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Thiola EC
Classes
All Other Urological Agents
Cystinuria Agents
Administration
Tiopronin immediate-release (IR) tablets
Administer in divided doses, the daily dose is usually divided and given 3 times per day.
Give doses on an empty stomach, at least 1 hour before or 2 hours after meals.
Tiopronin gastro-resistant delayed-release (EC) tablets
Administer in divided doses, the daily dose is usually divided and given 3 times per day.
Give doses at the same time each day, with or without food. Maintain a pattern with regard to meals.
For patients who cannot swallow the tablet(s) whole, they may be crushed and mixed with applesauce. Always crush 1 tablet at a time. In a container, mix the crushed tablet with 1 tablespoon of applesauce until the powder is well dispersed. Administer immediately or store in a refrigerator for up to 2 hours. Discard after 2 hours. After administration, add tap water to the same container, mix, and have the patient drink the water to ensure the entire dose has been consumed.
Tiopronin is released faster from tiopronin EC tablets in the presence of alcohol and the risk for adverse events when taken with alcohol is unknown. Avoid alcohol consumption 2 hours before and 3 hours after taking tiopronin EC tablets.
Concomitant Treatment with Tiopronin (all dosage forms)
Continue conservative treatment measures, including dietary adjustments to reduce cystine synthesis and high fluid intake to increase urine volume and lower the urinary cystine concentration.
Patients should be advised to drink at least 3 L (i.e., at least ten 300-mL glasses) of recommended fluids (e.g., water) per day, including 2 glasses with each meal and at bedtime. Patients should be advised of the need to awake at night to urinate and should be instructed to drink 2 additional glasses of water before returning to bed. Additional fluid should be consumed if there is excessive sweating or intestinal fluid loss. At minimum, urine output should be 2 L/day.
Modest alkali therapy (e.g., potassium citrate or sodium bicarbonate) should be administered to maintain a urinary pH of 6.5 to 7. Potassium salts are preferred over sodium salts due to the risk of calcium stone development and to limit dietary sodium intake. Avoid excessive alkali therapy. Urinary pH greater than 7 is associated with calcium phosphate nephrolithiasis due to enhanced supersaturation of hydroxyapatite in the alkaline environment.
Adverse Reactions
nephrotic syndrome / Delayed / Incidence not known
glomerulonephritis / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
pemphigus / Delayed / Incidence not known
proteinuria / Delayed / 6.0-10.0
anemia / Delayed / 2.0-6.0
chest pain (unspecified) / Early / 6.0-6.0
peripheral edema / Delayed / 6.0-6.0
impotence (erectile dysfunction) / Delayed / 0-6.0
flank pain / Delayed / Incidence not known
lymphadenopathy / Delayed / Incidence not known
dehydration / Delayed / Incidence not known
oral ulceration / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
nausea / Early / 12.0-25.0
diarrhea / Early / 6.0-18.0
arthralgia / Delayed / 12.0-12.0
vomiting / Early / 10.0-10.0
fever / Early / 8.0-8.0
urticaria / Rapid / 8.0-8.0
anorexia / Delayed / 8.0-8.0
pruritus / Rapid / 4.0-6.0
abdominal pain / Early / 6.0-6.0
cough / Delayed / 6.0-6.0
weakness / Early / 4.0-4.0
fatigue / Early / 4.0-4.0
myalgia / Early / 4.0-4.0
hypoesthesia / Delayed / Incidence not known
asthenia / Delayed / Incidence not known
musculoskeletal pain / Early / Incidence not known
malaise / Early / Incidence not known
back pain / Delayed / Incidence not known
vertigo / Early / Incidence not known
headache / Early / Incidence not known
dizziness / Early / Incidence not known
rash / Early / Incidence not known
xerosis / Delayed / Incidence not known
skin irritation / Early / Incidence not known
ecchymosis / Delayed / Incidence not known
hyperhidrosis / Delayed / Incidence not known
dysgeusia / Early / Incidence not known
flatulence / Early / Incidence not known
gastroesophageal reflux / Delayed / Incidence not known
dyspepsia / Early / Incidence not known
weight gain / Delayed / Incidence not known
xerostomia / Early / Incidence not known
eructation / Early / Incidence not known
Common Brand Names
Thiola, Thiola EC
Dea Class
Rx
Description
Oral thiol-based reducing agent; undergoes thiol-disulfide exchange with cystine to form a compound that is more soluble in the urine
Used in adult and pediatric patients to prevent cystine nephrolithiasis due to severe homozygous cystinuria, in combination with high fluid intake, alkali, and diet modification
Serious adverse reactions more likely if the patient has a history of toxicity to d-penicillamine
Dosage And Indications
800 mg/day PO initially, administered in 3 divided doses at least 1 hour before or 2 hours after meals. Adjust dosage to amount required to reduce urinary cystine concentration to below its solubility limit (usually less than 250 mg/L). The average dose is approximately 1,000 mg/day. Consider lower initial dose in patients who developed severe toxicity to d-penicillamine. Usual Max: Daily adult dosage in literature rarely exceeds 2,000 mg/day PO; up to 3,000 mg has been reported in rare patients. Continue conservative treatment, including diet modifications and alkali administration aimed at reducing cystine formation and high fluid intake to increase urine volume and decrease cystine concentration.
