- NAME OF THE MEDICINAL PRODUCT
Thioguanine Tablets 40mg Taj Pharma
- QUALITATIVE AND QUANTITATIVE COMPOSITION
Each uncoated tablet contains:
Thioguanine USP????????????? 40mg
For the full list of excipients, see section 6.1.
- PHARMACEUTICAL FORM
- CLINICAL PARTICULARS
4.1 Therapeutic indications
Thioguanine is indicated primarily for the treatment of acute leukaemias especially acute myelogenous leukaemia and acute lymphoblastic leukaemia.
4.2 Posology and method of administration
The exact dose and duration of administration will depend on the nature and dosage of other cytotoxic drugs given in conjunction with Thioguanine .
Thioguanine is variably absorbed following oral administration and plasma levels may be reduced following emesis or intake of food.
Thioguanine 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 section 4.4).
The usual dosage of Thioguanine ?is between 100 and 200 mg/m2?body surface area, per day.
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).
Thioguanine 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.
Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe Thioguanine ?toxicity from conventional doses of Thioguanine ?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 Thioguanine ?doses, but some may require dose reduction. Genotypic and phenotypic tests of TPMT are available (see sections 4.4 and 5.2).
Patients with NUDT15 variant
Patients with inherited mutated NUDT15 gene are at increased risk for severe Thioguanine ?toxicity (see 4.4). These patients generally require dose reduction; particularly those being NUDT15 variant homozygotes (see 4.4). Genotypic testing of NUDT15 variants may be considered before initiating Thioguanine ?therapy. In any case, close monitoring of blood counts is necessary.
Method of administration
Hypersensitivity to Thioguanine ?or to any of the excipients listed in section 6.1.
In view of the seriousness of the indications there are no absolute contra-indications.
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.
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.
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.
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.
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 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 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.
Patients with NUDT15 variant
Patients with inherited mutated NUDT15 gene are at increased risk for severe Thioguanine ?toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy. They generally require dose reduction, particularly those being NUDT15 variant homozygotes (see 4.2). The frequency of NUDT15 c.415C>T has an ethnic variability of approximately 10 % in East Asians, 4 % in Hispanics, 0.2 % in Europeans and 0 % in Africans. In any case, close monitoring of blood counts is 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.
Since Thioguanine ?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, Thioguanine ?is potentially mutagenic and carcinogenic.
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.
Patients treated with Thioguanine ?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 Thioguanine ?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.
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).
Other myelotoxic substances or radiation therapyDuring concomitant administration of other myelotoxic substances or radiation therapy, the risk of myelosuppression is increased.
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 Thioguanine ?therapy (see section 4.4).
4.6 Fertility, pregnancy and lactation
Thioguanine , like other cytotoxic agents is potentially teratogenic.
There have been isolated cases where men, who have received combinations of cytotoxic agents including Thioguanine , have fathered children with congenital abnormalities.
The use of Thioguanine ?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 Thioguanine .
There are no reports documenting the presence of Thioguanine ?or its metabolites in maternal milk. It is suggested that mothers receiving Thioguanine ?should not breast feed.
4.7 Effects on ability to drive and use machines
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. Thioguanine ?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 ?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
|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|
|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.|
|Metabolism and Nutrition disorders||Common||Hyperuricaemia|
|Renal and urinary disorders||Common||Hyperuricosuria and urate nephropathy (see section 4.4).|
|Skin and subcutaneous tissue disorders||Not Known||Photosensitivity (see see section 4.4)|
a?see description of selected adverse reactions
Description of selected adverse reactions
The liver toxicity associated with vascular endothelial damage occurs at a frequency of very common when Thioguanine ?is used in maintenance or similar long term continuous therapy which is not recommended (see sections 4.2 and 4.4).
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.
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.
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 Thioguanine .
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 center, where available.
- PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-neoplastic and immunomudulating agent/purine analogue.
Mechanism 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.
There is usually a cross-resistance between Thioguanine ?and mercaptopurine; it is therefore not to be expected that patients with a tumour resistant to one will respond to the other.
5.2 Pharmacokinetic properties
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 1.2 g 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 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).
Limited data on the distribution of Thioguanine ?in humans are available in the scientific literature.
Thioguanine ?penetrates into the CSF following constant IV infusion administration after doses of 20 mg/m2/h over 24 hours in children with ALL.
