DESCRIPTION SECTION.

11 DESCRIPTION. Tiopronin Delayed-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 Tiopronin Delayed-Release Tablet contains 100 or 300 mg of tiopronin. The inactive ingredients in Tiopronin Delayed-Release Tablets include lactose monohydrate, hydroxypropyl cellulose, hydroxypropyl cellulose (low substitute), magnesium stearate, hydroxypropyl methylcellulose E5, methacrylic acid: ethyl acrylate copolymer (Eudragit 100-55), talc, triethyl citrate. image.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 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)] 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 BioComp Pharma, Inc. at toll-free phone 1-866- 762-2365 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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 Tiopronin Tablets. In those without prior history of d-penicillamine treatment, 6% developed reactions of sufficient severity to require Tiopronin Tablets 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. image. 6.2 Postmarketing Experience. Adverse reactions have been reported from the literature, as well as during post-approval use of Tiopronin Tablets. 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 Tiopronin Tablets exposure. Adverse reactions reported during the postmarketing use of Tiopronin Tablets are listed by body system in Table 2. Image.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The 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. AbsorptionTiopronin Delayed-Release TabletsWhen Tiopronin Tablets and Tiopronin Delayed-Release Tablets single doses were given to fasted healthy subjects, the median time to peak plasma levels (T max) was (range: 0.5 to 2.1) and (range: 1.0 to 6.0) hours, respectively. The peak exposure (C max) and total exposure (AUC 0-t) of tiopronin from Tiopronin Delayed- Release Tablets were decreased by 22% and 7% respectively compared to Tiopronin Tablets. When Tiopronin Delayed-Release Tablets were administered crushed in applesauce, the median time to peak plasma levels of tiopronin (T max) was hour (range: 0.5 to 2.0) compared to 3.1 hours (range: 1.5 to 4.0) when administered as intact Tiopronin Delayed-Release Tablets. When Tiopronin Delayed-Release Tablets were administered crushed in applesauce, the maximum concentration (C max) and exposure (AUC 0-t) to tiopronin were increased by 38% and 14%, respectively, compared to Tiopronin Delayed-Release Tablets administered intact. Food EffectsAdministration of the Tiopronin Delayed-Release Tablet with food decreases max of tiopronin by 13% and AUC 0-t by 25% compared to Tiopronin Delayed-Release Tablets administered in fasted state. Since the drug is dosed to effect, the study results support administration of Tiopronin Delayed-Release Tablets with or without food; administer at the same time each day with routine pattern with regard to meals. EliminationExcretionWhen tiopronin is given orally, up to 48% of dose appears in 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 Tiopronin Delayed-Release Tablets. The study results showed that the addition of alcohol to the dissolution media increases the dissolution rate of Tiopronin Delayed-Release Tablets in the acidic media of 0.1N HCl [see Drug Interactions (7.1)].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Tiopronin Delayed-Release Tablets are contraindicated in patients with hypersensitivity to tiopronin or any other components of Tiopronin Delayed-Release Tablets [see Warnings and Precautions (5.2)]. Hypersensitivity to tiopronin or any component of Tiopronin Delayed-Release Tablets (4). Hypersensitivity to tiopronin or any component of Tiopronin Delayed-Release Tablets (4).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 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 Tiopronin Delayed-Release Tablets in divided doses at the same times each day, with or without food. Maintain routine pattern with regard to meals. Consider starting Tiopronin Delayed-Release Tablets at lower dosage in patients with history of severe toxicity to d-penicillamine. 2.2 Preparation and Administration InstructionsFor patients who cannot swallow the tablet whole, Tiopronin Delayed-Release Tablets can be crushed and mixed with applesauce. Administration of Tiopronin Delayed-Release Tablets with other liquids or foods has not been studied and is not recommended.Preparation and Administration of Tiopronin Delayed-Release Tablets Mixed in ApplesauceFor patients who can swallow semi-solid food, Tiopronin Delayed-Release Tablets can be crushed and mixed with applesauce: 1. Crush the Tiopronin Delayed-Release Tablet in clean pill crusher or mortar and pestle. Always crush one tablet at time. 2. Measure approximately one tablespoon of applesauce and transfer it into container with the crushed Tiopronin Delayed-Release Tablet.3. Mix the crushed Tiopronin Delayed-Release Tablet in the applesauce until the powder is well dispersed.4. Administer the entire Tiopronin Delayed-Release Tablets-applesauce mixture to the patients mouth immediately. (However, if this is not possible, the mixture can be stored in refrigerator for up to hours after adding the crushed tablet to the applesauce. Discard any mixture that has not been given within hours.) 