Label: THIOLA EC- tiopronin tablet, delayed release
- NDC Code(s): 0178-0901-90, 0178-0902-01
- Packager: Mission Pharmacal Company
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: New Drug Application
Updated March 15, 2021
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use THIOLA EC® safely and effectively. See full prescribing information for THIOLA EC.
THIOLA EC (tiopronin) delayed-release tablets, for oral use
Initial U.S. Approval: 1988
RECENT MAJOR CHANGES
Dosage and Administration (2.2) 03/2021
INDICATIONS AND USAGE
THIOLA EC 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. (5.1, 8.4)
- Measure urinary cystine 1 month after initiation of THIOLA EC and every 3 months thereafter (2.3)
- Administer THIOLA EC in 3 divided doses at the same times each day, with or without food. Maintain a routine pattern with regard to meals. (2.1)
- THIOLA EC can be crushed and mixed with applesauce. For preparation and administration instructions, see the full prescribing information. (2.2)
DOSAGE FORMS AND STRENGTHS
Tablets: 100 mg and 300 mg (3)
- Hypersensitivity to tiopronin or any component of THIOLA EC (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)
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
See 17 for PATIENT COUNSELING INFORMATION.
Table of Contents
FULL PRESCRIBING INFORMATION: CONTENTS*
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
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)].
Assess for proteinuria before treatment and every 3 to 6 months during treatment [see Warnings and Precautions (5.1)].
- 3 DOSAGE FORMS AND STRENGTHS
THIOLA EC is contraindicated in patients with hypersensitivity to tiopronin or any other components of THIOLA EC [see Warnings and Precautions (5.2)].
5 WARNINGS AND PRECAUTIONS
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
- 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
(N = 49)
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%)
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
Tiopronin is released faster from THIOLA EC in the presence of alcohol and the risk for adverse events associated with THIOLA EC when taken with alcohol is unknown. Avoid alcohol consumption 2 hours before and 3 hours after taking THIOLA EC [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
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.
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).
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 EC.
8.4 Pediatric Use
THIOLA EC 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, 2.3), Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
THIOLA EC 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
Each THIOLA EC tablet contains 100 or 300 mg of tiopronin. The inactive ingredients in THIOLA EC 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 tiopronin-cysteine. From this reaction, a water-soluble mixed disulfide is formed and the amount of sparingly soluble cystine is reduced.
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.
THIOLA EC Tablets
When THIOLA IR and THIOLA EC 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 THIOLA EC tablets were decreased by 22% and 7% respectively compared to THIOLA IR tablets.
When THIOLA EC tablets were administered crushed in applesauce, the median time to peak plasma levels of tiopronin (Tmax) was 1 hour (range: 0.5 to 2.0) compared to 3.1 hours (range: 1.5 to 4.0) when administered as intact EC tablets.
When THIOLA EC tablets were administered crushed in applesauce, the maximum concentration (Cmax) and exposure (AUC0-t) to tiopronin were increased by 38% and 14%, respectively, compared to THIOLA EC tablets administered intact.
Since the drug is dosed to effect, the study results support administration of THIOLA EC tablets with or without food; administer at the same time each day with a routine pattern with regard to meals.
An in vitro dissolution study was conducted to evaluate the impact of alcohol (5, 10, 20, and 40%) on the dose dumping of THIOLA EC tablets. The study results showed that the addition of alcohol to the dissolution media increases the dissolution rate of THIOLA EC tablets in the acidic media of 0.1N HCl [see Drug Interactions (7.1)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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.
SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
For patients who cannot swallow the tablet whole, the THIOLA EC tablets can be crushed and mixed with applesauce. See Dosage and Administration (2.2) for preparation and administration instructions.
Advise women that breastfeeding is not recommended during treatment with THIOLA EC [see Use in Specific Populations (8.2)].
- PRINCIPAL DISPLAY PANEL
INGREDIENTS AND APPEARANCE
tiopronin tablet, delayed release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0178-0902 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 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 Color WHITE Score no score Shape ROUND Size 8mm Flavor Imprint Code T1 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0178-0902-01 300 in 1 BOTTLE; Type 0: Not a Combination Product 06/28/2019 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA211843 06/28/2019 THIOLA EC
tiopronin tablet, delayed release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0178-0901 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength TIOPRONIN (UNII: C5W04GO61S) (TIOPRONIN - UNII:C5W04GO61S) TIOPRONIN 300 mg Inactive Ingredients Ingredient Name Strength 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 Color WHITE Score no score Shape ROUND Size 11mm Flavor Imprint Code T3 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0178-0901-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 06/28/2019 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA211843 06/28/2019 Labeler - Mission Pharmacal Company (008117095) Registrant - Mission Pharmacal Company (927726893) Establishment Name Address ID/FEI Business Operations Mission Pharmacal Company 927726893 MANUFACTURE(0178-0901, 0178-0902)