Tiopronin is an oral agent, also known as alpha-mercaptopropionylglycine (alpha-MPG), that is used to prevent cystine kidney stones. It is used for the prevention of nephrolithiasis due to severe homozygous cystinuria in combination with high fluid intake, alkali, and diet modification in adult and pediatric patients who are not responsive to these measures alone. Similar to d-penicillamine, tiopronin forms a more water-soluble complex with cystine, resulting in a decrease in the amount of sparingly soluble cystine in the urine. Compared to d-penicillamine, tiopronin is associated with fewer and less severe adverse reactions. However, serious adverse reactions and toxicity related to tiopronin are more likely to appear if the patient has a history of toxicity to d-penicillamine.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
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 to tiopronin are more likely to develop in patients who developed toxicities to d-penicillamine. According to data from a small, multicenter trial (n = 66), tiopronin may be associated with fewer or less severe adverse reactions than d-penicillamine. Among those who had to terminate d-penicillamine therapy due to toxicity, 64.7% could take tiopronin. In those without prior history of d-penicillamine treatment, only 5.9% developed reactions of sufficient severity to require tiopronin withdrawal.
In the clinical trial with tiopronin, anemia was reported in 2% of patients who had been previously treated with d-penicillamine and 6% of patients who were naive to d-penicillamine.
Proteinuria, nephrotic syndrome, and membranous nephropathy (membranous glomerulonephritis) have been reported with tiopronin use. In the clinical trial with tiopronin, proteinuria was reported in 10% of patients who had been previously treated with d-penicillamine and 6% of patients who were naive to d-penicillamine. Renal failure (unspecified) and decreased glomerular filtration rate have been reported during postmarketing use of tiopronin. Assess patients for proteinuria before starting treatment, and every 3 to 6 months during treatment. If a patient develops proteinuria during treatment, discontinuation of the drug is recommended.
In the clinical trial with tiopronin, chest pain (unspecified) was reported in 6% of patients who were naive to d-penicillamine. Peripheral edema was reported in 6% of patients who had been previously treated with d-penicillamine and 6% of patients who were naive to d-penicillamine. Congestive heart failure and chest pain (unspecified) have been reported during postmarketing experience with tiopronin.
Arthralgia (12%), fatigue (14%), and weakness (4% to 12%) were reported in the clinical trial with troponin. Arthralgia may occur as part of a hypersensitivity reaction to the drug. Adverse reactions reported during postmarketing experience with troponin include: arthralgia, back pain, flank pain, joint swelling, limb discomfort, musculoskeletal pain, myalgia, neck pain, pain in extremity, burning sensation, dizziness, headache, hypoesthesia, vertigo, asthenia, fatigue, malaise, pain, peripheral swelling, pyrexia, and swelling.
Hypersensitivity reactions (drug fever, rash, fever, arthralgia, and lymphadenopathy) have been reported during tiopronin therapy. During the tiopronin clinical trial, a rash was reported in 14%, urticaria was reported in 8%, and pruritus was reported in 4% of patients previously treated with d-penicillamine. Rash was reported in 12% and pruritus was reported in 6% of tiopronin-treated patients naive to d-penicillamine therapy. Fever was reported in 8% of tiopronin treated patients who had been previously treated with d-penicillamine, but none of the patients naive to d-penicillamine. During postmarketing experience with troponin, the following were reported: pruritus, rash, pruritic rash, and urticaria.
During the clinical trial with tiopronin, ecchymosis (6%) and skin wrinkling (6%) were reported. During postmarketing experience with troponin, the following additional dermatologic adverse reactions were reported: xerosis, hyperhidrosis, pemphigus foliaceus, skin irritation, abnormal skin texture, and skin wrinkling.
Dysgeusia may develop during tiopronin treatment, but the hypogeusia is often self-limiting. Chelation of trace metals by tiopronin is believed to be the cause of the taste disturbance. Furthermore, ageusia has been reported during postmarketing experience.
