Hanixol 50 mg Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Mercaptopurine
Available from:
Fontus Health Limited
ATC code:
L01BB; L01BB02
INN (International Name):
Mercaptopurine
Dosage:
50 milligram(s)
Pharmaceutical form:
Tablet
Therapeutic area:
Purine analogues; mercaptopurine
Authorization status:
Not marketed
Authorization number:
PA22756/001/001
Authorization date:
2019-08-19

PACKAGE LEAFLET: INFORMATION FOR THE USER

Hanixol 50 mg Tablets

6-mercaptopurine

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, pharmacist or nurse.

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 Hanixol 50 mg Tablets are and what they are used for

What you need to know before you take Hanixol 50 mg Tablets

How to take Hanixol 50 mg Tablets

Possible side effects

How to store Hanixol 50 mg Tablets

Contents of the pack and other information

1.

What Hanixol 50 mg Tablets are and what they are used for

Hanixol 50 mg Tablets contain a medicine called 6-mercaptopurine.

This belongs to a group of medicines called cytotoxics (also called chemotherapy). Hanixol 50

mg Tablets are used to treat cancer of the blood (leukaemia) in adults, adolescents and children.

It works by reducing the number of new blood cells your body makes.

2.

What you need to know before you take Hanixol 50 mg Tablets

Do not take Hanixol 50 mg Tablets:

If you are allergic to 6-mercaptopurine or any of the other ingredients of this medicine (listed in

section 6).

Warnings and precautions

Talk to your doctor before using Hanixol 50 mg Tablets:

If you have recently received, or are due to receive, a vaccination (vaccine). If you take

Hanixol, you should not have a live organism vaccine (for example; flu vaccine, measles

vaccine, BCG vaccine, etc.) until advised it is safe to do so by your doctor. This is because

some vaccines may give you an infection if you receive them while you are taking Hanixol

If you have a genetic disease called TPMT (thiopurine methyltransferase) deficiency.

If you are allergic to a medicine called azathioprine (also used to treat cancer).

If you have reduced liver function or liver damage.

If you have a genetic disease called Lesch-Nyhan syndrome.

If you have a kidney problem.

Tell your doctor whether you have, or have not, had chicken pox, shingles or hepatitis B

(a liver disease caused by a virus).

If you are pregnant or breast-feeding. If you are male, please note the risk of teratogenic

effect.

If you are taking at the same time allopurinol.

If you are taking at the same time warfarin or other drugs that may have blood thinning

effect (e.g. aminosalicylic acid).

If you have any intolerance to lactose.

If you are receiving immunosuppressive therapy, taking Hanixol 50 mg Tablets could put you at

greater risk of:

Tumours, including skin cancer. Therefore, when taking Hanixol 50 mg Tablets, avoid excessive

exposure to sunlight, wear protective clothing and use protective sunscreen with a high protection

factor.

Lymphoproliferative disorders:

- treatment with Hanixol 50 mg Tablets increases your risk of getting a type of cancer called

lymphoproliferative disorder. With treatment regimen containing multiple immunosuppressants

(including thiopurines), this may lead to death.

- a combination of multiple immunosuppressants, given concomitantly increases the risk of

disorders of the lymph system due to a viral infection (Epstein-Barr virus (EBV)- associated

lymphoproliferative disorders).

Taking Hanixol 50 mg Tablets could put you at greater risk of:

Developing a serious condition called Macrophage Activation Syndrome (excessive activation of

white blood cells associated with inflammation), which usually occurs in people who have certain

types of arthritis.

Blood tests

Hanixol 50 mg Tablets can affect your bone marrow. This means you may have a reduced number of

white blood cells, platelets and (less commonly) red blood cells in your blood. Your doctor will take

daily blood tests at the beginning of your treatment and at least once a week in your treatment

(maintenance). This is to check the levels of these cells in your blood. If you stop treatment early

enough, your blood cells will return to normal.

Other laboratory tests

Additional laboratory tests (urine, blood, etc.) may also be carried out as directed by your

doctor.

Hepatic function

Hanixol 50 mg Tablets are toxic to your liver. Therefore, your doctor will take regular blood tests

when you are taking Hanixol. This is to check and to ensure your liver is working correctly.

If you notice the whites of your eyes or your skin turn yellow (jaundice) tell your doctor immediately

as you may need to stop your treatment immediately

Infections

When you take Hanixol 50 mg Tablets you may be more prone to infections and your reaction to

these infections may be more serious than people not being treated with Hanixol 50 mg Tablets. Tell

your doctor immediately if you think you have an infection.

Sun and UV light

During your treatment with Hanixol 50 mg Tablets you are more sensitive to the sun and UV light.

You must be sure to limit your exposure to sunlight and UV light, wear protective clothing and use

sunscreen with a high SPF.

