Package Insert: Information for the Patient

Bertanel30 mg/1.5 ml injectable solution in pre-filled syringe

metotrexate

Read this package insert carefully before starting to use the medication, as it contains important information for you

-Keep this package insert, as you may need to refer to it again.

-If you have any questions, consult your doctor or pharmacist.

-This medication has been prescribed to you, and you should not give it to others, even if they have the same symptoms as you, as it may harm them.

-If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this package insert. See section 4.

1.What is Bertanel and what is it used for

2.What you need to know before starting to use Bertanel

3.How to use Bertanel

4.Possible adverse effects

5.Storage of Bertanel

6.Contents of the package and additional information

Bertanel is a medication with the following properties:

• interferes with the growth of certain cells in the body that multiply rapidly (antineoplastic agent)
• reduces unwanted reactions of the body's own defense mechanism (immunosuppressant) and
• has anti-inflammatory effects

Bertanel is used in patients with:

• active rheumatoid arthritis (RA) in adult patients.
• polyarticular forms (when five or more joints are involved) of active and severe juvenile idiopathic arthritis (JIA) when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate.

severe, disabling, and treatment-resistant psoriasis, which has not responded adequately to other forms of treatment such as phototherapy, PUVA, and retinoids, and severe psoriasis that affects the joints (psoriatic arthritis) in adult patients.

Do not use Bertanel:

• if you are allergic to methotrexate or any of the other components of this medication (listed in section 6)
• if you have any significant kidney disease (your doctor decides the severity of the disease)
• if you have any significant liver disease (your doctor decides the severity of your disease)
• if you have disorders of the system that forms blood components
• if you have a high alcohol consumption
• if you have an altered immune system
• if you have an existing or severe infection, for example, tuberculosis and HIV
• if you have active digestive ulcers (including mouth ulcers)
• if you are pregnant or breastfeeding (see section “Pregnancy, lactation and fertility”)
• if you are receiving live virus vaccines at the same time.

Warnings and precautions

Consult your doctor before starting to use Bertanel if you

• have diabetes mellitus treated with insulin
• have chronic inactive infections (e.g., tuberculosis, hepatitis B or C, herpes (herpes zoster))
• have or have had any liver or kidney disease
• have respiratory function problems
• have abnormal accumulation of fluid in the abdomen or in the cavity between the lungs and the thoracic wall (ascitis, pleural effusion)
• are dehydrated or have any condition that may cause dehydration (vomiting, diarrhea, stomatitis).

A pulmonary hemorrhage has been reported with methotrexate in patients with underlying rheumatological disease. If you observe blood when coughing or spitting, you should contact your doctor immediately.

The treatment is administeredonce a week.

Incorrect administration of methotrexate can cause severe side effects, including potentially fatal.

Read section 3 of this prospectus carefully.

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

If you have had skin problems after radiation therapy (radiation-induced dermatitis) and sunburns, these conditions may recur during methotrexate treatment (memory reaction).

If you, your partner or caregiver notice the appearance or worsening of neurological symptoms, such as general muscle weakness, visual disturbances, 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 severe brain infection called progressive multifocal leukoencephalopathy (PML).

Children and adolescents

The administration instructions depend on the patient's body weight. It is not recommended to use in children under 3 years of age due to insufficient experience with this age group.

Children on Bertanel treatment should have a particularly frequent follow-up with a specialist doctor to identify any possible adverse effects as soon as possible.

Older patients

Older patients on methotrexate treatment should be under close medical supervision by a specialist to detect any possible adverse effects as soon as possible.

The deterioration of liver and kidney functions associated with age, as well as having low folate reserves in older age, require the administration of a relatively low dose of methotrexate.

Psoriasis skin changes may worsen during Bertanel treatment if exposed to UV radiation at the same time.

Recommended examinations and precautions:

Even when Bertanel is administered at low doses, severe side effects can occur. To detect them as soon as possible, your doctor should perform follow-up reviews and laboratory tests.

