AZATHIOPRINE 25 MG FILM-COATED TABLETS - patient leaflet, side effects, dosage

What Azathioprine is and what it is used for

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What you need to know before you take Azathioprine

3 [How to take Azathioprine

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Possible side effects

5 [

How to store Azathioprine

6 [Contents of the pack and other information

What Azathioprine is and what it is used for

Azathioprine belongs to a group of medicines called immunosuppressants. These work by reducing the strength of the body's immune system. Azathioprine may be taken long-term as it can take weeks or months before an effect is seen.

Azathioprine is used to treat the following:

• To prevent the body from rejecting kidney, liver or heart transplants
• Inflammatory bowel disease (Crohn's disease or ulcerative colitis)
• Severe inflammatory disease of the joints (rheumatoid arthritis)
• Long-term inflammation of skin and/or intestines (systemic lupus erythematosus)
• Inflammation of the skin and muscles (dermatomyositis, polymyositis)
• Inflammation of the liver (hepatitis)
• Inflammation of the walls of the arteries (polyarteritis nodosa)
• Increased breakdown of red blood cells due to the presence of auto-antibodies active at body temperature (warm) causing anaemia (looking pale and feeling tired)
• Autoimmune disorder where the number of platelets circulating is reduced by the immune system destroying them, causing a rash and an increased tendency to bleed, persisting longer than 6 months without a specific cause and is not responsive to conventional treatment (chronic refractory idiopathic thrombocytopenic purpura)
• Blistering of the skin (pemphigus vulgaris)

What you need to know before you take Azathioprine

Do not take Azathioprine if:

• You are allergic to Azathioprine, 6-mercaptopurine

(a derivative of Azathioprine) or any of the other ingredients of this medicine (see section 6 „Contents of the pack and other information“)

Warnings and precautions

Talk to your doctor before taking Azathioprine:

• If you are going to have a vaccination (see „Other medicines and Azathioprine“ section)
• If you are currently taking ribavirin (see „Other medicines and Azathioprine“ section)
• If you suffer from kidney or liver problems
• If you have had Hepatitis B, a liver disease caused by a virus
• If you suffer from Lesch-Nyhan Syndrome, a rare hereditary disorder caused by a deficiency of the enzyme HPRT (hypoxanthine-guanine-phosphoribosyl­transferase)
• If you have, have been exposed to or have ever suffered from chickenpox or shingles (varicella zoster virus infection) as the infection can become severe if you are taking immunosuppressants
• If you are showing signs or symptoms (headache, loss of co-ordination, clumsiness, loss of speech, memory loss, vision problems, weakness of the legs and arms that gets worse) of having Progressive Multifocal Leukoencephalopathy [PML] (a rare infection caused by a virus that damages the material covering and protecting nerves in the brain) as treatment with Azathioprine should be withheld (see section 4 „Possible side effects, Very rare side effects…“)
• If you have an inherited mutation in the NUDT15 gene (a gene which is involved in the break-down of Azathioprine in the body)
• If you suffer from an inherited condition where your body produces too little of the enzyme thiopurine methyltransfe­rase (TPMT)
• If you or your partner are pregnant or planning to become pregnant (see section „Pregnancy, breast-feeding and fertility“)
• If you are receiving immunosuppressive therapy, taking Azathioprine could put you at greater risk of: tumours, including skin cancer. Therefore, avoid excessive exposure to sunlight and UV light, wear protective clothing and use a sunscreen with a high protection factor
• If you are receiving treatment with multiple immunosuppressants (including thiopurines) as this may increase the risk of a type of cancer called lymphoproliferative disorder and disorders of the lymph system due to a viral infection (Epstein-Barr virus (EBV)-associated lymphoproliferative disorders)
• If you suffer with autoimmune conditions such as inflammatory bowel disease (IBD), as this could put you at greater risk of developing a life-threatening disorder called Macrophage Activation Syndrome (excessive activation of white blood cells associated with inflammation)

Other medicines and Azathioprine

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including those obtained without a prescription. This includes herbal medicines.

