TIOPRONIN tablet, delayed release

TIOPRONIN by

Drug Labeling and Warnings

TIOPRONIN by is a Prescription medication manufactured, distributed, or labeled by Torrent Pharmaceuticals Limited, Torrent Pharma, Inc., Optimus Pharma Private Limited. 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 9 years of age and older with severe homozygous cystinuria, who are not responsive to these measures alone.

    Additional pediatric use information is approved for Mission Pharmacal Company’s Thiola EC (tiopronin delayed-release) tablets. However, due to Mission Pharmacal Company’s marketing exclusivity rights, this drug product is not labeled with that information.

  • 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 9 years of age and older 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, without food. 

    Consider starting tiopronin delayed-release tablets at a lower dosage in patients with history of severe toxicity to d-penicillamine.

    Additional pediatric use information is approved for Mission Pharmacal Company’s Thiola EC (tiopronin delayed-release) tablets. However, due to Mission Pharmacal Company’s marketing exclusivity rights, this drug product is not labeled with that information.

    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: White to off-white, round shaped, enteric coated tablets imprinted with "1A" with black ink on one side and plain on other side, free from physical defects.
    300 mg tablets: White to off-white, round shaped, enteric coated tablets imprinted with "3A" with black ink on one side and plain on other side, free from physical defects.

  • 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)].

  • 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. In those without prior history of d-penicillamine treatment, 6% developed reactions of sufficient severity to require tiopronin withdrawal.

    Table 1 presents adverse reactions ≥5% in either treatment group occurring in this trial.

    Table 1: Adverse Reactions Occurring in One or More Patients

    System Organ Class

    Adverse Reaction

    Group 1

    Previously treated

    with

    d-penicillamine

    (N = 49)

    Group 2

    Naïve to

    d-penicillamine

    (N = 17)

    Blood and Lymphatic System Disorders

    anemia

    1 (2%)

    1 (6%)

    Gastrointestinal Disorders

    nausea

    12 (25%)

    2 (12%)

    emesis

    5 (10%)

    –

    diarrhea/soft stools

    9 (18%)

    1 (6%)

    abdominal pain

    –

    1 (6%)

    oral ulcers

    6 (12%)

    3 (18%)

    General Disorders and Administration Site Conditions

    fever

    4 (8%)

    –

    weakness

    2 (4%)

    2 (12%)

    fatigue

    7 (14%)

    –

    peripheral (edema)

    3 (6%)

    1 (6%)

    chest pain

    –

    1 (6%)

    Metabolism and Nutrition Disorders

    anorexia

    4 (8%)

    –

    Musculoskeletal and Connective Tissue Disorders

    arthralgia

    –

    2 (12%)

    Renal and Urinary Disorders

    proteinuria

    5 (10%)

    1 (6%)

    impotence

    –

    1 (6%)

    Respiratory, Thoracic and Mediastinal Disorders

    cough

    –

    1 (6%)

    Skin and Subcutaneous Tissue Disorders

    rash

    7 (14%)

    2 (12%)

    ecchymosis

    3 (6%)

    –

    pruritus

    2 (4%)

    1 (6%)

    urticaria

    4 (8%)

    –

    skin wrinkling

    3 (6%)

    1 (6%)

    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. 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 exposure.

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

    Table 2: Adverse Reactions Reported for Tiopronin Pharmacovigilance by System Organ Class and Preferred Term

    System Organ Class

    Preferred Term

    Cardiac Disorders

    congestive heart failure

    Ear and Labyrinth Disorder

    vertigo

    Gastrointestinal Disorders

    abdominal discomfort; abdominal distension; abdominal pain; chapped lips; diarrhea; dry mouth; dyspepsia; eructation; flatulence; gastrointestinal disorder; gastroesophageal reflux disease; nausea; vomiting; jaundice; liver transaminitis

    General Disorders and Administration Site Conditions

    asthenia; chest pain; fatigue; malaise; pain; peripheral swelling; pyrexia; swelling

    Investigations

    glomerular filtration rate decreased; weight increased

    Metabolism and Nutrition Disorders

    decreased appetite; dehydration; hypophagia

    Musculoskeletal and Connective Tissue Disorders

    arthralgia; back pain; flank pain; joint swelling; limb discomfort; musculoskeletal discomfort; myalgia; neck pain; pain in extremity

    Nervous System Disorders

    ageusia; burning sensation; dizziness; dysgeusia; headache; hypoesthesia

    Renal and Urinary Disorders

    nephrotic syndrome; proteinuria; renal failure

    Skin and Subcutaneous Tissue Disorders

    dry skin; hyperhidrosis; pemphigus foliaceus; pruritus; rash; rash pruritic; skin irritation; skin texture abnormal; skin wrinkling; urticaria

  • 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

    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 9 years of age and older 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 or in pediatric patients unable to swallow tablets [see Dosage and Administration (2.1)].

