Special Warning : אזהרת שימוש

4.4      Special Warnings and Precautions for Use

Thioguanine is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.


Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended. In all cases, patients in remission should not receive live organism vaccines until at least 3 months after their chemotherapy treatment has been completed.

Hepatic Effects

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 sections 4.2 and 4.8).
This liver toxicity has been observed in a high proportion of children receiving thioguanine as part of maintenance therapy for acute lymphoblastic leukaemia 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 (hyperbilirubinaemia, 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 hepatis 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.

Monitoring

Patients must be carefully monitored during therapy including blood cell counts and weekly liver function 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.

Haematological Effects

Treatment with thioguanine causes bone marrow suppression leading to leucopenia and thrombocytopenia (see Hepatic effects). Anaemia has been reported less frequently.

Bone marrow suppression is readily reversible if thioguanine is withdrawn early enough.

There are individuals with an inherited deficiency of the enzyme 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. This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulphasalazine. Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is still necessary.

During remission induction in acute myelogenous leukaemia the patient may frequently have to survive a period of relative bone marrow aplasia and it is important that adequate supportive facilities are available.

Patients on myelosuppressive chemotherapy are particularly susceptible to a variety of infections.


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

Monitoring

Since tioguanine is strongly myelosuppresive full blood counts must be carried out frequently during remission induction. Patients must be carefully monitored during therapy.

The leucocyte and platelet counts continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in these counts, treatment should be temporarily discontinued.

Mutagenicity and carcinogenicity

In view of its action on cellular DNA, tioguanine is potentially mutagenic and carcinogenic.
It is recommended that the handling of Tioguanine tablets follows the Guidelines for the handling of cytotoxic drugs.

If halving of a tablet is required, care should be taken not to contaminate the hands or inhale the drug.

Lesch-Nyhan syndrome

Since the enzyme hypoxanthine guanine phosphoribosyl transferase 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 the drug.
Resistance to azathioprine (Imuran*), which has one of the same active metabolites as thioguanine, has been demonstrated in two children with Lesch-Nyhan syndrome.

UV exposure

Patients treated with tioguanine are more sensitive to the sun. Exposure to sunlight and UV light should be limited, and patients should be recommended to wear protective clothing and to use a sunscreen with a high protection factor.

Patients with lactose intolerance should be advised that tioguanine contains a small amount of lactose. Patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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