TIOPRONIN tablet, delayed release

Tiopronin by

Drug Labeling and Warnings

Tiopronin by is a Prescription medication manufactured, distributed, or labeled by Bio Comp Pharma, Inc., Mission Pharmacal Company. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 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.

  • 2 DOSAGE AND ADMINISTRATION

    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 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.


    2.2 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 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.


    2.3 Monitoring
    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 [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 a lower dosage after resolution of proteinuria.

    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 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.

    2.2 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 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.

    2.3 Monitoring

    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 [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 a lower dosage
    after resolution of proteinuria.

  • 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

  • 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)].

  • 5 WARNINGS AND PRECAUTIONS

    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)].

    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)].

  • 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)]

    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 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.

    image

    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 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.

    Image

  • 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 2 hours before and 3 hours after taking Tiopronin Delayed-Release Tablets [see Clinical
    Pharmacology (12.3)].

  • 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

    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/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).

    8.2 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 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 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, 2.3), 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.

  • 10 OVERDOSAGE

    There is no information on overdosage with tiopronin.

  • 11 DESCRIPTION

    Tiopronin Delayed-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:

    image
    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 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 L 100-55), talc, triethyl citrate.

  • 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 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 Delayed-Release Tablets
    When 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 1 (range: 0.5 to 2.1) and 3 (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 1 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 Effects
    Administration of the Tiopronin Delayed-Release Tablet with food decreases C max of tiopronin by 13% and
    AUC 0-t by 25% compared to Tiopronin Delayed-Release Tablets administered in a 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 a routine pattern with regard to meals.

    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.

    Drug Interactions
    Alcohol
    An 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)].

  • 13 NONCLINICAL TOXICOLOGY

    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.

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

  • 17 PATIENT COUNSELING INFORMATION

    Administration Instructions
    For 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.

    Lactation
    Advise women that breastfeeding is not recommended during treatment with Tiopronin Delayed-Release
    Tablets [see Use in Specific Populations (8.2)].

  • SPL UNCLASSIFIED SECTION

    image

  • PRINCIPAL DISPLAY PANEL

    Tiopronin Delayed-Release Tablets 100mg

    NDC 44523-054-01

    label

  • PRINCIPAL DISPLAY PANEL

    Tiopronin Delayed-Release Tablets 300mg

    NDC: 44523-055-01

    label

  • INGREDIENTS AND APPEARANCE
    TIOPRONIN 
    tiopronin tablet, delayed release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 44523-054
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    TIOPRONIN (UNII: C5W04GO61S) (TIOPRONIN - UNII:C5W04GO61S) TIOPRONIN100 mg
    Inactive Ingredients
    Ingredient NameStrength
    METHACRYLIC ACID-ETHYL ACRYLATE COPOLYMER (1:1) TYPE A (UNII: NX76LV5T8J)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    TRIETHYL CITRATE (UNII: 8Z96QXD6UM)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 9XZ8H6N6OH)  
    HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED (UNII: 2165RE0K14)  
    TALC (UNII: 7SEV7J4R1U)  
    Product Characteristics
    ColorwhiteScoreno score
    ShapeROUNDSize8mm
    FlavorImprint Code T1
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 44523-054-01300 in 1 BOTTLE; Type 0: Not a Combination Product12/05/2024
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDA authorized genericNDA21184312/05/2024
    TIOPRONIN 
    tiopronin tablet, delayed release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 44523-055
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    TIOPRONIN (UNII: C5W04GO61S) (TIOPRONIN - UNII:C5W04GO61S) TIOPRONIN300 mg
    Inactive Ingredients
    Ingredient NameStrength
    METHACRYLIC ACID-ETHYL ACRYLATE COPOLYMER (1:1) TYPE A (UNII: NX76LV5T8J)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    TRIETHYL CITRATE (UNII: 8Z96QXD6UM)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 9XZ8H6N6OH)  
    HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED (UNII: 2165RE0K14)  
    TALC (UNII: 7SEV7J4R1U)  
    Product Characteristics
    ColorwhiteScoreno score
    ShapeROUNDSize8mm
    FlavorImprint Code T3
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 44523-055-0190 in 1 BOTTLE; Type 0: Not a Combination Product12/05/2024
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDA authorized genericNDA21184312/05/2024
    Labeler - Bio Comp Pharma, Inc. (829249718)
    Registrant - Mission Pharmacal Company (927726893)
    Establishment
    NameAddressID/FEIBusiness Operations
    Mission Pharmacal Company927726893manufacture(44523-054, 44523-055) , label(44523-054, 44523-055) , analysis(44523-054, 44523-055) , pack(44523-054, 44523-055)
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