NDC 0178-0901 Thiola Ec

Tiopronin

NDC Product Code 0178-0901

NDC Code: 0178-0901

Proprietary Name: Thiola Ec What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Tiopronin What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
WHITE (C48325)
Shape: ROUND (C48348)
Size(s):
8 MM
11 MM
Imprint(s):
T1
T3
Score: 1

NDC Code Structure

  • 0178 - Mission Pharmacal Company
    • 0178-0901 - Thiola Ec

NDC 0178-0901-90

Package Description: 90 TABLET, DELAYED RELEASE in 1 BOTTLE

NDC Product Information

Thiola Ec with NDC 0178-0901 is a a human prescription drug product labeled by Mission Pharmacal Company. The generic name of Thiola Ec is tiopronin. The product's dosage form is tablet, delayed release and is administered via oral form.

Labeler Name: Mission Pharmacal Company

Dosage Form: Tablet, Delayed Release - A solid dosage form which releases a drug (or drugs) at a time other than promptly after administration. Enteric-coated articles are delayed release dosage forms.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Thiola Ec Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • TIOPRONIN 300 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • 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)
  • 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)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Cystine Disulfide Reduction - [MoA] (Mechanism of Action)
  • N-substituted Glycines - [CS]
  • Reducing and Complexing Thiol - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Mission Pharmacal Company
Labeler Code: 0178
FDA Application Number: NDA211843 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 06-28-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Thiola Ec Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1  Indications And Usage

THIOLA EC 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.

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 EC in 3 divided doses
at the same times each day, with or without food. Maintain a routine
pattern with regard to meals. Swallow THIOLA EC tablets whole.Consider starting THIOLA EC
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 EC and every 3 months thereafter. Adjust THIOLA
EC 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 EC in patients who develop proteinuria, and monitor urinary
protein and renal function. Consider restarting THIOLA EC 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 side300 mg tablets: round, white to off-white and
imprinted in red with “T3” on one side

4  Contraindications

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

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)].

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 ClassAdverse ReactionGroup 1Previously
treated withd‑penicillamine(N = 49)Group 2Naïve
to d‑penicillamine(N = 17)Blood and Lymphatic System Disordersanemia1 (2%)1 (6%)Gastrointestinal Disordersnausea12 (25%)2 (12%)emesis5 (10%)–diarrhea/soft stools9 (18%)1 (6%)abdominal pain–1 (6%)oral ulcers6 (12%)3 (18%)General Disorders and Administration
Site Conditionsfever4 (8%)–weakness2 (4%)2 (12%)fatigue7 (14%)–peripheral (edema)3 (6%)1 (6%)chest pain–1 (6%)Metabolism and Nutrition Disordersanorexia4 (8%)–Musculoskeletal and Connective Tissue
Disordersarthralgia–2 (12%)Renal and Urinary Disordersproteinuria5 (10%)1 (6%)impotence–1 (6%)Respiratory, Thoracic and Mediastinal
Disorderscough–1 (6%)Skin and
Subcutaneous Tissue Disordersrash7 (14%)2 (12%)ecchymosis3 (6%)–pruritus2 (4%)1 (6%)urticaria4 (8%)–skin wrinkling3 (6%)1 (6%)Taste DisturbanceA 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 TermSystem Organ ClassPreferred TermCardiac Disorderscongestive heart failureEar and Labyrinth DisordervertigoGastrointestinal Disordersabdominal discomfort; abdominal distension; abdominal
pain; chapped lips; diarrhea; dry mouth; dyspepsia; eructation; flatulence;
gastrointestinal disorder; gastroesophageal reflux disease; nausea;
vomiting; jaundice; liver transaminitisGeneral Disorders and Administration
Site Conditionsasthenia; chest pain; fatigue; malaise; pain; peripheral
swelling; pyrexia; swellingInvestigationsglomerular filtration rate decreased; weight increasedMetabolism and Nutrition Disordersdecreased appetite; dehydration; hypophagiaMusculoskeletal and Connective Tissue
Disordersarthralgia; back pain; flank pain; joint swelling;
limb discomfort; musculoskeletal discomfort; myalgia; neck pain; pain
in extremityNervous System Disordersageusia; burning sensation; dizziness; dysgeusia;
headache; hypoesthesiaRenal and Urinary Disordersnephrotic syndrome; proteinuria; renal failureSkin and Subcutaneous Tissue Disordersdry skin; hyperhidrosis; pemphigus foliaceus; pruritus;
rash; rash pruritic; skin irritation; skin texture abnormal; skin
wrinkling; urticaria

7.1 Alcohol

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)].

8.1 Pregnancy

Risk SummaryAvailable 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 ConsiderationsDisease-associated
maternal and/or embryo/fetal riskRenal stones
in pregnancy may increase the risk of adverse pregnancy outcomes,
such as preterm birth and low birth weight.DataAnimal DataNo 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 SummaryThere 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, 2.2), 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 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.

10  Overdosage

There is no information on overdosage with tiopronin.

11  Description

THIOLA EC (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: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 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.

12.1  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

AbsorptionTHIOLA
EC TabletsWhen THIOLA IR and THIOLA EC single
doses were given to fasted healthy subjects (n = 39) in a crossover
study, the median time to peak plasma levels (Tmax) were 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. Food EffectsAdministration of the THIOLA EC tablet with food decreases
Cmax of tiopronin by 13% and AUC0-t by 25% compared to THIOLA EC administered in a fasted
state. 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.EliminationExcretionWhen 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 InteractionsAlcoholAn 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)].

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

CarcinogenesisLong-term carcinogenicity studies in animals have not been performed.MutagenesisTiopronin was not genotoxic in the chromosomal aberration,
sister chromatid exchange, and in vivo micronucleus
assays.Impairment of FertilityHigh 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 0178-0902-01.300 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 0178-0901-90.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 InstructionsAdvise patients to swallow THIOLA EC tablets
intact and not to chew, crush, or split the tablets.LactationAdvise women that breastfeeding is not recommended during treatment
with THIOLA EC [see Use in Specific Populations (8.2)].Manufactured and packaged by Mission Pharmacal
Company, San Antonio, TX 78230 1355Distributed by Retrophin,
Inc., San Diego, CA 92130

* Please review the disclaimer below.

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