Leaflet: information for the user

Nordimet 7.5 mg pre-filled syringe solution for injection

Nordimet 10 mg pre-filled syringe solution for injection

Nordimet 12.5 mg pre-filled syringe solution for injection

Nordimet 15 mg pre-filled syringe solution for injection

Nordimet 17.5 mg pre-filled syringe solution for injection

Nordimet 20 mg pre-filled syringe solution for injection

Nordimet 22.5 mg pre-filled syringe solution for injection

Nordimet 25 mg pre-filled syringe solution for injection

metotrexate

Read this leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, as 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 they have the same symptoms as you, as it may harm them.
• If you experience any side effects, consult your doctor or pharmacist, even if they are not listed in this leaflet. See section 4.

Nordimet contains the active ingredient methotrexate, which:

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

Nordimet is a medication used to treat several inflammatory diseases:

• Active rheumatoid arthritis in adults. Active rheumatoid arthritis is an inflammatory disease that affects the joints.
• Active severe juvenile idiopathic arthritis in five or more joints (hence this condition is also known aspolyarthritis), in patients who have shown an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs).
• Moderate to severe plaque psoriasis in adults who are candidates for systemic treatment, as well as severe psoriasis that also affects the joints (psoriatic arthritis) in adult patients.
• Induction of remission in adults with moderate corticosteroid-dependent Crohn's disease, in combination with corticosteroids.
• Maintenance of remission of Crohn's disease in adults who have responded to methotrexate, in monotherapy.

No use Nordimet si:

• is allergic to methotrexate or any of the other components of this medication (listed in section 6).
• has severe kidney disease (your doctor may tell you if you have severe kidney disease).
• has severe liver disease (your doctor may tell you if you have severe liver disease).
• has hematopoietic system disorders.
• consumes a high amount of alcohol.
• has a weakened immune system.
• has a severe or existing infection, for example, tuberculosis or HIV.
• has gastrointestinal ulcers.
• is pregnant or breastfeeding (see the section “Pregnancy, breastfeeding and fertility”).
• is receiving live vaccines simultaneously.

Warnings and precautions

There have been reports of acute pulmonary hemorrhage in patients with underlying rheumatic disease treated with methotrexate. If you notice blood when coughing or spitting, contact your doctor immediately.

There may be an increase in lymph node size (lymphoma), in which case treatment should be interrupted.

Diarrea may be a toxic effect of Nordimet and requires treatment interruption.

If you experience diarrhea, speak with your doctor.

Certain brain disorders (encephalopathy/leukoencephalopathy) have been reported in cancer patients receiving methotrexate. These side effects cannot be ruled out when methotrexate is used to treat other diseases.

If you, your partner, or caregiver notice the appearance or worsening of neurological symptoms, such as general muscle weakness, vision changes, changes in thought, memory, and orientation that cause confusion and changes in personality, contact your doctor immediately, as these may be symptoms of a rare and serious brain infection called progressive multifocal leukoencephalopathy (PML).

Methotrexate may make your skin more sensitive to sunlight. Avoid intense sunlight and do not use tanning beds or ultraviolet lamps without medical advice. To protect your skin from intense sunlight, wear suitable clothing or use a high-protection sunscreen.

Important warning about Nordimet administration

Methotrexate should only be used for the treatment of rheumatic diseases, skin diseases, and Crohn's disease once a week. Incorrect administration of methotrexate may cause severe side effects that can be fatal. Read section 3 of this prospectus carefully.

Consult your doctor before starting to use Nordimet if:

• you have diabetes mellitus and receive insulin treatment;
• you have prolonged inactive infections (for example, tuberculosis, hepatitis B or C, herpes zoster);
• you have liver or kidney disease;
• you have respiratory function problems;
• you have severe obesity;
• you have abnormal fluid accumulation in the abdomen or between the lungs and the chest wall (ascitis, pleural effusions);
• you are dehydrated or have a disorder that causes dehydration (for example, dehydration due to vomiting, diarrhea, or inflammation of the mouth and lips).

If you have experienced skin problems after radiation therapy (radiation-induced dermatitis) or skin burns, these changes may reappear when taking Nordimet.

Children, adolescents, and elderly patients

Dosage instructions depend on the patient's body weight.

It is not recommended for use in children under 3 years due to insufficient experience with this medication in this age group.

Children, adolescents, and elderly patients treated with Nordimet should be closely monitored by a doctor to identify possible side effects as soon as possible.

The dosage for elderly patients should be reduced due to age-related decreases in liver and kidney function.