5. To assure that any leftover applesauce mixture from the container is recovered, add tap water to the same container, mix, and have the patient drink the water. 2.3 MonitoringMeasure urinary cystine month after starting Tiopronin Delayed-Release Tablets and every months thereafter. Adjust Tiopronin Delayed-Release Tablets 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 Tiopronin Delayed-Release Tablets in patients who develop proteinuria, and monitor urinary protein and renal function. Consider restarting Tiopronin Delayed-Release Tablets treatment at lower dosage after resolution of proteinuria.. The recommended initial dosage in adult patients is 800 mg/day. In clinical studies, the average dosage wasabout 1,000 mg/day. (2.1)The recommended initial dosage in pediatric patients 20 kg and greater is 15 mg/kg/day. Avoid dosages greaterthan 50 mg/kg per day in pediatric patients. (5.1, 8.4)Measure urinary cystine month after initiation of Tiopronin Delayed-Release Tablets and every monthsthereafter (2.3)Administer Tiopronin Delayed-Release Tablets in divided doses at the same times each day, with or withoutfood. Maintain routine pattern with regard to meals. (2.1)Tiopronin Delayed-Release Tablets can be crushed and mixed with applesauce. For preparation andadministration instructions, see the full prescribing information. (2.2). The recommended initial dosage in adult patients is 800 mg/day. In clinical studies, the average dosage was. The recommended initial dosage in pediatric patients 20 kg and greater is 15 mg/kg/day. Avoid dosages greater. Measure urinary cystine month after initiation of Tiopronin Delayed-Release Tablets and every months. Administer Tiopronin Delayed-Release Tablets in divided doses at the same times each day, with or without. Tiopronin Delayed-Release Tablets can be crushed and mixed with applesauce. For preparation and. 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 Tiopronin Delayed-Release Tablets in divided doses at the same times each day, with or without food. Maintain routine pattern with regard to meals. Consider starting Tiopronin Delayed-Release Tablets at lower dosage in patients with history of severe toxicity to d-penicillamine. 2.2 Preparation and Administration Instructions. For patients who cannot swallow the tablet whole, Tiopronin Delayed-Release Tablets can be crushed and mixed with applesauce. Administration of Tiopronin Delayed-Release Tablets with other liquids or foods has not been studied and is not recommended. Preparation and Administration of Tiopronin Delayed-Release Tablets Mixed in ApplesauceFor patients who can swallow semi-solid food, Tiopronin Delayed-Release Tablets can be crushed and mixed with applesauce: 1. Crush the Tiopronin Delayed-Release Tablet in clean pill crusher or mortar and pestle. Always crush one tablet at time. 2. Measure approximately one tablespoon of applesauce and transfer it into container with the crushed Tiopronin Delayed-Release Tablet. 3. Mix the crushed Tiopronin Delayed-Release Tablet in the applesauce until the powder is well dispersed. 4. Administer the entire Tiopronin Delayed-Release Tablets-applesauce mixture to the patients mouth immediately. (However, if this is not possible, the mixture can be stored in refrigerator for up to hours after adding the crushed tablet to the applesauce. Discard any mixture that has not been given within hours.) 5. To assure that any leftover applesauce mixture from the container is recovered, add tap water to the same container, mix, and have the patient drink the water. 2.3 Monitoring. Measure urinary cystine month after starting Tiopronin Delayed-Release Tablets and every months thereafter. Adjust Tiopronin Delayed-Release Tablets 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 Tiopronin Delayed-Release Tablets in patients who develop proteinuria, and monitor urinary protein and renal function. Consider restarting Tiopronin Delayed-Release Tablets treatment at lower dosage after resolution of proteinuria.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets for oral use: 100 mg tablets: round, white to off-white and imprinted in red with T1 on one side 300 mg tablets: round, white to off-white and imprinted in red with T3 on one side Tablets: 100 mg and 300 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Alcohol. Tiopronin is released faster from Tiopronin Delayed-Release Tablets in the presence of alcohol and the risk for adverse events associated with Tiopronin Delayed-Release Tablets when taken with alcohol is unknown. Avoid alcohol consumption hours before and hours after taking Tiopronin Delayed-Release Tablets [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 100 mg delayed-release, round, white to off-white tablet imprinted with T1 on one side with red ink and blank on the other side: Bottles of 300 NDC 44523-054-01. 300 mg delayed-release, round, white to off-white tablet imprinted with T3 on one side with red ink and blank on the other side: Bottles of 90 NDC 44523-055-01. Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Tiopronin Delayed-Release Tablets are 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.. Tiopronin Delayed-Release Tablets are 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 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 micronucleus assays. Impairment of FertilityHigh 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.

