Aspen

Lanvis 40 mg Tablets

Tablets containing 40 mg thioguanine.

Excipients: Also contains 150mg Lactose Monohydrate

For a full list of excipients, see section 6.1.

Tablets

Pale, green – yellow, biconvex, circular tablet with the Wellcome brand and code 'U3B' on one surface and a single score-line on the other.

The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

In the treatment of leukaemias, particularly acute myeloblastic leukaemia and acute lymphoblastic leukaemia.

Lanvis is also used in the treatment of chronic granulocytic leukaemia.

The exact dose and duration of administration will depend on the nature and dosage of other cytotoxic drugs given in conjunction with Lanvis

Lanvis is variably absorbed following oral administration and plasma drug levels may be reduced following emesis or intake of food

Lanvis can be used at any stage prior to maintenance therapy in short term cycles e.g. induction, consolidation, intensification. However it is not recommended for use during maintenance therapy or similar long term continuous treatments due to the high risk of liver toxicity (see Warnings and Precautions and Adverse Reactions).

• Adults

For adults, the usual dosage of thioguanine is between 60 and 200 mg/m2 body surface area per day.

• Children

For children, similar dosages to those used in adults, with appropriate correction for body surface area, have been used.

Use in the elderly:

There are no specific dosage recommendations in elderly patients. (See Dosage in renal or hepatic impairment).

Lanvis has been used in various combination chemotherapy schedules in elderly patients with acute leukaemia at equivalent dosages to those used in younger patients.

Dosage in renal or hepatic impairment:

Consideration should be given to reducing the dosage in patients with impaired hepatic or renal function.

Hypersensitivity to any component of the preparation

Use in the management of non-malignant disease

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 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.

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 thioguanine 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 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

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

The leucoycte 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 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, which has one of the same active metabolites as thioguanine, has been demonstrated in two children with Lesch-Nyhan syndrome

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

The marrow response to thioguanine is delayed and drug should be stopped or reduced as soon as significant leucocyte 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 dosage of thioguanine as is necessary with mercaptopurine and azathioprine.

As there is in vitro evidence that aminosalicylate derivatives (e.g. olsalazine, meslazine or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent Lanvis therapy (see Warnings and 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 matabolites in maternal milk. It is suggested that mothers receiving Lanvis should not breast-feed.

There are no data on the effect of thioguanine 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 (0.01% 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 thioguanine 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 thioguanine and alcohol

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

Signs: The principal toxic effect is on the bone-marrow and haematological toxicity is likely to be more profound with chronic overdosage than with a single ingestion of Lanvis.

Treatment: As there is no known antidote the blood picture should be closely monitored and general supportive measures, together with appropriate blood transfusion instituted if necessary.

ATC code: L01BB03

Mode of Action:

Thioguanine is a sulphydryl analogue of guanine and behaves as a purine antimetabolite. It is activated to its nucleotide, thioguanylic acid.

Thioguanine metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. Thioguanine is also incorporated into nucleic acids and DNA (deoxyribonucleic acid) incorporation is claimed to contribute to the agent's cytotoxicity. Cross-resistance usually exists between thioguanine and mercaptopurine, and it is not to be expected that patients resistant to one will respond to the other.

Thioguanine is extensively metabolised in vivo. There are two principal catabolic routes: methylation to 2-amino-6-methyl-thiopurine and deamination to 2-hydroxy-6-mercaptopurine, followed by oxidation to 6-thiouric acid.

Studies with radioactive thioguanine show that peak blood levels of total radioactivity are achieved about 8-10 hours after oral administration and decline slowly thereafter. Later studies using HPLC have shown 6-thioguanine to be the major thiopurine present for at least the first 8 hours after intravenous administration. Peak plasma concentrations of 61-118 nanomol (nmol)/ml are obtainable following intravenous administration of 1 to 1.2g of 6-thioguanine/ m² body surface area.

Plasma levels decay biexponentially with initial and terminal half-lives of 3 and 5-9 hours respectively. Following oral administration of 100mg/m², peak levels as measured by HPLC occur at 2-4 hours and lie in the range of 0.03-0.94 micromolar (0.03-0.94 nmol/ml). Levels are reduced by concurrent food intake (as well as vomiting).

Mutagenicity and carcinogenicity:

Thioguanine has been shown to be carcinogenic in animals. The theoretical possibility of a similar effect should be borne in mind when designing the long-term management of the patient.

Lactose monohydrate

Potato starch

Acacia

Stearic acid

Magnesium stearate

Not applicable.

5 years.

Do not store above 25°C. Store in the original bottle and in the carton in order to protect from light. Keep the bottle tightly closed in order to protect from moisture.

Lanvis tablets are supplied in amber (Type III) glass bottles with a polypropylene/HDPE child-resistant closure, containing 25 tablets.

Safe handling of Lanvis:

It is recommended that the handling of Lanvis Tablets follows the "Guidelines for the Handling of Cytotoxic Drugs" issued by the Royal Pharmaceutical Society of Great Britain Working Party on 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.

Pregnant staff should not handle cytotoxic agents.

Disposal:

Lanvis tablets surplus to requirements should be destroyed in a manner appropriate to the prevailing local regulations for the destruction of dangerous substances.

Aspen Pharma Trading Limited

12/13 Exchange Place

I.F.S.C.

Dublin 1, Ireland

PA 1691/6/1

1st April 1979/1st April 2009

January 2011