Before starting treatment:

Before starting treatment, a blood test will be performed to check if you have enough blood cells. Your liver function will also be checked, as well as hepatitis. In addition, your serum albumin (a blood protein) will be checked, as well as your hepatitis status and kidney function. Your doctor may also decide to perform other liver tests, some of which may involve imaging of your liver, and others may require a small sample of liver tissue for closer examination. Your doctor may also check if you have tuberculosis and may perform a chest X-ray or lung function test.

During treatment:

Your doctor may perform the following examinations:

-oral and pharyngeal examination to detect changes in the mucous membrane, such as inflammation or ulcers

-blood test/complete blood count, with number of blood cells and measurement of serum methotrexate levels

-blood test to control liver function

-imaging tests to control liver function

-taking a small sample of liver tissue for closer examination

-blood test to control kidney function

-respiratory tract control, and if necessary, lung function test

It is very important that you attend these scheduled tests.

If the results of any of these tests are abnormal, your doctor will adjust your treatment as necessary.

Special precautions for Bertanel treatment

Methotrexate temporarily affects the production of sperm and eggs, which is reversible in most cases. Methotrexate can cause miscarriages and severe birth defects. If you are a woman, 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 section “Warnings and precautions”).If you are a man, you should avoid fathering a child while taking methotrexate and for at least 3 months after stopping treatment.See also section “Pregnancy, lactation and fertility”.

Use of Bertanel with other medications

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication. Remember to inform your doctor about your Bertanel treatment if you are prescribed another medication while still on treatment.

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

• other treatments for rheumatoid arthritis or psoriasis, such as leflunomide, sulfasalazine (also used for ulcerative colitis), aspirin, phenylbutazone, or amidopyrine
• alcohol (should be avoided)
• live virus vaccines
• azathioprine (used to prevent organ transplant rejection)
• retinoids (used to treat psoriasis and other skin diseases)
• anticonvulsants (prevent seizures)
• chemotherapy
• barbiturates (help sleep)
• tranquilizers
• oral contraceptives
• probenecid (for gout)
• antibiotics
• Penicillins may reduce methotrexate excretion, potentially increasing the risk of adverse effects
• metamizol (synonyms novaminsulfon and dipirona) (pain reliever and fever reducer)
• pyrimethamine (used to prevent and treat malaria)
• vitamin preparations containing folic acid
• proton pump inhibitors (used to treat stomach acid or ulcers)
• theophylline (used to treat asthma)

Use of Bertanel with food, drinks, and alcohol

During Bertanel treatment, you should not consume alcohol and avoid excessive consumption of coffee, caffeinated soft drinks, and black tea.

Make sure to drink a large amount of fluids during Bertanel treatment, as dehydration can increase the toxicity of Bertanel.

Pregnancy, lactation, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medication.

Pregnancy

Do not use Bertanel during pregnancy or if you are planning to become pregnant. Methotrexate can cause birth defects, harm the fetus, or cause miscarriages. It is associated with skull, facial, heart, and blood vessel malformations, brain, and limb malformations. Therefore, it is very important that methotrexate is not administered to pregnant patients 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.

Avoid becoming pregnant while taking methotrexate and for at least 6 months after stopping treatment, using reliable contraceptive methods during this time (see also section “Warnings and precautions”).

If you become pregnant during treatment or suspect you may be pregnant, consult your doctor as soon as possible. You will be offered information on the risk of adverse effects on the child during treatment.

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

Lactation

Do not breastfeed during treatment, asmethotrexate passes into breast milk. If your doctor considers that methotrexate treatment is absolutely necessary, breastfeeding should be interrupted.

