contraindications ( 4 )] .

id 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. consider starting thiola ec 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, thiola ec can be crushed and mixed with applesauce. administration of thiola ec with other liquids or foods has not been studied and is not recommended. preparation and administration of thiola ec mixed in applesauce for patients who can swallow semi-solid food, thiola ec can be crushed and mixed with applesauce: crush the thiola ec 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 thiola ec tablet. mix the crushed thiola ec tablet in the applesauce until the powder is well dispersed. administer the entire thiola ec-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 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.

w. 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

linically 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/m 2 ). 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 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.

n 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/m 2 ).

o 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 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 (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 ec tablets. when thiola ec 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 thiola ec tablets administered intact. food effects administration of the thiola ec tablet with food decreases c max of tiopronin by 13% and auc 0-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. 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 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 )] .

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. 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 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 )] .