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4.4      Special warnings and precautions for use

 

UV exposure

 

Patients treated with Lanvis 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 (see section 5.3).

 

4.6      Fertility, pregnancy and lactation

 

Pregnancy

 

Lanvis like other cytotoxic agents is potentially teratogenic (see section 5.3)..

 

5.3      Preclinical safety data

 

Reproductive toxicity

Administration of tioguanine to pregnant rats, at a dose of 0.3 times the Maximum Recommended Human Dose (MRHD) was found to be highly toxic to rat fetuses but not to dams. The nature of the effects on foetal viability and development was highly dependent on the stage of gestation at the time of tioguanine administration.

Administration of Tioguanine before implantation induced 10 % of foetal death, 75% foetal resorption and 10% of complete destruction of the litters. When tioguanine was administered at the time of implantation, all of the foetuses died.

Tioguanine was teratogenic in rats at doses of 0.37 and 0.75 times the MRHD when administered on the 12th days of gestation (corresponding to the organogenesis period). It induced a decrease in placental weight and foetal malformations that included: i) skeletal defects, ii) ventral hernia, iii) hydrocephalous and, iv) situs inversus (see section 4.6).

Genotoxicity

Tioguanine at doses of 0.03 and 0.06 times the MRHD induced a highly significant dose-dependent increase in the frequency of micronucleated polychromatic erythrocytes in mice, indicating that it induces genotoxic damage in vivo. This in vivo data is supported by in vitro studies showing that cell culture treatment with tioguanine (at concentrations ranging from 0.01 to 4 uM) also induced DNA damage.

Biologically relevant doses of ultraviolet A (UVA) generate ROS in cultured cells with tioguanine-substituted DNA and tioguanine and UVA are synergistically mutagenic (see section 4.4).

Carcinogenicity

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

 

10.      DATE OF REVISION OF THE TEXT

 

April 2018 7

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4.2      Posology and method of administration

 

Special populations:

 

 

 

Patients with NUDT15 variant

 

Patients with inherited mutated NUDT15 gene are at increased risk for severe thiopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy and generally require substantial dose reduction. Patients of Asian ethnicity are particularly at risk, due to the increased frequency of the mutation in this population. The optimal starting dose for heterozygous or homozygous deficient patients has not been established.

 

Genotypic and phenotypic testing of NUDT15 variants should be considered before initiating thiopurine therapy in all patients (including paediatric patients) to reduce the risk of thiopurine-related severe leukocytopenia and alopecia, especially in Asian populations (see sections 4.4 and 5.2).

 

 

 

4.4       Special warnings and precautions for use

 

Thiopurine S-methyltransferase (TPMT) deficiency

There are individuals with an inherited deficiency of the enzyme 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.

 

NUDT15 Mutation

Patients with inherited mutated NUDT15 gene are at increased risk for severe thiopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy and generally require substantial dose reduction. Patients of Asian ethnicity are particularly at risk, due to the increased frequency of the mutation in this population. The optimal starting dose for heterozygous or homozygous deficient patients has not been established. Genotypic and phenotypic testing of NUDT15 variants should be considered before initiating thiopurine therapy in all patients (including paediatric patients) to reduce the risk of thiopurine-related severe leukocytopenia and alopecia, especially in Asian populations (see sections 4.2 and 5.2).

 

 4.5     Interaction with other medicinal products and other forms of interaction

 

Vaccines

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see section 4.4).

Other myelotoxic substances or radiation therapy

During concomitant administration of other myelotoxic substances or radiation therapy, the risk of myelosuppression is increased.

 

Allopurinol

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

 

Aminosalicylate derivatives

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  section 4.4).

 

4.8         Undesirable effects

 

 

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%).

 

Tabulated list of adverse reactions

 

 

4.9        Overdose

 

 

Symptoms and signs

 

TreatmentManagement

 

 

5.2         Pharmacokinetic properties

NUDT15 R139C (NUDT15 c.415C>T) Variant

Recent studies indicate that a strong association exists between the NUDT15 variant NUDT15 c.415C>T [p.Arg139Cys] (also known as NUDT15 R139C [rs116855232]), which is thought to lead to a loss of function of the NUDT15 enzyme, and thiopurine-mediated toxicity such as leukopenia and alopecia. The frequency of NUDT15 c.415C>T has an ethnic variability of 9.8 % in East Asians, 3.9 % in Hispanics, 0.2 % in Europeans and 0.0 % in Africans, indicating an increased risk for the Asian population. Patients who are NUDT15 variant homozygotes (NUDT15 T risk alleles) are at an excessive risk of thiopurine toxicity compared with the C homozygotes.

 

Reduced thiopurine doses for patients who carry the NUDT15 variants may decrease their risk of toxicity. Therefore, genotypic analysis determining NUDT15 genotype should be determined for all patients, including paediatric patients, prior to initiating thiopurine treatment (see section 4.2). The prescribing physician is advised to establish whether dose reduction is required based on patient response to treatment as well as their genetic profile.

 

Patients with variants in both the NUDT15 and TPMT enzymes are significantly less tolerant of thiopurines than those with risk alleles in only one of these two genes.

 

The precise mechanism of NUDT15-associated thiopurine-related toxicity is not understood.

 

10.      DATE OF REVISION OF THE TEXT

 

April 2017 Dec 2015

 

 

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2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Tablet containing 40 mg tioguanine.

 

Excipients with known effects:

 

Also contains 150 mg Lactose Monohydrate

 

For a the full list of excipients, see section 6.1.