Male fertility

The available data do not indicate a higher risk of malformations or miscarriages if the father takes a methotrexate dose of less than 30 mg/week. However, this risk cannot be completely ruled out. Methotrexate can be genotoxic, meaning it can cause genetic mutations. Methotrexate can affect sperm production and cause birth defects. 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 machinery

During Bertanel treatment, you may experience adverse effects that affect the central nervous system, such as fatigue and dizziness. In some cases, your ability to drive vehicles and/or operate machinery may be affected. If you feel tired or dizzy, do not drive or operate tools or machinery.

Bertanel contains sodium chloride and sodium hydroxide

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

Bertanel should only be prescribed by doctors familiar with the different characteristics of the medication and its mode of action.

Follow exactly the administration instructions ofthis medicationindicated by your doctor.In case of doubt, consultagainyour doctor or pharmacist.

Bertanel is administeredonly once a week.Along with your doctor, you will decide on a suitable day each week to receive your injection.

The incorrect administration of Bertanel may produce severe side effects, including potentially fatal ones.

The normal dose is:

Dosage in patients with rheumatoid arthritis

The initial recommended dose is 7.5 mg of methotrexateonce a week. Bertanel is administered in a single application in the form of an injection under the skin, in a muscle or in a vein (see section “Method and duration of administration”).

If this is not enough and if you tolerate the medication well, the doses of Bertanel can be increased. The average weekly dose is 15-20 mg. Generally, aweekly doseof 25 mg of Bertanel should not be exceeded. Once the desired therapeutic result is achieved, if possible, the dose should be gradually reduced to the lowest possible maintenance dose.

Dosage in children and adolescents under 16 years of age with polyarticular forms of juvenile idiopathic arthritis

The recommended dose is 10-15 mg/m2of body surfaceper week. In cases of inadequate response, the weekly dose can be increased to 20 mg/m2of body surface per week. However, more frequent controls should be performed. As there are very few data on intravenous administration (in vein) in children and adolescents, it should only be administered subcutaneously (under the skin) or intramuscularly (in muscle).

It is not recommended to use in children under 3 years of age, as experience in this age group is insufficient.

Adults with severe forms of psoriasis vulgar or psoriatic arthritis

A dose of 5-10 mg is recommended for a test dose to evaluate potential harmful effects.

This dose can be administered subcutaneously (under the skin), intramuscularly (in muscle) or intravenously (in vein).

If, one week later, no changes in blood count are observed, treatment will continue with a dose of approximately 7.5 mg. The dose can be increased progressively (in stages of 5-7.5 mg per week and controlling blood count) to achieve the desired therapeutic results. Generally, aweekly doseof 20 mg can be associated with significant increases in toxicity. A weekly dose of 30 mg should not be exceeded.

Once the desired therapeutic result is achieved, the dose should be reduced weekly toreach the lowest possible maintenance dose for the patient.

Patients with renal insufficiency

Patients with renal insufficiency may require lower doses.

Method and duration of administration

The doctor will determine the duration of treatment. Bertanel is injectedonce a week!. It is recommended to specify a particular day of the week as the “injection day”.

Bertanel is administered in the form of an injection under the skin, in a muscle or in a vein; in children and adolescents, it should not be administered intravenously.

The treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgar and psoriatic arthritis with Bertanel is a long-term treatment.

Rheumatoid arthritis

Generally, an improvement in symptoms can be expected within 4-8 weeks of treatment. Symptoms may recur after discontinuation of treatment with Bertanel.

Severe forms of psoriasis vulgar and psoriatic arthritis (psoriatic arthritis)

Generally, a response to treatment can be expected within 2-6 weeks.

Depending on the clinical picture and changes in laboratory parameters, treatment will continue or be discontinued.

At the beginning of treatment, Bertanel may be injected by medical personnel. However, your doctor may decide that you can learn to inject Bertanel yourself. You will receive the necessary training for this. In no circumstances should you attempt to inject yourself, unless you have been taught to do so.

If you use more Bertanel than you should

Follow the dosage recommendations given by your doctor. Do not change the dose on your own.

