Tiopronin

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. Tiopronin delayed-release tablets are 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 9 years of age and older with severe homozygous cystinuria, who are not responsive to these measures alone. ( 1 )

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. 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 Tiopronin Delayed-Release Tablets and every 3 months thereafter (2.3) 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. (2.1) Tiopronin Delayed-Release Tablets can be crushed and mixed with applesauce. For preparation and administration instructions, see the full prescribing information. (2.2) 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.

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)]. 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) 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)].

CONTRAINDICATIONS THIOLA is contraindicated in patients with hypersensitivity to tiopronin or any other components of THIOLA [see Warnings and Precautions (5.2)]. ----------------------------------------------CONTRAINDICATIONS------------------------------------------ • Hypersensitivity to tiopronin or any component of THIOLA (4)

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 )] .

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 )] 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 Cycle Pharmaceuticals Ltd at 1-857-437-3969 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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

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)].