Nordimet

Package leaflet: Information for the user

Nordimet 7.5 mg solution for injection in pre-filled pen, 10 mg solution for injection in pre-filled pen, 12.5 mg solution for injection in pre-filled pen, 15 mg solution for injection in pre-filled pen, 17.5 mg solution for injection in pre-filled pen, 20 mg solution for injection in pre-filled pen, 22.5 mg solution for injection in pre-filled pen, 25 mg solution for injection in pre-filled pen

methotrexate
Please read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to other people, even if their symptoms are the same as yours, because it may be harmful to them.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

1. What Nordimet is and what it is used for
2. What you need to know before using Nordimet
3. How to use Nordimet
4. Possible side effects
5. How to store Nordimet
6. Contents of the pack and other information

1. What Nordimet is and what it is used for

Nordimet contains the active substance methotrexate, which is indicated for:

• reducing inflammation or swelling, and
• reducing the activity of the immune system (the body's defence mechanism). An overactive immune system has been associated with inflammatory diseases.

Nordimet is a medicine used to treat several inflammatory conditions:

• active rheumatoid arthritis in adults. Active rheumatoid arthritis is an inflammatory condition affecting the joints;
• severe, active juvenile idiopathic arthritis affecting five or more joints (this is why the disease is called polyarticular), in patients who have had an inadequate response to non-steroidal anti-inflammatory drugs (NSAIDs);
• moderate to severe plaque psoriasis in adults eligible for systemic therapy, as well as severe psoriasis also affecting the joints (psoriatic arthritis) in adults;
• induction of remission in adults with moderate, steroid-dependent Crohn's disease, in combination with corticosteroids;
• maintenance of remission in Crohn's disease in adults who have responded to methotrexate, as monotherapy.

2. What you should know before using Nordimet

Do not use Nordimet if:

• you are allergic to methotrexate or to any of the other ingredients of this medicine

(listed in section 6)

• you have severe kidney disease (your doctor will determine whether you have severe kidney disease)
• you have severe liver disease (your doctor will determine whether you have severe liver disease)
• you have impaired bone marrow function (the system responsible for blood cell production)
• you consume large amounts of alcohol
• your immune system is compromised
• you have a severe or pre-existing infection, e.g., tuberculosis or HIV
• you have a gastrointestinal ulcer
• you are pregnant or breastfeeding (see section “Pregnancy, breastfeeding and fertility”)
• you are simultaneously receiving vaccination with live vaccines during treatment.

Warnings and precautions
Cases of acute pulmonary hemorrhage have been reported in patients with rheumatological diseases treated with methotrexate. If you notice blood in your saliva or after coughing, contact your doctor immediately.
Lymph node enlargement (lymphoma) may occur, and treatment must be discontinued.
Diarrhea may be a toxic effect of Nordimet and requires discontinuation of therapy. If you experience diarrhea, discuss it with your doctor.
Certain neurological disorders (encephalopathy/leukoencephalopathy) have been reported in cancer patients receiving methotrexate. These adverse effects cannot be excluded when methotrexate is used to treat other diseases.
If you, your partner, or your caregiver notice the onset or worsening of neurological symptoms, including generalized muscle weakness, visual disturbances, changes in thinking, memory, or orientation, leading to confusion and personality changes, contact your doctor immediately, as these may be symptoms of a very rare and serious brain infection called progressive multifocal leukoencephalopathy (PML).
Methotrexate may increase skin sensitivity to sunlight. Avoid strong sunlight and do not use sunbeds or tanning lamps without medical advice. To protect your skin from strong sunlight, wear appropriate clothing or use a sunscreen with a high protection factor.
Important information about Nordimet dosage
In the treatment of rheumatic diseases, skin disorders, and Crohn's disease, methotrexate must be used only once a week. Incorrect dosing of methotrexate may cause severe adverse effects, which can be fatal. Please read section 3 of this leaflet carefully.
Talk to your doctor before using Nordimet if:

• you have diabetes mellitus and are being treated with insulin
• you have inactive, long-lasting infections (e.g., tuberculosis, hepatitis B or C, shingles [herpes zoster])
• you have or have had liver or kidney disease
• you have impaired lung function
• you are severely overweight
• you have abnormal accumulation of fluid in the abdomen or in the pleural cavity (ascites, pleural effusion)
• you are dehydrated or in a condition causing dehydration (e.g., dehydration due to vomiting, diarrhea, or inflammation of the mouth and lips)

If you have experienced skin problems after radiation therapy (radiation dermatitis) or sunburn, these conditions may reappear during treatment with Nordimet.
Children, adolescents and elderly
Dosage instructions depend on the patient's body weight.
Use in children under 3 years of age is not recommended due to insufficient data on the use of this medicine in this age group.
Children, adolescents, and elderly patients treated with Nordimet must be closely monitored by the doctor to detect possible adverse effects as early as possible.
In elderly patients, the dose should be reduced due to age-related decline in liver and kidney function.
Special precautions for Nordimet treatment
Methotrexate temporarily affects sperm and egg production. Methotrexate may cause miscarriage and severe birth defects. During treatment with methotrexate and for at least 6 months after treatment ends, women must avoid becoming pregnant. Men must avoid fathering a child during treatment with methotrexate and for at least 3 months after treatment ends. See also section “Pregnancy, breastfeeding and fertility”.
Skin changes caused by psoriasis may worsen during treatment with Nordimet, especially upon exposure to ultraviolet radiation.
Recommended monitoring tests and precautions
Even when methotrexate is used at low doses, serious adverse effects may occur. To detect them early, your doctor should perform regular check-ups and laboratory tests.
Before starting therapy:
Before starting treatment, your blood will be tested to check whether you have sufficient blood cells. Your blood will also be analyzed to assess liver function and to detect hepatitis. Additionally, serum albumin (a blood protein), hepatitis status (liver infection), and kidney function will be evaluated. Your doctor may also decide to perform further liver tests, some of which may include liver imaging, while others may require a small liver tissue sample for more detailed examination.
Your doctor may also check for tuberculosis and may perform a chest X-ray or lung function tests.
During treatment:
Your doctor may perform the following tests:

