Tiopronin

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 a 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.

2 DOSAGE AND ADMINISTRATION

2.1Recommended 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 . Administer Tiopronin Delayed-Release Tablets in 3 divided doses at the same times each day, with or without food.

Maintain a routine pattern with regard to meals. Consider starting Tiopronin Delayed-Release Tablets at a lower dosage in patients with history of severe toxicity to d-penicillamine.

2.2Preparation 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 Applesauce For 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 a clean pill crusher or mortar and pestle. Always crush one tablet at a time. 2. Measure approximately one tablespoon of applesauce and transfer it into a 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 patient’s mouth immediately. (However, if this is not possible, the mixture can be stored in a refrigerator for up to 2 hours after adding the crushed tablet to the applesauce. Discard any mixture that has not been given within 2 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.

2.3Monitoring Measure

urinary cystine 1 month after starting Tiopronin Delayed-Release Tablets and every 3 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 3 to 6 months during treatment . 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 a lower dosage after resolution of proteinuria.

The recommended initial dosage in adult patients is 800 mg/day. In clinical studies, the average dosage was about 1,000 mg/day. The recommended initial dosage in pediatric patients 20 kg and greater is 15 mg/kg/day. Avoid dosages greater than 50 mg/kg per day in pediatric patients. (5.1, 8.4) Measure urinary cystine 1 month after initiation of Tiopronin Delayed-Release Tablets and every 3 months thereafter Administer Tiopronin Delayed-Release Tablets in 3 divided doses at the same times each day, with or without food.

Maintain a routine pattern with regard to meals. Tiopronin Delayed-Release Tablets can be crushed and mixed with applesauce. For preparation and administration instructions, see the full prescribing information.

2.1Recommended 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 . Administer Tiopronin Delayed-Release Tablets in 3 divided doses at the same times each day, with or without food.

Maintain a routine pattern with regard to meals. Consider starting Tiopronin Delayed-Release Tablets at a lower dosage in patients with history of severe toxicity to d-penicillamine.

2.2Preparation 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 Applesauce For 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 a clean pill crusher or mortar and pestle. Always crush one tablet at a time. 2. Measure approximately one tablespoon of applesauce and transfer it into a 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 patient’s mouth immediately. (However, if this is not possible, the mixture can be stored in a refrigerator for up to 2 hours after adding the crushed tablet to the applesauce. Discard any mixture that has not been given within 2 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.

2.3Monitoring Measure

urinary cystine 1 month after starting Tiopronin Delayed-Release Tablets and every 3 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 3 to 6 months during treatment . 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 a lower dosage after resolution of proteinuria.

5 WARNINGS AND PRECAUTIONS

5.1Proteinuria 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 . Monitor patients for the development of proteinuria and discontinue therapy in patients who develop proteinuria .

5.2Hypersensitivity Reactions Hypersensitivity

reactions (drug fever, rash, fever, arthralgia and lymphadenopathy) have been reported . 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)

5.1Proteinuria 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 . Monitor patients for the development of proteinuria and discontinue therapy in patients who develop proteinuria .

5.2Hypersensitivity Reactions Hypersensitivity

reactions (drug fever, rash, fever, arthralgia and lymphadenopathy) have been reported .

Tiopronin Delayed-Release Tablets are contraindicated in patients with hypersensitivity to tiopronin or any other components of Tiopronin Delayed-Release Tablets . Hypersensitivity to tiopronin or any component of Tiopronin Delayed-Release Tablets

Lactation: Breastfeeding is not recommended. Geriatric: Choose dose carefully and monitor renal function in the elderly. See 17 for PATIENT COUNSELING INFORMATION. Revised: 07/2021 Lactation: Breastfeeding is not recommended. Geriatric: Choose dose carefully and monitor renal function in the elderly.

8.1Pregnancy 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 . 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/m2). 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/m2).

8.2Lactation 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 Delayed-Release Tablets.

8.4Pediatric 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 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 . Tiopronin Delayed-Release Tablets are not approved for use in pediatric patients weighing less than 20 kg .

8.5Geriatric 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.

The following adverse reactions are discussed in greater detail in other sections of the labeling: • Proteinuria • Hypersensitivity Most common adverse reactions (≥10%) are nausea, diarrhea or soft stools, oral ulcers, rash, fatigue, fever, arthralgia, proteinuria, and emesis. 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.

6.1Clinical 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 Tiopronin Tablets. In those without prior history of d-penicillamine treatment, 6% developed reactions of sufficient severity to require Tiopronin Tablets 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. image

6.2Postmarketing 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.

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