Mercaptopurine vis

Package leaflet: Information for the patient

MERCAPTOPURINUM VIS,
50 mg, tablets
Mercaptopurinum
Please read this leaflet carefully before taking this medicine, because it contains important
information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, please ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm someone else, even if their symptoms are the same.
• If you experience any adverse reactions, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of the leaflet:

1. What MERCAPTOPURINUM VIS is and what it is used for
2. Important information before taking MERCAPTOPURINUM VIS
3. How to take MERCAPTOPURINUM VIS
4. Possible side effects
5. How to store MERCAPTOPURINUM VIS
6. Contents of the pack and other information

1. What MERCAPTOPURINUM VIS is and what it is used for
Mercaptopurine is a cytotoxic agent, meaning it inhibits cell division and exerts toxic effects on rapidly dividing cells.
It is used to achieve remission and for maintenance therapy in:

• Acute lymphoblastic leukemia (excessive proliferation of lymphocytes),
• Acute myeloblastic leukemia (excessive proliferation of myeloblasts, i.e., immature white blood cells).
  It may also be used in chronic granulocytic leukemia (excessive proliferation of granulocytes).
  The drug is used in the treatment of ulcerative colitis and Crohn's disease (inflammatory bowel disease).

2. Important information before taking MERCAPTOPURINUM VIS

When not to use MERCAPTOPURINUM VIS:

• If the patient is allergic to 6-mercaptopurine or any of the other ingredients of this medicine (listed in section 6)
• Pregnancy
• Severe leukopenia (white blood cell count less than 1,500/μL, neutrophil count less than 200/μL)
• Severe thrombocytopenia (platelet count less than 75,000/μL)
• Bone marrow suppression
• Severe renal impairment
• Severe hepatic impairment
  The physician will decide whether the drug can be administered depending on the patient's condition.

Warnings and precautions
Before starting treatment with Mercaptopurinum VIS, discuss this with your doctor.
In patients receiving immunosuppressive therapy, administration of Mercaptopurinum VIS may increase the risk of developing:

• Tumors, including skin cancer; therefore, during treatment with Mercaptopurinum VIS, excessive exposure to sunlight should be avoided, protective clothing should be worn, and sunscreen products with high protection factor should be used.
• Lymphoproliferative disorders: treatment with Mercaptopurinum VIS increases the risk of developing a type of tumor called lymphoproliferative disorder; concomitant use of treatment regimens containing multiple immunosuppressive drugs (including thiopurines) may lead to death.
  o Concurrent use of multiple immunosuppressive drugs increases the risk of lymphatic system disorders caused by viral infection [Epstein-Barr virus (EBV)-related lymphoproliferative disorders].
  Administration of Mercaptopurinum VIS may lead to an increased risk of:
  • Development of a severe condition called macrophage activation syndrome (excessive activation of white blood cells associated with inflammation), usually occurring in patients with specific types of arthritis.
    Special caution is required in elderly patients, children, and patients with impaired liver or kidney function. In such cases, the physician will determine the appropriate dose based on the patient's condition.
    Treatment with mercaptopurine may cause bone marrow suppression leading to leukopenia (lower than normal white blood cell count), thrombocytopenia (lower than normal platelet count), and less frequently anemia (lower than normal hemoglobin level). During treatment, the physician will monitor blood parameters at intervals depending on the patient's condition and, in case of excessive reduction in white blood cells and platelets, will decide on further management.
    Bone marrow suppression is reversible. After discontinuation of mercaptopurine, bone marrow function returns to normal.
    The drug's action may increase susceptibility to infections, delay wound healing, and cause bleeding from the gums.
    The patient should maintain proper oral hygiene and complete any dental procedures before starting therapy with 6-mercaptopurine.
    Due to increased risk of infection during 6-mercaptopurine treatment, the physician may, when justified, initiate prophylactic antibiotic therapy.
    Patients with congenital deficiency of the enzyme thiopurine methyltransferase (TPMT) may be highly sensitive to the effects of 6-mercaptopurine and may experience rapid-onset bone marrow suppression induced by this drug.
    Mercaptopurine may damage the liver; therefore, liver function parameters (AspAT, AlAT, and bilirubin) should be monitored, especially in patients previously diagnosed with liver disease or those receiving other hepatotoxic drugs.
    During treatment, there is a risk of excessive increase in serum uric acid levels and/or excessive urinary excretion of uric acid, leading to urate nephropathy (kidney disease). The physician will monitor these parameters.
    If symptoms of jaundice occur—yellowing of the skin, mucous membranes, and whites of the eyes—the patient should contact the physician immediately. The physician will decide whether treatment should be discontinued.