• examination of the oral cavity and pharynx to detect mucosal changes such as inflammation or ulceration
• blood tests including complete blood count with measurement of blood cell counts and serum methotrexate levels
• blood tests to monitor liver function
• imaging tests to monitor liver condition
• liver biopsy (a small tissue sample taken from the liver for detailed examination)
• blood tests to monitor kidney function
• respiratory monitoring and, if necessary, lung function tests

It is very important that you attend these scheduled examinations.
If any of these test results are significant, your doctor will adjust your treatment accordingly.
Other medicines and Nordimet
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
It is especially important to inform your doctor if you are taking:

• other medications for rheumatoid arthritis or psoriasis such as leflunomide, sulfasalazine (a medicine used not only for arthritis and psoriasis but also for ulcerative colitis), aspirin, phenylbutazone, or amidopyrine
• cyclosporine (to suppress the immune system)
• azathioprine (a medicine used to prevent organ transplant rejection)
• retinoids (used to treat psoriasis and other skin diseases)
• anticonvulsant medicines (used to prevent seizures), such as phenytoin, valproate, or carbamazepine
• cancer treatments
• barbiturates (injections for anesthesia)
• tranquilizers
• oral contraceptives
• probenecid (used to treat gout)
• antibiotics (e.g., penicillin, glycopeptides, trimethoprim-sulfamethoxazole, sulfonamides, ciprofloxacin, cephalothin, tetracyclines, chloramphenicol)
• pyrimethamine (used for prevention and treatment of malaria)
• vitamin preparations containing folic acid
• proton pump inhibitors (medicines that reduce stomach acid production, used to treat severe heartburn or ulcers), such as omeprazole or pantoprazole
• theophylline (used to treat asthma)
• colestyramine (used to treat high cholesterol, itching, or diarrhea)
• NSAIDs, non-steroidal anti-inflammatory drugs (used to treat pain or inflammation)
• para-aminobenzoic acid (used to treat skin disorders)
• any vaccination with a live vaccine (must be avoided), such as those against measles, mumps, or yellow fever
• metamizole (synonyms: novaminsulfone, dipyrone) (a medicine to relieve severe pain and/or fever)
• nitrous oxide (a gas used in general anesthesia)

Nordimet with food, drinks and alcohol
During treatment with Nordimet, you must not drink alcohol and should avoid excessive coffee, caffeinated beverages, and black tea, as these may increase adverse effects or interfere with the effectiveness of Nordimet. Additionally, during Nordimet treatment, you should drink plenty of fluids to prevent dehydration (reduction of body fluids), which may increase Nordimet toxicity.
Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, consult your doctor before taking this medicine.
Pregnancy
Do not use Nordimet during pregnancy or if you are trying to become pregnant. Methotrexate may cause birth defects, harm the fetus, or cause miscarriage. It is associated with malformations affecting the skull, face, heart and blood vessels, brain, and limbs. Therefore, it is very important that pregnant women or women planning pregnancy are not treated with methotrexate. Thus, in women of childbearing potential, pregnancy must be ruled out before starting treatment using appropriate measures, such as a pregnancy test. During treatment with methotrexate and for at least 6 months after treatment ends, you must avoid pregnancy by using a reliable contraceptive method (see also section “Warnings and precautions”).
If you become aware or suspect you are pregnant during treatment, contact your doctor immediately for medical advice regarding the risk of harmful effects on the unborn child throughout the treatment period.
If you plan a pregnancy, consult your doctor, who may refer you to a specialist before the planned start of treatment.
Breastfeeding
You must not breastfeed during treatment with methotrexate, as methotrexate passes into breast milk. If your doctor considers methotrexate treatment absolutely necessary during breastfeeding, you must stop breastfeeding.
Male fertility
Available data do not indicate an increased risk of birth defects or miscarriages if the father takes less than 30 mg of methotrexate per week. However, a risk cannot be completely excluded. Methotrexate may be genotoxic, meaning it may cause genetic mutations. Methotrexate may affect sperm production and potentially cause birth defects. Therefore, while taking methotrexate and for at least 3 months after treatment ends, you must avoid fathering a child or donating sperm. Methotrexate treatment may cause infertility.
Driving and using machines
During treatment with Nordimet, adverse effects on the central nervous system such as fatigue and dizziness may occur. In some cases, the ability to drive or operate machinery may be impaired. If you feel tired or dizzy, do not drive or operate machinery.
Nordimet contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially “sodium-free”.

3. How to use Nordimet

Important warnings regarding Nordimet dosage
Use Nordimet only once a week for the treatment of rheumatoid arthritis, active juvenile idiopathic
arthritis, psoriasis, psoriatic arthritis, and Crohn's disease, all of which require a single weekly dose.
Taking an excessive dose of Nordimet can be fatal. Read section 3 of this patient information leaflet carefully.
If you have any questions, consult your doctor or pharmacist before taking this medicine.
Always use this medicine exactly as instructed by your doctor. If in doubt, consult your doctor or
pharmacist.
Nordimet must be administered once weekly only. You and your doctor may decide on a suitable day
for the injection, which should remain the same every week.
Incorrect administration of metotrexate may cause serious adverse effects, which can be fatal.

Recommended dose
Dose in adults with rheumatoid arthritis
The recommended starting dose is 7.5 mg of methotrexate once a week.
Your doctor may increase the dose if the current dose is not effective but well tolerated. The average
weekly dose is 15–20 mg. In general, the weekly dose should not exceed 25 mg. Once the desired
therapeutic effect has been achieved, your doctor may gradually reduce the dose of Nordimet to the
lowest effective dose for maintenance therapy.
Improvement of symptoms is generally expected after 4–8 weeks of treatment. Symptoms may recur if
treatment with Nordimet is discontinued.

Use in adult patients with moderate to severe plaque psoriasis and severe psoriatic arthritis
Your doctor will administer a single test dose of 5–10 mg to assess the occurrence of possible adverse
effects.
If the test dose is well tolerated, treatment will continue one week later with a dose of approximately
7.5 mg.
In general, response to treatment is expected within 2–6 weeks. Depending on treatment effects and
results of blood and urine tests, therapy will either continue or be discontinued.

