TIOPRONIN

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 molecular formula C 5 H 9 NO 3 S and a molecular weight of 163.19 g/mol. 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 300 mg of tiopronin. The inactive ingredients in tiopronin delayed-release tablets include lactose monohydrate, hydroxypropyl cellulose, hydroxypropyl cellulose (low substitute), magnesium stearate, hydroxypropyl methylcellulose E5, methacrylic acid and ethyl acrylate copolymer (Eudragit L 100-55), talc, triethyl citrate. Each tablet is imprinted with red pharmaceutical ink which contains: alcohol, butyl alcohol, FD & C Red # 40, propylene glycol, shellac and titanium dioxide. structure

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)

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 9 years of age and older 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 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) ]. 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. 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: Crush the tiopronin delayed-release tablet in a clean pill crusher or mortar and pestle. Always crush one tablet at a time. Measure approximately one tablespoon of applesauce and transfer it into a container with the crushed tiopronin delayed-release tablet. Mix the crushed tiopronin delayed-release tablet in the applesauce until the powder is well dispersed. Administer the entire tiopronin delayed-release tablet-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. 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.

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) ] . Hypersensitivity to tiopronin or any component of tiopronin delayed-release tablets. ( 4)

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 Amneal Pharmaceuticals at 1-877-835-5472 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 Post-marketing 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 post-marketing 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

7.1 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) ] .