Purimmun 50 mg Tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

06-02-2020

Produktens egenskaper Produktens egenskaper (SPC)

06-02-2020

Aktiva substanser:
merkaptopurin (monohydrat)
Tillgänglig från:
2care4 Generics ApS,
ATC-kod:
L01BB02
INN (International namn):
mercaptopurine (monohydrate)
Dos:
50 mg
Läkemedelsform:
Tablett
Sammansättning:
merkaptopurin (monohydrat) 50 mg Aktiv substans; laktos (vattenfri) Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Burk, 25 tabletter; Burk, 50 (2x25) tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
55791
Tillstånd datum:
2018-05-18

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

24-05-2021

Produktens egenskaper Produktens egenskaper - engelska

24-05-2021

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

18-05-2018

Läs hela dokumentet

Package leaflet: Information for the user

Purimmun 50 mg tablets

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, 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, nurse or pharmacist. This includes any

possible side effects not listed in the leaflet. See section 4.

What is in this leaflet

What Purimmun is and what it is used for

What you need to know before you take Purimmun

How to take Purimmun

Possible side effects

How to store Purimmun

Contents of the pack and other information

1.

What Purimmun is and what it is used for

Purimmun tablets contain a medicine called 6-mercaptopurine.

This belongs to a group of medicines called cytotoxic (also called chemotherapy). Purimmun

tablets are used to treat a certain type of blood cancer, acute promyelocytic leukaemia. It works

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

2.

What you need to know before you take Purimmun

Do not take Purimmun:

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

in section 6).

Do not get vaccinated

with yellow fever vaccine whilst you are taking Purimmun because it may

be fatal.

Warnings and precautions

Talk to your doctor before using Purimmun:

If you have recently been or should be vaccinated.

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

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

If you have liver disease.

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

If you are planning to have a baby. This applies to both men and women. Purimmun may

harm your sperm or your eggs (see “Pregnancy, breast-feeding and fertility” below).

If you have reduced kidney function.

The tablets should be handled carefully.

Women who are pregnant, planning to be or breast-feeding should not handle Purimmun.

Please see “Safe handling of the tablets” in section 3 “How to take Purimmun”.

If you are receiving immunosuppressive therapy, taking Purimmun could put you at greater risk

Tumours,

including

skin

cancer.

Therefore,

when

taking

Purimmun,

avoid

excessive

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

protection factor.

Lymphoproliferative disorders:

treatment with Purimmun 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 Purimmun could put you at greater risk of:

Developing a serious condition called Macrophage Activation Syndrome (MAS, excessive

activation of white blood cells associated with inflammation), which usually occurs in people

who have certain types of arthritis.

Blood tests

Purimmun can affect your bone marrow. 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 blood cells in your blood. If the treatment is completed, the number of blood cells

in your blood return to normal.

Hepatic function

When you take Purimmun 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.

Infections

When you take Purimmun you may be more prone to suffer infections and your reaction to these

infections may be more serious than people not being treated with Purimmun. Tell your doctor

immediately if you think you have an infection.

NUDT15-

gene mutation

If you have an inherited mutation in the NUDT15-gene (a gene which is involved in the break-

down of Purimmun 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.

Sun and UV light

During your treatment with Purimmun 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 using

sunscreen with a high SPF.

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

taking Purimmun.

Other medicines and Purimmun

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 mainly to treat cancers)

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

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

(skin)

Warfarin or acenocoumarol (anticoagulants).

Having vaccines

If you are going to have a vaccination during or after treatment, speak to your doctor or nurse

before you have it. This is because live vaccines (like polio, measles, mumps and rubella) may

give you an infection if it is given before your immune system has recovered.

Do not get vaccinated

with yellow fever vaccine whilst you are taking Purimmun because it may

be fatal.

Purimmun tablets with food and alcohol

You can take Purimmun with food or on an empty stomach, but the way you choose should be the

same, day to day. You should take Purimmun at least 1 hour before or 2 hours after ingestion of

milk or dairy products.

