Version May 2024
Prevention of nephrolithiasis (cystine): Oral:
Initial: 800 mg/day in 3 divided doses; average dose: 1,000 mg/day. Consider a lower initial dose in patients with history of severe toxicity to d-penicillamine.
Maintenance: Adjust dose to reduce urinary cystine level to <250 mg/L.
Proteinuria: Discontinue therapy; monitor urinary protein and renal function. May consider restarting therapy at a lower dosage after resolution of proteinuria.
Refer to adult dosing.
(For additional information see "Tiopronin: Pediatric drug information")
Prevention of nephrolithiasis (cystine): Limited data available in patients weighing <20 kg: Note: Use in combination with high fluid intake, alkali, and diet modification; consider initiating at lower doses in patients with a history of severe toxicity to d-penicillamine:
Children ≥2 years and Adolescents: Immediate-release tablet (eg, Thiola), delayed-release tablets (eg, Thiola EC): Oral: Initial: 15 mg/kg/day in 3 divided doses; titrate dose to reduce urinary cysteine level to <250 mg/L. Maximum daily dose: 50 mg/kg/day. In one trial, patients with cystinuria (n=18, ages: 1.8 to 24 years), 16 patients received tiopronin in combination with urinary alkalinization to prevent nephrolithiasis or reduce size of current stones. Mean dose required was 24.65 mg/kg/day (range: 13.8 to 51 mg/kg/day). Older children required lower mg/kg dosing than younger (smaller) children. Stone episodes decreased from 0.28 per year to 0.03 per year and several had reductions in size and number of pre-existing stones (Ref).
Dosing adjustment for toxicity:
Proteinuria: Discontinue tiopronin in patients who develop proteinuria; once proteinuria resolves, consider resuming at a lower dose.
There are no dosage recommendations provided in the manufacturer's labeling.
There are no dosage recommendations provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Central nervous system: Fatigue (14%)
Dermatologic: Skin rash (12% to 14%)
Gastrointestinal: Nausea (12% to 25%), oral mucosa ulcer (12% to 18%), diarrhea (6% to 18%)
Neuromuscular & skeletal: Arthralgia (12%), asthenia (4% to 12%)
1% to 10%:
Cardiovascular: Chest pain (6%), peripheral edema (6%)
Dermatologic: Urticaria (8%), ecchymoses (6%), wrinkling of skin (6%), pruritus (4% to 6%)
Gastrointestinal: Vomiting (10%), anorexia (8%), abdominal pain (6%)
Genitourinary: Proteinuria (6% to 10%), impotence (6%)
Hematologic & oncologic: Anemia (2% to 6%)
Respiratory: Cough (6%)
Miscellaneous: Fever (8%)
Postmarketing: Abdominal distension, abdominal distress, ageusia, back pain, burning sensation, cardiac failure, cheilosis, decreased appetite, decreased estimated GFR (eGFR), dehydration, dermatologic disorders (abnormal skin texture), dizziness, dysgeusia, dyspepsia, eructation, flank pain, flatulence, gastroesophageal reflux disease, gastrointestinal disease, headache, hyperhidrosis, hypersensitivity reaction, hypoesthesia, increased serum transaminases, jaundice, joint swelling, limb pain, malaise, membranous glomerulonephritis, musculoskeletal pain, myalgia, neck pain, nephrotic syndrome, pain, pemphigus foliaceus, renal failure syndrome, skin irritation, swelling, vertigo, weight gain, xeroderma, xerostomia
Hypersensitivity to tiopronin or any component of the formulation.
Concerns related to adverse effects:
• Goodpasture syndrome: Tiopronin is structurally similar to penicillamine. Penicillamine has rarely been associated with fatalities due to Goodpasture syndrome; therefore, the potential of Goodpasture syndrome in tiopronin-treated patients is possible; discontinue therapy if signs or symptoms occur.
• Hematologic effects: Tiopronin is structurally similar to penicillamine. Penicillamine has been associated with hematologic toxicities. Signs of toxicity include leukopenia without eosinophilia and thrombocytopenia. Advise patients to report early signs and symptoms including fever, sore throat, mouth ulcers, infections, easy bruising, or petechial or purpuric hemorrhage. Therapy should be discontinued if platelet count falls to <100,000/mm3 or WBC <3,500/mm3.
• Hypersensitivity: Hypersensitivity reactions (drug fever, rash, fever, arthralgia, and lymphadenopathy) have been reported.
• Myasthenia gravis: Tiopronin is structurally similar to penicillamine. Penicillamine has rarely been associated with fatalities due to myasthenia gravis; therefore, the potential of myasthenia gravis in tiopronin-treated patients is possible; discontinue therapy if signs or symptoms occur.