Dose in adult patients with Crohn's disease
Your doctor will prescribe an initial weekly dose of 25 mg. In general, response to treatment is expected
after 8–12 weeks. Depending on the treatment effects over time, your doctor may decide to reduce the
dose to 15 mg/week.

Use in children and adolescents under 16 years of age with polyarticular forms of juvenile idiopathic arthritis
Your doctor will calculate the required dose based on the child's body surface area (m²). The dose is
expressed in mg/m².
Use in children under 3 years of age is not recommended due to insufficient data in this age group.

Method and duration of administration
Nordimet is administered by subcutaneous injection (under the skin). It must be injected once a week,
and it is recommended to administer the Nordimet injection on the same day each week.
At the beginning of treatment, Nordimet will be administered by medical personnel. However, your
doctor may decide that you are capable of learning how to self-administer Nordimet injections. In this
case, you will receive adequate training. Under no circumstances should you attempt to self-inject before
receiving proper training.
The duration of treatment will be determined by your treating physician.
Treatment of rheumatoid arthritis, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, and
Crohn's disease with Nordimet is a long-term treatment.

How to self-administer Nordimet injections
If you have difficulty using the pen, consult your doctor or pharmacist. Do not attempt to self-inject unless
you have received proper training. If you are unsure about what to do, contact your doctor or nurse
immediately.

Before self-administerering a Nordimet injection

• Check the expiry date of the medicine. Do not use the medicine if the expiry date has passed.
• Check that the pen is undamaged and that the solution inside is a clear, yellow liquid. If not, use another pen.
• Check the site of the previous injection for redness, skin color changes, swelling, discharge, or pain. If you notice any of these symptoms, contact your doctor or nurse.
• Choose the injection site. Change the injection site each time.

Instructions for self-administerering Nordimet injections

1. Wash your hands thoroughly with soap and water.
2. Sit or lie down in a relaxed and comfortable position. Ensure that the skin area where you intend to
   administer the injection is clearly visible.
3. The pen is pre-filled and ready to use. Visually inspect the pen. You should see a yellow liquid through
   the viewing window. A small air bubble may be visible, but this does not affect the injection and is not
   dangerous.
   A drop of liquid may appear at the needle tip. This is normal.
4. Choose an injection site and clean it with the alcohol swab provided. Allow 30–60 seconds for the
   disinfection to take effect. Suitable injection sites are the skin of the abdomen and the front of the
   thigh.
5. Holding the body of the pen in your hand, remove the green protective cap by pulling it straight off the
   unit without twisting or bending it.
   After removing the cap, hold the pen carefully. The pen must not touch anything to prevent accidental
   activation and to keep the needle clean.

6. At the injection site, pinch the skin by holding it between your thumb and index finger. Maintain the
   skin fold throughout the entire injection.
7. Bring the pen close to the skin fold (injection site), with the yellow needle guard facing directly toward
   the injection site. Place the yellow needle guard on the injection site so that the entire edge of the
   guard is in contact with the skin.

8. Press the pen firmly against the skin until you feel and hear a "click".
   This activates the pen, and the solution is automatically injected into the skin.

9. The injection process lasts up to 10 seconds. When the injection is complete, you will feel and hear a
   second "click".

10. Wait 2–3 seconds before removing the pen from the skin. The pen's safety shield is now locked in place
    to prevent needle-stick injuries. You may now release the skin fold.

11. Visually inspect the pen through the viewing window. Green plastic should now be visible. This
    indicates that all the liquid has been injected. Dispose of the used pen in the sharps container provided.
    Close the container lid tightly and store it out of the reach of children. If methotrexate comes into
    accidental contact with the skin or soft tissues, rinse the area thoroughly with water.

If you use more Nordimet than you should
Follow the dosing recommendations provided by your doctor. Do not change the dose without consulting
your doctor.
If you think you have used too much Nordimet, contact your doctor or the nearest hospital immediately.
Show the medicine packaging and this leaflet to the doctor or hospital staff.
An excessive dose of methotrexate can cause severe toxic reactions. Symptoms of overdose include
easy bruising or bleeding, unusual weakness, sore mouth, nausea, vomiting, black or bloody stools, coughing
up blood or vomiting material resembling coffee grounds, and reduced urine output. See also section 4.

If you forget to use Nordimet
Do not take a double dose to make up for the missed dose. Continue using the prescribed dose as usual.
Consult your doctor for advice.

If you stop using Nordimet
Do not stop or discontinue treatment with Nordimet without first discussing it with your doctor. If you
think you are experiencing an adverse reaction, contact your doctor immediately for advice.

If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you suddenly develop wheezing, difficulty breathing, swelling of the eyelids, face or lips, a rash or itching (especially all over the body), contact your doctor immediately.

Serious side effects
Contact your doctor immediately if you notice one or more of the following side effects:

• lung inflammation (symptoms may include general feeling of being unwell, dry and irritating cough, shortness of breath, breathlessness at rest, chest pain or fever)
• blood in saliva or coughed-up sputum
• severe peeling or blistering of the skin
• unusual bleeding (including vomiting blood) or bruising
• severe diarrhoea
• mouth ulcers
• black or tarry stools
• blood in urine or stools
• small red spots on the skin
• fever
• yellowing of the skin (jaundice)
• pain or difficulty urinating
• excessive thirst and/or frequent need to urinate
• seizures
• loss of consciousness
• blurred or reduced vision

The following side effects have also been reported:
Very common (may affect more than 1 in 10 people)
Loss of appetite, nausea, stomach ache, inflammation of the oral mucosa, digestive disorders and increased liver enzyme levels.

Common (may affect up to 1 in 10 people)
Reduced production of blood cells, leading to lower numbers of white blood cells and/or red blood cells and/or platelets (leucopenia, anaemia, thrombocytopenia), headache, fatigue, drowsiness, lung inflammation (pneumonitis) with dry, non-productive cough, shortness of breath, fever, mouth ulcers, diarrhoea, skin rashes, skin redness, itching.