If you suspect that you (or someone else) has taken too much Bertanel, please contact your doctor or go immediately to the nearest hospital or consult theToxicology Information Service, phone 91 562 04 20 indicating the medication and the amount used. They will decide on the necessary treatment measures, depending on the severity of the overdose.

A methotrexate overdose can produce severe toxic reactions. Symptoms of overdose may include unusual bleeding or bruising, unusual weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood or vomit resembling coffee grounds, and decreased urine production. See section 4.

Carry the medication packaging with you if you visit your doctor or a hospital.

The antidote for overdose is folic acid.

If you forget to use Bertanel

Do not use a double dose to make up for the missed doses,continue using the prescribed dose. If you have doubts, consult your doctor.

If you interrupt treatment with Bertanel

You should not interrupt treatment with Bertanel unless your doctor has told you to. If you suspect severe side effects, consult your doctor immediately.

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

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

Inform your doctor immediately if you experience wheezing, difficulty breathing, swelling of the eyelids, face, or lips, rash or itching (especially if it affects the entire body) and if you feel like you are going to faint (these could be symptoms of severe allergic reactions or anaphylactic shock).

Severe side effects

If any of the following side effects occur, contact your doctor immediately:

• Respiratory problems (symptoms may include general discomfort, dry and irritating cough, difficulty breathing, feeling of lack of air at rest, chest pain, or fever)
• Bleeding when coughing or sneezing
• Formation of blisters or severe skin peeling (this can also affect the mouth, eyes, and genitals)
• Unusual bleeding (including vomiting blood) or bruises
• Severe diarrhea
• Mouth ulcers
• Black or tar-like stools
• Blood in urine or stools
• Small red spots on the skin
• Fever
• Yellow discoloration of the skin (jaundice)
• Pain or difficulty urinating
• Swelling of hands, ankles, or feet, or changes in urination frequency or decreased or absent urination (symptoms of kidney failure)
• Thirst and/or frequent urination
• Seizures (convulsions)
• Loss of consciousness
• Blurred vision or decreased vision

The following side effects have also been reported:

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

• Loss of appetite, nausea (feeling dizzy), vomiting, abdominal pain
• Inflammation and ulcers in the mouth and throat
• Increased liver enzymes

Common(may affect up to 1 in 10 people):

• Reduced formation of blood cells with decreased white blood cells, red blood cells, or platelets (leukopenia, anemia, thrombocytopenia)
• Headache
• Fatigue, drowsiness
• Itching, tingling, pinching, or burning of the skin, urticaria, skin redness, itching
• Pneumonitis (inflammation of the lungs)
• Diarrhea

Uncommon(may affect up to 1 in 100 people):

• Herpes (herpes zoster)
• Lymphoma (which in some cases remitted spontaneously as soon as treatment with Bertanel was discontinued)
• Decreased number of blood cells and platelets
• Severe allergic reactions
• Diabetes
• Depression
• Weakness on one side of the body
• Dizziness, confusion
• Seizures
• Cerebral damage (leucoencephalopathy/encephalopathy)
• Inflammation of blood vessels
• Pulmonary damage, pulmonary edema
• Ulcers and bleeding in the digestive tract
• Pancreatitis (inflammation of the pancreas)
• Hepatic disorders
• Decreased proteins in the blood
• Urticaria (alone), sensitivity to light, brown discoloration of the skin
• Severe skin toxic reactions, including blistering and shedding of the upper layer of the skin (Stevens-Johnson syndrome, Lyell syndrome)
• Hair loss
• Increased rheumatoid nodules
• Painful psoriasis
• Reactions similar to sunburn due to increased skin sensitivity to sunlight
• Muscle or joint pain
• Osteoporosis (reduction of bone mass)
• Inflammation and ulcers of the bladder (possibly with blood in the urine), pain while urinating
• Fetal malformations
• Inflammation and ulcers in the vagina
• Sensation of burning or damage to the tissue after injection of Bertanel in the muscle.

