LANVIS Tablets 40 mg

1. Name Of The Medicinal Product

Lanvis^® Tablets 40 mg

2. Qualitative And Quantitative Composition

40 mg Tioguanine BP per tablet

3. Pharmaceutical Form

Tablet

4. Clinical Particulars

4.1 Therapeutic Indications

Lanvis is indicated primarily for the treatment of acute leukaemias especially acute myelogenous leukaemia and acute lymphoblastic leukaemia.

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

4.2 Posology And Method Of Administration

Route of administration: oral.

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 levels may be reduced following emesis or intake of food.

Lanvis can be used at various stages of treatment in short term cycles. 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 Special Warnings and Precautions for Use and Undesirable Effects).

Adults

The usual dosage of Lanvis is between 100 and 200 mg/m² body surface area, per day.

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 doses 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.

4.3 Contraindications

In view of the seriousness of the indications there are no absolute contra-indications.

4.4 Special Warnings And Precautions For Use

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 Posology and Method of Administration and Undesirable Effects). This liver toxicity has been observed in a high proportion of children receiving Lanvis 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. Anaemia has been reported less frequently.

Bone marrow suppression is readily reversible if Lanvis 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 Lanvis 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 sulphasalzine. 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 indication 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.

In view of its action on cellular DNA, tioguanine is potentially mutagenic and carcinogenic.

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.

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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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

As there is in vitro evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent Lanvis therapy (see Special Warnings and Precautions for Use).

4.6 Pregnancy And Lactation

Lanvis, like other cytotoxic agents 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. Its use should be avoided whenever possible 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.

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.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

For this product there is a lack of modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Lanvis is usually one component of combination chemotherapy and consequently it is not possible to ascribe the side effects unequivocally to this drug alone.

The following convention has been utilised for the classification of frequency of undesirable effects:- Very common

Blood and lymphatic system disorders

Very Common: Bone marrow suppression

Gastrointestinal disorders

Common: stomatitis, gastrointestinal intolerance

Rare: intestinal necrosis and perforation

Hepato-biliary disorders

Very Common: liver toxicity associated with vascular endothelial damage when Lanvis 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. Histopathalogical 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 Lanvis and alcohol.

4.9 Overdose

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. 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.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Tioguanine is a sulphydryl analogue of guanine and behaves as a purine antimetabolite. It is activated to its nucleotide, thioguanylic acid. Tioguanine metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. Tioguanine 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 tioguanine and mercaptopurine, and it is not to be expected that patients resistant to one will respond to the other.

5.2 Pharmacokinetic Properties

Tioguanine 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 tioguanine 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-tioguanine 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 1.2 g of 6-tioguanine/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 100 mg/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).

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose	NF
Starch, potato	HSE
Acacia	NF
Stearic acid	NF
Magnesium stearate	NF
Purified water	USP

6.2 Incompatibilities

None known.

6.3 Shelf Life

60 months (unopened).

6.4 Special Precautions For Storage

Store below 25°C

Keep dry

Protect from light

6.5 Nature And Contents Of Container

Amber glass bottles with child-resistant polyethylene/polypropylene closures

Pack size 25

6.6 Special Precautions For Disposal And Other Handling

None

Administrative Data

7. Marketing Authorisation Holder

ALKOPHARMA SARL

45-47, rte d'Arlon

L – 1140 Luxembourg

8. Marketing Authorisation Number(S)

PL 36637/0009

9. Date Of First Authorisation/Renewal Of The Authorisation

01 December 2008

10. Date Of Revision Of The Text

September 2010

11. LEGAL STATUS

POM