Mercaptopurinum VIS and other medicines
Inform your doctor about all medicines currently or recently taken, as well as any medicines you plan to take.
Cross-resistance usually occurs between 6-mercaptopurine and 6-thioguanine.
The physician may decide to adjust the dosage of concomitant medicines when 6-mercaptopurine is administered with:

• Other drugs that suppress bone marrow function.
• Warfarin (6-mercaptopurine reduces its anticoagulant effect).
• Allopurinol, thiopurinol, and oxypurinol (prolong and enhance the effect of 6-mercaptopurine).
• Drugs inhibiting TPMT, such as olsalazine, mesalazine, or sulfasalazine (increase bone marrow suppression).
  Due to reduced immunity, vaccine responses may be weakened.
  During treatment with 6-mercaptopurine, vaccination with live microbial vaccines should be avoided.

Infections
Patients treated with Mercaptopurinum VIS have an increased risk of viral, fungal, and bacterial infections, which may be more severe. See also section 4.
Before starting treatment, inform your doctor if the patient has had chickenpox, shingles, or hepatitis B (liver disease caused by virus).

NUDT15 gene mutation
If the patient has a congenital mutation in the NUDT15 gene (a gene responsible for the metabolism of the drug Xaluprine in the body), they are at increased risk of infections and hair loss; therefore, the physician may decide to reduce the dose in such cases.

Mutagenicity and carcinogenicity:
An increased number of chromosomal mutations in peripheral lymphocytes has been observed in patients during treatment.
The potential carcinogenic effect of 6-mercaptopurine on DNA should be considered.
Isolated cases of non-lymphocytic acute leukemia or myeloid leukemia have been reported in patients who received 6-mercaptopurine in combination with other drugs for the treatment of non-neoplastic diseases.
During treatment, the physician will periodically check blood morphology, platelet count, and liver and kidney function parameters.
If adverse effects such as decreased levels of certain blood cells (granulocytes, platelets) occur, the physician will decide whether to reduce the dose or discontinue treatment.

Mercaptopurinum VIS with food and drink:
The medicine should preferably be taken after a meal, with water.

Other:
When splitting tablets, avoid dispersing dust or particles, and do not touch them with bare hands.
Any unused product or waste material should be disposed of in accordance with local regulations.

Use of Mercaptopurinum VIS in patients with impaired kidney and/or liver function:
In patients with impaired liver or kidney function, the physician will individually determine the dose.

Use of Mercaptopurinum VIS in elderly patients:
Studies have not been conducted in elderly humans. In these patients, the physician will monitor kidney and liver function and may decide to adjust the dosage.

Pregnancy, breastfeeding, and effects on fertility
During pregnancy, breastfeeding, or if pregnancy is suspected or planned, consult your doctor before using this medicine.
In each individual case, the physician will weigh the potential risk to the fetus against the expected benefit to the mother.
Appropriate contraceptive measures are recommended if either partner is being treated with mercaptopurine.
Women receiving Mercaptopurinum VIS should not breastfeed.

Driving and operating machinery
There is no data on the effect of 6-mercaptopurine on the ability to drive or operate machinery; however, during prolonged use, the decision should be left to the physician.

Mercaptopurinum VIS contains lactose.
If the patient has previously been diagnosed with intolerance to certain sugars, the patient should consult a doctor before taking this medicine.

3. How to use MERCAPTOPURINUM VIS

This medicine should always be used as directed by the physician.
If in doubt, consult your doctor.
Treatment should be initiated in a hospital setting or in specialist outpatient clinics under the supervision of a physician experienced in administering this medicine.
Mercaptopurinum VIS is administered orally, after a meal.

Use in children
In adults and children, the usual initial dose is 2.5 mg/kg body weight/day or 50 to 75 mg/m² body surface area per day. Tablets may be divided into equal doses. The dose and duration of treatment depend on the type and dosage of other cytotoxic drugs administered concomitantly with mercaptopurine. If no therapeutic effect is observed within 4 weeks, the physician may decide to increase the dose up to the maximum of 5 mg/kg body weight/day.
When concomitant administration with allopurinol, thiopurinol, or oxypurinol is necessary, the physician will individually adjust the dosage.

In patients with ulcerative colitis or Crohn's disease, the usual dose is 1 to 1.5 mg/kg body weight/day.

If you feel the medicine's effect is too strong or too weak, consult your doctor.

Use of a higher than recommended dose of Mercaptopurinum VIS

Early signs of overdose may include gastrointestinal symptoms such as nausea, vomiting, diarrhea, and loss of appetite. Chronic overdose may lead to a more pronounced reduction in the number of certain blood cells (leukocytes and platelets). Liver damage as well as inflammation of the stomach and intestines may also occur.

Management in case of overdose

Since there is no known antidote for mercaptopurine overdose, it is essential to monitor the patient's blood morphology so that appropriate treatment (e.g., blood transfusion) can be administered if adverse effects occur. Activated charcoal or gastric lavage should be administered within 60 minutes after ingestion of mercaptopurine, as they will otherwise be ineffective.

If a higher than recommended dose has been taken, seek immediate medical advice from a doctor or pharmacist.

Missed dose of Mercaptopurinum VIS

Take the next dose as soon as possible.
Do not take a double dose to make up for a missed dose.

