Tabloid thioguanine 40 mg Tablet, 25-count — NDC 80725-630-25 (Billing 80725-0630-25)

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.… [Excerpted — this section continues on DailyMed.]

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.

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).

PRECAUTIONS General 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. Information for Patients 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. Laboratory Tests Prescribers should be aware that some laboratories offer testing for TPMT deficiency (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). 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). Carcinogenesis, Mutagenesis, Impairment of Fertility In view of its action on cellular DNA, thioguanine is potentially mutagenic and carcinogenic, and consideration should be given to the theoretical risk of carcinogenesis when thioguanine is administered (see WARNINGS). Pregnancy Teratogenic Effects: See WARNINGS section.

Lactation It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity shown for thioguanine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use See DOSAGE AND ADMINISTRATION section.

Geriatric Use Clinical studies of thioguanine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardia… [Excerpted — this section continues on DailyMed.]