Pregnancy, breast-feeding and fertility

If you think you could be pregnant, or if you are planning to become pregnant, check with your

doctor before taking Purimmun.

Treatment with Purimmun is not recommended during pregnancy, particularly in the first three

months, because it may cause permanent damage to a foetus.

Your doctor will consider the risks and benefits to you and your baby of taking Purimmun.

Do not take Purimmun 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 the treatment and for

at least 3 months after end of treatment with Purimmun, if you or your partner is taking

Purimmun.

Do not breast-feed while taking Purimmun. Ask your doctor, pharmacist or midwife for advice.

Driving and using machines

There is no data about the effects of 6-mercaptopurine on the ability to drive vehicles and use

machines and such effects could not be attributed to the pharmacological properties of Purimmun.

Purimmun 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.

3.

How to take Purimmun

Purimmun will be prescribed to you by a specialist doctor who is experienced in treating blood

problems.

- During treatment with Purimmun 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 your uric acid levels. Uric

acid is a natural body chemical, levels of which can rise while taking

- Your doctor may sometimes change your dose of Purimmun as a result of these tests.

Always take this medicine exactly as described in this leaflet or as your doctor or pharmacist has

told you. Check with your doctor or pharmacist if you are not sure.

Your doctor will calculate and adjust your dose based on your weight, or your body surface area

and 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. 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

Purimmun at least 1 hour before or 2 hours after ingestion of milk or dairy products. The tablets

should be taken in the evening.

Safe handling of the tablets

If you are a parent or carer who provides the medicine, wash your hands before and after you give

a dose. Spilled medicine should be collected immediately. In order to reduce the risk of exposure

you should wear disposable gloves when handling Purimmun.

Immediately and thoroughly rinse with soap and water if Purimmun comes into contact with skin,

eyes or nose.

Women who are pregnant, planning to be or breast-feeding should not handle Purimmun.

Accidental ingestion can be lethal for children. Keep Purimmun out of the reach and sight of

children, preferably in a locked cupboard.

If you take more Purimmun than you should:

If you take too many Purimmun or if someone else took your medication by mistake, please

immediately contact your doctor for advice or contact the nearest hospital or call the poison

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

pharmacist.

If you forget to take Purimmun

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

4.

Possible side effects

Like all medicines, this medicines can cause side effects, although not everybody gets them.

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

medicinal 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 Purimmun.

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

Purimmun affects your bone marrow and will cause a reduction in your white blood cells

and platelets (this is a very common side effect)

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 white blood cells and platelets (may show up in blood tests)

Common (may affect up to 1 in 10 people)

Nausea (you feel sick) or vomiting (being sick)

Low red blood cell count (anemia)

Liver damage – this may show up in blood tests

Uncommon (may affect up to 1 in 100 people)

Loss of appetite

Infections, general malaise, tendency to sore throat and fever. Can get serious. If you get a

fever, consult a doctor or emergency room.

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

Mouth ulcers

Inflammation of the pancreas (pancreatitis); symptoms may include abdominal pain, or

feeling or being sick

Severe damage to liver cells (hepatic necrosis)

Hair Loss

Various types of cancers including cervix, lymph, supporting tissue and skin cancers

Joint pain, skin rash, fever due to hypersensitivity

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

Blood cancer (leukemia)

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

Swollen face due to hypersensitivity

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

Increased sensitivity to sunlight and UV light

Additional side effects in children

– frequency is not known

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

reported in some children receiving Purimmun; 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 the national

reporting system listed in Appendix V.* By reporting side effects you can help provide more

information on the safety of this medicine.

5.

How to store Purimmun

Keep this medicine out of the sight and reach of children, preferably in a locked cupboard.

Accidental ingestion can be lethal for children.

Do not use this medicine after the expiry date which is stated on the bottle after EXP. The expiry

date refers to the last day of that month.

Any unused contents or waste material should be discarded in accordance with local requirements

for cytotoxic drugs.