Children and adolescents

Low blood sugar levels (sweating more than usual, nausea, dizziness, confusion, etc.) have been

reported in some children receiving Hanixol; however, most of the children were under the age of six

years old and had a low body weight.

If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before taking

Hanixol 50 mg Tablets.

Other medicines and Hanixol 50 mg Tablets

Tell your doctor or pharmacist 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:

Ribavirin (used to treat viral infections)

Other cytotoxic drugs (used to treat cancer)

Allopurinol thiopurinol, oxypurinol or febuxostat (used mainly to treat gout)

Olsalazine (used to treat bowel problems called, ulcerative colitis)

Mesalazine (used to treat bowel problems called Crohn's disease and ulcerative colitis)

Sulfasalazine (used for rheumatoid arthritis or ulcerative colitis)

Methotrexate (used to treat cancers, rheumatoid arthritis or severe psoriasis)

Infliximab (used to treat bowel disorders Crohn's disease and ulcerative colitis), rheumatoid

arthritis, inflammation of the spinal column (ankylosing spondylitis) or severe psoriasis

Warfarin or acenocoumarol (anticoagulants).

Having vaccines while you are taking Hanixol 50 mg Tablets

If you are going to have a vaccination, speak to your doctor or nurse before you have it. This is

because some live vaccines (like polio, measles, mumps and rubella) may give you an infection if you

have them whilst you are taking Hanixol 50 mg Tablets.

Hanixol 50 mg tablets with food and drink

You can take Hanixol 50 mg Tablets with food or on an empty stomach, but the way you choose

should be the same, day to day. You should take Hanixol 50 mg Tablets at least 1 hour before or 2

hours after ingestion of milk or dairy products.

Pregnancy, breast-feeding and fertility

Treatment with Hanixol 50 mg Tablets is not recommended during pregnancy, particularly in the first

three months, because it may cause permanent damage to a foetus. If you think you could be pregnant,

or if you are planning to become pregnant, check with your doctor before taking Hanixol 50 mg

Tablets. Your doctor will consider the risks and benefits to you and your baby of taking Hanixol 50

mg Tablets.

Do not take Hanixol 50 mg Tablets if you are planning to have a baby. This applies to both men and

women. Reliable contraceptive precautions must be taken to avoid pregnancy during treatment with

Hanixol 50 mg Tablets and for at least 3 months afterwards.

Breastfeeding should not occur during treatment with Hanixol 50 mg Tablets as Hanixol has been

detected in human milk.

Driving and using machines

It is not expected that Hanixol will affect your ability to drive or use machines, but no studies have

been done to confirm this.

Hanixol 50 mg Tablets contain lactose.

If you have been told by your doctor that you have an intolerance to lactose, contact her/him before

taking this medicine.

3.

How to take Hanixol 50 mg Tablets

Hanixol 50 mg Tablets should only be given to you by a specialist doctor who is experienced in

treating cancers of the blood.

During treatment with Hanixol 50 mg Tablets, 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 also ask for other blood and urine tests to monitor how your kidneys are

working and to measure your uric acid levels. Uric acid is a natural body chemical, levels of

which can rise while taking Hanixol. High levels of uric acid may damage your kidneys.

Your doctor may sometimes change your dose of Hanixol 50 mg Tablets as a result of these tests.

Always take Hanixol 50 mg Tablets exactly as your doctor or pharmacist has told you. Check with

your doctor or pharmacist if you are not sure. It is important that the Tablets are taken at the right

time.

The recommended dose for adults and children is 2.5 mg per kilogram of body weight per day (or

alternatively, 50 to 75 mg per square meter (m

) of body surface area per day). Your doctor will

calculate and adjust your dose based on your weight, the results of your blood tests, if you take other

chemotherapy drugs, as well as your kidney and liver function.

Swallow the tablets whole with some water. The tablets should not be broken or crushed. You can

take your medicine with food or on an empty stomach, but the way you choose should be the

same day to day. You should take Hanixol 50 mg Tablets at least 1 hour before or 2 hours after

ingestion of milk or dairy products

If you take more Hanixol 50 mg Tablets than you should

If you take too many Hanixol 50 mg Tablets or if someone else took your medication by mistake,

immediately contact your doctor for advice or go to the nearest hospital. Take the medicine pack with

you. If you have any further questions on the use of this product, ask your doctor or pharmacist.

If you forget to take Hanixol 50 mg Tablets

If you forget to take a dose, inform your doctor. Do not take a double dose to make up for a forgotten

dose.

If you stop taking Hanixol

If you stop taking Hanixol, tell your doctor immediately.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, Hanixol 50 mg Tablets can cause side effects, although not everybody gets them.

The side effects of Hanixol 50 mg Tablets relate to the pharmacological effects of 6-mercaptopurine

If you get any of the following, talk to your specialist doctor straight away or seek urgent medical

advice:

An allergic reaction with swelling of the face and sometimes mouth and throat (this is a very rare

side effect).

