Azathioprine vis

Package leaflet: Information for the patient

AZATHIOPRINE VIS, 50 mg, tablets
Azathioprinum
Please read this leaflet carefully before using the medicine, as it contains
important information for the patient.

• Keep this leaflet for future reference.
• If you have any questions, please consult your doctor, pharmacist, or nurse.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. The medicine may harm someone else, even if their symptoms are similar.
• If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Table of contents of the leaflet

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

1. What Azathioprine VIS is and what it is used for

Azathioprine is an immunosuppressive medicine. It is used as monotherapy or, more commonly, in combination with other medicines (usually corticosteroids):
in autoimmune diseases,
such as: systemic lupus erythematosus, severe rheumatoid arthritis, dermatomyositis, polymyositis, polyarteritis nodosa, pemphigus vulgaris-bullous pemphigoid, autoimmune haemolytic anaemia, chronic refractory thrombocytopenic purpura, autoimmune chronic hepatitis.
Azathioprine is used when these diseases do not respond to corticosteroid treatment, cannot be treated with corticosteroids, or require corticosteroid doses that cause severe adverse effects. In the latter case, azathioprine allows for reduction of maintenance steroid doses;
for the treatment of moderate to severe inflammatory bowel diseases,
such as: Crohn's disease or ulcerative colitis – in patients requiring corticosteroid treatment, in patients who do not tolerate corticosteroid treatment, or in patients whose disease is resistant to other standard basic treatments;
after organ transplantation,
such as: kidneys, heart, and liver, azathioprine is used to prolong the survival time of transplanted organs; after kidney transplantation – to reduce corticosteroid doses.
The medicine acts by preventing the proliferation of cells involved in the immune response.
Due to its mechanism of action, the therapeutic effect of the medicine may only become apparent after weeks or months of treatment.

2. Important information before using Azathioprine VIS

When not to use Azathioprine VIS:

• if the patient is allergic to azathioprine, 6-mercaptopurine, or any of the other ingredients of this medicine (listed in section 6);
• if the patient has leukopenia, i.e. reduced number of white blood cells (leukocytes) in a peripheral blood count;
• if the patient has low activity of an enzyme called thiopurine methyltransferase (TPMT);
• if the patient is pregnant or breastfeeding.

Warnings and precautions
Before starting treatment with Azathioprine VIS, discuss this with your doctor, pharmacist, or
nurse.
Liver damage
Treatment with Azathioprine VIS may affect the liver. Your doctor will regularly monitor liver function. If the patient develops symptoms of liver damage, inform the doctor immediately (see section 4 "Possible side effects").
Infections
Patients treated with Azathioprine VIS have an increased risk of viral, fungal, and bacterial infections, and infections may be more severe. See also section 4.
Before starting treatment, inform the doctor if the patient has ever had chickenpox, shingles, or hepatitis B (a liver disease caused by a virus).
NUDT15 gene mutation
If the patient has an inherited mutation in the NUDT15 gene (a gene responsible for the breakdown of Azathioprine VIS in the body), there is an increased risk of infections and hair loss. In such cases, the doctor may decide to reduce the dose.
Vitamin B3 deficiency (pellagra)
Contact the doctor immediately if the patient develops diarrhoea, localized pigmented rash, memory impairment, logical thinking, or other cognitive impairments, as these symptoms may indicate vitamin B3 deficiency (niacin deficiency/pellagra).
In patients receiving immunosuppressive therapy, treatment with Azathioprine VIS may increase the risk of:

• tumours, including skin cancer; therefore, during treatment with Azathioprine VIS, excessive exposure to sunlight should be avoided, protective clothing should be worn, and sunscreen products with high sun protection factor should be used;
• lymphoproliferative disorders: treatment with Azathioprine VIS increases the risk of developing a type of tumour called lymphoproliferative disorder; concomitant use of treatment regimens containing multiple immunosuppressive drugs (including thiopurines) may lead to death; simultaneous use of multiple immunosuppressive drugs increases the risk of lymphatic system disorders caused by viral infection [Epstein-Barr virus (EBV)-associated lymphoproliferative disorders].

Treatment with Azathioprine VIS may increase the risk of:

• developing a serious condition called macrophage activation syndrome (excessive activation of white blood cells associated with inflammation), which usually occurs in people with certain types of arthritis.

Special caution is required when using Azathioprine VIS:

• in patients with liver impairment; the doctor will order regular complete blood counts and liver function tests. Depending on the results, the dose of azathioprine may be reduced.
• in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome); azathioprine has limited therapeutic efficacy and therefore its use is not recommended in patients with this syndrome.