Thioguanine ?is extensively metabolised?in vivo. The four different enzymes responsible for Thioguanine ?metabolism are as follows: hypoxanthine (guanine) phosphoribosyl transferase (H(G)PRT), which converts Thioguanine ?into thioguanosine monophosphate (6-TGMP), which is further metabolized by protein kinases to the active species, thioguanine nucleotides (6-TGN); TPMT, which converts Thioguanine ?to 6-methylthioguanine (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 Thioguanine ?into inactive metabolites. Thioguanine ?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
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
- PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate, Starch, potato Acacia, Stearic acid, Magnesium stearate, Purified water.
6.3 Shelf life
6.4 Special precautions for storage
Store below 25?C.
Protect from light.
6.5 Nature and contents of container
Tablets are packed in Bottle.
Pack Size of: 7, 14, 28, 30, 50, 60, 90, 100 or 200 Tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
It is recommended that the handling of Thioguanine ?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.
7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).
Thioguanine Tablets 40mg Taj Pharma
Package Leaflet: Information for the User
Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, nurse or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
- What Thioguanine is and what it is used for
2. What you need to know before you take Thioguanine
3. How to take Thioguanine
4. Possible side effects
5. How to store Thioguanine
6. Contents of the pack and other information
- WHAT THIOGUANINE IS AND WHAT IT IS USED FOR
Thioguanine ?tablets contain a medicine called Thioguanine . This belongs to a group of medicines called cytotoxics (also called chemotherapy). Thioguanine ?is used for certain blood problems and cancers of the blood. It works by reducing the number of new blood cells your body makes.
Thioguanine ?is used for acute (fast-growing) leukaemias, especially:
- Acute myelogenous leukaemia(also called?acute myeloid leukaemia or AML) – a fast-growing disease that increases the number of white blood cells produced by the bone marrow. This can cause infections and bleeding.
- Acute lymphoblastic leukaemia(also called?acute lymphocytic leukaemia?or?ALL) – a fast-growing disease which increases the number of immature white blood cells. These immature white blood cells are unable to grow and function properly and therefore cannot fight infections and may cause bleeding.
Ask your doctor if you would like more explanation about these diseases.
- WHAT YOU NEED TO KNOW BEFORE YOU TAKE THIOGUANINE
Do not take Thioguanine :
if you are allergic (hypersensitive) to Thioguanine ?or any of the other ingredients of this medicine (listed in section 6).
Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking Thioguanine :
- if you have been taking this medicine for a long period of time. This may increase the chance of side effects, such as liver problems
- if you have a condition where your body produces too little of something called TPMT or ?thiopurine methyltransferase?
- if you have ?Lesch-Nyhan Syndrome?. This is a rare condition that runs in families caused by a lack of something called HPRT or ?hypoxanthine-guanine-phosphoribosyltransferase?.
If you are not sure if any of the above apply to you, talk to your doctor, nurse or pharmacist before taking Thioguanine .
If you have an inherited mutation in the NUDT15-gene (a gene which is involved in the break-down of Thioguanine ?in the body), you have a higher risk of infections and hair loss and your doctor may in this case give you a lower dose. Your doctor may also perform genetic testing (i.e. looking at your TPMT and/or NUDT15 genes) before or during your treatment to determine if your response to this medication may be affected by your genetics. Your doctor may change your dose of Thioguanine ?after these tests.
Thioguanine ?and the sun
While taking Thioguanine ?you may become sensitive to the sunlight which can cause skin discolouration or a rash. Take care to avoid too much sun, cover up and use sunscreen.
Other medicines and Thioguanine
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.
In particular tell your doctor or pharmacist if you are taking any of the following:
- olsalzine or mesalazine ? used for a bowel problem called ulcerative colitis.
- sulfasalazine ? used for rheumatoid arthritis or ulcerative colitis.
- medicines that can have a harmful effect on the bone marrow, like other chemotherapy or radiotherapy. This can lead to bone marrow damage and the dose of Thioguanine may need to be reduced.
Having vaccines while you are taking Thioguanine
If you are going to have a vaccination speak to your doctor or nurse before you have it. This is because some vaccines (like polio, measles, mumps and rubella) may give you an infection if you have them whilst you are taking Thioguanine .
