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

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

2.2 Monitoring

Measure urinary cystine 1 month after starting Tiopronin Tablets and every 3 months thereafter. Adjust
Tiopronin Tablets 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)].

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)].

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.

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 a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal relationship to Tiopronin Tablets
exposure.

Adverse reactions reported during the postmarketing use of Tiopronin Tablets are listed by body system in
Table 2.

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 Tiopronin Tablets.

8.4 Pediatric Use

Tiopronin 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 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)].

Tiopronin 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.

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
Tiopronin Tablets
When Tiopronin Tablets 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.