Medicines which may interact with or be affected by Azathioprine:

Before a surgical procedure tell the anaesthesiologist that you are taking azathioprine because muscle relaxants used during anaesthesia may interact with azathioprine

• Medicines used to treat gout such as allopurinol, oxipurinol, thiopurinol or other xanthine oxidase inhibitors, such as febuxostat. If these medicines are given concomitantly with Azathioprine, the dose of Azathioprine must be reduced to a quarter of the original dose
• Muscle relaxants such as atracurium, rocuronium, cisatracurium or suxamethonium (also known as succinylcholine) and tubocurarine (neuromuscular blocking agents)
• Medicines used to treat chronic inflammatory bowel diseases such as olsalazine, mesalazine, sulfasalazine (aminosalicylate derivatives) as lower doses of Azathioprine may need to be considered when given concomitantly
• Medicines used to thin the blood such as warfarin, acenocoumarol (anti-coagulants)
• Medicines used to treat high blood pressure or heart failure e.g. captopril (Angiotensin-Converting Enzyme [ACE] Inhibitors)
• Medicines used to treat infections such as trimethoprim, sulphamethoxazole also known as co-trimoxazole (antibiotics)
• Medicines used to treat stomach ulcers such as cimetidine (H2-receptor antagonist)
• Medicines used to treat certain rheumatic disorders such as indomethacin (Non-Steroidal Anti-Inflammatory Drugs [NSAIDs])
• Cytostatic medicines (used to treat cancer)
• Medicines which may have a myelosuppressive effect (decrease in bone marrow activity resulting in fewer red and white blood cells and platelets) such as penicillamine (mainly used in the treatment of rheumatoid arthritis)
• Live vaccines and also inactive vaccines such as hepatitis B (see section 2 „Warnings and precautions“)
• Ribavirin, used to treat chronic hepatitis C
• Methotrexate, used to treat auto-immune conditions and cancers
• Infliximab, mainly used in the treatment of ulcerative colitis and Crohn's disease
• Azathioprine may be taken with food or on an empty stomach.
• Azathioprine should be taken 1 hour before or 2 hours after milk or dairy products.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Pregnancy

Do not take Azathioprine if you are pregnant, trying to become pregnant or think you may be pregnant.

Breast-feeding

It is recommended that women receiving Azathioprine should avoid breast-feeding (unless the benefits outweighs the potential risks) as 6-Mercaptopurine, a derivative of Azathioprine is passed into breast milk.

Fertility

The specific effect of Azathioprine on fertility is unknown. Adequate contraceptive precautions should be used when either partner is taking Azathioprine.

Driving and using machines

Azathioprine is not known to affect your ability to drive or use machinery. If you experience any side effect from this medicine, you may not be able to drive or operate machinery.

Azathioprine contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

How to take Azathioprine

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

• These tablets are to be taken orally and may be taken with food or on an empty stomach.
• These tablets should be taken at least 1 hour before or

2 hours after milk or dairy products.

Adults

You should be adequately monitored throughout the duration of treatment. Particular care should be taken to monitor your response and to reduce the maintenance dose to the lowest dose possible.

Organ transplants

• An initial dose of up to 5mg per kg of bodyweight per day may be given.
• The maintenance dose should range from 1–4mg per kg of bodyweight per day.
• Treatment with Azathioprine should be maintained indefinitely, even if only low doses are necessary, because of the risk of rejection.
• The starting dose is 1–3mg per kg of bodyweight per day and should be adjusted (within these limits) according to the effectiveness of treatment (which may be evident only after weeks or months).
• The maintenance dose should be reduced to the lowest dose possible. If no improvement occurs within 3 months, consideration should be given to withdrawing this medicine. However, for patients with inflammatory bowel disease, a treatment duration of at least 12 months should be considered as a response to treatment may not be apparent until after 3–4 months of treatment.

Kidney and/or liver disorders

If you suffer from kidney and/or mild to moderate liver disorders, the dose should be given at the lower end of the normal range.

TPMT (thiopurine S-methyltransferase) deficiency

• If you have (inherited) little or no TPMT activity (metabolic abnormality that increases the risk of adverse drug effects if you are treated with thiopurine medicines), you are at increased risk of severe toxicity from conventional doses of Azathioprine and generally will require substantial dose reduction.
• Most patients with heterozygous TPMT deficiency (intermediate TPMT enzyme activity) can tolerate recommended Azathioprine doses, but some may require dose reduction.

NUDT15 gene mutation

If you have an inherited mutation in the NUDT15 gene

(a gene which is involved in the break-down of Azathioprine in the body), you are at increased risk of severe toxicity and generally will require dose reduction.

Elderly

It is advisable to monitor kidney and liver function and to consider reducing the dose if there is impairment.

Use in children

The recommended doses are the same as those given for adults.

Children considered to be overweight may require doses at the higher end of the range and therefore close monitoring of response to treatment is recommended.

If you take more Azathioprine than you should

If you accidentally take too many tablets, contact your doctor or nearest hospital emergency department immediately for advice. Remember to take this leaflet or any remaining tablets with you.

