TABLOID brand Thioguanine is indicated for remission induction and remission consolidation treatment of acute nonlymphocytic leukemias. However, it is not recommended for use during maintenance therapy or similar long-term continuous treatments due to the high risk of liver toxicity (see WARNINGS and ADVERSE REACTIONS).
The response to this agent depends upon the age of the patient (younger patients faring better than older) and whether thioguanine is used in previously treated or previously untreated patients. Reliance upon thioguanine alone is seldom justified for initial remission induction of acute nonlymphocytic leukemias because combination chemotherapy including thioguanine results in more frequent remission induction and longer duration of remission than thioguanine alone.
TABLOID brand Thioguanine is not effective in chronic lymphocytic leukemia, Hodgkin’s lymphoma, multiple myeloma, or solid tumors. Although thioguanine is one of several agents with activity in the treatment of the chronic phase of chronic myelogenous leukemia, more objective responses are observed with MYLERAN® (busulfan), and therefore busulfan is usually regarded as the preferred drug.
Thioguanine should not be used in patients whose disease has demonstrated prior resistance to this drug. In animals and humans, there is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine.
SINCE DRUGS USED IN CANCER CHEMOTHERAPY ARE POTENTIALLY HAZARDOUS, IT IS RECOMMENDED THAT ONLY PHYSICIANS EXPERIENCED WITH THE RISKS OF THIOGUANINE AND KNOWLEDGEABLE IN THE NATURAL HISTORY OF ACUTE NONLYMPHOCYTIC LEUKEMIAS ADMINISTER THIS DRUG.
THIOGUANINE IS NOT RECOMMENDED FOR MAINTENANCE THERAPY OR SIMILAR LONG-TERM CONTINUOUS TREATMENTS DUE TO THE HIGH RISK OF LIVER TOXICITY ASSOCIATED WITH VASCULAR ENDOTHELIAL DAMAGE (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS). This liver toxicity has been observed in a high proportion of children receiving thioguanine as part of maintenance therapy for acute lymphoblastic leukemia and in other conditions associated with continuous use of thioguanine. This liver toxicity is particularly prevalent in males. Liver toxicity usually presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or with signs of portal hypertension (splenomegaly, thrombocytopenia, and oesophageal varices). Histopathological features associated with this toxicity include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis.
Thioguanine therapy should be discontinued in patients with evidence of liver toxicity as reversal of signs and symptoms of liver toxicity have been reported upon withdrawal.
Patients must be carefully monitored (see PRECAUTIONS, Laboratory Tests). Early indications of liver toxicity are signs associated with portal hypertension such as thrombocytopenia out of proportion with neutropenia and splenomegaly. Elevations of liver enzymes have also been reported in association with liver toxicity but do not always occur.
The most consistent, dose-related toxicity is bone marrow suppression. This may be manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. Any one of these findings may also reflect progression of the underlying disease. Since thioguanine may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an abnormally large fall in any of the formed elements of the blood.
Evaluate patients with repeated severe myelosuppression for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency. TPMT genotyping or phenotyping (red blood cell TPMT activity) and NUDT15 genotyping can identify patients who have reduced activity of these enzymes. Patients with homozygous TPMT or NUDT15 deficiency require substantial dosage reductions. Bone marrow suppression could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, or sulphasalazine.
It is recommended that evaluation of the hemoglobin concentration or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained frequently while the patient is on thioguanine therapy. In cases where the cause of fluctuations in the formed elements in the peripheral blood is obscure, bone marrow examination may be useful for the evaluation of marrow status. The decision to increase, decrease, continue, or discontinue a given dosage of thioguanine must be based not only on the absolute hematologic values, but also upon the rapidity with which changes are occurring. In many instances, particularly during the induction phase of acute leukemia, complete blood counts will need to be done more frequently in order to evaluate the effect of the therapy. The dosage of thioguanine may need to be reduced when this agent is combined with other drugs whose primary toxicity is myelosuppression.
Myelosuppression is often unavoidable during the induction phase of adult acute nonlymphocytic leukemias if remission induction is to be successful. Whether or not this demands modification or cessation of dosage depends both upon the response of the underlying disease and a careful consideration of supportive facilities (granulocyte and platelet transfusions) which may be available. Life-threatening infections and bleeding have been observed as consequences of thioguanine-induced granulocytopenia and thrombocytopenia.
The effect of thioguanine on the immunocompetence of patients is unknown.
Pregnancy Category D. Drugs such as thioguanine are potential mutagens and teratogens. Thioguanine may cause fetal harm when administered to a pregnant woman. Thioguanine has been shown to be teratogenic in rats when given in doses 5 times the human dose. When given to the rat on the 4th and 5th days of gestation, 13% of surviving placentas did not contain fetuses, and 19% of offspring were malformed or stunted. The malformations noted included generalized edema, cranial defects, and general skeletal hypoplasia, hydrocephalus, ventral hernia, situs inversus, and incomplete development of the limbs. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Although the primary toxicity of thioguanine is myelosuppression, other toxicities have occasionally been observed, particularly when thioguanine is used in combination with other cancer chemotherapeutic agents.
A few cases of jaundice have been reported in patients with leukemia receiving thioguanine. Among these were 2 adult male patients and 4 pediatric patients with acute myelogenous leukemia and an adult male with acute lymphocytic leukemia who developed hepatic veno-occlusive disease while receiving chemotherapy for their leukemia. Six patients had received cytarabine prior to treatment with thioguanine, and some were receiving other chemotherapy in addition to thioguanine when they became symptomatic. While hepatic veno-occlusive disease has not been reported in patients treated with thioguanine alone, it is recommended that thioguanine be withheld if there is evidence of toxic hepatitis or biliary stasis, and that appropriate clinical and laboratory investigations be initiated to establish the etiology of the hepatic dysfunction. Deterioration in liver function studies during thioguanine therapy should prompt discontinuation of treatment and a search for an explanation of the hepatotoxicity.
Administration of live vaccines to immunocompromised patients should be avoided.
Patients should be informed that the major toxicities of thioguanine are related to myelosuppression, hepatotoxicity, and gastrointestinal toxicity. Patients should never be allowed to take the drug without medical supervision and should be advised to consult their physician if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia. Women of childbearing potential should be advised to avoid becoming pregnant.
Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities or repeated episodes of myelosuppression. (see WARNINGS).
It is advisable to monitor liver function tests (serum transaminases, alkaline phosphatase, bilirubin) at weekly intervals when first beginning therapy and at monthly intervals thereafter. It may be advisable to perform liver function tests more frequently in patients with known pre-existing liver disease or in patients who are receiving thioguanine and other hepatotoxic drugs. Patients should be instructed to discontinue thioguanine immediately if clinical jaundice is detected (see WARNINGS).
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