An allergic reaction with joint pain, skin rashes, high temperature (fever) (this is a rare side effect).

Yellowing of the skin and whites of the eyes. If you get such symptoms, you should stop taking

Hanixol.

Any signs of a high temperature or infection (feeling very tired or unwell, sore throat, sore mouth or

urinary problems) or any unexplained bruising or bleeding.

Treatment with Hanixol affects your bone marrow causing a reduction in your white blood cells and

platelets (this is a very common side effect).

Therefore, your doctor will periodically take blood samples.

Talk to your doctor if you have any of the following side effects, which may also happen with this

medicine:

Common (may affect up to 1 in 10 people)

- Nausea or vomiting

- Anaemia

Uncommon (may affect up to 1 in 100 people)

- Loss of appetite

Rare (may affect up to 1 in 1,000 people)

- Mouth ulcers

- Inflammation of the pancreas which may include abdominal pain, nausea or vomiting

- Severe damage to liver cells (hepatic necrosis)

- Hair Loss

- Various types of cancers including blood, lymph and skin cancers

Very rare (may affect up to 1 in 10,000 people)

- Blood cancer (Leukaemia)

- Cancer of the liver and spleen (in patients with a disease called inflammatory bowel disease)

- Ulcers in the intestines, with symptoms such as abdominal pain and bleeding

- In men: low sperm count has been reported

Not known (frequency cannot be estimated from the available data)

- Increased sensitivity to sunlight and UV light

Additional side effects in children

Low blood sugar levels (Sweating more than usual, nausea, dizziness, confusion, etc.) have been

reported in some children receiving Hanixol; however, most of the children were under the age of six

years old and had a low body weight.

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. You can also report side effects directly 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.. By reporting side effects you can help provide more information on the

safety of this medicine.

5.

How to store Hanixol 50 mg Tablets

Keep this medicine out of the sight and reach of children.

Do not use Hanixol 50 mg Tablets after the expiry date which is stated on the bottle after EXP. The

expiry date refers to the last day of that month.

Store in the original package in order to protect from light.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Hanixol 50 mg Tablets contain

The active ingredient is 6-mercaptopurine. One tablet contains 50 mg of Hanixol.

The other ingredients are: Lactose anhydrous; Maize starch; Starch, pregelatinized; Stearic acid;

Magnesium stearate

What Hanixol 50 mg Tablets look like and contents of the pack

Hanixol 50 mg Tablets are round 7.4 mm yellowish tablets.

Type III 20 ml amber glass bottle containing 25 tablets with a polypropylene child-proof cap and

silica gel desiccant.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Fontus Health Ltd

70 Northumberland Road,

Ballsbridge, Dublin 4,

D04 VH66

Ireland

Manufacturer:

Idifarma Desarrollo farmacéutico S.L.

Polígono Mocholi. C/ Noain 1

Navarra

31110

Spain

This leaflet was last approved in 11/2019

Other sources of information

To request the leaflet in Braille, large print or audio please contact the MA

holder at the address above.

Health Products Regulatory Authority

16 April 2020

CRN009Q75

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Hanixol 50 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Tablet contains 50 mg of 6-mercaptopurine.

Excipients with known effect:

-Lactose anhydrous: 59 mg per tablet

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablets.

Round 7.4 mm yellowish tablet, scored

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Hanixol 50 mg tablets is indicated for the treatment of APL (acute promyelocytic leukaemia) and AML M3 (acute myeloid

leukaemia M3) in adults, adolescents and children.

4.2 Posology and method of administration

Posology

6-mercaptopurine treatment should be initiated and supervised by a doctor or other healthcare professional experienced in

the management of patients with acute leukemia.

6-mercaptopurine may be taken with food or on an empty stomach, but patients should standardise the method of

administration. 6-mercaptopurine should not be taken with milk or dairy products (see section 4.5). 6-mercaptopurine should

be taken at least 1 hour before or 2 hours after ingestion of milk or dairy products.

Populations

Adults and children

For adults and children, the usual dose is 2.5 mg/kg bodyweight per day, or 50 to 75 mg/m

body surface area per day, but the

dose and duration of administration depend on the nature and dosage of other cytotoxic agents given in conjunction with

6-mercaptopurine.

The dosage should be carefully adjusted to suit the individual patient.

6-mercaptopurine has been used in various combination therapy schedules and the literature should be consulted for details.

Studies carried out in children with acute lymphoblastic leukaemia suggested that administration of 6-mercaptopurine in the

evening lowered the risk of relapse compared with morning administration.

Elderly

It is advisable to monitor renal and hepatic function in these patients, and if there is any impairment, consideration should be

given to reducing the 6-mercaptopurine dosage.

Renal impairment

Consideration should be given to reducing the dosage in patients with impaired renal function (see section 5.2).

