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Glaxo Wellcome
Antileukemic Agent
Action And Clinical Pharmacology: Thioguanine is a close relative of mercaptopurine and like the latter is an antimetabolite which blocks purine metabolism. It causes depletion of human bone marrow producing neutropenia, reticulopenia, anemia, thrombocytopenia, and prolongation of clotting time. The protracted but reversible aplasia of bone marrow closely resembles the effects of ionizing radiations. In man, thioguanine is extensively converted to 2-amino-6-methyl-mercaptopurine which is much less toxic and less effective than the parent compound. Unlike mercaptopurine and azathioprine, its metabolism is not inhibited by the xanthine oxidase inhibitor, allopurinol.

Thioguanine has multiple metabolic effects and at present it is not possible to designate one major site of action. Its tumor inhibitory properties may be due to one or more of its effects on (a) feedback inhibition of de novo purine synthesis; (b) inhibition of purine nucleotide interconversions; or (c) incorporation into the DNA and the RNA. The net consequence of its actions is a sequential blockade of the synthesis and utilization of the purine nucleotides.

Clinical studies have shown that the absorption of an oral dose of thioguanine in man is incomplete and variable, averaging approximately 30% of the administered dose (range: 14 to 46%). Following oral administration of 5-6-thioguanine, total plasma radioactivity reached a maximum at 8 hours and declined slowly thereafter. The parent drug represented only a very small fraction of the total plasma radioactivity at any time, being virtually undetectable throughout the period of measurements.

Thioguanine is extensively metabolized in vivo. There are 2 principal catabolic routes: methylation to 2-amino-6-methyl-thiopurine and deamination to 2-hydroxy-6-mercaptopurine, followed by oxidation to 6-thiouric acid. Deamination and subsequent oxidation to thiouric acid occurs only to a small extent. The product of deamination by guanase, 6-thioxanthine is inactive, having negligible antitumor activity. This pathway of thioguanine inactivation is not dependent on the action of xanthine oxidase, and an inhibitor of that enzyme (such as allopurinol) will not block the detoxification of thioguanine even though the inactive 6-thioxanthine is normally further oxidized by xanthine oxidase to thiouric acid before it is eliminated. The product of methylation, 2-amino-6-methylthiopurine, is also substantially less active and less toxic than thioguanine, and its formation is likewise unaffected by the presence of allopurinol. Appreciable amounts of inorganic sulfate are also found in urine, presumably arising from further metabolism of the methylated derivatives.

The oral administration of radiolabeled thioguanine revealed only trace quantities of parent drug in the urine. However, the methylated metabolite, 2-amino-6-methylthiopurine (MTG), appeared very early, rose to a maximum 6 to 8 hours after drug administration, and was still being excreted after 12 to 22 hours. Radiolabeled sulfate appeared somewhat later than MTG but was the principal metabolite after 8 hours. Thiouric acid and some unidentified products were found in the urine in small amounts.

Plasma levels decay biexponentially with initial and terminal half-lives of 3 and 5 to 9 hours respectively.

Thioguanine is incorporated into the DNA and the RNA of human bone marrow cells. Studies with i.v. 5-6-thioguanine have shown that the amount of thioguanine incorporated into nucleic acids is more than 100 times higher after 5 daily doses than after a single dose. With the 5-dose schedule, from one-half to virtually all of the guanine in the residual DNA was replaced by thioguanine. Tissue distribution studies of 5-6-thioguanine in mice showed only traces of radioactivity in the brain after oral administration. Thioguanine concentrations in human cerebrospinal fluid (CSF) have not been measured, but observations on tissue distribution in animals, together with the lack of CNS penetration by the closely related compound, mercaptopurine, suggest that thioguanine does not reach therapeutic concentrations in the CSF.

Monitoring of plasma levels of thioguanine during therapy is of questionable value. There is technical difficulty in determining plasma concentrations, which are seldom greater than 1 to 2 µg/mL after a therapeutic oral dose. More significantly, thioguanine enters rapidly into the anabolic and catabolic pathways for purines, and the active intracellular metabolites have appreciably longer half-lives than the parent drug. The biochemical effects of a single dose of thioguanine are evident long after the parent drug has disappeared from the plasma. Because of this rapid metabolism of thioguanine to active intracellular derivatives, hemodialysis would not be expected to appreciably reduce toxicity of the drug.

In some animal tumors, resistance to the effect of thioguanine correlates with the loss of HGPRTase activity and the resulting inability to convert thioguanine to thioguanylic acid. However, other resistance mechanisms, such as increased catabolism of TGMP by a nonspecific phosphatase, may be operative. Although not invariable, it is usual to find cross-resistance between thioguanine and its close analogue, mercaptopurine.

Indications And Clinical Uses: For the treatment of acute leukemia. It has also been used for the treatment of chronic granulocytic (myelocytic, myeloid, myelogenous) leukemia. Although superior results are generally obtained with busulfan in the treatment of chronic granulocytic leukemia, thioguanine may be useful during periods of thrombocytopenia induced by busulfan or other therapy. Cross-resistance exists between thioguanine and mercaptopurine and generally it is not to be expected that patients who no longer respond to mercaptopurine will respond to thioguanine, or vice versa. Thioguanine is not effective for the treatment of chronic lymphocytic leukemia or solid tumors.

Contra-Indications: Should not be used in patients whose disease has demonstrated prior resistance to this drug. In animals and man, there is usually complete cross-resistance between mercaptopurine and thioguanine.

Should not be given to patients with previous hypersensitivity reaction to the drug or any of its components.

