d 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.
Overdosage
Signs and symptoms of overdosage may be immediate, such as nausea, vomiting, malaise, hypotension, and diaphoresis; or delayed, such as myelosuppression and azotemia. It is not known whether Thioguanine is dialyzable. Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation of Thioguanine into active metabolites with long persistence. The oral LD50 of Thioguanine was determined to be 823 mg/kg ± 50.73 mg/kg and 740 mg/kg ± 45.24 mg/kg for male and female rats, respectively. Symptoms of overdosage may occur after a single dose of as little as 2.0 to 3.0 mg/kg Thioguanine. As much as 35 mg/kg has been given in a single oral dose with reversible myelosuppression observed. There is no known pharmacologic antagonist of Thioguanine. The drug should be discontinued immediately if unintended toxicity occurs during treatment. Severe hematologic toxicity may require supportive therapy with platelet transfusions for bleeding, and granulocyte transfusions and antibiotics if sepsis is documented. If a patient is seen immediately following an accidental overdosage of the drug, it may be useful to induce emesis.
Thioguanine 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.
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 (see WARNINGS). Prescribers should be aware that some laboratories offer testing for TPMT deficiency.
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 proto |
