Highlights Of Prescribing Information

Manufactured and packaged by Mission Pharmacal Company, San Antonio, TX 78230 1355

Distributed by Travere Therapeutics, Inc., San Diego, CA 92130

Copyright © 2024 Mission Pharmacal Company. All rights reserved.

L090201R0824

THL_T13758R0824

There is no information on overdosage with tiopronin.

THIOLA (tiopronin) immediate-release tablets are a 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 C ₅H ₉NO ₃S and a molecular weight of 163.20. In this drug product tiopronin

exists as a dl racemic mixture.

Tiopronin is a 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 E 100), hydroxy-propyl cellulose, lactose monohydrate, magnesium

stearate, povidone, sugar, talc, titanium dioxide.

THIOLA is contraindicated in patients with hypersensitivity to tiopronin or any other components of THIOLA

[see Warnings and Precautions (5.2)].

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.

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.

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 a mixed disulfide of tiopronincysteine.

From this reaction, a 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. A reduction in

urinary cystine of 250-350 mg/day at tiopronin dosage of 1 g/day, and a decline of approximately 500 mg/day

at a dosage of 2 g/day, might be expected. Tiopronin has a rapid onset and offset of action, showing a fall in

cystine excretion on the first day of administration and a 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 1 (range: 0.5 to 2.1) hours.

Elimination

Excretion

When tiopronin is given orally, up to 48% of dose appears in urine during the first 4 hours and up to 78% by

72 hours.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-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 2 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.

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)].

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 THIOLA in 3 divided doses at the same times each day at least one hour before or 2 hours after

meals.

Consider starting THIOLA at a lower dosage in patients with history of severe toxicity to d-penicillamine.

2.2 Monitoring

Measure urinary cystine 1 month after starting THIOLA and every 3 months thereafter. Adjust THIOLA dosage

to maintain urinary cystine concentration less than 250 mg/L.

Assess for proteinuria before treatment and every 3 to 6 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 a lower dosage after resolution of proteinuria.

Tablets for oral use:

100 mg tablets: round, white and imprinted in red with “M” on one side

8.1 Pregnancy

Risk Summary

Available published case report data with tiopronin have not identified a 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 2 times a 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 a 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 Considerations

Disease-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 2 times the highest recommended human dose of 2 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. A 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 a

trial in patients 9 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.

Lactation

Advise women that breastfeeding is not recommended during treatment with THIOLA [see Use in Specific

Populations (8.2)].

100 mg round, white, immediate-release tablet imprinted in red with “M” on one side and blank on the other

side: Bottles of 100 NDC 0178-0900-01.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Manufactured and packaged by Mission Pharmacal Company, San Antonio, TX 78230 1355

Distributed by Travere Therapeutics, Inc., San Diego, CA 92130

Copyright © 2024 Mission Pharmacal Company. All rights reserved.

L090201R0824

THL_T13758R0824

There is no information on overdosage with tiopronin.

THIOLA (tiopronin) immediate-release tablets are a 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 C ₅H ₉NO ₃S and a molecular weight of 163.20. In this drug product tiopronin

exists as a dl racemic mixture.

Tiopronin is a 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 E 100), hydroxy-propyl cellulose, lactose monohydrate, magnesium

stearate, povidone, sugar, talc, titanium dioxide.

THIOLA is contraindicated in patients with hypersensitivity to tiopronin or any other components of THIOLA

[see Warnings and Precautions (5.2)].

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.

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.

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 a mixed disulfide of tiopronincysteine.

From this reaction, a 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. A reduction in

urinary cystine of 250-350 mg/day at tiopronin dosage of 1 g/day, and a decline of approximately 500 mg/day

at a dosage of 2 g/day, might be expected. Tiopronin has a rapid onset and offset of action, showing a fall in

cystine excretion on the first day of administration and a 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 1 (range: 0.5 to 2.1) hours.

Elimination

Excretion

When tiopronin is given orally, up to 48% of dose appears in urine during the first 4 hours and up to 78% by

72 hours.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-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 2 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.

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)].

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 THIOLA in 3 divided doses at the same times each day at least one hour before or 2 hours after

meals.

Consider starting THIOLA at a lower dosage in patients with history of severe toxicity to d-penicillamine.

2.2 Monitoring

Measure urinary cystine 1 month after starting THIOLA and every 3 months thereafter. Adjust THIOLA dosage

to maintain urinary cystine concentration less than 250 mg/L.

Assess for proteinuria before treatment and every 3 to 6 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 a lower dosage after resolution of proteinuria.

Tablets for oral use:

100 mg tablets: round, white and imprinted in red with “M” on one side

8.1 Pregnancy

Risk Summary

Available published case report data with tiopronin have not identified a 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 2 times a 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 a 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 Considerations

Disease-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 2 times the highest recommended human dose of 2 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. A 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 a

trial in patients 9 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.

Lactation

Advise women that breastfeeding is not recommended during treatment with THIOLA [see Use in Specific

Populations (8.2)].

100 mg round, white, immediate-release tablet imprinted in red with “M” on one side and blank on the other

side: Bottles of 100 NDC 0178-0900-01.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].