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.

Store in the original glass container in order to protect from light.

6. Contents of the pack and other information

What Purimmun contains

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

other

ingredients

are:

Lactose;

maize

starch;

starch,

pregelatinized;

stearic

acid;magnesium stearate

What Purimmun look like and contents of the pack

Purimmun are round 6 mm yellowish tablet.

Purimmun is packed in amber glass container and a child-proof propylene cap with silicagel.

Pack sizes

: 25 tablets, 50 (2x25) tablets.

Marketing Authorisation Holder and Manufacturer

<To be completed nationally>

This leaflet was last approved in 22 April 2021

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Purimmun 50 mg tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg of mercaptopurine.

Excipient with known effect:

-Lactose: 59 mg per tablet

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Tablet.

Round 6 mm yellowish tablet

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Purimmun is indicated for the treatment of acute promyelocytic leukemia (APL) / acute myeloid

leukemia M3 (AML M3) in adults, adolescents and children.

4.2

Posology and method of administration

Posology

Treatment with Purimmun must be under the supervision of a physician or other healthcare

professional experienced in the treatment of patients with acute promyelocytic leukemia (AML

M3).

Method of administration

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.

6-mercaptopurine displays diurnal variation in pharmacokinetics and efficacy. Administration in

the evening compared to morning administration may lower the risk of relapse. Therefore the

daily dose of 6-mercaptopurine should be taken in the evening.

Populations

Adults and children

For adults and children, the usual dose is 2.5 mg/kg bodyweight per day, or 50 to 75 mg/m2 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 Purimmun.

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

6-mercaptopurine has been used in various combination therapy schedules for acute leukemia and

the literature should be consulted for details.

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 Purimmun dosage.

Renal impairment

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

(see section 5.2).

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 (see section 4.5).

TPMT deficient patients

Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased

risk for 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 5.2).

Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe 6-mercaptopurine

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 6-mercaptopurine therapy. In any case, close monitoring of blood

counts is necessary.

4.3

Contraindications

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

Concomitant use with yellow fever vaccine (see section 4.5).

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

live

organism

vaccine

potential

cause

infection

immunocompromised hosts. Therefore, immunisations with live organism vaccines are not

recommended. In all cases patients in remission should not receive live organism vaccines, until

patient

able

respond

vaccine.

interval

between

discontinuation

chemotherapy and restoration of the patient’s ability to respond to the vaccine depends on the

intensity and type of immunosuppressants used, the underlying disease and other factors.

Safe handling of Purimmun

See section 6.6.

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

efficacy and increase toxicity of 6-mercaptopurine (see section 4.5).

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 leucopenia and

thrombocytopenia and, less frequently, anemia. Full blood counts must be taken daily during

remission induction and careful monitoring of hematological parameters should be conducted

during maintenance therapy.

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.

The dosage of Purimmun may need to be reduced when this agent is combined with other drugs

whose primary or secondary toxicity is myelosuppression (see section 4.5).

Hepatotoxicity

Purimmun is hepatotoxic and liver function tests should be monitored weekly during treatment.

The level of gamma glutamyl transferase (GT) in plasma can be especially predictive of

discontinuation due to hepatotoxicity. More frequent monitoring may be advisable in those with

preexisting liver disease or receiving other potentially hepatotoxic therapy. The patient should be

instructed to discontinue Purimmun immediately if jaundice becomes apparent.

Tumor 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 coadministration with drugs that inhibit

TPMT, such as olsalazine, mesalazine or sulfazalazine. Also, a possible association between

decreased TPMT activity and secondary leukemias 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.

Renal and/or hepatic impairment

Caution

advised

during

administration

6-mercaptopurine

patients

with

renal

impairment and/or hepatic impairment. Consideration should be given to reducing the dosage in

these patients and hematological response should be carefully monitored (see section 4.2 and

section 5.2 Pharmacokinetic).

