cystine produced by tiopronin is generallyproportional to the dose. reduction in urinary cystine of 250-350mg/day at tiopronin dosage of g/day, and decline of approximately500 mg/day at dosage of g/day, might be expected. Tiopronin hasa rapid onset and offset of action, showing fall in cystine excretionon the first day of administration and rise on the first day ofdrug withdrawal.. 12.3 Pharmacokinetics. AbsorptionTHIOLA EC TabletsWhen THIOLA IR and THIOLA EC single doses were givento fasted healthy subjects, the median time to peak plasma levels(Tmax) was (range: 0.5 to 2.1) and (range:1.0 to 6.0) hours, respectively. The peak exposure (Cmax) and total exposure (AUC0-t) of tioproninfrom THIOLA EC tablets were decreased by 22% and 7% respectively comparedto THIOLA IR tablets.When THIOLA EC tablets were administered crushed in applesauce, themedian time to peak plasma levels of tiopronin (Tmax) was hour (range: 0.5 to 2.0) compared to 3.1 hours (range: 1.5to 4.0) when administered as intact EC tablets.When THIOLA EC tablets were administeredcrushed in applesauce, the maximum concentration (Cmax) and exposure (AUC0-t) to tiopronin wereincreased by 38% and 14%, respectively, compared to THIOLA EC tabletsadministered intact.Food EffectsAdministration ofthe THIOLA EC tablet with food decreases Cmax of tiopronin by 13% and AUC0-t by 25% comparedto THIOLA EC administered in fasted state.Since the drug is dosed to effect, the studyresults support administration of THIOLA EC tablets with or withoutfood; administer at the same time each day with routine patternwith regard to meals.EliminationExcretionWhen tiopronin is given orally, up to 48% of dose appearsin urine during the first hours and up to 78% by 72 hours.Drug InteractionsAlcoholAn in vitro dissolution study was conducted to evaluate the impact of alcohol(5, 10, 20, and 40%) on the dose dumping of THIOLA EC tablets. Thestudy results showed that the addition of alcohol to the dissolutionmedia increases the dissolution rate of THIOLA EC tablets in the acidicmedia of 0.1N HCl [see Drug Interactions (7.1)].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. THIOLA EC is contraindicated in patients with hypersensitivityto tiopronin or any other components of THIOLA EC [see Warningsand Precautions (5.2)].. Hypersensitivity to tiopronin or any component of THIOLAEC (4) Hypersensitivity to tiopronin or any component of THIOLAEC (4).

DESCRIPTION SECTION.