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Hepatic function

Consideration should be given to reducing the dosage in patients with impaired hepatic function (see section 5.2)

Medicinal product interactions

When xanthine oxidase inhibitors, such as allopurinol, and 6-mercaptopurine are administered concomitantly, it is essential

that only 25 % of the usual dose of 6-mercaptopurine is given since allopurinol decreases the rate of catabolism of

6-mercaptopurine. Concomitant administration of other xanthine oxidase inhibitors, such as febuxostat, should be avoided

(see section 4.5).

TPMT deficient patients

Patients

with

inherited

little

thiopurine

S-methyltransferase

(TPMT)

activity

increased

risk

severe

6-mercaptopurine toxicity from conventional doses of 6-mercaptopurine and generally require substantial dose reduction.

The optimal starting dose for homozygous deficient patients has not been established (see section 4.4 and section 5.2).

Most patients with heterozygous TPMT deficiency can tolerate recommended 6-mercaptopurine doses, but some may require

dose reduction. Genotypic and phenotypic tests of TPMT are available (see section 4.4 and section 5.).

4.3 Contraindications

Hypersensitivity to mercaptopurine 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

6-mercaptopurine is an active cytotoxic agent for use only under the direction of physician 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 the patient is deemed to be able to respond to the vaccine. The interval between discontinuation of

chemotherapy and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of

immunosuppression-causing medications used, the underlying disease, and other factors.

Co-administration of ribavirin and 6-mercaptopurine is not advised. Ribavirin may reduce efficacy and increase toxicity of

6-mercaptopurine (see section 4.5).

Safe handling of Hanixol Tablets

See section 6.6.

Monitoring

Since 6- mercaptopurine is strongly myelosuppressive full blood counts must be taken daily during remission induction.

patients must be carefully monitored during therapy.

Bone marrow suppression

Treatment with 6-mercaptopurine causes bone marrow suppression leading to leukopenia and

thrombocytopenia and, less frequently, anaemia. Full blood counts must be taken frequently during remission induction and

careful monitoring of haematological parameters should be conducted during maintenance therapy and more frequently if

high dosage is used or if severe renal and/or hepatic disorder is present.

The leucocyte and platelet counts continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in

the counts, treatment should be interrupted immediately.

Bone marrow suppression is reversible if 6-mercaptopurine is withdrawn early enough.

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.

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The dosage of 6-mercaptopurine may need to be reduced when this agent is combined with other drugs whose primary or

secondary toxicity is myelosuppression (see section 4.5).

Increased haematological monitoring of the patient is advised when switching between different pharmaceutical formulations

of mercaptopurine.

Hepatotoxicity

6-mercaptopurine is hepatotoxic and liver function tests should be monitored weekly during treatment. The level of gamma

glutamyl transferase (GGT) in plasma will be especially important to determine if discontinuation is necessary due to

hepatotoxicity. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other

potentially hepatotoxic therapy. The patient should be instructed to discontinue 6-mercaptopurine immediately if jaundice

becomes apparent.

Tumour lysis syndrome

During remission induction when rapid cell lysis is occurring, uric acid levels in blood and urine should be monitored as

hyperuricaemia and/or hyperuricosuria may develop, with the risk of uric acid nephropathy.

TPMT deficiency

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually

sensitive to the myelosuppressive effect of 6-mercaptopurine and prone to developing rapid bone marrow depression

following the initiation of treatment with 6-mercaptopurine. This problem could be exacerbated by co-administration with

drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfazalazine. Also, a possible association between decreased TPMT

activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6–mercaptopurine in

combination with other cytotoxics (see Section 4.8).

About 0.3% (1: 300) of patients have low or no detectable enzyme activity. Approximately 10% of patients with low or

intermediate TPMT activity, and 90% of patients have normal TPMT activity. There may also be a group of around 2% with a

very high TPMT activity. 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.

Cross resistance

Cross resistance usually exists between 6-mercaptopurine and 6-tioguanine.

Hypersensitivity

Patients suspected of having suffered a hypersensitivity reaction to 6-mercaptopurine should not be recommended to use its

pro-drug azathioprine, unless the patient has been confirmed to be hypersensitive to 6-mercaptopurine by allergological tests,

and tested negative for azathioprine. As azathioprine is a pro-drug of 6-mercaptopurine, patients with a previous history of

hypersensitivity to azathioprine must be assessed for hypersensitivity to 6-mercapopurine prior to initiating treatment.

Renal and/or hepatic impairment:

Caution is advised during the administration of 6-mercaptopurine in patients with renal impairment and/or hepatic impairment.

Consideration should be given to reducing the dosage in these patients and haematological response should be carefully

monitored (see section 4.2 and section 5.2 Pharmacokinetic).