Gastrointestinal-related adverse reactions have been reported in patients treated with tiopronin, including: nausea (12% to 25%), vomiting (10%), diarrhea or soft stools (6% to 18%), abdominal pain (6%), anorexia (8%), and oral ulceration (12% to 18%). The following GI adverse reactions were reported during postmarketing experience with tiopronin: abdominal discomfort, abdominal distension, abdominal pain, chapped lips, diarrhea, xerostomia, dyspepsia, eructation, flatulence, gastrointestinal disorder, gastroesophageal reflux disease, nausea, vomiting, decreased appetite, dehydration, weight gain, and hypophagia (dysphagia).
Jaundice and liver transaminitis (elevated hepatic enzymes) have been reported during postmarketing experience with tiopronin.
Cough was reported in 6% of patients receiving tiopronin who were naive to d-penicillamine.
Impotence (erectile dysfunction) was reported in 1 male (6%) receiving tiopronin during clinical trials who was naive to d-penicillamine. 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.
Tiopronin is contraindicated in patients with a known tiopronin hypersensitivity or any hypersensitivity to any of its inactive ingredients. Hypersensitivity reactions (drug fever, rash, fever, arthralgia and lymphadenopathy) have been reported.
Routine, periodic urinalysis is suggested to help early detection of renal complications during tiopronin therapy. Proteinuria, including nephrotic syndrome and membranous nephropathy (glomerulonephritis), can occur with tiopronin therapy. These reactions may be more common in patients who have had serious reactions to d-penicillamine. Pediatric patients receiving greater than 50 mg/kg of tiopronin per day may be at increased risk for proteinuria. Discontinue tiopronin in patients who develop proteinuria and monitor urinary protein and renal function. Consider restarting tiopronin treatment at a lower dosage after the resolution of proteinuria.
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.
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.
Tiopronin is indicated in pediatric patients weighing 20 kg or more. Tiopronin is not approved for use in pediatric patients (neonates, infants, or children) weighing less than 20 kg or in those pediatric patients unable to swallow tablets. Proteinuria, including nephrotic syndrome, has been reported in pediatric patients; recommended doses should not be exceeded. Pediatric patients receiving greater than 50 mg/kg tiopronin per day may be at greater risk.
For the prevention of cystine nephrolithiasis due to severe homozygous cystinuria, in combination with high fluid intake, alkali, and diet modification in patients who are not responsive to these measures alone:
Oral dosage (e.g., tiopronin immediate-release tablet; e.g., Thiola):
Adults: 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.
Children and Adolescents weighing 20 kg or more: 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.
Oral dosage (gastro-resistant delayed-release tablets; e.g., Thiola EC):
Adults: 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.
Children and Adolescents of weighing 20 kg or more: 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.
Therapeutic Drug Monitoring:
Monitor for compliance with dietary and hydration recommendations and alkali therapy. Measure urinary cystine at baseline, at 1 month after starting treatment and every 3 months thereafter. Adjust therapy to maintain urinary cystine concentration less than 250 mg/L. When thiol-containing drugs such as tiopronin are used, a total urine cystine measurement is not as useful, because not only free but also bound cystine is measured, and the literature suggests using a test that also measures unbound (free) urinary cystine.
Assess for proteinuria before starting tiopronin treatment and every 3 to 6 months during treatment. Discontinue tiopronin in patients who develop proteinuria, and monitor urinary protein and renal function. Consider restarting tiopronin treatment at a lower dosage after resolution of proteinuria. Experts also recommend monitoring a complete blood count (CBC with differential) and liver function tests (LFTs) during tiopronin treatment.
A radiograph (X-ray) of the kidneys, ureters, and bladder (KUB), otherwise known as an abdominal roentgenogram, is advised every year to monitor the size and appearance/disappearance of stone(s). Other management may be suggested for these patients.
Maximum Dosage Limits:
-Adults
Usual maximum rarely exceeds 2,000 mg/day PO; literature reports up to 3,000 mg/day PO in some patients.
-Geriatric
Usual maximum rarely exceeds 2,000 mg/day PO; literature reports up to 3,000 mg/day PO in some patients.
-Adolescents
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.
-Children
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.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
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.
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
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.
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
-Route-Specific Pharmacokinetics
Oral Route
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.
-Special Populations
Renal Impairment
Tiopronin is substantially eliminated by the kidney. There are no specific data for renal impairment; the drug dose is titrated to clinical effect at reducing urinary cystine concentrations.