Special precautions for Nordimet treatment

Methotrexate temporarily affects semen and ovulation production. Methotrexate can cause severe birth defects and miscarriage. If you are a woman, do not become pregnant while taking methotrexate and for at least 6 months after stopping treatment. If you are a man, do not father a child while taking methotrexate and for at least 3 months after stopping treatment.

See also the section “Pregnancy, breastfeeding, and fertility”.

Skin changes caused by psoriasis may worsen during Nordimet treatment with exposure to ultraviolet radiation.

Follow-up examinations and recommended precautions

Even when used at low doses, methotrexate may cause severe side effects. To detect them in time, your doctor will perform follow-up examinations and laboratory tests.

Before starting treatment:

Before starting treatment, a blood test will be performed to determine if you have enough blood cells. A blood test will also be performed to check liver function and detect hepatitis. In addition, your doctor will check your albumin serum levels (a blood protein), the state of hepatitis (hepatic infection), and kidney function. Your doctor may also decide to perform other liver tests, which may include imaging of the liver or taking a small sample of liver tissue for further examination. Your doctor may also check if you have tuberculosis and perform a chest X-ray or lung function test.

During treatment:

Your doctor may perform the following examinations:

• Oral cavity and pharynx examination to detect changes in the mucosa, such as inflammation or ulcers.
• Blood test/hemogram with blood cell count and measurement of serum methotrexate levels.
• Blood test to control liver function.
• Imaging tests to control liver status.
• Taking a small sample of liver tissue for further examination.
• Blood test to control kidney function.
• Respiratory tract examination and, if necessary, lung function test.

It is very important to attend these scheduled examinations.

If some of these test results are abnormal, your doctor will adjust your treatment accordingly.

Other medications and Nordimet

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication.

It is especially important to inform your doctor if you are taking:

• other treatments for rheumatoid arthritis or psoriasis, such as leflunomide, sulfasalazine (a medication used for rheumatoid arthritis, psoriasis, and ulcerative colitis), acetylsalicylic acid, phenylbutazone, or amidopyrine;
• ciclosporin (used to suppress the immune system);
• azathioprine (used to prevent organ rejection after transplantation);
• retinoids (used to treat psoriasis and other skin disorders);
• anticonvulsants (used to prevent seizures), such as phenytoin, valproate, or carbamazepine;
• cancer treatments;
• barbiturates (injection for sleep);
• tranquilizers;
• oral contraceptives;
• probenecid (used to treat gout);
• antibiotics (for example, penicillin, glucopetides, trimethoprim-sulfamethoxazole, sulfonamides, ciprofloxacin, cephalothin, tetracyclines, chloramphenicol);
• pirimetamina (used to prevent and treat malaria);
• vitamin preparations with folic acid;
• inhibitors of proton pumps (medications that reduce stomach acid production and are used to treat heartburn or severe ulcers), such as omeprazole or pantoprazole;
• theophylline (used to treat asthma);
• colestiramine (used to treat high cholesterol, itching, or diarrhea);
• NSAIDs, nonsteroidal anti-inflammatory drugs (used to treat pain or inflammation);
• para-aminobenzoic acid (used to treat skin disorders);
• any live vaccine (avoid it), such as vaccines for measles, mumps, flu, and yellow fever;
• metamizol (synonyms: novaminsulfon and dipirona) (medication for intense pain and/or fever);
• nitrous oxide (a gas used in general anesthesia)

Nordimet with food, drinks, and alcohol

During treatment with Nordimet, avoid consuming alcohol and excessive amounts of coffee, caffeinated soft drinks, and black tea, as they may increase side effects or interfere with Nordimet's effectiveness. Also, make sure to drink plenty of liquids during treatment with Nordimet, as dehydration (reduced body water) may increase Nordimet's toxicity.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, consult your doctor before using this medication.

Pregnancy

Do not use Nordimet during pregnancy or if you are planning to become pregnant. Methotrexate may cause congenital abnormalities, harm the fetus, or cause miscarriage. It is associated with skull, face, heart, and blood vessel malformations, brain, and limb malformations. Therefore, it is very important not to administer methotrexate to pregnant women or those planning to become pregnant. In fertile women, any possibility of pregnancy should be excluded with appropriate measures, such as a pregnancy test, before starting treatment. You should avoid becoming pregnant while taking methotrexate and for at least 6 months after stopping treatment using reliable contraceptive methods during this time (see also the section “Warnings and precautions”).

If you become pregnant during treatment or suspect you may be pregnant, speak with your doctor as soon as possible. They should inform you about the risk of harmful effects on the fetus during treatment.

If you want to become pregnant, consult your doctor, who may refer you to a specialist before starting treatment.