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

• Sepsis
• Very large red blood cells (megaloblastic anemia)
• Mood changes
• Temporary problems with perception
• Weakness of voluntary movement in the entire body
• Speech problems
• Severe eye problems
• Low blood pressure
• Blood clots
• Throat pain
• Interruption of breathing
• Inflammation of the digestive tract, stools with blood
• Inflammation of the gums
• Acute hepatitis (inflammation of the liver)
• Changes in nail color, nail loss
• Acne, red or purple spots due to blood vessel rupture
• Fractures of bones due to exertion
• Electrolyte imbalances
• Abortion
• Defective sperm formation
• Menstrual irregularities

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

• Herpes labialis (herpes simplex)
• Hepatitis
• Severe bone marrow insufficiency
• Immunodeficiency (hypogammaglobulinemia)
• Pain
• Muscle weakness
• Changes in taste (metallic taste)
• Inflammation of the meninges that causes paralysis or vomiting
• Red eyes
• Inflammation of the pericardial cavity, fluid in the pericardial cavity
• Pneumonia, respiratory problems, asthma
• Vomiting blood
• Liver failure
• Infection around the nails, furuncles, small blood vessels in the skin
• Proteins in the urine
• Fetal death
• Problems with ovum formation (female) and sperm formation (male)
• Loss of libido
• Erectile dysfunction
• Vaginal discharge
• Infertility
• Mild local reactions in the skin if Bertanel is administered subcutaneously
• Lymphoproliferative disorders (excessive increase in white blood cells)
• Sensation of numbness or tingling/sensitivity to stimuli less than normal

Frequency unknown(cannot be estimated from available data):

• Infections that in some cases can be fatal
• Inflammation of lymph nodes
• Malfunction of the immune system
• Fever
• Inflammation of small blood vessels caused by an allergic reaction
• Inflammation of the peritoneum
• Slow healing of wounds
• Pulmonary hemorrhage
• Fractures of the jaw bones (secondary to excessive increase in white blood cells)
• Destruction of tissue at the injection site
• Redness and peeling of the skin
• Swelling

When metotrexate is administered intramuscularly, local side effects may frequently occur at the injection site (burning sensation) or lesions (formation of sterile abscesses, destruction of fatty tissue). Subcutaneous administration of metotrexate has good local tolerance. Only mild local skin reactions have been observed, decreasing during treatment.

Metotrexate may reduce the number of white blood cells, potentially decreasing their resistance to infection. If you experience symptoms such as fever and severe deterioration of your general condition, or fever with local infection symptoms such as sore throat/pharyngitis/dental pain or urinary problems, you should see your doctor immediately. A blood test will be performed to check for possible leukopenia. It is essential to inform your doctor about your medication.

Metotrexate can cause severe side effects (sometimes life-threatening). Therefore, your doctor will perform tests to check for blood abnormalities (e.g., leukopenia, thrombocytopenia, lymphoma) and changes in the kidneys and liver.

Reporting of side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through the Spanish System for Pharmacovigilance of Medicines for Human Use:www.notificaRAM.es. By reporting side effects, you can contribute to providing more information on the safety of this medication.

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 syringe label and on the packaging after “CAD”. The expiration date is the last day of the month indicated.

Store in the original packaging to protect it from light.

Do not store at a temperature above 25°C.

The product must be used immediately after opening the packaging.

Do not use Bertanel if the solution is not transparent and contains particles.

For single use. Dispose of any unused solution remainder!

Medicines should not be thrown down the drain or in the trash. Deposit the packaging and unused medicines at the SIGRE point of the pharmacy. If in doubt, ask your pharmacist how to dispose of unused packaging and medicines. By doing so, you will help protect the environment.

Composition of Bertanel

The active principle is methotrexate.

1 ml of injectable solution contains 20 mg of methotrexate (equivalent to 21.94 mg of methotrexate disodium).