OVERDOSAGE SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Tiopronin Delayed-Release Tablets 100mgNDC 44523-054-01 label.

PATIENT COUNSELING INFORMATION.

17 PATIENT COUNSELING INFORMATION. Administration InstructionsFor patients who cannot swallow the tablet whole, the Tiopronin Delayed-Release Tablets can be crushed and mixed with applesauce. See Dosage and Administration (2.2) for preparation and administration instructions. LactationAdvise women that breastfeeding is not recommended during treatment with Tiopronin Delayed-Release Tablets [see Use in Specific Populations (8.2)].

SPL UNCLASSIFIED SECTION.

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 Tiopronin Delayed-Release Tablets in divided doses at the same times each day, with or without food. Maintain routine pattern with regard to meals. Consider starting Tiopronin Delayed-Release Tablets at lower dosage in 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 function in the elderly. (8.5)See 17 for PATIENT COUNSELING INFORMATION.Revised: 07/2021. Lactation: Breastfeeding is not recommended. (8.2). Geriatric: Choose dose carefully and monitor renal function in the elderly. (8.5). Lactation: Breastfeeding is not recommended. (8.2)Geriatric: Choose dose carefully and monitor renal function in the elderly. (8.5). Lactation: Breastfeeding is not recommended. (8.2). Geriatric: Choose dose carefully and monitor renal function in the elderly. (8.5). 8.1 Pregnancy. Risk 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/m2). 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 riskRenal stones in pregnancy may increase the risk of adverse pregnancy outcomes, such as preterm birth and low birth weight. DataAnimal DataNo 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/m2). 8.2 Lactation. Risk SummaryThere 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 Tiopronin Delayed-Release Tablets. 8.4 Pediatric Use. Tiopronin Delayed-Release Tablets are 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, 2.3), Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Tiopronin Delayed-Release Tablets are not approved for use in pediatric patients weighing less than 20 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 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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 (2.3), 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 (2.3)]. 5.2 Hypersensitivity ReactionsHypersensitivity reactions (drug fever, rash, fever, arthralgia and lymphadenopathy) have been reported [see Contraindications (4)]. 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). Proteinuria, including nephrotic syndrome, and membranous nephropathy, has been reported with tiopronin use.. Hypersensitivity reactions have been reported during tiopronin treatment. (4, 5.2). 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 (2.3), 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 (2.3)]. 5.2 Hypersensitivity Reactions. Hypersensitivity reactions (drug fever, rash, fever, arthralgia and lymphadenopathy) have been reported [see Contraindications (4)].