Breastfeeding

Do not breastfeed during treatment, as methotrexate passes into breast milk. If your doctor considers that treatment with methotrexate is absolutely necessary during breastfeeding, you should stop breastfeeding.

Male fertility

Available evidence does not indicate an increased risk of malformations or miscarriage if the father takes less than 30 mg/week of methotrexate. However, it is not possible to completely rule out a certain risk. Methotrexate may be genotoxic. This means that the medication may cause genetic mutations. Methotrexate may affect sperm production and cause congenital abnormalities. Therefore, you should avoid fathering a child or donating semen while taking methotrexate and for at least 3 months after stopping treatment.

Driving and operating machines

Side effects affecting the central nervous system, such as fatigue and dizziness, may occur during treatment with Nordimet. In some cases, your ability to drive vehicles and/or operate machines may be reduced. If you feel fatigued or dizzy, do not drive or operate machines.

Nordimet contains sodium

This medication contains less than 1 mmol (23 mg) of sodium per dose, which is essentially “sodium-free”.

Follow exactly the administration instructions of this medication indicated by your doctor. In case of doubt, consult your doctor or pharmacist again.

Nordimet is administeredonly once a week. You and your doctor may agree on which day of the week you will receive the injection each week.

Incorrect administration of Nordimet may produce severe adverse effects that can be fatal.

The recommended dose is:

Dose in patients with rheumatoid arthritis

The initial recommended dose is 7.5 mg of methotrexateonce a week.

Your doctor may increase the dose if the dose used is not effective, but is well tolerated. The weekly average dose is 15-20 mg. Generally, a weekly dose of 25 mg should not be exceeded. When Nordimet starts to work, your doctor may gradually reduce the dose to the lowest effective maintenance dose possible.

Generally, symptom improvement is expected after 4-8 weeks of treatment. Symptoms may return if treatment with Nordimet is interrupted.

Use in adults with moderate to severe plaque psoriasis or severe psoriatic arthritis

Your doctor will administer a single test dose of 5-10 mg to evaluate potential adverse effects.

If the test dose is well tolerated, treatment will continue after one week with an approximate dose of 7.5 mg.

Generally, treatment response can be expected after approximately 2-6 weeks. Depending on treatment effects and blood and urine analysis results, treatment will continue or be discontinued.

Dose in adult patients with Crohn's disease

Your doctor will start treatment with a weekly dose of 25 mg. Generally, treatment response can be expected after 8-12 weeks. Depending on treatment effects, your doctor may decide to reduce the dose to 15 mg per week at a later time.

Use in children and adolescents under 16 years with polyarticular juvenile idiopathic arthritis

Your doctor will calculate the necessary dose based on the child's body surface area (m2), and the dose is expressed in mg/m2.

Use in children <3>

Method and duration of administration

Nordimet is administered by subcutaneous injection. It should be injected once a week and it is recommended to inject Nordimet always on the same day of the week.

At the beginning of your treatment, your doctor may inject Nordimet for you. However, your doctor may decide that you should learn to inject Nordimet yourself. You will receive the necessary training to do so. Under no circumstances should you attempt to self-inject, unless you have been taught how to do so.

The duration of treatment will be determined by the doctor responsible for your treatment. Treatment of rheumatoid arthritis, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, and Crohn's disease with Nordimet is a long-term treatment.

Information on how to inject Nordimet yourself

If you have difficulty handling the pen, consult your doctor or pharmacist. Do not attempt to self-inject if you have not been taught how to do so. If you are unsure, consult your doctor or nurse immediately.

Before self-injecting Nordimet

• Check the expiration date of the medication. Do not use it if it has expired.
• Check that the pen is not damaged and that the medication is a clear yellow solution. If not, use another pen.
• Examine the site of the last injection to check if it caused redness, skin color changes, swelling, or supuration, or if it still hurts. In that case, talk to your doctor or nurse.
• Decide where you will inject the medication. Change the location where you self-inject the medication each time.

Instructions on how to self-inject Nordimet

1) Wash your hands thoroughly with water and soap.

2) Sit or lie down in a comfortable and relaxed position. Make sure you can see the area of skin where you will make the injection.

3) The pen is preloaded and ready to use. Visually inspect the pen. You should be able to see a yellow liquid through the viewing window. You may see a small air bubble, which will not affect the injection and will not cause any harm.

You may see a drop at the tip of the needle. This is normal.

4) Choose an injection site and clean it with the alcohol-soaked swab provided. It takes between 30 and 60 seconds to take effect. Suitable areas for injection are the skin of the front of the abdominal wall and the skin of the front of the thigh.