Mutagenicity and carcinogenicity

Patients

receiving

immunosuppressive

therapy,

including

mercaptopurine

increased

risk

developing

lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and nonmelanoma), sarcomas (Kaposi's

and non-Kaposi's) and uterine cervical cancer in situ. The increased risk appears to be related to the degree and duration of

immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the

lymphoproliferative disorder.

A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution

this

could

lead

lymphoproliferative

disorders,

some

with

reported

fatalities.

combination

multiple

immunosuppressants,

given

concomitantly

increases

risk

Epstein-Barr

virus

(EBV)associated

lymphoproliferative

disorders.

Increases in chromosomal aberrations were observed in the peripheral lymphocytes of leukaemic patients, in a hypernephroma

patient who received an unstated dose of 6-mercaptopurine and in patients with chronic renal disease treated at doses of 0.4

to 1.0 mg/kg/day.

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cases

have

been

documented

occurrence

acute

non-lymphatic

leukaemia

patients

received

6mercaptopurine, in combination with other drugs, for non-neoplastic

disorders. A single case has been reported where a patient was treated for pyoderma gangrenosum with 6mercaptopurine and

later developed acute non-lymphatic leukaemia, but it is not clear whether this was part of the natural history of the disease or

if the 6-mercaptopurine played a causative role.

A patient with Hodgkin's disease treated with 6-mercaptopurine and multiple additional cytotoxic agents developed acute

myelogenous leukaemia.

Twelve and a half years after 6-mercaptopurine treatment for myasthenia gravis, a female patient developed chronic myeloid

leukaemia.

Reports of hepatosplenic T-cell lymphoma in the inflammatory bowel disease (IBD) population have been received when

6-mercaptopurine is used in combination with anti-TNF agents as unlicensed indication (see section 4.8).

Infections

Patients treated with 6-mercaptopurine monotherapy or in combination with other immunosuppressive drugs, including

corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical

infection and reactivation of the virus. Infectious disease and complications can be more serious in these patients than in

patients who did not undergo treatment.

Prior exposure to or infection with the varicella zoster should be considered prior to initiation of therapy. Local guidelines may

be taken into account, including prophylactic treatment if necessary. Serological tests for hepatitis B should be considered

before starting treatment. Local guidelines may be taken into account, including prophylactic treatment in cases where

serological tests are positive. If patients experience infection during treatment, appropriate measures, which may include

antiviral therapy and supportive care.

Paediatric population

Cases of symptomatic hypoglycaemia have been reported in children with ALL receiving 6-mercaptopurine (see Section 4.8

Undesirable Effects). The majority of reported cases were in children under the age of six or with a low body mass index.

Macrophage activation syndrome

Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with autoimmune

conditions, in particular with inflammatory bowel disease (IBD) (unlicensed indication), and there could potentially be an

increased susceptibility for developing the condition with the use of mercaptopurine. If MAS occurs, or is suspected, evaluation

and treatment should be started as early as possible, and treatment with mercaptopurine should be discontinued. Physicians

should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.

Lesch-Nyhan syndrome

Limited evidence suggests that neither the 6-mercaptopurine nor its pro-drug azathioprine are effective in patients with the

rare inherited disease associated with complete hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan

syndrome). The use of 6-mercaptopurine or azathioprine is not recommended in these patients.

UV exposure

Patients treated with 6-mercaptopurine is more sensitive to sunlight. Exposure to sunlight and UV light should be limited, and

patients should be advised to wear protective clothing and use sunscreen with a high protection factor.

Lactose

Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should

not take this medicine.

Xanthine oxidase inhibitors

When xanthine oxidase inhibitors, such as allopurinol, and 6-mercaptopurine are administered concomitantly it is essential that

only

usual

dose

6-mercaptopurine

given,

since

allopurinol

decreases

rate

catabolism

6-mercaptopurine (see section 4.2 and 4.5)

Anticoagulants

Inhibition

anticoagulant

effect

warfarin

acenocoumarol

been

reported

when

co-administered

with

6mercaptopurine; therefore higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are

closely monitored when anticoagulants are concurrently administered with 6-mercaptopurine.

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16 April 2020

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4.5 Interaction with other medicinal products and other forms of interactions

Vaccination with a live vaccine is not recommended in patients with impaired immune response (see section 4.4)

Taking 6-mercaptopurine with food may decrease systemic exposure slightly. 6-mercaptopurine can be taken with food or on

an empty stomach, but patients should use a standard method of administration to avoid large variations in exposure. The

dose must not be taken with milk or dairy products since they contain xanthine oxidase, an enzyme that metabolizes

6-mercaptopurine and therefore may lead to reduced plasma concentrations of mercaptopurine.

Effect of concomitant medicinal products on 6mercaptopurine:

Ribavirin

Ribavirin inhibits the enzyme, inosine monophosphate dehydrogenase (IMPDH), leading to a lower production of the active

6-thioguanine nucleotides. Severe myelosuppression has been reported following concomitant administration of a pro-drug of

6-mercaptopurine and ribavirin; therefore concomitant administration of ribavirin and 6-mercaptopurine is not advised (see

section 4.4 and 5.2).