• Pemphigus: Tiopronin is structurally similar to penicillamine. Penicillamine has been associated with pemphigus. Discontinue treatment if pemphigus-type reactions occur; additional therapy may be needed.
• Proteinuria: Proteinuria, including nephrotic syndrome and membranous nephropathy, have been reported. Risk may be increased in pediatric patients receiving >50 mg/kg/day. Monitor for the development of proteinuria; interrupt therapy in patients who develop proteinuria.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Thiola: 100 mg
Generic: 100 mg
Tablet Delayed Release, Oral:
Thiola EC: 100 mg, 300 mg
May be product dependent
Tablet, EC (Thiola EC Oral)
100 mg (per each): $33.85
300 mg (per each): $101.55
Tablets (Thiola Oral)
100 mg (per each): $33.85
Tablets (Tiopronin Oral)
100 mg (per each): $32.16
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Oral:
Delayed release tablets: Administer consistently with or without regard to meals. For patients unable to swallow tablet whole, tablet may be crushed and mixed with applesauce; administration with other liquids or foods is not recommended (has not been studied). Crush 1 tablet at a time (in a pill crusher or mortar and pestle) and mix with ~1 tablespoonful of applesauce until powder is well dispersed. Administer mixture immediately (or mixture may be stored in refrigerator for ≤2 hours). To ensure applesauce mixture is consumed, add tap water to the mixture container, mix, and have patient drink the water.
IR tablets: Administer 1 hour before or 2 hours after meals.
Oral: High daily fluid intake should continue while taking tiopronin.
Immediate release (eg, Thiola): Administer 1 hour before or 2 hours after meals; administer at the same times each day.
Delayed release (eg, Thiola EC): Administer with or without food; however, it is recommended to be consistent with regards to meals. For patients unable to swallow tablet whole, tablet may be crushed and mixed with applesauce; administration with other liquids or foods is not recommended (has not been studied). Crush 1 tablet at a time (in a pill crusher or with mortar and pestle); mix crushed tablet with ~1 tablespoonful of applesauce until powder is well dispersed. Administer mixture immediately (or mixture may be stored in refrigerator for ≤2 hours). Add tap water to any leftover applesauce mixture remaining in the container and have patient consume.
Nephrolithiasis (cystine), prevention: Prevention of cystine stone formation in adults and pediatric patients ≥20 kg with severe homozygous cystinuria who are resistant to treatment with high fluid intake, alkali, and diet modification.
Note: Based on the American Urologic Association (AUA) guidelines for the medical management of kidney stones, tiopronin is recommended as the agent of choice for the prevention of recurrent cystine stones in patients that are unresponsive to increased fluid intake, restriction of sodium and protein intake, and urinary alkalinization or who have large recurrent stone burdens (AUA [Pearle 2014]; Pak 1986).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May increase the bioavailability of Tiopronin. Risk C: Monitor therapy
Tiopronin is released faster from delayed-release tablets in the presence of alcohol, and the risk for adverse events when taken with alcohol is unknown. Management: Avoid alcohol 2 hours before and 3 hours after taking delayed-release tablets.
Adverse events have not been observed in animal reproduction studies.
It is not known if tiopronin is present in breast milk.
Tiopronin can decrease prolactin concentrations, which may decrease milk production in lactating women (Akrivis 2000). Breastfeeding is not recommended by the manufacturer.
IR tablets should be taken 1 hour before or 2 hours after meals. Tiopronin EC can be taken with or without food; however, it is important to keep consistency with regard to food.
Renal function, 24-hour urinary protein and urinalysis at baseline then every 3 to 6 months, urinary cystine 1 month after treatment begins then every 3 months; monitor for stone formation (eg, X-ray, ultrasound).
As an active reducing agent, tiopronin undergoes thiol-disulfide exchange with cystine to form tiopronin-cystine disulfide, which is more water soluble than cystine. As a result, the amount of sparingly soluble cystine in the urine is decreased and the formation of cystine calculi is reduced.
Note: Delayed release tablets: Cmax and AUC increased by 38% and 14%, respectively, when administered crushed in applesauce compared to intact tablets.
Onset: Rapid.
Time to peak, plasma:
Delayed release (intact tablets): 3 hours (median) (range: 1 to 6 hours).
Delayed release (crushed; mixed in applesauce): 1 hour (median) (range: 0.5 to 2 hours).
Immediate release: 1 hour (median) (range: 0.5 to 2.1 hours).
Excretion: Urine (48% within 4 hours; 78% within 72 hours).
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