Stopping Mercaptopurinum VIS

Do not discontinue treatment unless instructed by your doctor. If you have any further questions regarding the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.
The adverse effects are listed below by MedDRA organ system and class, and within each group according to frequency, from most common to least common:

• Very common: occurs in more than 1 in 10 patients;
• Common: occurs in 1 to 10 in 100 patients;
• Uncommon: occurs in 1 to 10 in 1,000 patients;
• Rare: occurs in 1 to 10 in 10,000 patients;
• Very rare: occurs in less than 1 in 10,000 patients;
• Frequency not known: cannot be estimated from the available data.

Blood and lymphatic system disorders:
During treatment with 6-mercaptopurine, leukopenia (lower than normal white blood cell count) and thrombocytopenia (lower than normal platelet count) are common. Rarely: megaloblastic anemia (presence in blood and bone marrow of large, immature red blood cells) and macrocytosis (red blood cells larger than normal). Very rarely: bone marrow failure. Frequency not known: acute myeloblastic leukemia (excessive proliferation of myeloblasts, i.e. immature white blood cells) – the relationship to 6-mercaptopurine therapy requires confirmation.
These disorders may appear several weeks or even months after discontinuation of 6-mercaptopurine therapy. Bone marrow suppression is the primary manifestation of the toxic effect of 6-mercaptopurine. It may persist for a considerable time after stopping the drug and is often related to the activity of thiopurine methyltransferase (TPMT) enzyme.

Renal and urinary disorders:
During treatment with 6-mercaptopurine, hyperuricemia (increased blood levels of uric acid) and/or hyperuricosuria (increased excretion of uric acid in urine) are common, as well as gout attacks. Accumulation of uric acid results from cell destruction and release of substances called purines. Your doctor will initiate appropriate treatment. Rarely, crystalluria (presence of crystals in urine) and hematuria (blood in urine) have been observed, and very rarely renal failure, especially after administration of high doses.

Metabolism and nutrition disorders:
Nausea (especially during the initial phase of treatment), vomiting, and loss of appetite are common. Rarely, inflammation of gastrointestinal and oral mucosa, diarrhea, oral ulcers, increased blood amylase levels, and acute pancreatitis may occur.

Hepatobiliary disorders:
Jaundice (yellowing of the skin and whites of the eyes) is common, as well as increased levels of conjugated bilirubin, transaminases, and alkaline phosphatase. Liver function abnormalities and cholestatic jaundice (caused by obstruction of bile flow) usually resolve quickly after discontinuation of treatment. Rarely, hepatitis occurs; very rarely, liver failure (including hepatocellular necrosis) and portal hypertension (increased pressure in the portal vein entering the liver) may occur.

General disorders and administration site conditions:
Skin and subcutaneous tissue disorders during 6-mercaptopurine treatment are rare. Rare skin changes include erythema, nodular lesions, lichenoid eruptions, and Sweet’s syndrome. Very rarely, alopecia, palmoplantar erythema, and skin pigmentation changes may occur.

Rarely observed: decreased resistance to infections; very rarely: photosensitivity, fatigue, early morning hypoglycemia, drug-induced fever; frequency not known: interstitial lung disease, herpes zoster, phlebitis, and hypersensitivity reactions.

Very rarely, male infertility has been reported, which resolves after discontinuation of treatment.

Other adverse effects include:
Rare (occur in less than 1 in 1,000 patients):

• Various types of tumors, including blood cancers, lymphatic system cancers, and skin cancer.

If any of the following adverse effects occur, you should inform your doctor or seek immediate medical attention at a hospital:
Any symptom indicating fever or infection (sore throat, oral pain, or problems with urination).
If any adverse effects occur, including any possible adverse effects not listed in this leaflet, consult your doctor.

Reporting of adverse effects
If any adverse effects occur, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. Adverse effects can be reported directly to the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: +48 22 49-21-301, fax: +48 22 49-21-309, e-mail: [email protected]
Reporting adverse effects helps to provide more information on the safety of this medicine.
Adverse effects can also be reported to the marketing authorization holder.

5. How to store Mercaptopurinum VIS

Keep this medicine out of sight and reach of children.
Mercaptopurinum VIS should be stored below 25°C in a dry place.
Do not use this medicine after the expiry date stated on the packaging (label and carton) following "Expiry date". The expiry date refers to the last day of the stated month.

6. Contents of the package and other information

What Mercaptopurinum VIS contains

• The active substance is 50 mg of 6-mercaptopurine.
• The other ingredients are: potato starch, lactose, povidone, talc, magnesium stearate.

What Mercaptopurinum VIS looks like and contents of the pack
Pack: an amber glass jar or tablet container containing 30 tablets, in a cardboard box.
Marketing Authorisation Holder and Manufacturer
Zakłady Chemiczno-Farmaceutyczne ,,VIS” Spółka z o.o.
ul. Św. Elżbiety 6a
41-905 Bytom
tel./fax (32) 2589555
e-mail: [email protected]
For further information, please contact the local representative of the Marketing Authorisation Holder.