Label: THIOLA- tiopronin tablet, sugar coated

  • NDC Code(s): 0178-0900-01
  • Packager: Mission Pharmacal Company
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated June 1, 2019

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use THIOLA ® safely and effectively. See full prescribing information for THIOLA.

    THIOLA (tiopronin) tablets, for oral use
    Initial U.S. Approval: 1988

    INDICATIONS AND USAGE

    THIOLA is 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. (1)

    DOSAGE AND ADMINISTRATION

    • The recommended initial dosage in adult patients is 800 mg/day. In clinical studies, the average dosage was about 1,000 mg/day. (2.1)
    • 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. (2.1, 5.1, 8.4)
    • Administer THIOLA in 3 divided doses at the same times each day at least one hour before or 2 hours after meals. (2.1)
    • Measure urinary cystine 1 month after initiation of THIOLA and every 3 months thereafter. (2.1)

    DOSAGE FORMS AND STRENGTHS

    Tablets: 100 mg (3)

    CONTRAINDICATIONS

    • Hypersensitivity to tiopronin or any component of THIOLA (4)

    WARNINGS AND PRECAUTIONS

    • 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)

    ADVERSE REACTIONS

    Most common adverse reactions (≥10%) are nausea, diarrhea or soft stools, oral ulcers, rash, fatigue, fever, arthralgia, proteinuria, and emesis. (6)


    To report SUSPECTED ADVERSE REACTIONS, contact Mission Pharmacal Company at toll-free phone # 1-800-298-1087 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    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: 6/2019

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  • FULL PRESCRIBING INFORMATION: CONTENTS*
  • 1 INDICATIONS AND USAGE

    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.

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  • 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 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.

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  • 3 DOSAGE FORMS AND STRENGTHS

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

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  • 4 CONTRAINDICATIONS

    THIOLA is contraindicated in patients with hypersensitivity to tiopronin or any other components of THIOLA [see Warnings and Precautions (5.2)].

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  • 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 (2.2), 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)].

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  • 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 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.

    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 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.

    Table 2: Adverse Reactions Reported for THIOLA 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
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  • 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 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) [see 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 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.

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  • 10 OVERDOSAGE

    There is no information on overdosage with tiopronin.

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  • 11 DESCRIPTION

    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-structure

    Tiopronin has the empirical formula C5H9NO3S 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.

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  • 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 250-350 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 (Tmax) 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.

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  • 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.

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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    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].

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  • 17 PATIENT COUNSELING INFORMATION

    Lactation
    Advise women that breastfeeding is not recommended during treatment with THIOLA [see Use in Specific Populations (8.2)].

    Manufactured and packaged by Mission Pharmacal Company, San Antonio, TX 78230 1355
    Distributed by Retrophin, Inc., San Diego, CA 92130

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  • PRINCIPAL DISPLAY PANEL

    THIOLA ® Label
    NDC: 0178-0900-01

    Thiola Label NDC 0178-0900-01
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  • INGREDIENTS AND APPEARANCE
    THIOLA 
    tiopronin tablet, sugar coated
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0178-0900
    Route of Administration ORAL
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    TIOPRONIN (UNII: C5W04GO61S) (TIOPRONIN - UNII:C5W04GO61S) TIOPRONIN 100 mg
    Inactive Ingredients
    Ingredient Name Strength
    POVIDONE, UNSPECIFIED (UNII: FZ989GH94E)  
    HYDROXYPROPYL CELLULOSE (70000 WAMW) (UNII: 66O7AQV0RT)  
    SUCROSE (UNII: C151H8M554) 123 mg
    CALCIUM CARBONATE (UNII: H0G9379FGK) 42.7 mg
    LACTOSE (UNII: J2B2A4N98G) 39 mg
    DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER (UNII: 905HNO1SIH) 28.8 mg
    ETHYLCELLULOSES (UNII: 7Z8S9VYZ4B) 20 mg
    MAGNESIUM SILICATE (UNII: 9B9691B2N9) 14.4 mg
    MAGNESIUM STEARATE (UNII: 70097M6I30) 5.4 mg
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP) 1.7 mg
    CARNAUBA WAX (UNII: R12CBM0EIZ) 0.05 mg
    FD&C RED NO. 40 (UNII: WZB9127XOA)  
    ALUMINUM OXIDE (UNII: LMI26O6933)  
    Product Characteristics
    Color WHITE Score no score
    Shape ROUND Size 8mm
    Flavor Imprint Code M
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0178-0900-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 08/11/1988
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA019569 08/11/1988
    Labeler - Mission Pharmacal Company (008117095)
    Registrant - Mission Pharmacal Company (927726893)
    Establishment
    Name Address ID/FEI Business Operations
    Mission Pharmacal Company 927726893 MANUFACTURE(0178-0900)
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