Myelosuppressive agents

When 6-mercaptopurine is combined with other myelosuppressive agents caution should be used; dose reductions may be

needed based on haematological monitoring (see section 4.4).

Allopurinol / oxipurinol / thiopurinol and other xanthine oxidase inhibitors

Xanthine oxidase activity is inhibited by allopurinol, oxipurinol and thiopurinol, which results in reduced conversion of

biologically active 6-thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol, oxipurinol and/or thiopurinol

and 6-mercaptopurine are administered concomitantly it is essential that only 25 % of the usual dose of 6-mercaptopurine is

given (see section 4.2).

Other xanthine oxidase inhibitors, such as febuxostat, decrease metabolism of 6-mercaptopurine. Co-administration is not

recommended, because data are insufficient to determine an adequate dose reduction.

Aminosalicylates

There is in vitro and in vivo evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfazalazine) inhibit the

TPMT enzyme. Therefore, lower doses of 6-mercaptopurine may need to be considered when administered concomitantly with

aminosalicylate derivatives (see section 4.4).

Methotrexate

Methotrexate (20 mg/m2 orally) increased 6-mercaptopurine AUC by approximately 31% and methotrexate (2 or 5 g/m2

intravenously)

increased

6-mercaptopurine

93%,

respectively.

Therefore,

when

6-mercaptopurine

administered concomitantly with high dose methotrexate, the dose should be adjusted to maintain a suitable white blood cell

count.

Infliximab

Interactions have been observed between azathioprine and infliximab. Patients treated with azathioprine had transient

increases in the levels of 6-TGN (6-tioguaninnukleotid, an active metabolite of azathioprine) and decreases in the average

number of leukocytes in the first weeks after infusion of infliximab, which returned to previous levels after 3 months.

Effect of 6-mercaptopurine on other medicinal products

Anticoagulants

Inhibition

anticoagulant

effect

warfarin

acenocoumarol

been

reported

when

co-administered

with

6-mercaptopurine; therefore higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are

closely monitored when anticoagulants are concurrently administered with 6-mercaptopurine.

4.6 Fertility, pregnancy and lactation

Fertility

effect

6-mercaptopurine

therapy

human

fertility

largely

unknown

there

reports

successful

fatherhood/motherhood after receiving treatment during childhood or adolescence.

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Transient oligospermia has been reported following exposure to 6-mercaptopurine.

Pregnancy

Substantial transplacental and transamniotic transmission of 6-mercaptopurine and its metabolites from the mother to the

foetus have been shown to occur.

The use of 6-mercaptopurine 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 if either partner is receiving

6-mercaptopurine Tablets, during treatment and for at least three months after receiving the last dose.

Studies of 6-mercaptopurine in animals have shown reproductive toxicity (see Section 5.3 Preclinical safety data). The potential

risk for humans is largely unknown.

Maternal exposure:

Normal offspring have been born after 6-mercaptopurine therapy administered as a single chemotherapy

agent during human pregnancy, particularly when given prior to conception or after the first trimester.

Abortions and prematurity have been reported after maternal exposure. Multiple congenital abnormalities have been reported

following maternal 6-mercatopurine treatment in combination with other chemotherapy agents.

Paternal exposure: Congenital abnormalities and spontaneous abortion have been reported after paternal exposure to

6-mercaptopurine.

Breastfeeding

6-mercaptopurine has been detected in the breast milk of renal transplant patients receiving immunosuppressive therapy with

a pro-drug of 6-mercaptopurine. It is recommended that mothers receiving 6-mercaptopurine should not breast feed.

4.7 Effects on ability to drive and use machines

There is no data about the effects of 6-mercaptopurine on the ability to drive vehicles and use machines. A detrimental effect

on these activities cannot be predicted from the pharmacology of mercaptopurine.

4.8 Undesirable effects

Summary of the safety profile

For 6-mercaptopurine there is a lack of modern clinical documentation which can serve as support for accurately determining

the frequency of undesirable effects. The frequency categories assigned to the adverse drug reactions below are estimates: for

most reactions, suitable data for calculating incidence are not available. Undesirable effects may vary in their incidence

depending on the dose received and also when given in combination with other therapeutic agents.

main

side

effect

treatment

with

6-mercaptopurine

bone

marrow

suppression

leading

leucopenia

thrombocytopenia.

Tabulated list of adverse reactions

The following convention has been utilised for the classification of frequency:

Very common ≥1/10

Common ≥1/100 and < 1/10

Uncommon ≥1/1000 and <1/100

Rare ≥1/10,000 and <1/1000

Very rare <1/10,000

Not known (frequency cannot be estimated from the available data)

Organ system

Frequency

Adverse effect

Neoplasms benign, malignant and unspecified

Rare

Neoplasms including lymphoproliferative disorders, skin

cancers (melanomas and nonmelanomas), sarcomas (Kaposi's

and non-Kaposi's) and uterine cervical cancer in situ (see

section 4.4).