Uncommon (may affect up to 1 in 100 people)
Decreased number of blood cells and platelets, throat inflammation, dizziness, confusion, depression, inflammation of blood vessels, ulcers and bleeding in the digestive tract, intestinal inflammation, vomiting, pancreatitis, liver disorders, diabetes, decreased blood proteins, herpes-like skin rash, urticaria, sunburn-like reactions due to increased skin sensitivity to sunlight, hair loss, increase in rheumatoid nodules, skin ulcers, shingles, joint or muscle pain, osteoporosis (reduced bone mass), bladder inflammation and ulcers (possibly with blood in urine), reduced kidney function, painful urination, vaginal inflammation and ulcers.

Rare (may affect up to 1 in 1,000 people)
Infection (incl. reactivation of inactive chronic infection), sepsis, red eyes, allergic reactions, anaphylactic shock, decreased number of antibodies in blood, inflammation of the membrane surrounding the heart (pericarditis), fluid accumulation around the heart (pericardial effusion), impaired heart filling due to fluid around the heart (cardiac tamponade), vision disorders, mood changes, low blood pressure, blood clot formation, scarring of lung tissue (pulmonary fibrosis), Pneumocystis jiroveci pneumonia, breathing interruption, asthma, fluid accumulation in the membrane lining the lungs (pleural effusion), inflamed gums, acute hepatitis (liver inflammation), brown skin discoloration, acne, red or purple spots due to bleeding from blood vessels, allergic inflammation of blood vessels, bone fractures, kidney failure, reduced urine output or absence of urine, electrolyte imbalances, fever, delayed wound healing.

Very rare (may affect up to 1 in 10,000 people)
Reduction in certain white blood cells (agranulocytosis), severe bone marrow failure, liver failure, swollen glands, insomnia, pain, muscle weakness, numbness or tingling/reduced sensitivity to stimulation, taste changes (metallic taste), seizures, inflammation of the lining of the brain causing paralysis or vomiting, vision disorders, damage to the retina of the eye, vomiting blood, toxic megacolon (enlargement of the large intestine with severe pain), abnormal sperm formation (oligospermia), Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), increased nail pigmentation, loss of sexual desire, erectile dysfunction, nail infections, severe gastrointestinal complications, pimples, visible enlargement of small blood vessels in the skin, menstrual disorders, vaginal discharge, infertility, breast enlargement in men (gynaecomastia), lymphoproliferative disorders (excessive growth of white blood cells).

Frequency not known (cannot be estimated from available data)
Increase in certain white blood cells (eosinophilia), certain brain disorders (encephalopathy/leukoencephalopathy), nosebleeds, lung haemorrhage, bone damage affecting the jaw/mandible (secondary to excessive white blood cell growth), protein in urine, feeling of weakness, tissue damage at injection site, skin redness and peeling, swelling.

With Nordimet treatment, only mild local skin reactions have been observed, which decreased during therapy.

Nordimet may reduce the number of white blood cells, and your resistance to infections may decrease. If you develop an infection with symptoms such as fever and a significant worsening of your general condition, or fever with local signs of infection such as sore throat/pharynx/mouth, or urinary problems, contact your doctor immediately. A blood test will be performed to check for a possible reduction in white blood cells (agranulocytosis). It is important that you inform your doctor that you are using Nordimet.

It is known that methotrexate can cause bone problems such as joint and muscle pain and osteoporosis. The frequency of these risks in children is unknown.

Nordimet can cause serious side effects (which may sometimes be fatal). Your doctor will carry out blood tests to monitor for possible changes in blood cells (e.g. reduced number of white blood cells, platelets, lymphoma) and changes affecting the kidneys and liver.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Nordimet

Keep this medicinal product out of the sight and reach of children.
Do not use this medicinal product after the expiry date stated on the pre-filled pen label and on the
carton box after EXP. The expiry date refers to the last day of that month.
Store below 25°C.
Keep the pre-filled pen in the outer carton to protect it from light.
Do not freeze.
Do not use this medicinal product if the solution is not clear or contains suspended particles.
Nordimet is for single use only. All used pens must be disposed of.
Do not dispose of any medicinal product via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Nordimet contains
The active substance is methotrexate. 1.0 mL of solution contains 25 mg of methotrexate.
The other components are sodium chloride, sodium hydroxide and water for injections.
The following pens are available:
Pre-filled pens of 0.3 mL containing 7.5 mg of methotrexate
Pre-filled pens of 0.4 mL containing 10 mg of methotrexate
Pre-filled pens of 0.5 mL containing 12.5 mg of methotrexate
Pre-filled pens of 0.6 mL containing 15 mg of methotrexate
Pre-filled pens of 0.7 mL containing 17.5 mg of methotrexate
Pre-filled pens of 0.8 mL containing 20 mg of methotrexate
Pre-filled pens of 0.9 mL containing 22.5 mg of methotrexate
Pre-filled pens of 1.0 mL containing 25 mg of methotrexate

Description of the appearance of Nordimet and contents of the pack
The pre-filled pens of Nordimet contain a clear, yellow injectable solution.
Nordimet is available in packs containing 1 or 4 pre-filled pens and 1 or 4 alcohol-impregnated swabs, and in multiple packs with 4 or 6 cardboard boxes, each containing 1 pre-filled pen and one alcohol-impregnated swab.
Nordimet is also available in multiple packs with 3 cardboard boxes, each containing 4 pre-filled pens and alcohol-impregnated swabs.
It is possible that not all pack sizes are marketed.

Marketing Authorization Holder
Nordic Group B.V.
Siriusdreef 41
2132 WT Hoofddorp
The Netherlands

Manufacturer
CENEXI - Laboratoires Thissen
Rue de la Papyrée 2-6
B-1420 Braine-l’Alleud
Belgium
Sever Pharma Solutions AB
Agneslundsvagen 27
P.O. Box 590
SE-201 25 Malmö
Sweden
FUJIFILM Diosynth Biotechnologies Denmark ApS
Biotek Allé 1
3400 Hillerød
Denmark

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/

Package leaflet: information for the user

Nordimet 7.5 mg injectable solution in pre-filled syringe, 10 mg injectable solution in pre-filled syringe, 12.5 mg injectable solution in pre-filled syringe, 15 mg injectable solution in pre-filled syringe, 17.5 mg injectable solution in pre-filled syringe, 20 mg injectable solution in pre-filled syringe, 22.5 mg injectable solution in pre-filled syringe, 25 mg injectable solution in pre-filled syringe

methotrexate
Please read this entire leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any adverse reaction, including those not listed in this leaflet, contact your doctor or pharmacist. This includes possible adverse reactions not mentioned in this leaflet. See section 4.