    Additional pediatric use information is approved for Mission Pharmacal Company’s Thiola EC (tiopronin delayed-release) tablets. However, due to Mission Pharmacal Company’s marketing exclusivity rights, this drug product is not labeled with that information.

    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:

    structural formula

    Tiopronin has the empirical formula C5H9NO3S and a molecular weight of 163.19. In this drug product tiopronin exists as a dl racemic mixture.

    Tiopronin is a white to off-white color 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, low substitute hydroxypropyl cellulose, hydroxypropyl cellulose, magnesium stearate, hypromellose 2910, methacrylic acid: ethyl acrylate copolymer (Eudragit L 100-55), talc, triethyl citrate. The imprinting ink contains shellac, ferrosoferric oxide and propylene glycol.

  • 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 tiopronin-cysteine. 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 to 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 IR and tiopronin delayed-release tablets single doses were given to fasted healthy subjects, the median time to peak plasma levels (Tmax) was 1 (range: 0.5 to 2.1) and 3 (range: 1.0 to 6.0) hours, respectively. The peak exposure (Cmax) and total exposure (AUC0-t) of tiopronin from tiopronin delayed-release tablets were decreased by 22% and 7% respectively compared to tiopronin IR tablets.

    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, white to off-white, round shaped, enteric-coated tablets imprinted with "1A" with black ink on one side and plain on other side, free from physical defects.
    Bottles of 300 with child-resistant closure, NDC 13668-691-03.

    300 mg delayed-release, white to off-white, round shaped, enteric-coated tablets imprinted with "3A" with black ink on one side and plain on other side, free from physical defects.
    Bottles of 90 with child-resistant closure, NDC 13668-692-90.

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

  • 17 PATIENT COUNSELING INFORMATION

    Lactation

    Advise women that breastfeeding is not recommended during treatment with tiopronin delayed-release tablets [see Use in Specific Populations (8.2)].

    logo

    Manufactured for:
    Torrent Pharmaceuticals Limited, India

    Distributed by:
    Torrent Pharma Inc., Basking Ridge, NJ 07920

    8088451                                                     Revised: June 2023

  • PRINCIPAL DISPLAY PANEL

    100 mg - 300 Tablets 

    image description

    300 mg - 90 Tablets

    image description

  • INGREDIENTS AND APPEARANCE
    TIOPRONIN 
    tiopronin tablet, delayed release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 13668-691
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    TIOPRONIN (UNII: C5W04GO61S) (TIOPRONIN - UNII:C5W04GO61S) TIOPRONIN100 mg
    Inactive Ingredients
    Ingredient NameStrength
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 9XZ8H6N6OH)  
    HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED (UNII: 2165RE0K14)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A (UNII: NX76LV5T8J)  
    TALC (UNII: 7SEV7J4R1U)  
    TRIETHYL CITRATE (UNII: 8Z96QXD6UM)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    Product Characteristics
    ColorWHITEScoreno score
    ShapeROUNDSize8mm
    FlavorImprint Code 1A
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 13668-691-03300 in 1 BOTTLE; Type 0: Not a Combination Product01/30/2024
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21699001/30/2024
    TIOPRONIN 
    tiopronin tablet, delayed release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 13668-692
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    TIOPRONIN (UNII: C5W04GO61S) (TIOPRONIN - UNII:C5W04GO61S) TIOPRONIN300 mg
    Inactive Ingredients
    Ingredient NameStrength
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 9XZ8H6N6OH)  
    HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED (UNII: 2165RE0K14)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A (UNII: NX76LV5T8J)  
    TALC (UNII: 7SEV7J4R1U)  
    TRIETHYL CITRATE (UNII: 8Z96QXD6UM)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    Product Characteristics
    ColorWHITEScoreno score
    ShapeROUNDSize11mm
    FlavorImprint Code 3A
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 13668-692-9090 in 1 BOTTLE; Type 0: Not a Combination Product01/30/2024
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21699001/30/2024
    Labeler - Torrent Pharmaceuticals Limited (650175722)
    Registrant - Torrent Pharma, Inc. (790033935)
    Establishment
    NameAddressID/FEIBusiness Operations
    Optimus Pharma Private Limited675474672MANUFACTURE(13668-692, 13668-691)
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