Use in elderly patients
In elderly patients, lower doses within the lower range of the recommended dosage are recommended. To achieve full therapeutic effect, the drug must be administered for several weeks to several months. Particular caution is required when combining azathioprine with immunosuppressive drugs with different mechanisms of action, such as: steroids, cyclosporine, or antithymocyte globulin (ATG).
Azathioprine VIS and other medicines
Inform your doctor or pharmacist about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take.
In particular, inform the doctor if the patient is taking:

• muscle relaxants, e.g. tubocurarine, pancuronium, and succinylcholine (used during surgery);
• anticoagulants, such as warfarin (medicines preventing blood clots);
• aminosalicylates, such as olsalazine, mesalazine, or sulfasalazine (medicines used, among others, in the treatment of ulcerative colitis and Crohn's disease);
• allopurinol, oxypurinol, thiopurinol, or other xanthine oxidase inhibitors, such as febuxostat (medicines used mainly in the treatment of gout); in such cases, the azathioprine dose should be reduced to even ¼ of the usual dose;
• cytarabine (used in the treatment of leukaemia and certain types of lymphoma);
• cimetidine (used in the treatment of peptic ulcer disease);
• other drugs that suppress bone marrow function, e.g. penicillamine (used, among others, in the treatment of rheumatoid arthritis);
• cysteine – the effect of azathioprine may be weakened;
• co-trimoxazole (an antibiotic used to treat bacterial infections);
• captopril (used, among others, in arterial hypertension);
• indomethacin (a pain-relieving and anti-inflammatory drug);
• gold salts and antimalarial drugs;
• if the patient is taking azathioprine, they should inform the anaesthetist before undergoing surgery, as muscle relaxants used during anaesthesia may interact with azathioprine.

Vaccination during treatment with Azathioprine VIS
During treatment with azathioprine, patients should not be vaccinated with vaccines containing live microorganisms. A weakened immune response to inactivated vaccines, e.g. against hepatitis B virus, is possible.
Azathioprine VIS with food and drink
The medicine should preferably be taken after meals, with water.
Pregnancy, breastfeeding, and effects on fertility
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to have a child, she should consult her doctor or pharmacist before using this medicine.
The medicine is contraindicated in pregnant women.
Breastfeeding must be discontinued during treatment.
If intense itching without rash occurs during pregnancy, contact the doctor immediately. Nausea and loss of appetite may also occur together with itching, indicating a condition called intrahepatic cholestasis of pregnancy (a liver disorder occurring during pregnancy). This condition may harm the unborn child.
Driving and operating machinery
No studies have been conducted on the effect of the medicine on the ability to drive vehicles or operate machinery. However, caution should be exercised due to possible side effects.
Azathioprine VIS contains lactose
If the patient has previously been diagnosed with intolerance to certain sugars, the patient should contact the doctor before taking this medicine.

3. How to use Azathioprine VIS

This medicine should always be used exactly as prescribed by the doctor. In case of doubt, consult
your doctor or pharmacist.
Dosage in organ transplantation
The medicine is administered orally after a meal, and the daily dose may be taken at once.
The dose will be individually determined by the doctor, depending on the patient's clinical condition and bone marrow function.
On the first day after organ transplantation – 5 mg/kg body weight per day, followed by a maintenance dose of 1 to 4 mg/kg b.w. per day.
This dose should be adjusted according to clinical response and hematological tolerance. Due to the risk of transplant rejection, treatment with azathioprine should be continued lifelong, although sometimes using very low doses of the drug.
Dosage in other indications
In other indications, the medicine is used in adults and children at a daily dose of 1 to 3 mg/kg b.w.
After a clear clinical effect has been achieved, the treating physician may consider reducing the maintenance dose to the lowest possible level. The dose may range from less than 1 mg/kg b.w. to 3 mg/kg b.w. If the patient's condition does not improve after 3 months of treatment, the physician may consider discontinuing Azathioprine VIS. However, in patients with inflammatory bowel disease, the physician may consider a treatment duration of at least 12 months, and response to treatment may not become clinically evident until after 3 to 4 months of therapy.
Dosage in elderly patients
In elderly patients, the physician will recommend lower doses within the lower end of the recommended range. Particular caution should be exercised when azathioprine is used concomitantly with immunosuppressive drugs with a different mechanism of action, such as steroids, cyclosporine, or antithymocyte globulin (ATG).
Dosage in patients with renal and/or hepatic impairment
Patients with impaired liver or kidney function should be given the lowest recommended doses (1 mg/kg b.w. per day), with regular monitoring of hematopoietic system function. If signs of hematopoietic system damage (signs of infection, unexplained petechiae, bleeding, or other signs of bone marrow suppression) or liver damage occur, contact your doctor.
If you feel the medicine's effect is too strong or too weak, consult your doctor.
Use of a higher than recommended dose of Azathioprine VIS
If more medicine is taken than prescribed, contact your doctor or pharmacist immediately.
Management in case of overdose
Overdose initially leads to a decrease in the number of leukocytes and platelets. Further consequences may include more pronounced bone marrow suppression and pancytopenia (reduction in all blood cell elements: red blood cells, white blood cells, and platelets). Other adverse effects related to bone marrow toxicity may also become more severe.
In extreme cases, if cytopenia (reduced blood cell count) poses a risk of complications (severe thrombocytopenia, agranulocytosis), symptomatic hematological treatment may be required.
Missed dose of Azathioprine VIS
If a dose of azathioprine is missed, take it as soon as possible, unless it is almost time for the next dose. Then continue with the normal dosing schedule. Do not take a double dose to make up for a missed dose.
Stopping Azathioprine VIS
Do not stop taking this medicine unless instructed by your doctor. If you have any further questions about 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.
If any of the serious adverse effects listed below occur, stop taking Azathioprine VIS immediately and contact your doctor straight away or go immediately to the nearest hospital emergency department:

• reversible brain swelling with symptoms such as severe headache, vision disturbances, seizures, confusion and reduced level of consciousness, with or without high blood pressure [Posterior Reversible Encephalopathy Syndrome (PRES)];
• allergic reactions, which may include: general fatigue, dizziness, nausea, vomiting or diarrhoea, high body temperature (fever), tremor or chills, skin redness, skin nodules or rash, muscle or joint pain, change in urine colour (kidney function disorders), chest pain, shortness of breath or leg swelling (heart function disorders), confusion, feeling faint or weak (due to low blood pressure);
• skin rash (raised, red, pink or purple painful lumps), particularly on arms, hands, fingers, face and neck, accompanied by fever (Sweet’s syndrome, also known as acute febrile neutrophilic dermatosis). The frequency of these adverse effects is unknown (cannot be estimated from available data);
• liver function disorders and cholestasis, with symptoms such as yellowing of the skin or whites of the eyes (these may be common adverse effects). These symptoms may also be associated with hypersensitivity reactions. In patients, especially those undergoing long-term treatment, cases of severe, potentially life-threatening liver damage have been reported (e.g. liver injury, portal hypertension not related to liver cirrhosis, vascular disorders of the portal vein and hepatic sinusoids). Inform your doctor if you experience any of the following symptoms: yellowing of the skin and whites of the eyes (jaundice), easy bruising, abdominal discomfort, loss of appetite, fatigue, nausea or vomiting. The frequency of these adverse effects is unknown (cannot be estimated from available data);
• blood or bone marrow problems, including symptoms such as: weakness, fatigue, paleness, easy bruising, unusual bleeding or infections;
• any sign indicating fever or infection (sore throat, mouth pain or problems with urination).

The following adverse effects have also been reported:

Very common (may affect more than 1 in 10 people)

• leukopenia (reduced white blood cell count)

Common (may affect up to 1 in 10 people)

• thrombocytopenia (reduced platelet count)
• low blood pressure
• heart rhythm disorders
• nausea, vomiting, loss of appetite

Uncommon (may affect up to 1 in 100 people)

• granulocytopenia (reduced granulocyte count), anaemia
• diarrhoea (in patients with inflammatory bowel disease, severe diarrhoea has been reported, recurring upon re-exposure to the medicine).

Rare (may affect up to 1 in 1000 people)

• viral, bacterial and fungal infections, particularly affecting the respiratory tract (especially in transplant patients),
• various types of tumours, including blood cancers, lymphatic system cancers and skin cancer.

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

• agranulocytosis (severe reduction in granulocytes), pancytopenia (reduction in all blood cells and platelets) and aplastic anaemia
• vasculitis
• pancreatitis (particularly after kidney transplantation or in patients with inflammatory bowel disease)
• colitis, diverticulitis and intestinal perforation (observed in organ transplant patients)
• reversible, interstitial, drug-induced lung inflammation
• alopecia (in many cases, this resolved spontaneously despite continuing treatment with a reduced dose of the medicine).

Frequency not known (frequency cannot be estimated from available data):

• vitamin B3 deficiency (pellagra) associated with pigmented skin rash, diarrhoea and disturbances in memory, logical thinking and other cognitive functions
• parotitis (inflammation of the salivary gland)
• tremor.

Reporting of adverse effects
If any adverse effects occur, including any adverse effects not listed in this leaflet, inform your doctor, pharmacist or nurse. Adverse effects can be reported directly to the Department for Monitoring Adverse Drug Reactions of the 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, website: https://smz.ezdrowie.gov.pl
Reporting adverse effects helps to provide more information on the safety of this medicine.
Adverse effects can also be reported to the marketing authorisation holder.

5. How to store Azathioprine VIS

Keep this medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging (label and carton). The expiry date refers to the last day of the stated month.
Store below 25°C, in the original packaging.

6. Contents of the packaging and other information

What Azathioprine VIS contains

• The active substance is azathioprine. One tablet contains 50 mg of azathioprine.
• The other components (excipients) are: potato starch, monohydrate lactose, povidone, talc, magnesium stearate.

What Azathioprine VIS looks like and contents of the packaging
Azathioprine VIS is in the form of light yellow, biconvex tablets marked with
“A/50” and a dividing score line on one side. The tablet can be divided into equal doses.
Packaging: amber glass jar with a polyethylene cap containing 30, 50 or 100 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.: +48 32 2589555
E-mail: [email protected]