Initially, 15 mg/kg/day PO administered in 3 divided doses at least 1 hour before or 2 hours after meals. Adjust dosage to amount required to reduce urinary cystine concentration to below its solubility limit (usually less than 250 mg/L). Consider lower initial dose in patients who developed severe toxicity to d-penicillamine. Usual maintenance doses of 20 to 40 mg/kg/day PO have been used in practice. The manufactuer states to avoid dosages greater than 50 mg/kg/day in pediatric patients. Adult Usual Max: 2,000 mg/day, rarely exceeding 3,000 mg/day. One smaller pediatric report noted a mean dose of 24.65 mg/kg/day PO (range 13.8 to 51 mg/kg/day). The dosage required to achieve target goal depended on the patient's body weight; older children required a lower dose to achieve target goals. Continue conservative treatment, including diet modifications aimed at reducing cystine formation and high fluid intake to increase urine volume and decrease cystine concentration.
800 mg/day PO initially, administered in 3 divided doses at the same time each day, with or without food. Adjust dosage to amount required to reduce urinary cystine concentration to below its solubility limit (usually less than 250 mg/L). The average dose is approximately 1,000 mg/day. Consider lower initial dose in patients who developed severe toxicity to d-penicillamine. Usual Max: Daily adult dosage in literature rarely exceeds 2,000 mg/day PO; up to 3,000 mg has been reported in rare patients. Continue conservative treatment measures for the disease, including diet modifications and alkali administration aimed at reducing cystine formation and high fluid intake to increase urine volume and decrease cystine concentration.
Initially, 15 mg/kg/day PO administered in 3 divided doses at the same time each day, with or without food. Adjust dosage to amount required to reduce urinary cystine concentration to below its solubility limit (usually less than 250 mg/L). Usual maintenance doses of 20 to 40 mg/kg/day PO have been used in practice. The manufactuer states to avoid dosages greater than 50 mg/kg/day in pediatric patients. Adult Usual Max: 2,000 mg/day, rarely exceeding 3,000 mg/day. Continue conservative treatment, including diet modifications aimed at reducing cystine formation and high fluid intake to increase urine volume and decrease cystine concentration.
Dosing Considerations
Specific guidelines for dosage adjustments in hepatic impairment are not available. During treatment, should jaundice and abnormal liver function tests occur, tiopronin should be discontinued and the patient treated by appropriate measures.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears no dosage adjustments are needed. Tiopronin is primarily excreted in the urine. During treatment, should severe renal complications (e.g., nephrotic syndrome) occur, tiopronin should be discontinued and the patient treated by appropriate measures.
Drug Interactions
Ethanol: (Major) Avoid alcohol consumption 2 hours before and 3 hours after taking tiopronin EC. Tiopronin is released faster from tiopronin EC in the presence of alcohol; the risk for adverse events associated with tiopronin EC when taken with alcohol is unknown. (Moderate) Avoid alcohol consumption 2 hours before and 3 hours after taking tiopronin EC. Tiopronin is released faster from tiopronin EC in the presence of alcohol; the risk for adverse events associated with tiopronin EC when taken with alcohol is unknown.