5) While holding the pen body, remove the green protective cap by pulling it straight out of the unit. Do not twist or bend it.

After removing the cap, hold the pen in your hand. Avoid letting the pen come into contact with any other object. This measure ensures that the pen does not accidentally activate and the needle remains clean.

6) Form a fold in the skin by gently pinching the skin at the injection site with your index and thumb fingers. Make sure to hold the skin fold throughout the injection.

7) Move the pen towards the skin fold (injection site) with the needle guard pointing directly at the injection site. Place the yellow needle guard against the injection site, so that the entire edge of the needle guard is in contact with the skin.

8) Apply downward pressure on the pen until you hear and feel a click.

This will activate the pen and the solution will be automatically injected into the skin.

9) The injection takes a maximum of 10 seconds. You will hear and feel a second click when the injection is complete.

10) Wait 2-3 seconds before removing the pen from the skin. The safety guard of the pen will lock to prevent needlestick injuries. Now you can release the skin fold.

11) Visually inspect the pen through the viewing window. You should be able to see a green plastic. This means that all the liquid has been injected. Dispose of the used pen in the sharps container provided. Close the container lid tightly and place it out of reach of children. In case of accidental contact of methotrexate with the skin or soft tissues, rinse the area with plenty of water.

If you use more Nordimet than you should

Follow the dose recommendations of the doctor responsible for your treatment. Do not change the dose without consulting your doctor.

If you suspect you have used more Nordimet than you should, inform your doctor or immediately contact the nearest hospital. Attend your doctor's consultation or the hospital with the medication packaging and this prospectus.

A methotrexate overdose can produce severe toxic reactions. Symptoms of overdose may include rapid formation of hematomas or hemorrhages, unusual weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood or vomiting with coffee ground appearance, and decreased urination (urine evacuation from the bladder). See section 4.

If you forgot to use Nordimet

Do not use a double dose to compensate for the missed doses, but continue using the prescribed dose as usual. Consult your doctor if you have any doubts.

If you interrupt treatment with Nordimet

You should not interrupt or discontinue treatment with Nordimet without discussing it with your doctor. If you suspect you are experiencing adverse effects, consult your doctor immediately.

If you have any other doubts about the use of this medication, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Inform your doctor if you experience sudden dizziness, difficulty breathing, swelling of the eyelids, face, or lips, skin rash, or itching (especially affecting your entire body).

Severe side effects

If you develop any of the following severe side effects, contact your doctor immediately:

• Pneumonia (symptoms may include general illness, dry and irritating cough, difficulty breathing, shortness of breath at rest, chest pain, or fever).
• Bleeding when coughing or sneezing.
• Severe skin peeling or blistering.
• Bleeding (including vomiting blood) or unusual bruising.
• Severe diarrhea.
• Mouth ulcers.
• Black or tar-like stools.
• Blood in the urine or stools.
• Red spots on the skin.
• Fever.
• Yellow discoloration of the skin (jaundice).
• Pain and difficulty urinating.
• Excessive thirst and/or frequent urination.
• Seizures (convulsions).
• Loss of consciousness.
• Loss of vision or blurred vision.

The following side effects have been reported:

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

Loss of appetite, nausea (desire to vomit), stomach pain, inflammation of the mouth lining, abnormal digestion, and increased liver enzymes.

Common(may affect up to 1 in 10 people)

Mild anemia (low red blood cell count) with decreased white blood cell count and/or platelet count (leukopenia, anemia, thrombocytopenia), headache, fatigue, drowsiness, pneumonia with dry and unproductive cough, difficulty breathing, and fever, mouth ulcers, diarrhea, skin rash, skin redness, and itching.

Uncommon(may affect up to 1 in 100 people)

Decreased red and white blood cell count, throat inflammation, dizziness, confusion, depression, inflammation of blood vessels, mouth and digestive tract ulcers and bleeding, intestinal inflammation, vomiting, pancreatitis, liver disorders, diabetes, decreased blood proteins, herpes zoster-like skin rash, hives, sunburn-like reactions due to increased skin sensitivity to sunlight, hair loss, rheumatoid nodules, skin ulcers, herpes zoster, joint or muscle pain, osteoporosis (bone mass reduction), bladder inflammation and ulcers (possibly with blood in the urine), reduced kidney function, painful urination, vaginal inflammation and ulcers.