Manufacturers' Warnings In Clinical States: Thioguanine is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs. Blood counts should be taken weekly. Discontinue or reduce the dosage immediately at the first sign of abnormal depression of the bone marrow.

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 decrease in any of the formed elements of the blood. Blood counts should be made at least once weekly. Life-threatening infections and bleeding have been observed as consequences of thioguanine-induced granulocytopenia and thrombocytopenia.

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.

The effect of thioguanine on the immunocompetence of patients is unknown.

Pregnancy : Drugs of this type have potential teratogenic activity and the benefits and risks must be weighed before use during pregnancy. Whenever possible, use of the drug should be deferred until after the first trimester of pregnancy.

Precautions: General: A few cases of jaundice have been reported in patients with leukemia who received thioguanine. Among these were 2 adult male patients and 4 children with acute myelogenous leukemia, and an adult male with acute lymphocytic leukemia who developed veno-occlusive hepatic 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 veno-occlusive hepatic 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.

During remission induction particularly, when rapid cell lysis is occurring, adequate precautions should be taken to avoid hyperuricemia and/or hyperuricosuria and the risk of uric acid nephropathy.

There are rare individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of thioguanine and prone to developing rapid bone marrow depression following the initiation of treatment with thioguanine.

Since the enzyme hypoxanthine guanine phosphoribosyltransferase is responsible for the conversion of thioguanine to its active metabolite, it is possible that patients deficient in this enzyme, such as those suffering from Lesch-Nyhan syndrome, may be resistant to thioguanine.

Pregnancy : As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving thioguanine (see Warnings).

Lactation : It is not known whether thioguanine 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.

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.

Patients with Special Diseases and Conditions: Consideration should be given to reducing the dosage in patients with impaired hepatic or renal function.

Drug Interactions: Mercaptopurine: There is usually complete cross-resistance between mercaptopurine and thioguanine.

Busulfan: In one study, 12 of approximately 330 patients receiving continuous busulfan and thioguanine therapy for treatment of chronic myelogenous leukemia were found to have esophageal varices associated with abnormal liver function tests. Subsequent liver biopsies were performed in 4 of these patients, all of which showed evidence of nodular regenerative hyperplasia. Duration of combination therapy prior to the appearance of esophageal varices ranged from 6 to 45 months. With the present analysis of the data, no cases of hepatotoxicity have appeared in the busulfan alone arm of the study. Long-term continuous therapy with thioguanine and busulfan should be used with caution.

Laboratory Tests: 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 with other hepatotoxic drugs. Patients should be instructed to discontinue thioguanine immediately if clinical jaundice is detected (see Precautions, General).

Adverse Reactions: 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 affected 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 allopurinol. Unlike mercaptopurine and azathioprine, thioguanine may be continued in the usual dosage when allopurinol is used conjointly to inhibit uric acid formation.

Gastrointestinal: 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. Esophageal varices have been reported in patients receiving continuous busulfan and thioguanine therapy for treatment of chronic myelogenous leukemia (see Precautions, Drug Interactions).

While on the whole no significant clinical difference between thioguanine and mercaptopurine has been noted with respect to action or side effects, it has been observed that occasionally patients may experience better gastrointestinal tolerance to one or another drug of this type.

Hepatic Effects: Liver enzyme and other liver function studies are occasionally abnormal. If jaundice, hepatomegaly, or anorexia with tenderness in the right hypochondrium occurs, thioguanine should be withheld until the exact etiology can be determined. There have been reports of veno-occlusive liver disease occurring in patients who received combination chemotherapy including thioguanine (see Precautions, General).

One case of centrilobular hepatic necrosis was reported in a patient who had been treated for acute myelogenous leukemia with high cumulative doses of thioguanine and cytosine arabinoside. This patient was also taking oral contraceptives.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Signs and symptoms of overdosage may be immediate, such as nausea, vomiting, malaise, hypertension, 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 incorporation of thioguanine into active metabolites with long persistence.

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.

Dosage And Administration: The dosage must be carefully adjusted for each patient to obtain optimum benefit without toxic effects. The usual initial dose is approximately 2 mg/kg body weight/day, orally. If after 4 weeks on this dosage there is no clinical improvement and no leukocyte depression, the dosage may be cautiously increased to 3 mg/kg/day.

The total daily dose may be given at one time. It is usually calculated to the closest multiple of 20 mg. Although the effect usually occurs slowly over a period of 2 to 4 weeks, occasionally there may be a rapid fall in leukocyte count within 1 or 2 weeks. This may occur in some adults with acute leukemia and high total leukocyte counts as well as in certain adults with chronic granulocytic leukemia. For this reason it is important to observe such patients closely.

It is advisable to provide maintenance therapy, usually 2 mg/kg/day to provide a sustained remission and avoid early relapse. Unlike mercaptopurine and azathioprine, thioguanine may be continued in the usual dosage when allopurinol is used conjointly to inhibit uric acid formation.

Special Instructions: All materials which have come in contact with cytotoxic drugs should be segregated and incinerated at 1 000°C or more.

Tablets should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport.

Personnel regularly involved in the preparation and handling of cytotoxic agents should have biannual blood examinations.

Care should be taken when handling or halving the tablets so as not to contaminate hands or to inhale the drug.

Availability And Storage: Each pale, greenish-yellow, biconvex tablet, plain on one side and scored on the other side, with Wellcome on the upper half and U3B on the lower half, contains: thioguanine 40 mg. Nonmedicinal ingredients: gum acacia, lactose, magnesium stearate, potato starch and stearic acid. Bottles of 25. Store between 15 and 25°C, in a dry place.