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Very rare

Secondary Leukaemia and myelodysplasia (see section 4.4) ;

hepatosplenic T-cell

lymphoma in patients with IBD (an

unlicensed indication) when used in combination with

anti-TNF

agents (see section 4.4.)

Blood and lymphatic system disorders

Very common

Myelosuppression: leukopenia and thrombocytopenia

Common

Anaemia

Immune system disorders

Rare

Hypersensitivity reactions with the following manifestations

have been reported: Arthralgia; skin rash; drug fever.

Very rare

Hypersensitivity reactions with the following manifestations

have been reported: Facial oedema

Metabolism and nutrition disorders

Uncommon

Anorexia

Not known

Hypoglycaemia*

Gastrointestinal disorders

Common

Nausea; vomiting; pancreatitis in the IBD population (an

unlicensed indication)

Rare

Oral ulceration, pancreatitis during treatment (in the licensed

indications)

Very rare

Intestinal ulceration.

Hepatobiliary disorders

Common

Biliary stasis; hepatotoxicity

Rare

Hepatic necrosis

Skin and subcutaneous tissue disorders

Rare

Alopecia.

Not known

Photosensitivity

Reproductive system and breast disorders

Very rare

Temporary oligospermia.

*In paediatric population

Description of selected adverse reactions:

Hepatobiliary disorders

6-mercaptopurine is hepatotoxic in animals and man. The histological findings in man have shown hepatic necrosis and biliary

stasis.

The incidence of hepatotoxicity varies considerably and can occur with any dose but more frequently when the recommended

dose of 2.5 mg/kg bodyweight daily or 75 mg/m2 body surface area per day is exceeded.

Monitoring of liver function tests may allow early detection of hepatotoxicity. Gamma glutamyl transferase (GGT) levels in

plasma may be particularly predictive of withdrawal due to hepatotoxicity. This is usually reversible if 6-mercaptopurine therapy

is stopped soon enough but fatal liver damage has occurred.

Reporting of suspected adverse reactions:

Reporting

suspected

adverse

reactions

after

authorisation

medicinal

product

important.

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:

Gastrointestinal effects, including nausea, vomiting and diarrhoea and anorexia may be early symptoms of overdosage having

occurred. The principal toxic effect is on the bone marrow, resulting in myelosuppression .

Haematological toxicity is likely to be

more

profound

with

chronic

overdosage

than

with

single

ingestion

6-mercaptopurine.

Liver

dysfunction

gastroenteritis may also occur.

The risk of overdosage is also increased when allopurinol is being given concomitantly with 6-mercaptopurine (see Section 4.5).

Treatment:

As there is no known antidote, blood counts should be closely monitored and general supportive measures, together with

appropriate blood transfusion, instituted if necessary. Active measures (such as the use of activated charcoal) may not be

effective in the event of 6-mercaptopurine overdose unless the procedure can be undertaken within 60 minutes of ingestion.

Further management should be as clinically indicated or as recommended by the National Poisons Center.

5 PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, Antimetabolites, Purine analogues

ATC-Code: L01BB02.

Mechanism of action

6-mercaptopurine

sulphydryl

analogue

purine

bases,

adenine

hypoxanthine,

acts

cytotoxic

antimetabolite.

6-Mercaptopurine is an inactive pro-drug that acts as purine antagonist after cellular uptake and intracellular conversion into

thioguanine-nucleotides (TGN) for cytotoxicity.

6-mercaptopurine metabolites suppress the de novo

synthesis of purine and purine-nucleotide formation. The thioguanine

nucleotides are also incorporated into nucleic acids and this leads to the cytotoxic effect of the drug.

Pharmacodynamic effects

The cytotoxic effect of 6-mercaptopurine may be related to the levels of thioguanine nucleotides in red blood cells, but not to

the plasma concentration of 6-mercaptopurine.

5.2 Pharmacokinetic properties

Absorption

The bioavailability of oral 6-mercaptopurine shows considerable inter-individual variability`. When administered at a dosage of

75 mg/m

to seven paediatric patients, the bioavailability averaged 16% of the administered dose, with a range of 5 to 37%.

The variable bioavailability probably results from the metabolism of a significant portion of 6-mercaptopurine during first-pass

hepatic metabolism.

After oral administration of 6-mercaptopurine 75 mg/m

to 14 children with acute lymphoblastic leukaemia, the mean Cmax

was 0.89μM, with a range of 0.29 - 1.82μM and Tmax was 2.2 hours with a range of 0.5 - 4 hours.