Symptoms of overdose include: ulcers in the throat, unexplained infections, bruising and bleeding. These signs are more likely to occur following long-term overdose rather than a single sudden overdose. Effects of a single overdose may include feeling and/or being sick (nausea, vomiting), diarrhoea, mild reduction in white blood cells (leukopenia) and mild abnormalities in liver function.

If you forget to take Azathioprine

Take it as soon as you remember, unless it is time for your next dose. If you miss a dose do not take a double dose to make up for a forgotten dose.

If you stop taking Azathioprine

It is important that you keep taking Azathioprine for as long as your doctor has told you to. Withdrawal of Azathioprine should always be a gradual process performed under close monitoring.

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

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Possible side effects

How to store Azathioprine

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

Seek medical advice immediately if you develop the following symptoms:

• Allergic reactions: swelling of the face, throat or tongue, difficulty breathing or dizziness.
• Severe blistering of the skin (toxic epidermal necrolysis), mouth, eyes and genitals (Stevens-Johnson syndrome)
• Various types of cancers including blood, lymph and skin cancers (see section 2, „Warnings and precautions“)
• You may develop a rash (raised red, pink or purple lumps which are sore to touch), particularly on your arms, hands, fingers, face and neck, which may also be accompanied by a fever (Sweet's Syndrome, also known as acute febrile neutrophilic dermatosis). The rate at which these side effects occur is not known (cannot be estimated from available data).
• A certain type of lymphomas (hepatosplenic T-cell lymphoma)
• Any evidence of infections, unexpected bruising or bleeding as these may be signs of bone marrow depression. This condition is reversible if Azathioprine is withdrawn early enough
• Yellowing of the skin or whites of the eyes (jaundice)
• Or if you come into contact with anyone who is suffering from chickenpox or shingles.
• Viral, fungal and bacterial infections (if you are a transplant patient receiving Azathioprine in combination with other immunosuppressants)
• A reduction in white blood cells (leukopenia)
• Reduction of bone marrow function
• A reduction in blood platelets, which increases risk of bleeding or bruising (thrombocytopenia)
• Feeling sick (nausea). This may be relieved by taking the tablets after meals

Uncommon side effects (may affect up to 1 in 100 people)

• Viral, fungal and bacterial infections in other patient populations
• Looking pale and feeling tired (anaemia)
• Inflammation of the pancreas (pancreatitis)
• Build-up of bile acids in the bloodstream causing persistent itch (cholestasis) and worsening of liver function tests (usually reversible on withdrawal of treatment)
• Various types of cancers including soft tissue (sarcomas), uterine and cervical (see section 2, „Warnings and precautions“)
• Life-threatening liver damage
• Hair loss (alopecia)
• Blood and bone marrow disorders
• Virus-associated PML following the use of Azathioprine in combination with other immunosuppressants (see section 2, „Warnings and precautions“)
• Inflammation of the lungs (reversible pneumonitis)
• Inflammation which causes abdominal pain or diarrhoea (colitis/diver­ticulitis)
• Bowel perforation if you are a transplant patient
• Severe diarrhoea if you suffer from inflammatory bowel disease
• Abnormal sensitivity of the skin to sunlight (photosensitivity)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date which is stated on the carton/blister after EXP. The expiry date refers to the last day of that month.
• Store below 25°C. Protect from light.
• Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

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Contents of the pack and other information

What Azathioprine contains:

• Each 25mg tablet contains 25mg of Azathioprine
• Each 50mg tablet contains 50mg of Azathioprine

The other ingredients are: lactose monohydrate, maize starch, povidone, colloidal silicon dioxide, magnesium stearate, hypromellose, microcrystalline cellulose, polyoxyl-8-stearate, talc and titanium dioxide (E171).

What Azathioprine looks like and contents of the pack:

• Azathioprine 25mg are white to yellowish-white, round, biconvex, film-coated tablets of diameter 6.0–6.4mm and height of 3.1–3.7mm, with no score-line
• Azathioprine 50mg are white to yellowish-white, biconvex, film-coated tablets, of diameter 7.9–8.3mm and height of 3.6–4.2mm with a score-line on one side

Azathioprine is available in:

Azathioprine tablets are available in blister packs of:

• Azathioprine 25mg Tablets: 20, 28, 30, 50 or 100 tablets.
• Azathioprine 50mg Tablets: 30, 50, 56 or 100 tablets.

Not all pack sizes may be marketed.

Product Licence Numbers:

• Azathioprine 25mg Tablets: PL 11311/0475
• Azathioprine 50mg Tablets: PL 11311/0476