4.1     Therapeutic Indications

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

4.2     Posology and method of administration

Posology

Lanvis can be used at any stage prior to mainte

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

nance 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 section 4.4).

Paediatric populationChildren

 

 

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

 

TPMT-deficient patients

 

Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe tioguanine toxicity from conventional doses of Lanvis and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established (see sections 4.4 and 5.2).

 

Most patients with heterozygous TPMT deficiency can tolerate recommended Lanvis doses, but some may require dose reduction. Genotypic and phenotypic tests of TPMT are available (see sections 4.4 and 5.2). Consideration should be given to reducing the dosage in patients with impaired hepatic function.

 

Method of administration

 

Oral

4.3     Contraindications

 

Hypersensitivity to tioguanine or to any of the excipients listed in section 6.1.

 

In view of the seriousness of the indications there are no other absolute contraindications.

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. In all cases, patients in remission should not receive live organism vaccines until at least 3 months after their chemotherapy treatment has been completed.

Monitoring

 

SINCE TIOGUANINE IS STRONGLY MYELOSUPPRESIVE FULL BLOOD COUNTS MUST BE CARRIED OUT FREQUENTLY DURING REMISSION INDUCTION. PATIENTS MUST BE CAREFULLY MONITORED DURING THERAPY.

UV exposure

 

Patients treated with Lanvis 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.

 

Lactose intolerance

 

Patients with lactose intolerance should be advised that Lanvis 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.

 

Cross-resistance

 

There is usually a cross-resistance between tioguanine and mercaptopurine; it is therefore not to be expected that patients with a tumour resistant to one will respond to the other.

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see section 4.4).

 

During concomitant administration of other myelotoxic substances or radiation therapy, the risk of myelosuppression is increased.

 

4.6     Fertility, pregnancy and lactation

Pregnancy

 

Breastfeeding

Fertility

4.8         Undesirable effects

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%).

 

System Organ Class	Frequency	Side effects
Blood and lymphatic system disorders	Very common	Bone marrow failure (see section 4.4).
Gastrointestinal disorders	Common	Stomatitis, gastrointestinal disorder.
	Rare	Necrotising colitis.
Hepatobiliary disordersa	Very common	Venoocclusive liver disease: hyperbilirubinaemia, hepatomegaly, weight increased due to fluid retention and ascites.   Portal hypertension: splenomegaly, varices oesophageal and thrombocytopenia.    Hepatic enzyme increased, blood alkaline phosphatase increased and gamma glutamyltransferase increased, jaundice, portal fibrosis, nodular regenerative hyperplasia, peliosis hepatitis.
	Common	Venoocclusive liver disease in short-term cyclical therapy.
	Rare	Hepatic necrosis.
Metabolism and nutrition disorders	Common	Hyperuricaemia (see section 4.4).
Renal and urinary disorders	Common	Hyperuricosuria and urate nephropathy (see section 4.4).

^a see description of selected adverse reactions

 

Description of selected adverse reactions:

 

Hepatobiliary disorders

 

The liver toxicity associated with vascular endothelial damage occurs at a frequency of very common when tioguanine is used in maintenance or similar long term continuous therapy which is not recommended (see  sections 4.2 and 4.4).

 

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2. Tel: +353 1 6764971. Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: medsafety@hpra.ie

4.9     Overdose

 

Symptoms and signs

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. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-neoplastic and immunomodulating agent/purine analogue, ATC code: L01BB03

Pharmacodynamic effects

 

There is usually a cross-resistance between tioguanine and mercaptopurine; it is therefore not to be expected that patients with a tumour resistant to one will respond to the other.

Distribution

Limited data on the distribution of tioguanine in humans are available in the scientific literature.
6- tioguanine penetrates into the cerebrospinal fluid (CSF) following constant IV infusion administration after doses of 20 mg/m2/h over 24 hours in the paediatric population with acute lymphoblastic leukaemia.

Biotransformation

Tioguanine is extensively metabolised in vivo. The four different enzymes responsible for tioguanine metabolism are as follows: hypoxanthine (guanine) phosphoribosyl transferase (H(G)PRT), which converts tioguanine into thioguanosine monophosphate (6-TGMP), which is further metabolized by protein kinases to the active species, tioguanine nucleotides (6-TGN); TPMT, which converts tioguanine to 6-methyltioguanine (6-MTG, inactive metabolite) as well as 6-TGMP to 6-methyl-TGMP (an inactive metabolite) and xanthine oxidase (XDH or XO) and aldehyde oxidase (AO), which also convert tioguanine into inactive metabolites. Tioguanine is initially deaminated by guanine deaminase (GDA) to form 6-thioxanthine (6-TX) and this becomes a substrate for the XDH catalysed formation of 6-thiouric acid (6-TUA).

5.3     Preclinical safety data

 

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

 

Disposal

 

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

 

 

8.       MARKETING AUTHORISATION NUMBER

 

PA 1691/006/001

10. DATE OF REVISION OF THE TEXT

 

December March 2015

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7. Marketing Authorisation Holder
Aspen Pharma Trading Limited
12/13 Exchange Place
IFSC
Dublin 1
3016 Lake Drive
Citywest Business Campus
Dublin 24
Ireland

10.  Date of Revision of Text
December 2011  December 2013

Consistent spelling of Tioguanine and thioguanine

Improved presentation

Change of product ownership from GSK to Aspen, change of PL numbers and date of revision of text

Section 10

Changed Nov 2004 to Dec 2004