Contents of this leaflet

1. What Nordimet is and what it is used for
2. What you need to know before using Nordimet
3. How to use Nordimet
4. Possible side effects
5. How to store Nordimet
6. Contents of the pack and other information

1. What Nordimet is and what it is used for

Nordimet contains the active substance methotrexate, which is indicated for:

• reducing inflammation or swelling, and
• reducing the activity of the immune system (the body's defence mechanism). An overactive immune system has been linked to inflammatory diseases.

Nordimet is a medicine used to treat several inflammatory conditions:

• active rheumatoid arthritis in adults. Active rheumatoid arthritis is an inflammatory condition affecting the joints;
• severe active juvenile idiopathic arthritis affecting five or more joints (this is why the disease is called polyarticular), in patients who have had an inadequate response to non-steroidal anti-inflammatory drugs (NSAIDs);
• moderate to severe plaque psoriasis in adults eligible for systemic therapy, as well as severe psoriasis affecting the joints (psoriatic arthritis) in adults;
• induction of remission in adult patients with moderate, steroid-dependent Crohn’s disease, in combination with corticosteroids;
• maintenance of remission in Crohn’s disease in adults who have responded to methotrexate as monotherapy.

2. What you need to know before using Nordimet

Do not use Nordimet if:

• you are allergic to methotrexate or to any of the other ingredients of this medicine (listed in section 6)
• you have severe kidney disease (your doctor will determine whether you have severe kidney disease)
• you have severe liver disease (your doctor will determine whether you have severe liver disease)
• you have dysfunction of the system responsible for blood cell production in the body
• you consume large amounts of alcohol
• your immune system is compromised
• you have a severe or pre-existing infection, e.g. tuberculosis or HIV
• you have a gastrointestinal ulcer
• you are pregnant or breastfeeding (see section “Pregnancy, breastfeeding and fertility”)
• you are simultaneously receiving vaccination with live vaccines.

Warnings and precautions
Cases of acute pulmonary hemorrhage have been reported in patients with rheumatological diseases treated with methotrexate. If you notice blood in your saliva or after coughing, contact your doctor immediately.
Lymph node enlargement (lymphoma) may occur and treatment should be discontinued.
Diarrhea may be a toxic effect of Nordimet and requires interruption of therapy. If you experience diarrhea, discuss it with your doctor.
Certain brain disorders (encephalopathy/leukoencephalopathy) have been reported in cancer patients receiving methotrexate. These adverse effects cannot be excluded when methotrexate is used to treat other diseases.
If you, your partner, or caregiver notice the onset or worsening of neurological symptoms, including generalized muscle weakness, visual disturbances, changes in thinking, memory, or orientation, leading to confusion and personality changes, contact your doctor immediately, as these may be symptoms of a very rare and serious brain infection called progressive multifocal leukoencephalopathy (PML).
Methotrexate may increase skin sensitivity to sunlight. Avoid intense sunlight and do not use sunbeds or tanning lamps without medical advice. To protect your skin from strong sunlight, wear appropriate clothing or use a sunscreen with high sun protection factor.

Important dosage warnings for Nordimet
In the treatment of rheumatic diseases, skin conditions, and Crohn's disease, methotrexate must be used only once a week. Incorrect dosing of methotrexate may cause serious adverse effects, which could be fatal. Please read section 3 of this leaflet very carefully.

Talk to your doctor before using Nordimet if:

• you have diabetes mellitus and are being treated with insulin
• you have inactive, long-standing infections (e.g. tuberculosis, hepatitis B or C, shingles [herpes zoster])
• you have/have had liver or kidney disease
• you have problems with lung function
• you are severely overweight
• you have abnormal fluid accumulation in the abdomen or in the cavity between the lungs and the chest wall (ascites, pleural effusion)
• you are dehydrated or in a condition causing dehydration (e.g. dehydration due to vomiting, diarrhea, or inflammation of the mouth and lips)

If you have previously experienced skin problems following radiation therapy (radiation-induced dermatitis) or sunburn, these conditions may reappear during treatment with Nordimet.

Children, adolescents and elderly
Dosing instructions depend on the patient's body weight.
Use in children under 3 years of age is not recommended due to insufficient data on the use of this medicine in this age group.
Children, adolescents, and elderly patients treated with Nordimet must be closely monitored by the doctor to detect possible adverse effects as early as possible.
In elderly patients, the dose should be reduced due to age-related decline in liver and kidney function.

Special precautions for Nordimet treatment
Methotrexate temporarily affects sperm and egg cell production. Methotrexate may cause miscarriage and severe birth defects. During treatment with methotrexate and for at least 6 months after treatment ends, women must avoid becoming pregnant. Men must avoid fathering a child during treatment with methotrexate and for at least 3 months after treatment ends. See also section “Pregnancy, breastfeeding and fertility”.
Psoriasis-related skin changes may worsen during treatment with Nordimet upon exposure to ultraviolet light.

Recommended monitoring tests and precautions
Even when methotrexate is used at low doses, serious adverse effects may occur. To detect them early, your doctor must perform regular check-ups and laboratory tests.

Before starting therapy:
Before starting treatment, your blood will be tested to ensure you have sufficient blood cells. Your blood will also be analyzed to assess liver function and to check for hepatitis. Additionally, serum albumin (a protein in the blood), hepatitis status (liver infection), and kidney function will be evaluated. Your doctor may also decide to perform further liver tests, some of which may include liver imaging, while others may require a small tissue sample from the liver for more detailed examination.
Your doctor may also check for tuberculosis and may perform a chest X-ray or lung function tests.

During treatment:
Your doctor may perform the following tests:

• examination of the oral cavity and pharynx to detect changes in the mucosa, such as inflammation or ulceration
• blood tests / complete blood count with measurement of blood cell counts and serum methotrexate levels
• blood tests to monitor liver function
• imaging tests to monitor liver condition
• liver biopsy (small tissue sample taken from the liver for detailed examination)
• blood tests to monitor kidney function
• respiratory monitoring and, if necessary, lung function tests

It is very important that you attend these scheduled examinations.
If any of these test results are significant, your doctor will adjust your treatment accordingly.