11 DESCRIPTION. THIOLA EC (tiopronin) delayed-release tabletsare reducing and cystine-binding thiol drug (CBTD) for oral use.Tiopronin is N-(2-Mercaptopropionyl) glycine and has the followingstructure: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 EC tablet contains 100 or 300mg of tiopronin. The inactive ingredients in THIOLA EC tablets includelactose monohydrate, hydroxypropyl cellulose, hydroxypropyl cellulose(low substitute), magnesium stearate, hydroxypropyl methylcelluloseE5, methacrylic acid: ethyl acrylate copolymer (Eudragit 100-55),talc, triethyl citrate.. Tiopronin Chemical 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. (5.1, 8.4)Measure urinary cystine month after initiation of THIOLAEC and every months thereafter (2.3)Administer THIOLA EC in divided doses at the same timeseach day, with or without food. Maintain routine pattern with regardto meals. (2.1)THIOLA EC can be crushed and mixed with applesauce. Forpreparation and administration instructions, see the full prescribinginformation. (2.2). 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. (5.1, 8.4). Measure urinary cystine month after initiation of THIOLAEC and every months thereafter (2.3). Administer THIOLA EC in divided doses at the same timeseach day, with or without food. Maintain routine pattern with regardto meals. (2.1). THIOLA EC can be crushed and mixed with applesauce. Forpreparation and administration instructions, see the full prescribinginformation. (2.2). 2.1 Recommended Dosage. Adults:The recommended initial dosage in adult patients is 800 mg/day. Inclinical studies, the average dosage was about 1,000 mg/day.Pediatrics: The recommended initial dosage in pediatric patients weighing 20kg and greater is 15 mg/kg/day. Avoid dosages greater than 50 mg/kgper day in pediatric patients [see Warnings and Precautions(5.1), Use in Specific Populations(8.4)].Administer THIOLA EC in divided doses atthe same times each day, with or without food. Maintain routinepattern with regard to meals.Consider starting THIOLA EC at lower dosagein patients with history of severe toxicity to d-penicillamine.. 2.2 Preparation and Administration Instructions. For patients who cannot swallowthe tablet whole, THIOLA EC can be crushed and mixed with applesauce.Administration of THIOLA EC with other liquids or foods has not beenstudied and is not recommended.Preparationand Administration of THIOLA EC Mixed in ApplesauceFor patients who can swallow semi-solid food, THIOLA EC can be crushedand mixed with applesauce:Crush the THIOLA EC tablet in cleanpill crusher or mortar and pestle. Always crush one tablet at time.Measure approximately one tablespoonof applesauce and transfer it into container with the crushed THIOLAEC tablet.Mix the crushed THIOLA EC tablet in theapplesauce until the powder is well dispersed.Administer the entire THIOLA EC-applesaucemixture to the patients mouth immediately. (However, if this is notpossible, the mixture can be stored in refrigerator for up to 2hours after adding the crushed tablet to the applesauce. Discard anymixture that has not been given within hours.)To assure that any leftover applesaucemixture from the container is recovered, add tap water to the samecontainer, mix, and have the patient drink the water.. Crush the THIOLA EC tablet in cleanpill crusher or mortar and pestle. Always crush one tablet at time.. Measure approximately one tablespoonof applesauce and transfer it into container with the crushed THIOLAEC tablet.. Mix the crushed THIOLA EC tablet in theapplesauce until the powder is well dispersed.. Administer the entire THIOLA EC-applesaucemixture to the patients mouth immediately. (However, if this is notpossible, the mixture can be stored in refrigerator for up to 2hours after adding the crushed tablet to the applesauce. Discard anymixture that has not been given within hours.). To assure that any leftover applesaucemixture from the container is recovered, add tap water to the samecontainer, mix, and have the patient drink the water.. 2.3 Monitoring. Measure urinary cystine month after starting THIOLA EC and every3 months thereafter. Adjust THIOLA EC dosage to maintain urinary cystineconcentration less than 250 mg/L.Assess for proteinuria before treatment andevery to months during treatment [see Warnings and Precautions(5.1)].Discontinue THIOLA EC in patients who developproteinuria, and monitor urinary protein and renal function. Considerrestarting THIOLA EC treatment at lower dosage after resolutionof proteinuria.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGEFORMS AND STRENGTHS. Tablets for oral use:100 mgtablets: round, white to off-white and imprinted in red with T1on one side300 mg tablets: round, white to off-white andimprinted in red with T3 on one side. Tablets: 100 mg and 300 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUGINTERACTIONS. 7.1 Alcohol. Tiopronin is released faster from THIOLA EC in the presence of alcoholand the risk for adverse events associated with THIOLA EC when takenwith alcohol is unknown. Avoid alcohol consumption hours beforeand hours after taking THIOLA EC [see Clinical Pharmacology(12.3)].

GERIATRIC USE SECTION.

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 patientswith impaired renal function. Because elderly patients are more likelyto have decreased renal function, care should be taken in dose selection,and it may be useful to monitor renal function.

HOW SUPPLIED SECTION.