Mutagenicity and carcinogenicity

Patients receiving immunosuppressive therapy, including mercaptopurine are at an increased risk

of 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 as this could lead to lymphoproliferative disorders, some with

reported

fatalities.

combination

multiple

immunosuppressants,

given

concomitantly

increases the risk of Epstein-Barr virus (EBV)associated lymphoproliferative disorders.

Increases in chromosomal aberrations were observed in the peripheral lymphocytes of leukemic

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.

Two cases have been documented of the occurrence of acute non-lymphatic leukemia in patients

who received 6-mercaptopurine, in combination with other drugs, for nonneoplastic disorders. A

single case has been reported where a patient was treated for pyoderma gangrenosum with 6-

mercaptopurine and later developed acute non-lymphatic leukemia, 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 leukemia.

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

developed chronic myeloid leukemia.

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 (see section 4.8).

Infections

Patients

treated

with

6-mercaptopurine

monotherapy

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 before starting treatment should be considered for hepatitis B. Local

guidelines may be taken into account, including prophylactic treatment in cases where serological

tests gave positive affirmation. Cases of infections associated with neutropenia have been reported

patients

receiving

6-mercaptopurine.

patients

experience

infection

during

treatment,

appropriate measures, which may include antiviral therapy and supportive care.

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 total hypoxanthine-deficient (Lesch-Nyhan

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

UV exposure

Patients treated with Purimmun 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, total lactase deficiency or glucose-

galactose malabsorption should not take this medicine.

Xanthine oxidase inhibitors

When

xanthine

oxidase

inhibitors,

such

allopurinol,

oxipurinol

thiopurinol,

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

(see section 4.2 and 4.5)

nticoagulants

Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-

administered with 6-mercaptopurine; therefore higher doses of the anticoagulant may be needed.

recommended

that

coagulation

tests

closely

monitored

when

anticoagulants

concurrently administered with 6-mercaptopurine.

Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe 6-mercaptopurine

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.

4.5

Interaction with other medicinal products and other forms of interaction

Taking 6-mercaptopurine with food may decrease systemic exposure slightly. Purimmun can be

taken with food or on an empty stomach, but patients should keep to a route 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 6-mercaptopurine:

Concomitant administration of yellow fever vaccine is contraindicated, due to the risk of fatal

disease in immune compromised patients (see section 4.3).

Vaccinations with other live organism vaccines are not recommended in patients with impaired

immune response (see section 4.4).

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 hematological 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 (e.g. 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 AUC by 69 and 93%,

respectively. Therefore, when 6-mercaptopurine is 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 was hit by 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 of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-

administered with 6-mercaptopurine; therefore higher doses of the anticoagulant may be needed.

recommended

that

coagulation

tests

closely

monitored

when

anticoagulants

concurrently administered with 6-mercaptopurine.

4.6

Fertility, pregnancy and lactation

Fertility

The effect of Mercaptopurine therapy on human fertility is largely unknown but there are reports

of successful fatherhood/motherhood after receiving treatment during childhood or adolescence.

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 Purimmun 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 during

the treatment and for at least 3 months after end of treatment if either partner is receiving

Purimmun tablets.

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 and breastfeeding should be discontinued.

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 and such effects could not be attributed to the pharmacological properties of Purimmun

50 mg tablets.

4.8

Undesirable effects

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.

The main side effect of treatment with 6-mercaptopurine is bone marrow suppression leading to

leucopenia and thrombocytopenia.

The following definitions of frequencies are used:

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

cannot be estimated from the available data

Organ system

Frequency

Adverse effect

Infections and infestations

Uncommon

Bacterial and viral infections,

infections associated with

neutropenia

Neoplasms benign, malignant

and unspecified (including cysts

Very rare

Secondary Leukaemia and myelodysplasia

(see section 4.4); hepatosplenic T-cell

most

frequently

reported

side

effect

6-mercaptopurine

dose-dependent

myelosuppression, and as a result leukopenia and thrombocytopenia.

*In pediatric population

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 reaction via the national reporting system.