The mean relative bioavailability of 6-mercaptopurine was approximately 26 % lower following administration with food and

milk compared to an overnight fast. 6-mercaptopurine is not stable in milk due to the presence of xanthine oxidase (30 %

degradation within 30 minutes) (see Section 4.2 Posology and method of administration).

Distribution

Concentrations of 6-mercaptopurine in cerebrospinal fluid (CSF) are low or negligible after IV or oral administration (CSF:

plasma ratios of 0.05 to 0.27). Concentrations in the CSF are higher after intrathecal administration.

Biotransformation

6-mercaptopurine is extensively metabolized by many multi-step pathways to active and inactive metabolites. Because of the

complex

metabolism,

inhibition

enzyme

does

explain

cases

lack

efficacy

and/or

pronounced

myelosuppression. The predominant enzymes responsible for the metabolism of 6-mercaptopurine or its downstream

metabolites are: the polymorphic enzyme thiopurine S-methyltransferase (TPMT), xanthine oxidase, inosine monophosphate

dehydrogenase (IMPDH) and hypoxanthine guanine phosphribosyltransferase (HPRT). Additional enzymes involved in the

formation of active and inactive metabolites are: guanosine monophosphate synthetase (GMPS, which form TGNs) and inosine

triphosphate pyrophosphatase (ITPase). There are also multiple inactive metabolites formed via other pathways.

There is evidence that polymorphisms in the genes encoding the different enzyme systems involved with metabolism of

6-mercaptopurine may predict adverse drug reactions to 6-mercaptopurine therapy. For example, individuals with TPMT

deficiency develop very high cytotoxic thioguanine nucleotide concentrations (see Section 4.4).

Elimination

In a study with 22 adult patients the mean 6-mercaptopurine clearance and half-life after IV infusion was 864 mL/min/m2 and

0.9 hours respectively. The mean renal clearance reported in 16 of these patients was 191 mL/min/m2. Only about 20 % of the

dose was excreted in the urine as intact medicinal product after IV administration. In a study with 7 children patients the mean

6-mercaptopurine clearance and half-life after IV infusion was 719 (+/-610) ml/min/m2 and 0.9 (+/-0.3) hours respectively.

Special patient populations

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Older population

No specific studies have been carried out in the elderly (see Section 4.2 Posology and method of administration).

Renal impairment

Studies with a pro-drug of 6-mercaptopurine have shown no difference in 6-mercaptourine pharmacokinetics in uremic

patients compared to renal transplant patients. Little is known about the active metabolites of 6-mercaptopurine in renal

impairment (see Section 4.2 Posology and method of administration).

6-mercaptopurine and/or its metabolites are eliminated by haemodialysis, with approximately 45 % of radioactive metabolites

eliminated during dialysis of 8 hours.

Hepatic impairment

A study with a pro-drug of 6-mercaptopurine was performed in three groups of renal transplant patients: those without liver

disease, those with hepatic impairment (but no cirrhosis) and those with hepatic impairment and cirrhosis. The study

demonstrated that 6-mercaptopurine exposure was 1.6 times higher in patients with hepatic impairment (but no cirrhosis) and

6 times higher in patients with hepatic impairment and cirrhosis, compared to patients without liver disease (see Section 4.2

Posology and method of administration).

5.3 Preclinical safety data

Carcinogenesis, mutagenesis

6-Mercaptopurine is mutagenic in man and chromosome damage has been reported in mice, rats and man.

In view of its action on cellular deoxyribonucleic acid (DNA) 6-mercaptopurine is potentially carcinogenic and consideration

should be given to the theoretical risk of carcinogenesis with this treatment.

Teratogenicity

6-Mercaptopurine causes growth arrest, severe embryo-lethality and teratogenic effects in mice, rats, hamsters and rabbits

(such as cleft palate, eye and skeletal malformations) at doses that are nontoxic to pregnant females. In all species, the degree

of embryotoxicity and the type of malformations are dependent on the dose and stage of the gestation at the time of

administration.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose anhydrous

Maize starch

Starch, pregelatinized

Stearic acid

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

After first opening the bottle: 7 months

6.4 Special precautions for storage

Store in the original package in order to protect from light

6.5 Nature and contents of container

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Type III 20 ml amber glass bottle containing 25 tablets with a polypropylene child-proof cap and silica gel desiccant.

6.6 Special precautions for disposal and other handling

Safe handling:

It is recommended that 6-mercaptopurine Tablets should be handled following the prevailing local recommendations and/or

regulations for the handling and disposal of cytotoxic agents.

Disposal

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

7 MARKETING AUTHORISATION HOLDER

Fontus Health Limited

70 Northumberland Road

Ballsbridge

D04 VH66

Ireland

8 MARKETING AUTHORISATION NUMBER

PA22756/001/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19

August 2019

10 DATE OF REVISION OF THE TEXT

March 2020

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