16 HOWSUPPLIED/STORAGE AND HANDLING. 100 mg delayed-release, round, white to off-white tablet imprintedwith T1 on one side with red ink and blank on the other side: Bottlesof 300 NDC 0178-0902-01.300 mg delayed-release, round, white tooff-white tablet imprinted with T3 on one side with red ink andblank on the other side: Bottles of 90 NDC 0178-0901-90.Store at 25C (77F); excursionspermitted to 15-30C (59-86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONSAND USAGE. THIOLA EC is indicated,in combination with high fluid intake, alkali, and diet modification,for the prevention of cystine stone formation in adults and pediatricpatients 20 kg and greater with severe homozygous cystinuria, whoare not responsive to these measures alone.. THIOLA EC is reducing and complexingthiol indicated, in combination with high fluid intake, alkali, anddiet modification, for the prevention of cystine stone formation inadults and pediatric patients 20 kg and greater with severe homozygouscystinuria, who are not responsive to these measures alone. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Administration InstructionsFor patients who cannot swallow the tablet whole, the THIOLA ECtablets can be crushed and mixed with applesauce. See Dosageand Administration (2.2) forpreparation and administration instructions.LactationAdvise women that breastfeeding is not recommended during treatmentwith THIOLA EC [see Use in Specific Populations (8.2)].Manufactured and packaged by Mission PharmacalCompany, San Antonio, TX 78230 1355Distributed by TravereTherapeutics, Inc., San Diego, CA 92130Copyright(C) 2021 Mission Pharmacal Company.All rights reserved.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-term carcinogenicity studies in animals have not been performed.MutagenesisTiopronin was not genotoxic in the chromosomal aberration,sister chromatid exchange, and in vivo micronucleusassays.Impairment of FertilityHigh doses of tioproninin experimental animals have been shown to interfere with maintenanceof pregnancy and viability of the fetus. In published male fertilitystudies in rats, tiopronin at 20 mg/kg/day intramuscular (IM) for60 days induced reductions in testis, epididymis, vas deferens, andaccessory sex glands weights and in the count and motility of caudaepididymal sperm.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no information on overdosage with tiopronin.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Thiola EC(R) NDC: 0178-0902-01Thiola EC(R) NDC: 0178-0901-90. Thiola EC 100-mg Tablets label. Thiola EC 300-mg Tablets label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. THIOLAEC is indicated in pediatric patients weighing 20 kg or more withsevere homozygous cystinuria, in combination with high fluid intake,alkali, and diet modification, for the prevention of cystine stoneformation who are not responsive to these measures alone. This indicationis based on safety and efficacy data from trial in patients yearsto 68 years of age and clinical experience. Proteinuria, includingnephrotic syndrome, has been reported in pediatric patients. Pediatricpatients receiving greater than 50 mg/kg tiopronin per day may beat greater risk [see Dosage and Administration (2.1, 2.3), Warnings and Precautions (5.1)and Adverse Reactions (6.1)].THIOLA EC tabletsare not approved for use in pediatric patients weighing less than20 kg [see Dosage and Administration (2.1)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The decrement in urinary cystine produced by tiopronin is generallyproportional to the dose. reduction in urinary cystine of 250-350mg/day at tiopronin dosage of g/day, and decline of approximately500 mg/day at dosage of g/day, might be expected. Tiopronin hasa rapid onset and offset of action, showing fall in cystine excretionon the first day of administration and rise on the first day ofdrug withdrawal.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionTHIOLA EC TabletsWhen THIOLA IR and THIOLA EC single doses were givento fasted healthy subjects, the median time to peak plasma levels(Tmax) was (range: 0.5 to 2.1) and (range:1.0 to 6.0) hours, respectively. The peak exposure (Cmax) and total exposure (AUC0-t) of tioproninfrom THIOLA EC tablets were decreased by 22% and 7% respectively comparedto THIOLA IR tablets.When THIOLA EC tablets were administered crushed in applesauce, themedian time to peak plasma levels of tiopronin (Tmax) was hour (range: 0.5 to 2.0) compared to 3.1 hours (range: 1.5to 4.0) when administered as intact EC tablets.When THIOLA EC tablets were administeredcrushed in applesauce, the maximum concentration (Cmax) and exposure (AUC0-t) to tiopronin wereincreased by 38% and 14%, respectively, compared to THIOLA EC tabletsadministered intact.Food EffectsAdministration ofthe THIOLA EC tablet with food decreases Cmax of tiopronin by 13% and AUC0-t by 25% comparedto THIOLA EC administered in fasted state.Since the drug is dosed to effect, the studyresults support administration of THIOLA EC tablets with or withoutfood; administer at the same time each day with routine patternwith regard to meals.EliminationExcretionWhen tiopronin is given orally, up to 48% of dose appearsin urine during the first hours and up to 78% by 72 hours.Drug InteractionsAlcoholAn in vitro dissolution study was conducted to evaluate the impact of alcohol(5, 10, 20, and 40%) on the dose dumping of THIOLA EC tablets. Thestudy results showed that the addition of alcohol to the dissolutionmedia increases the dissolution rate of THIOLA EC tablets in the acidicmedia of 0.1N HCl [see Drug Interactions (7.1)].