How Supplied
Thiola EC Oral Tab DR: 100mg, 300mg
Thiola/Tiopronin Oral Tab: 100mg
Maximum Dosage
Usual maximum rarely exceeds 2,000 mg/day PO; literature reports up to 3,000 mg/day PO in some patients.
Usual maximum rarely exceeds 2,000 mg/day PO; literature reports up to 3,000 mg/day PO in some patients.
Weight at least 20 kg: FDA-approved Max 50 mg/kg/day PO. Pediatric doses do not usually exceed adult maximum daily dose.
Weight less than 20 kg: Safety and efficacy have not been established.
At least 20 kg weight: FDA-approved Max 50 mg/kg/day PO. Pediatric doses do not usually exceed adult maximum daily dose.
Less than 20 kg weight: Safety and efficacy have not been established.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Mechanism Of Action
In patients who are homozygous for cystinuria, cystine stones form as a result of poor aqueous solubility of cystine and urinary supersaturation of cystine. When treating cystinuria, the goal of therapy is to reduce urinary cystine concentration to below its solubility limit. Dietary modifications and high fluid intake may be effective at reducing cystine formation and decreasing urinary cystine concentration; however, for some patients with severe cystinuria, more aggressive treatment with d-penicillamine or tiopronin is necessary. Tiopronin is an active reducing and complexing thiol compound that undergoes thiol-disulfide exchange with cystine, thus forming a more water-soluble compound (i.e., thiol-cysteine).
Since there are no known inhibitors of the crystallization of cystine, cystine stone formation is determined primarily by the urinary supersaturation of cystine. Thus, cystine stones could theoretically form whenever urinary cystine concentration exceeds the solubility limit. Cystine solubility in urine is pH-dependent, and ranges from 170 to 300 mg/L at pH 5, to 190 to 400 mg/L at pH 7, and 220 to 500 mg/L at pH 7.5. The addition of tiopronin to the conservative regimen of increased fluid intake, alkalinization of the urine, and dietary modification further decreases cystine concentrations in the urine. The decrement in urinary cystine produced by tiopronin is generally proportional to the dose. A reduction in urinary cystine of 250 to 350 mg/day at a tiopronin dosage of 1 gram/day, and a decline of approximately 500 mg/day at a dosage of 2 grams/day, might be expected.
Pharmacokinetics
Tiopronin is administered orally. Up to 48% of an oral dose is excreted in the urine during the first 4 hours, and up to 78% is excreted in the urine by 72 hours. 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 discontinuation.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None
When tiopronin immediate-release (IR) and tiopronin enteric coated delayed-release (EC) tablet 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 to 6) hours, respectively. The peak exposure (Cmax) and total exposure (AUC) of tiopronin from tiopronin EC tablets were decreased by 22% and 7%, respectively, compared to tiopronin IR tablets. Administration of the tiopronin EC tablet with food decreases Cmax of tiopronin by 13% and exposure by 25% compared to tiopronin EC administered in a fasted state. Since the drug is dosed to effect, the data support administration of tiopronin EC tablets with or without food.
After the administration of crushed tiopronin EC tablets in applesauce, the Tmax was 1 hour (range: 0.5 to 2) compared to 3.1 hours (range: 1.5 to 4) when administered as intact EC tablets. The Cmax and AUC increased by 38% and 14%, respectively, compared to intact tiopronin EC tablets.
Pregnancy And Lactation
Available published case report data with tiopronin in pregnancy have not identified a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, there were no adverse developmental outcomes with oral administration of tiopronin to pregnant mice and rats during organogenesis at doses of up to 2 times the 2 grams/day highest recommended oral human dose (based on mg/m2). High doses of tiopronin in experimental animals have been shown to interfere with maintenance of pregnancy and viability of the fetus. Renal stones in pregnancy may increase the risk of adverse pregnancy outcomes, such as preterm birth and low birth weight.[42024]
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 breast-feeding is not recommended during treatment with tiopronin.[42024]