Other medicines and Nordimet
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
It is especially important to inform your doctor if you are taking:

• other medicines for rheumatoid arthritis or psoriasis such as leflunomide, sulfasalazine (a medicine used not only for arthritis and psoriasis but also for ulcerative colitis), aspirin, phenylbutazone, or amidopyrine
• cyclosporine (to suppress the immune system)
• azathioprine (a medicine used to prevent organ transplant rejection)
• retinoids (used to treat psoriasis and other skin diseases)
• anticonvulsant medicines (used to prevent seizures), such as phenytoin, valproate, or carbamazepine
• cancer treatments
• barbiturates (injections for anesthesia)
• tranquillizers
• oral contraceptives
• probenecid (used to treat gout)
• antibiotics (e.g. penicillin, glycopeptides, trimethoprim-sulfamethoxazole, sulfonamides, ciprofloxacin, cephalothin, tetracyclines, chloramphenicol)
• pyrimethamine (used to prevent and treat malaria)
• vitamin preparations containing folic acid
• proton pump inhibitors (medicines that reduce stomach acid production, used to treat severe heartburn or ulcers), such as omeprazole or pantoprazole
• theophylline (used to treat asthma)
• cholestyramine (used to treat high cholesterol, itching, or diarrhea)
• NSAIDs, non-steroidal anti-inflammatory drugs (used to treat pain or inflammation)
• p-aminobenzoic acid (used to treat skin disorders)
• any vaccination with a live vaccine (must be avoided), such as those against measles, mumps, or yellow fever
• metamizole (synonyms: novaminsulfone and dipyrone) (a medicine to relieve severe pain and/or fever)
• nitrous oxide (a gas used in general anesthesia)

Nordimet with food, drinks and alcohol
During treatment with Nordimet, you must not drink alcohol and should avoid excessive consumption of coffee, caffeine-containing beverages, and black tea, as these may increase adverse effects or interfere with the effectiveness of Nordimet. Additionally, during treatment with Nordimet, you should drink plenty of fluids to prevent dehydration (reduction of body fluids), which may increase Nordimet toxicity.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, consult your doctor before taking this medicine.

Pregnancy
Do not use Nordimet during pregnancy or if you are trying to become pregnant. Methotrexate may cause birth defects, harm the fetus, or cause miscarriage. It is associated with malformations affecting the skull, face, heart and blood vessels, brain, and limbs. For these reasons, it is very important that pregnant patients or those planning pregnancy are not treated with methotrexate. Therefore, in women of childbearing potential, pregnancy must be ruled out before starting treatment using appropriate measures, for example, by performing a pregnancy test. During treatment with methotrexate and for at least 6 months after treatment ends, you must avoid pregnancy by using a reliable contraceptive method (see also section “Warnings and precautions”).
If you become aware or suspect you are pregnant during treatment, contact your doctor as soon as possible for medical advice regarding the risk of harmful effects on the unborn child throughout the duration of treatment.
If you plan to become pregnant, you should consult your doctor, who may refer you to a specialist before the planned start of treatment.

Breastfeeding
You must not breastfeed during treatment with methotrexate, as methotrexate passes into breast milk. If your doctor considers methotrexate treatment absolutely necessary during breastfeeding, you must stop breastfeeding.

Male fertility
Available data do not indicate an increased risk of birth defects or miscarriage if the father takes less than 30 mg of methotrexate per week. However, a risk cannot be completely ruled out. Methotrexate may be genotoxic, i.e. this medicine may cause genetic mutations. Methotrexate may affect sperm production and potentially cause birth defects. Therefore, while using methotrexate and for at least 3 months after treatment ends, you must avoid fathering a child or donating sperm.

Driving and using machines
During treatment with Nordimet, adverse effects on the central nervous system such as fatigue and dizziness may occur. In some cases, the ability to drive vehicles and/or use machinery may be impaired. If you feel tired or dizzy, do not drive or operate machinery.

Nordimet contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially “sodium-free”.

3. How to use Nordimet

Important warnings about Nordimet dosage
Use Nordimet once weekly only for the treatment of rheumatoid arthritis, active juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, and Crohn's disease, all of which require a single weekly dose. Overdosing with Nordimet can be fatal.
Read section 3 of this leaflet carefully. If you have any questions, consult your doctor or pharmacist before taking this medicine.
Always use this medicine exactly as instructed by your doctor. Contact your doctor or pharmacist if you are unsure.

Nordimet must be administered once a week only. You and your doctor may decide on a suitable day for the injection, which should remain the same every week.
Incorrect administration of methotrexate may cause serious adverse effects, which could be fatal.

Recommended dose:
Dose in adult patients with rheumatoid arthritis
The recommended starting dose is 7.5 mg of methotrexate once a week.
Your doctor may increase the dose if the current dose is not effective but well tolerated. The average weekly dose is 15–20 mg. In general, the weekly dose should not exceed 25 mg.
Once the desired therapeutic effect has been achieved, your doctor may gradually reduce the dose of Nordimet to the lowest effective dose for maintenance therapy.
Improvement in symptoms is generally expected after 4–8 weeks of treatment. Symptoms may recur if treatment with Nordimet is discontinued.

Use in adult patients with moderate to severe plaque psoriasis and severe psoriatic arthritis
Your doctor will administer a single test dose of 5–10 mg to assess the occurrence of possible adverse effects.
If the test dose is well tolerated, treatment will continue one week later with a dose of approximately 7.5 mg.
Generally, response to treatment is expected after 2–6 weeks. Depending on treatment effects and blood and urine test results, therapy should be continued or discontinued.

Dose in adult patients with Crohn's disease
Your doctor will prescribe an initial weekly dose of 25 mg. Generally, response to treatment is expected after 8–12 weeks. Depending on the treatment effects over time, your doctor may decide to reduce the dose to 15 mg/week.

