Thiola (tiopronin) Adverse Reactions

About Thiola^®

Some patients may develop drug fever, usually during the first month of therapy. Thiola^® treatment should be discontinued until the fever subsides. It may be reinstated at a small dose, with a gradual increase in dosage until the desired level is achieved.

A generalized rash (erythematous, maculopapular or morbilliform) accompanied by pruritis may develop during the first few months of treatment. It may be controlled by antihistamine therapy, typically recedes when Thiola^® treatment is discontinued, and seldom recurs when Thiola^® treatment is restarted at a lower dosage. Less commonly, rash may appear late in the course of treatment (of more than 6 months). Located usually in the trunk, the late rash is associated with intense pruritis, recedes slowly after discontinuing treatment, and usually recurs upon resumption of treatment.

A drug reaction simulating lupus erythematous, manifested by fever, arthralgia and lymphadenopathy may develop. It may be associated with a positive antinuclear antibody test, but not necessarily with nephropathy. It may require discontinuance of Thiola^® treatment.

A reduction in taste perception may develop. It is believed to be the result of chelation of trace metals by Thiola^®. Hypogeusia is often self-limiting.

Unlike during d-penicillamine therapy, vitamin B6 deficiency is uncommonly associated with Thiola^® treatment.

Some patients may complain of wrinkling and friability of skin. This complication usually occurs after long-term treatment, and is believed to result from the effect of Thiola^® on collagen.

A multiclinic trial involving 66 cystinuric patients in the United States indicated that Thiola^® is associated with fewer or less severe adverse reactions than d-penicillamine. Among those who had to stop taking d-penicillamine due to toxicity, 64.7% could take Thiola^®. In those without prior history of d-penicillamine treatment, only 5.9% developed reactions of sufficient severity to require Thiola^® withdrawal. A review of available literature supports the findings from this trial.

Despite this apparent reduced toxicity to Thiola^® relative to d-penicillamine, Thiola^® treatment may potentially be associated with all the adverse reactions reported with d-penicillamine. They include: Gastrointestinal side-effects (nausea, emesis, diarrhea or softstools, anorexia, abdominal pain, bloating or flatus) in about 1 in 6 patients; Impairment in taste and smell in about 1 in 25 patients; Dermatologic complications (pharyngitis, oral ulcers, rash, ecchymosis, prurites, uritcaria, warts, skin wrinkling, pemphigus, elastosis perforans serpiginosa) in about 1 in 6 patients; Hypersensitivity reactions (laryngeal edema, dyspnea, respiratory distress, fever, chills, arthralgia, weakness, fatigue, myalgia, adenopathy) in about 1 in 25 patients; Hematologic abnormalities (increased bleeding, anemia, leukopenia, thrombocytopenia, eosinophilia) in about 1 in 25 patients; Renal complications (proteinuria, nephrotic syndrome, hematuria) in about 1 in 20 patients; Pulmonary manifestations (bronchiolitis, hemoptysis, pulmonary infiltrates, dyspnea) in about 1 in 50 patients; Neurologic complications (myasthenic syndrome) in about 1 in 50 patients.

These reactions are more likely to develop during Thiola^® therapy among patients who had previously shown toxicity to d-penicillamine.

In patients who had previously manifested adverse reactions to d-penicillamine, adverse reactions to Thiola^® are more likely to occur than in patients who took Thiola^® for the first time. A close supervision with a careful monitoring of potential side effects is mandatory during Thiola^® treatment. Patients should be told to report promptly any symptoms suggesting toxicity. The treatment with Thiola^® should be stopped if severe toxicity develops.

Jaundice and abnormal liver function tests have been reported during Thiola^® therapy for non-cystinuric conditions. A direct cause and effect relationship, based upon these foreign reports, has not been established. Although such complications were not encountered in the small multi-center trials in the United States, patients should be carefully monitored and if any abnormalities are noted, the drug should be discontinued and the patient treated by appropriate measures.