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,

lymphoma in patients with IBD (an

unlicensed indication) when used in

combination with anti-TNF

agents (see section 4.4.)

and polyps)

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).

Very common

Bone marrow suppression; leucopenia and

thrombocytopenia

Blood and lymphatic system

disorders

Common

Anemia

Rare

Hypersensitivity reactions with the following

manifestations have been reported: Arthralgia;

skin rash; drug fever.

Immune system disorders

Very rare

Hypersensitivity reactions with the following

manifestations have been reported: Facial

oedema

Uncommon

Anorexia

Metabolism and nutrition

disorders

Not known

Hypoglycaemia *

Common

Nausea; vomiting; pancreatitis in the IBD

population (an unlicensed indication)

Rare

Oral ulceration, pancreatitis (in the licensed

indications).

Gastrointestinal disorders

Very rare

Intestinal ulceration.

Common

Biliary stasis; hepatotoxicity

Hepatobiliary disorders

Rare

Hepatic necrosis

Rare

Alopecia.

Skin and subcutaneous tissue

disorders

Not known

Photosensitivity

Reproductive system and breast

disorders

Very rare

Temporary oligospermia.

resulting in myelosuppression

.

Hematological toxicity is likely to be more profound with chronic

overdosage than with a single ingestion of Purimmun. Liver dysfunction and 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

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Cytostatic, ATC-Code: L01BB02.

6-mercaptopurine is an inactive pro-drug that acts as purine antagonist after cellular uptake and

intracellular conversion into thioguanine-nucleotides 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.

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

Pharmacokinetics

Absorption

The bioavailability of oral 6-mercaptopurine shows considerable inter-individual variability.

When administered at a dosage of 75 mg/m2 to seven pediatric 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.

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, with no one enzyme predominating. Because of the complex metabolism,

inhibition of one enzyme does not explain all cases of lack of 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 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 drug 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/m

and 0.9

(+/-0.3) hours respectively.

Special Patient Populations

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. Since little is known

about the active metabolites of 6-mercaptopurine in renal impairment, consideration should be

given to reducing the dosage in patients with impaired renal function

(see Dosage and

Administration)

6-mercaptopurine and/or its metabolites are eliminated by hemodialysis, 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

6-Mercaptopurine, in common with other antimetabolites, is potentially mutagenic in man and

chromosome damage has been reported in mice, rats and man.

Teratogenicity

6-Mercaptopurine causes embryolethality and severe teratogenic effects in the mouse, rat,

hamster and rabbit at doses that are nontoxic to the mother. 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

Maize starch

Starch, pregelatinized

Stearic acid

Magnesium stearate

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years

6.4

Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

Store in the original glass container in order to protect from light.

6.5

Nature and contents of container

Purimmun 50 mg tablets are packed in amber glass container and a child-proof propylene cap

with silicagel.

25 tablets in amber glass container.

25 tablets/pack

50 (2x25) tablets/pack

6.6

Special precautions for disposal and other handling

Safe handling:

It is recommended that Purimmun tablets should be handled following the prevailing local

recommendations and/or regulations for the handling and disposal of cytotoxic drugs.

Anyone handling Purimmun should wash their hands before and after administering a dose. To

decrease the risk of exposure, parents and care givers should wear disposable gloves when

handling Purimmun.

Purimmun contact with skin or mucous membrane must be avoided. If Purimmun comes into

contact with skin or mucosa, it should be washed immediately and thoroughly with soap and

water.

Women who are pregnant, planning to be or breast-feeding should not handle Purimmun.

Parents / care givers and patients should be advised to keep Purimmun out of the reach and sight

of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.

Disposal

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

requirements for cytotoxic drugs.

7.

MARKETING AUTHORISATION HOLDER

[to be completed nationally]

8.

MARKETING AUTHORISATION NUMBER

[to be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<Date of first authorisation: {DD month YYYY}>

10.

DATE OF REVISION OF THE TEXT

22 April 2021

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