TABLOID

INDICATIONS AND USAGE a) Acute Nonlymphocytic Leukemias 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. b) Other Neoplasms 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.

DOSAGE AND ADMINISTRATION TABLOID brand Thioguanine is administered orally. The dosage which will be tolerated and effective varies according to the stage and type of neoplastic process being treated. Because the usual therapies for adult and pediatric acute nonlymphocytic leukemias involve the use of thioguanine with other agents in combination, physicians responsible for administering these therapies should be experienced in the use of cancer chemotherapy and in the chosen protocol. Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency. Most of the patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reduction. Reduce the dosage based on tolerability. Ninety-six (59%) of 163 pediatric patients with previously untreated acute nonlymphocytic leukemia obtained complete remission with a multiple-drug protocol including thioguanine, prednisone, cytarabine, cyclophosphamide, and vincristine. Remission was maintained with daily thioguanine, 4-day pulses of cytarabine and cyclophosphamide, and a single dose of vincristine every 28 days. The median duration of remission was 11.5 months. Fifty-three percent of previously untreated adults with acute nonlymphocytic leukemias attained remission following use of the combination of thioguanine and cytarabine according to a protocol developed at The Memorial Sloan-Kettering Cancer Center. A median duration of remission of 8.8 months was achieved with the multiple-drug maintenance regimen which included thioguanine. On those occasions when single-agent chemotherapy with thioguanine may be appropriate, the usual initial dosage for pediatric patients and adults is approximately 2 mg/kg of body weight per day. If, after 4 weeks on this dosage, there is no clinical improvement and no leukocyte or platelet depression, the dosage may be cautiously increased to 3 mg/kg/day. The total daily dose may be given at one time. The dosage of thioguanine used does not depend on whether or not the patient is receiving ZYLOPRIM (allopurinol); this is in contradistinction to the dosage reduction which is mandatory when PURINETHOL ( mercaptopurine ) or IMURAN (azathioprine) is given simultaneously with allopurinol . Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

CONTRAINDICATIONS 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.

WARNINGS 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. There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effects of thioguanine and prone to developing rapid bone marrow suppression following the initiation of treatment. Substantial dosage reductions may be required to avoid the development of life-threatening bone marrow suppression in these patients. Prescribers should be aware that some laboratories offer testing for TPMT deficiency. Since bone marrow suppression may be associated with factors other than TPMT deficiency, TPMT testing may not identify all patients at risk for severe toxicity. Therefore, close monitoring of clinical and hematologic parameters is important. 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 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.

Drug Interactions There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy (see WARNINGS).

ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Waylis Therapeutics LLC Toll-Free at 1-888-514-4727 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . The most frequent adverse reaction to thioguanine is myelosuppression. The induction of complete remission of acute myelogenous leukemia usually requires combination chemotherapy in dosages which produce marrow hypoplasia. Since consolidation and maintenance of remission are also effected by multiple-drug regimens whose component agents cause myelosuppression, pancytopenia is observed in nearly all patients. Dosages and schedules must be adjusted to prevent life-threatening cytopenias whenever these adverse reactions are observed. Hyperuricemia frequently occurs in patients receiving thioguanine as a consequence of rapid cell lysis accompanying the antineoplastic effect. Adverse effects can be minimized by increased hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase inhibitor such as ZYLOPRIM ® (allopurinol). Unlike PURINETHOL (mercaptopurine) and IMURAN ® (azathioprine), thioguanine may be continued in the usual dosage when allopurinol is used conjointly to inhibit uric acid formation. Less frequent adverse reactions include nausea, vomiting, anorexia, and stomatitis. Intestinal necrosis and perforation have been reported in patients who received multiple-drug chemotherapy including thioguanine. Hepatic Effects Liver toxicity associated with vascular endothelial damage has been reported when thioguanine is used in maintenance or similar long-term continuous therapy which is not recommended (see WARNINGS and DOSAGE AND ADMINISTRATION). This usually presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or signs and symptoms of portal hypertension (splenomegaly, thrombocytopenia, and esophageal varices). Elevation of liver transaminases, alkaline phosphatase, and gamma glutamyl transferase and jaundice may also occur. Histopathological features associated with this toxicity include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis. Liver toxicity during short-term cyclical therapy presents as veno-occlusive disease. Reversal of signs and symptoms of this liver toxicity has been reported upon withdrawal of short-term or long-term continuous therapy. Centrilobular hepatic necrosis has been reported in a few cases; however, the reports are confounded by the use of high doses of thioguanine, other chemotherapeutic agents, and oral contraceptives and chronic alcohol abuse.

Pregnancy 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. Pregnancy Teratogenic Effects: See WARNINGS section.