Use in children and adolescents under 16 years of age with polyarticular forms of juvenile idiopathic arthritis
Your doctor will calculate the required dose based on the child's body surface area (m²). The dose is expressed in mg/m².
Use in children under 3 years of age is not recommended due to insufficient data in this age group.

Method and duration of administration
Nordimet is administered by subcutaneous injection (under the skin). It must be injected once a week, and it is recommended to administer the Nordimet injection on the same day each week.
At the beginning of treatment, Nordimet will be injected by medical personnel. However, your doctor may determine that you are capable of learning how to self-administer Nordimet injections. In this case, you will receive adequate training. Under no circumstances should you attempt to self-inject before receiving proper training.

The duration of treatment will be determined by your treating physician. Treatment of rheumatoid arthritis, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, and Crohn's disease with Nordimet is intended as long-term therapy.

How to self-administer Nordimet injections
If you have difficulty using the syringe, contact your doctor or pharmacist. Do not attempt to self-inject unless you have received proper training. If you are uncertain about what to do, contact your doctor or nurse immediately.

Before self-administering a Nordimet injection

• Check the expiry date of the medicine. Do not use the medicine if the expiry date has passed.
• Ensure the syringe is undamaged and that the solution inside is clear and yellow. If not, use another syringe.
• Check the site of the previous injection for redness, skin color changes, swelling, discharge, or pain. If you notice any of these symptoms, contact your doctor or nurse.
• Choose the site for the injection. Change the injection site each time.

Instructions for self-administering Nordimet injections

1. Wash your hands thoroughly with soap and water.
2. Sit or lie down in a relaxed and comfortable position. Ensure the skin area where you intend to inject is clearly visible.
3. The syringe is pre-filled and ready to use. Open the blister pack by completely removing the top layer as shown in the figure.

Blister
Top layer
4) Caution: DO NOT lift the product by the plunger or cap. Remove the syringe from the package by holding the body as shown in the figure below.

5. Visually inspect the syringe. You should see a yellow fluid through the inspection window. A small air bubble may be visible, which does not negatively affect the injection and is not dangerous.
6. Choose an injection site and clean it with the alcohol swab provided. Allow 30–60 seconds for the disinfection to take effect. Suitable injection sites are the skin of the abdomen and the front of the thigh.
7. While holding the syringe body steady, remove the cap.

Do not press the plunger before injecting to remove air bubbles. Doing so may result in loss of medication. After removing the cap, hold the syringe. Avoid touching anything with the syringe to ensure the needle remains clean.
8) Hold the syringe in the hand you write with (as if holding a pencil), and with the other hand, pinch the skin at the injection site between your thumb and index finger to form a skin fold. Maintain this skin fold throughout the injection.
9) Bring the syringe close to the skin fold (injection site), with the needle guard pointing directly toward the injection site. Insert the needle completely into the skin fold.
10) Press the plunger with your finger until the syringe is empty. This will deliver the medicine under the skin.

11. Remove the needle by pulling it straight out. This action automatically activates the needle safety shield, covering the needle and preventing needlestick injuries. You may now release the skin fold.

Note: The safety mechanism that activates the needle shield can only be triggered if the syringe has been completely emptied by fully depressing the plunger.
12) Dispose of the used syringe in the sharps container provided. Close the container lid tightly and store it out of the reach of children. If methotrexate comes into accidental contact with the skin or soft tissues, rinse the affected area thoroughly with plenty of water.

If you use more Nordimet than you should
Follow the dosing recommendations provided by your doctor. Do not change the dose without consulting your doctor.
If you think you have used too much Nordimet, contact your doctor or the nearest hospital immediately. Show the medicine packaging and this leaflet to the doctor or hospital staff.
An overdose of methotrexate may cause severe toxic reactions. Symptoms of overdose include easy bruising or bleeding, unusual weakness, sore mouth, nausea, vomiting, black or bloody stools, coughing up blood, vomiting that looks like coffee grounds, and reduced urine output. See also section 4.

If you forget to use Nordimet
Do not use a double dose to make up for a missed dose. Continue using the prescribed dose as usual. Consult your doctor for advice.

If you stop using Nordimet
Do not stop or discontinue treatment with Nordimet without first discussing it with your doctor. If you think you are experiencing an adverse effect, contact your doctor immediately for advice.

If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
If you suddenly develop wheezing, breathing difficulties, swelling of the eyelids, face or lips, a skin rash or itching (especially all over the body), contact your doctor immediately.

Serious side effects
Contact your doctor immediately if you experience one or more of the following side effects:

• Lung inflammation (symptoms may include general feeling of being unwell, dry and irritating cough, shortness of breath, breathlessness at rest, chest pain or fever)
• Blood in saliva or when coughing
• Severe peeling or blistering of the skin
• Unusual bleeding (including vomiting blood) or bruising
• Severe diarrhoea
• Mouth ulcers
• Black or tarry stools
• Blood in the urine or stools
• Red spots on the skin
• Fever
• Yellowing of the skin (jaundice)
• Pain or difficulty passing urine
• Thirst and/or frequent need to pass urine
• Seizures
• Loss of consciousness
• Blurred or reduced vision

The following side effects have also been reported:
Very common (may affect more than 1 in 10 people)
Loss of appetite, nausea, stomach ache, inflammation of the oral mucosa, digestive disorders and increased liver enzyme levels.

Common (may affect up to 1 in 10 people)
Decreased production of blood cells, resulting in reduced numbers of white blood cells and/or red blood cells and/or platelets (leucopenia, anaemia, thrombocytopenia), headache, fatigue, drowsiness, lung inflammation (pneumonitis) with dry, non-productive cough, shortness of breath, fever, oral ulcers, diarrhoea, skin rashes, skin redness, itching.

Uncommon (may affect up to 1 in 100 people)
Decreased number of blood cells and platelets, inflammation of the throat, dizziness, confusion, depression, inflammation of blood vessels, ulcers and bleeding in the digestive tract, intestinal inflammation, vomiting, inflammation of the pancreas, liver disorders, diabetes, decreased blood proteins, herpes-like skin rash, urticaria, sunburn-like reactions due to increased sensitivity of the skin to sunlight, hair loss, increase in rheumatoid nodules, skin ulcers, shingles, joint or muscle pain, osteoporosis (reduced bone mass), inflammation and ulcers of the bladder (with possible blood in the urine), reduced kidney function, painful urination, inflammation and ulcers of the vagina.