Pregnancy, breast-feeding and fertility
If you are pregnant or are planning to have a baby, ask your doctor for advice before you take Thioguanine . This applies to both men and women. Thioguanine ?may harm your sperm or eggs. Reliable contraceptive precautions must be taken to avoid pregnancy whilst you or your partner are taking these tablets. If you are breast-feeding, ask your doctor or midwife for advice before taking Thioguanine .
Thioguanine ?contains lactose.
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
- HOW TO TAKE THIOGUANINE
Thioguanine ?should only be given to you by a specialist doctor who is experienced in treating blood problems.
Always take this medicine exactly as your doctor has told you. It is important to take your medicine at the right times. The label on your pack will tell you how many tablets to take and how often to take them. Check with your doctor, pharmacist or nurse if you are not sure.
- Swallow your tablets whole with a glass of water.
- If you need to break your tablet in half, do not inhale any tablet powder. Wash your hands afterwards. The scoreline is only there to help you break the tablet if you have difficulty swallowing it whole.
- When you take Thioguanine your doctor will take regular blood tests. This is to check the number and type of cells in your blood and to ensure your liver is working correctly. Your doctor may sometimes change your dose as a result.
The dose of Thioguanine ?you are given will be worked out by your doctor based on:
- your body size (surface area).
- the results of your blood test.
- the disease being treated.
- The recommended dose is between 100 and 200 mg/m2body surface area per day. If you have a problem with your kidneys or liver you may be given a lower dose of Thioguanine .
If you take more Thioguanine ?than you should
If you take more Thioguanine ?than you should, tell your doctor immediately or go to a hospital straight away. Take the medicine pack with you.
If you forget to take Thioguanine
Tell your doctor.?Do not take a double dose to make up for a forgotten dose.
- POSSIBLE SIDE EFFECTS
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you get any of the following, talk to your specialist doctor or go to hospital straight away:
- any signs of fever or infection (sore throat, sore mouth or urinary problems).
- any?unexpectedbruising or bleeding, as this could mean that too few blood cells of a particular type are being produced.
- if you?suddenlyfeel unwell (even with a normal temperature).
- any yellowing of the whites of the eyes or skin (jaundice).
Talk to your doctor if you have any of the following side effects which may also happen with this medicine:
Very common (may affect more than 1 in 10 people)
- a drop in the number of your blood cells and platelets.
- jaundice (skin and the whites of the eyes turn yellow) and severe liver damage (symptoms include fatigue and nausea followed by pruritus, dark urine and may include rash or fever) – with long term use or high doses of Thioguanine ? this may also show up in your blood tests.
Common (may affect up to 1 in 10 people)
- liver damage which can cause jaundice (skin and the whites of the eyes turn yellow) or an enlarged liver (a swelling below your ribcage) ? with short term use of Thioguanine ? this may also show up in your blood tests.
- feeling or being sick (nausea or vomiting), diarrhoea and mouth ulcers.
- Increased uric acid concentrations in the blood (hyperuricaemia), which can sometimes lead to decreased kidney function.
Rare (may affect up to 1 in 1,000 people)
- a problem with your bowels, called necrotising colitis, which can cause severe stomach ache, being sick, diarrhoea, vomiting and fever.
- severe liver damage when used with other chemotherapy drugs, oral contraceptives and alcohol.
Not known: frequency cannot be estimated from the available data
- Sensitivity to light.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.
- HOW TO STORE THIOGUANINE
- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the pack after ?Exp?.
- Do not store your Thioguanine ?tablets above 25?C. Keep dry and protect from light.
- If your doctor tells you to stop taking the tablets, it is important to return any which are left over to your pharmacist, who will destroy them according to disposal of dangerous substance guidelines. Only keep the tablets if your doctor tells you to.
- CONTENTS OF THE PACK AND OTHER INFORMATION
What Thioguanine ?contains
The active substance is Thioguanine. Each Thioguanine tablet contains 40 mg of Thioguanine.
The other ingredients are lactose monohydrate, starch (potato), acacia, stearic acid, magnesium stearate and purified water.
What Thioguanine ?looks like and contents of the pack
Thioguanine tablets are white to off-white tablets, round, biconvex scored and imprinting ?T40? on upper side, without score and debossing on lower side. Your Thioguanine tablets are in bottles of 25 tablets.
7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).