LANVIS Ref.[4462] Active ingredients: Tioguanine

LANVIS 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.

Hepatic Effects

LANVIS 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 tioguanine as part of maintenance therapy for acute lymphoblastic leukaemia and in other conditions associated with continuous use of tioguanine. 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.

Lanvis 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 Lanvis 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Bone-marrow suppression is readily reversible if the drug is withdrawn early enough.

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

DURING REMISSION INDUCTION FULL BLOOD COUNTS MUST BE CARRIED OUT FREQUENTLY.

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.

Lesch-Nyhan syndrome: Since the enzyme hypoxanthine guanine phosphoribosyl transferase is responsible for the conversion of Lanvis 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 Lanvis, has been demonstrated in two children with Lesch-Nyhan syndrome.

Cross-resistance occurs with mercaptopurine and patients will not respond to tioguanine if they no longer respond to mercaptopurine.

The marrow response to tioguanine is delayed and drug should be stopped or reduced as soon as a significant leukocyte decrease is detected.

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Warnings and Precautions).

The concomitant use of allopurinol to inhibit uric acid formation does not necessitate reduction of the dosage of tioguanine as is necessary with mercaptopurine and azathioprine.

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 Lanvis therapy (see warnings precautions).

Teratogenicity and effects on fertility

Lanvis, like other cytotoxics is potentially teratogenic.

There have been isolated cases where men, who have received combinations of cytotoxic agents including Lanvis, have fathered children with congenital abnormalities.

Use in pregnancy

The use of Lanvis should be avoided during pregnancy, particularly during the first trimester. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.

As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Lanvis.

Lactation

There are no reports documenting the presence of Lanvis or its metabolites in maternal milk. It is suggested that mothers receiving Lanvis should not breast-feed.

There are no data on the effect of tioguanine on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of the drug.

The following convention has been utilised for the classification of frequency of undesirable effects:- Very common ≥1/10 (≥10%), Common ≥1/100 and <1/10 (≥1% and <10%), Uncommon ≥1/1000 and <1/100 (≥0.1% and <1%), Rare ≥1/10,000 and <1/1000 (≥0.1% and <0.1%), Very rare <1/10,000 (0.01%)

Blood and lymphatic system disorders

Very common: Bone marrow suppression (see warnings and precautions)

Gastrointestinal Disorders

Common: stomatitis, gastrointestinal intolerance

Rare: intestinal necrosis and perforation

Hepato-biliary disorders

Very Common: Liver toxicity associated with vascular endothelial damage when tioguanine is used in maintenance or similar long term continuous therapy which is not recommended (see Dosage and Administration and Warnings and Precautions)

Usually presenting as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinaemia, tender hepatomegaly, weight gain due to fluid retention and ascites) or signs and symptoms of portal hypertension (splenomegaly, thrombocytopenia and oesophageal 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 hepatis and periportal fibrosis.

Common: Liver toxicity during short term cyclical therapy presenting 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.

Rare: Centrilobular hepatic necrosis has been reported in a few cases including patients receiving combination chemotherapy, oral contraceptives, high dose tioguanine and alcohol.

The following events have been reported rarely: photosensitivity, electrolyte disturbances, ataxia, rash, tinnitus, cardiovascular disturbances, deafness and oculogyric crisis.

Not applicable.