Rare (may affect up to 1 in 1,000 people)
Infection (incl. reactivation of inactive chronic infection), sepsis, red eyes, allergic reactions, anaphylactic shock, decreased number of antibodies in the blood, inflammation of the membrane surrounding the heart, fluid accumulation in the membrane surrounding the heart, obstruction of cardiac filling due to fluid in the membrane around the heart, vision disorders, mood changes, low blood pressure, blood clot formation, scar tissue formation in the lungs (pulmonary fibrosis), Pneumocystis jiroveci pneumonia, respiratory arrest, asthma, fluid accumulation in the membrane lining the lungs, inflamed gums, acute hepatitis (liver inflammation), brown skin discoloration, acne, red or purple spots due to bleeding from blood vessels, allergic inflammation of blood vessels, bone fractures, kidney failure, reduced urine output or absence of urine, electrolyte disturbances, fever, delayed wound healing.

Very rare (may affect up to 1 in 10,000 people)
Reduction in certain white blood cells (agranulocytosis), severe bone marrow failure, liver failure, swollen glands, insomnia, pain, muscle weakness, numbness or tingling sensation/reduced sensitivity to stimulation compared to normal, changes in taste (metallic taste), seizures, inflammation of the lining of the brain causing paralysis or vomiting, vision disorders, damage to the retina of the eye, vomiting blood, toxic megacolon (enlargement of the colon with severe pain), abnormal sperm formation (oligospermia), Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), increased pigmentation of the nails, loss of sexual desire, erection problems, infections around the nails, severe gastrointestinal complications, pimples, visible enlargement of small blood vessels in the skin, menstrual disorders, vaginal discharge, infertility, breast enlargement in men (gynaecomastia), lymphoproliferative disorders (excessive growth of white blood cells).

Frequency not known (cannot be estimated from the available data)
Increase in certain white blood cells (eosinophilia), certain brain disorders (encephalopathy/leukoencephalopathy), nosebleeds, pulmonary haemorrhage, bone damage affecting the jaw/mandible (secondary to excessive growth of white blood cells), protein in the urine, feeling of weakness, tissue destruction at the injection site, redness and peeling of the skin, swelling.

With Nordimet treatment, only mild local skin reactions have been observed, which decreased during therapy.

Nordimet may cause a reduction in the number of white blood cells, and your resistance to infections may decrease. If you develop an infection with symptoms such as fever and a marked worsening of your general condition, or fever with local signs of infection such as sore throat/pharynx/mouth, or urinary problems, contact your doctor immediately. A blood test will be performed to check for a possible reduction in the number of white blood cells (agranulocytosis). It is important that you inform your doctor that you are using Nordimet.

It is known that methotrexate causes bone problems such as joint and muscle pain and osteoporosis. The frequency of these risks in children is not known.

Nordimet can cause serious side effects (which may sometimes be fatal). Your doctor will carry out tests to monitor whether blood changes (e.g. reduced number of white blood cells, platelets, lymphoma) or changes affecting the kidneys and liver are developing.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. This includes possible side effects not mentioned in this leaflet. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Nordimet

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the pre-filled syringe label and on the outer carton after EXP. The expiry date refers to the last day of that month.
Store below 25°C.
Keep the syringe in the outer carton to protect it from light.
Do not freeze.
Do not use this medicine if the solution is not clear or contains suspended particles.
Nordimet is for single use only. All used syringes must be discarded.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Nordimet contains
The active substance is methotrexate. 1.0 mL of solution contains 25 mg of methotrexate.
The other components are sodium chloride, sodium hydroxide and water for injections.
The following syringes are available:
Pre-filled syringes of 0.3 mL containing 7.5 mg of methotrexate.
Pre-filled syringes of 0.4 mL containing 10 mg of methotrexate.
Pre-filled syringes of 0.5 mL containing 12.5 mg of methotrexate.
Pre-filled syringes of 0.6 mL containing 15 mg of methotrexate.
Pre-filled syringes of 0.7 mL containing 17.5 mg of methotrexate.
Pre-filled syringes of 0.8 mL containing 20 mg of methotrexate.
Pre-filled syringes of 0.9 mL containing 22.5 mg of methotrexate.
Pre-filled syringes of 1.0 mL containing 25 mg of methotrexate.

Description of the appearance of Nordimet and contents of the pack
Nordimet pre-filled syringes contain a clear, yellow injectable solution.
Nordimet is available in packs containing 1 pre-filled syringe and two alcohol swabs,
and in multiple packs with 4, 6 or 12 cardboard boxes, each containing 1 pre-filled syringe
and two alcohol swabs.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Nordic Group B.V.
Siriusdreef 41
2132 WT Hoofddorp
The Netherlands

Manufacturer
CENEXI - Laboratoires Thissen
Rue de la Papyrée 2-6
B-1420 Braine-l’Alleud
Belgium
Sever Pharma Solutions AB
Agneslundsvagen 27
P.O. Box 590
SE-201 25 Malmö
Sweden

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE TERMS
OF THE MARKETING AUTHORISATION

Scientific conclusions
Taking into account the assessment by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Report (PSUR) for methotrexate, the scientific conclusions of the PRAC are as follows:
In view of the available data on photosensitivity reactions from spontaneous reports, including one fatal case, and from the literature, the PRAC considers that the adverse drug reaction of photosensitivity should be added or amended, and that a warning on the risk of photosensitivity should be included in the product information for medicinal products containing methotrexate.
In view of the available data on the pharmacological interaction between methotrexate and metamizole from spontaneous reports and the literature, the PRAC considers that concomitant use of methotrexate and metamizole may increase haematotoxicity, particularly in elderly patients.
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the overall conclusions and reasoning of the recommendation.

Reasons for the variation of the terms of the marketing authorisation
Based on the scientific conclusions on methotrexate, the CHMP considers that the benefit-risk balance of medicinal products containing methotrexate remains favourable, subject to the proposed changes to the product information.
The CHMP recommends a variation to the terms of the marketing authorisation.