1 pre-filled syringe of 1.5 ml of injectable solution contains 30 mg of methotrexate.

The other components are: sodium chloride, sodium hydroxide for pH adjustment, and water for injectable preparations.

Appearance of the product and contents of the package

Bertanel is an injectable solution that is marketed in pre-filled syringes with a transparent yellowish solution for injection.

Each box contains 1 pre-filled syringe or multipack containers containing 4, 5, 6, 12, or 30 pre-filled syringes with 1.5 ml of injectable solution, single-use injection needles with or without a safety cannula, and alcohol-soaked cotton balls.

Only some package sizes may be marketed.

Marketing authorization holder

Ebewe Pharma Ges.m.b.H. Nfg.KG

Mondseestrasse 11

4866 Unterach, Austria

Responsible for manufacturing

Ebewe Pharma Ges.m.b.H. Nfg.KG

Mondseestrasse 11

4866 Unterach, Austria

Salutas Pharma GmbH

Otto-von-Guericke-Alle 1

D-39179 Barleben

Germany

Fareva Unterach GmbH

Mondseestraße 11

4866 Unterach

Austria

For further information about this medicinal product, please contact the local representative of the marketing authorization holder:

Local representative

Laboratorios Farmacéuticos ROVI, S.A.

Julián Camarillo, 35

28037 Madrid

Spain

This medicinal product is authorized in the Member States of the European Economic Area with the following names:

Last review date of this leaflet:September 2024

For detailed and updated information about this medicinal product, please visit the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) http://www.aemps.gob.es/

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This information is intended solely for healthcare professionals:

Bertanel 30 mg/1,5 ml injectable solution in pre-filled syringe

Instructions for use, handling, and disposal

The solution must be transparent and free of particles.

The handling and disposal of the medicinal product must be carried out as with other cytotoxic preparations and in accordance with local regulations. If any female healthcare personnel were pregnant, they should not handle and/or administer Bertanel.

For single use only. Dispose of any unused solution.

The disposal of unused medicinal products and waste materials must be carried out in accordance with local regulations.

Incompatibilities

In the absence of compatibility studies, this medicinal product should not be mixed with others.

Special precautions for storage

Store in the original packaging to protect it from light.

Do not store above25°C.

Step-by-step instructions for subcutaneous injection:

Step 1:

• Remove the inner packaging containing the pre-filled syringe, needle, and cannula from the box.
• Open the inner packaging by pulling the tab on the corner. Remove the pre-filled syringe.
• Turn the grey rubber stopper covered with plastic on the syringe without touching the opening of the pre-filled syringe (see figure 1).

Figure 1.

Step 2:

• Place the syringe back in the inner packaging. The yellow solution will not spill.
• Check the label on the plastic case containing the needle. The label must be intact (see figure 2).

Figure 2.

Step 3:

• Remove the cap from the plastic case of the needle by turning it and then pulling it. See figure 3.1
• Turn the needle carefully along with the plastic case in the syringe as far as it goes. See figure 3.2

Figure 3.1 Figure 3.2

Step 4:

• Choose the injection site in the abdominal or thigh area and clean it with an alcohol-soaked cotton ball. Do not touch this area before the injection (see figures 4.1 and 4.2).

Figure 4.1Figure 4.2

Step 5:

• Remove the cannula cover and set it aside.

• Do not touch the sterile cannula. If this occurs, ask your doctor or pharmacist about the possibility of using another cannula. With two fingers, make a fold in the skin and then insert the needle into it almost vertically.

Step 6:

• Insert the cannula completely into the skin fold. Then, slowly push the plunger down and inject all the liquid under the skin.

Step 7:

• Carefully remove the cannula and clean the injection site with an alcohol-soaked cotton ball. Do not rub it, as this may cause irritation at the injection site.

• To avoid injury, dispose of used syringes in a container.