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

Infection (including reactivation of a chronic inactive infection), septicemia, red eyes, allergic reactions, anaphylactic shock, decreased antibody count in the blood, pericarditis, fluid accumulation in the pericardium, cardiac filling obstruction due to fluid in the pericardium, visual disorders, mood fluctuations, low blood pressure, blood clots, pulmonary fibrosis, Pneumocystis jirovecii pneumonia, respiratory arrest, asthma, pleural fluid accumulation, gum inflammation, acute hepatitis (liver inflammation), skin darkening, acne, red or purple spots due to bleeding in blood vessels, allergic vasculitis, bone fractures, renal insufficiency, decreased or absent urine, electrolyte disorders, fever, slow wound healing.

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

Aganulocytosis (reduced white blood cell count), severe bone marrow insufficiency, liver insufficiency, gland inflammation, insomnia, pain, muscle weakness, numbness or tingling/hypoesthesia, changes in taste (metallic taste), seizures, brain lining inflammation with paralysis or vomiting, visual disturbances, retinal damage, vomiting with blood, toxic megacolon (intestinal enlargement associated with intense pain), defective sperm formation (oligospermia), Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome), nail pigmentation increase, loss of libido, erectile dysfunction, nail infection, severe gastrointestinal complications, furuncles, visible small blood vessel dilation on the skin, menstrual disorders, vaginal discharge, infertility, gynecomastia (breast enlargement in men) in men, and lymphoproliferative disorders (excessive growth of white blood cells).

Frequency not known(cannot be estimated from available data)

Increased eosinophil count, certain brain disorders (encephalopathy/leukoencephalopathy), nasal bleeding, pulmonary hemorrhage, jawbone damage (secondary to excessive white blood cell growth), protein in the urine, weakness, tissue destruction at the injection site, skin redness and peeling, inflammation.

Only local skin reactions (such as burning sensations, erythema, swelling, discoloration, intense itching, and pain) were observed with Nordimet, which decreased during treatment.

Nordimet may cause a decrease in white blood cell count and may reduce your resistance to infections. If you experience an infection with symptoms such as fever and severe deterioration of your overall health, or fever with local infection symptoms such as sore throat/pharynx/mouth, or urinary problems, contact your doctor immediately. They will perform a blood test to examine possible white blood cell count decrease (agranulocytosis). It is essential to inform your doctor if you are taking Nordimet.

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

Nordimet may cause severe side effects (sometimes potentially fatal). Your doctor will perform tests to verify any abnormalities that develop in the blood (e.g., low white blood cell count, low platelet count, lymphoma) and changes in the kidneys and liver.

Reporting side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is not listed in this prospectus. You can also report them directly through the national notification system included in theAppendix V. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the preloaded pen label and on the box after CAD. The expiration date is the last day of the month indicated.

Store at a temperature below 25 °C.

Store the pen in the outer packaging to protect it from light.

Do not freeze.

Do not use this medication if you observe that the solution is not transparent or contains particles.

Nordimet is for single use only. Any used pen must be discarded. Medications should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the containers and medications you no longer need. By doing so, you will help protect the environment.

Composition of Nordimet

The active principle is methotrexate. 1.0 ml of solution contains 25 mg of methotrexate.

The other components are sodium chloride, sodium hydroxide, and water for injection preparations.

The following syringes are available:

Preloaded syringe of 0.3 ml with 7.5 mg of methotrexate

Preloaded syringe of 0.4 ml with 10 mg of methotrexate

Preloaded syringe of 0.5 ml with 12.5 mg of methotrexate

Preloaded syringe of 0.6 ml with 15 mg of methotrexate

Preloaded syringe of 0.7 ml with 17.5 mg of methotrexate

Preloaded syringe of 0.8 ml with 20 mg of methotrexate

Preloaded syringe of 0.9 ml with 22.5 mg of methotrexate

Preloaded syringe of 1.0 ml with 25 mg of methotrexate

Appearance of Nordimet and content of the container

The preloaded syringes with Nordimet contain a transparent and yellowish injectable solution.

Nordimet is available in containers that contain 1 or 4 preloaded syringes and 1 or 4 cotton balls impregnated with alcohol, and in multiple containers that contain 4 or 6 boxes, each containing 1 preloaded syringe and a cotton ball impregnated with alcohol. Nordimet is also available in multiple containers that contain 3 boxes (with 4 preloaded syringes and cotton balls).

Only some sizes of containers may be commercially marketed.

Marketing authorization holder

Nordic Group B.V.

Siriusdreef 41

2132 WT Hoofddorp

Netherlands

Responsible 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 Malmo

Sweden

FUJIFILM Diosynth Biotechnologies Denmark ApS

Biotek Allé 1

3400 Hillerød

Denmark

Last review date of this leaflet:

Other sources of information

The detailed information on this medicine is available on the European Medicines Agency website: http//www.ema.europa.eu.