Thiola® is a prescription drug that helps prevent cystine (kidney) stones from forming in patients who are resistant to treatment with a modified diet and high fluid intake, or patients who have adverse reactions to the drug d-penicillamine.

Important Safety Information

Thiola® is not for everyone. Its safety and effectiveness have not been established for patients under the age of 9, and there are no adequate and well-controlled studies in pregnant women.

Do not take Thiola® if you are pregnant or may become pregnant, unless your doctor has discussed the risks with you and determined that the prevention of stones outweighs possible risks to the fetus. If you are nursing, Thiola® may pass through your breast milk and lead to potentially serious side effects for your infant, so you should not breastfeed while taking Thiola®.

High doses of Thiola® in laboratory animals have been shown to interfere with pregnancy and survival of the fetus. Additionally, d-penicillamine has been shown to cause birth defects in animals at very high doses, so although these results were not found with Thiola®, a similar outcome is possible. No long-term animal studies have been done to examine the cancer-causing potential of Thiola®, so you should discuss the risks with your doctor and only take Thiola® if it is necessary.

Do not take Thiola® if you have a history of blood disorders such as aplastic anemia (a condition in which the body does not produce enough new blood cells), agranulocytosis (a disorder characterized by a drop in white blood cells called granulocytes), or thrombocytopenia (an abnormal decrease in the number of platelets).

If you take Thiola®, your doctor may conduct a variety of blood and urine tests to check for possible complications and perform annual abdominal scans to monitor the size and appearance of stones.

Some patients may develop a drug-induced fever while taking Thiola®, usually during the first month of treatment. If this occurs, talk with your doctor and discontinue use until the fever subsides. Your doctor may instruct you to begin taking a small dose, and then increase it gradually until you reach the appropriate dosage.

You may notice a reduced sense of taste while taking Thiola®. Some patients also experience wrinkling or fragile skin after long-term treatment.

Other side effects of Thiola® may include a generalized rash accompanied by itching, which typically occur during the first few months of treatment. Antihistamines can help reduce the itching, and the rash will normally disappear once you stop taking Thiola®. Less often, patients who take Thiola® for more than 6 months may develop a rash late in the course of treatment. This rash is usually located on the upper body and associated with intense itching. It typically goes away slowly after discontinuing treatment and returns after re-starting treatment.

No deaths have been reported as a result of Thiola® treatment; however, a fatal outcome has been reported with certain complications of d-penicillamine therapy, including reduced white blood cells, red blood cells, or platelets; Goodpasture's syndrome (an autoimmune disorder that affects the lungs and kidneys); and myasthenia gravis (an autoimmune disorder characterized by muscle weakness). Do not take Thiola® if you have a history of these conditions.

Seek immediate medical attention and discontinue use if you notice symptoms such as fever, sore throat, chills, bleeding, easy bruisability, coughing up blood, muscle weakness, blistering or raw areas on the skin or mucous membranes, joint pain, swelling of the lymph nodes, or swelling in your legs, as these may be signs of a serious reaction to the drug.

Although Thiola® is reportedly less toxic than d-penicillamine, it could potentially cause all the side effects reported for d-penicillamine. Additional side effects might include a reduced sense of smell, throat inflammation, nausea, vomiting, diarrhea or soft stools, loss of appetite, abdominal pain, bloating, gas, oral ulcers, hives, warts, swelling of the throat, difficulty breathing, respiratory distress, fatigue, muscle pain, swelling or fluid build-up in the lungs, and blood or high amounts of protein in urine. These reactions are more likely to develop during Thiola® therapy among patients who had previous reactions to d-penicillamine. Talk to your doctor about any unusual side effects.

Jaundice and abnormal liver function tests were reported during Thiola® treatment for conditions unrelated to cystine stones, however, these results were not directly linked to Thiola®.

To report negative side effects, contact Mission Pharmacal Company at 1-800-298-1087 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.