PREGNANCY SECTION.

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 Clinical Considerations). In animal reproduction studies, there were no adversedevelopmental outcomes with oral administration of tiopronin to pregnantmice and rats during organogenesis at doses up to times 2 grams/dayhuman dose (based on mg/m2). The estimatedbackground risk of major birth defects and miscarriage for the indicatedpopulation is unknown. All pregnancies have background risk of birthdefect, loss, or other adverse outcomes. In the U.S. general population,the estimated background risk of major birth defects and miscarriagein clinically recognized pregnancies are 2% to 4% and 15% to 20%,respectively.Clinical ConsiderationsDisease-associatedmaternal and/or embryo/fetal riskRenal stonesin pregnancy may increase the risk of adverse pregnancy outcomes,such as preterm birth and low birth weight.DataAnimal DataNo findings of fetal malformationscould be attributed to the drug in reproduction studies in mice andrats at doses up to times the highest recommended human dose of2 grams/day (based on mg/m2).

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.2)03/2021.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage. Adults:The recommended initial dosage in adult patients is 800 mg/day. Inclinical studies, the average dosage was about 1,000 mg/day.Pediatrics: The recommended initial dosage in pediatric patients weighing 20kg and greater is 15 mg/kg/day. Avoid dosages greater than 50 mg/kgper day in pediatric patients [see Warnings and Precautions(5.1), Use in Specific Populations(8.4)].Administer THIOLA EC in divided doses atthe same times each day, with or without food. Maintain routinepattern with regard to meals.Consider starting THIOLA EC at lower dosagein patients with history of severe toxicity to d-penicillamine.

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 Clinical Considerations). In animal reproduction studies, there were no adversedevelopmental outcomes with oral administration of tiopronin to pregnantmice and rats during organogenesis at doses up to times 2 grams/dayhuman dose (based on mg/m2). The estimatedbackground risk of major birth defects and miscarriage for the indicatedpopulation is unknown. All pregnancies have background risk of birthdefect, loss, or other adverse outcomes. In the U.S. general population,the estimated background risk of major birth defects and miscarriagein clinically recognized pregnancies are 2% to 4% and 15% to 20%,respectively.Clinical ConsiderationsDisease-associatedmaternal and/or embryo/fetal riskRenal stonesin pregnancy may increase the risk of adverse pregnancy outcomes,such as preterm birth and low birth weight.DataAnimal DataNo findings of fetal malformationscould be attributed to the drug in reproduction studies in mice andrats at doses up to times the highest recommended human dose of2 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 THIOLAEC.. 8.4 Pediatric Use. THIOLAEC is indicated in pediatric patients weighing 20 kg or more withsevere homozygous cystinuria, in combination with high fluid intake,alkali, and diet modification, for the prevention of cystine stoneformation who are not responsive to these measures alone. This indicationis based on safety and efficacy data from trial in patients yearsto 68 years of age and clinical experience. Proteinuria, includingnephrotic syndrome, has been reported in pediatric patients. Pediatricpatients receiving greater than 50 mg/kg tiopronin per day may beat greater risk [see Dosage and Administration (2.1, 2.3), Warnings and Precautions (5.1)and Adverse Reactions (6.1)].THIOLA EC tabletsare not approved for use in pediatric patients weighing less than20 kg [see Dosage and Administration (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 patientswith impaired renal function. Because elderly patients are more likelyto have decreased renal function, care should be taken in dose selection,and it may be useful to monitor renal function.

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 nephroticsyndrome, and membranous nephropathy, have been reported with tioproninuse. Pediatric patients receiving greater than 50 mg/kg of tioproninper day may be at increased risk for proteinuria. [see Dosageand Administration (2.3), AdverseReactions (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 (2.3)].. 5.2 Hypersensitivity Reactions. Hypersensitivity reactions (drug fever,rash, fever, arthralgia and lymphadenopathy) have been reported [see Contraindications (4)].