Package Insert: Information for the User

Bertanel 7.5 mg/0.75 ml Pre-filled Syringe

Bertanel 10 mg/1 ml Pre-filled Syringe

Bertanel 15 mg/1.5 ml Pre-filled Syringe

metotrexato

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 alone and should not be given 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.

Bertanel is a medication that contains methotrexate. Methotrexate is a substance that has 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 juvenile idiopathic arthritis (JIA) in children over 3 years old, active and severe, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate
• resistant and severe disabling psoriasis, which does not respond adequately to other forms of treatment such as phototherapy, PUVA, and retinoids, and severe psoriasis that affects the joints (psoriatic arthritis) in adult patients.

.

Ask your doctor or pharmacist if you have any doubts before using Bertanel.

Do not use Bertanel

• if you are allergic (hypersensitive) to methotrexate or any of the other components of this medication (listed in section 6)
• if you have any existing or severe infection
• if you have active mouth inflammation or digestive ulcers
• 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 (your doctor decides the severity of your disease)
• if you have increased alcohol consumption (if you have liver disease caused by alcohol or other chronic liver disease)
• if you have an altered immune system (e.g., AIDS)
• if you are pregnant or breastfeeding (see section “Pregnancy, breastfeeding and fertility”).

Warnings and precautions

Important warning regarding methotrexate dosing:

Methotrexate for the treatment of rheumatic or skin diseases should only be used once a week.

Always use Bertanel exactly as your doctor has instructed.

Incorrect methotrexate dosing can cause severe adverse effects, including fatal consequences. Read section 3 of this prospectus carefully.

Speak with your doctor before using Bertanel.

Especially in elderly people, deaths have been reported after accidental daily use of the weekly dose.

Methotrexate should only be prescribed by doctors who have sufficient experience in treating the disease with methotrexate.

Your doctor will inform you about the possible benefits and risks (including the first signs and symptoms of toxicity) of methotrexate therapy.

You need to be closely monitored during therapy so that signs of possible toxic effects or adverse reactions can be detected as soon as possible.

If you notice symptoms of intoxication (please see section 4 "Possible adverse effects"), contact your doctor immediately. Your doctor will decide if it is necessary to control and treat the symptoms of intoxication and inform you of additional measures.

Consult with your doctor or pharmacist before using Bertanel if you:

• have diabetes mellitus treated with insulin
• have chronic inactive infections (e.g., tuberculosis, hepatitis B or C, herpes (herpes zoster)), as these diseases may reactivate
• have or have had any liver or kidney disease
• have or have had problems with lung function
• are obese
• have abnormal accumulation of fluid in the abdomen or in the cavity between the lungs and the thoracic wall (ascitis, pleural effusion)

Liver function

Methotrexate can damage the liver; during treatment with Bertanel, you should avoid drinking alcohol and taking other medications that can damage the liver. Before and during treatment with Bertanel, your doctor should perform blood tests to monitor liver function. Please also see sections "Other medications and Bertanel" and “Bertanel with food and alcohol” and section 4.

Renal function

Bertanel can damage the kidneys. Your doctor should perform blood tests before and during treatment to monitor your renal function. If you are dehydrated or have any condition that may cause dehydration (vomiting, diarrhea, stomatitis), the toxicity of methotrexate may increase. Your doctor may suspend the therapy with Bertanel. Please also see section 4.

Blood formation system and immune system

Treatment with Bertanel may damage your bone marrow (bone marrow depression). This can cause severe infections and/or bleeding and anemia.

Your doctor will perform blood tests so that these can be treated as soon as possible.

Contact your doctor if you experience fever, sore throat, mouth ulcers, symptoms similar to the flu, fatigue, bruises or bleeding.

Methotrexate can affect the efficacy of vaccines or immune response tests due to its effect on the immune system.

Nervous system

Certain brain disorders (encephalitis/encephalopathy), which can be fatal, have been reported with methotrexate administered intravenously. There have been reports of leukoencephalopathy in patients treated with oral methotrexate. If you, your partner or caregiver notice the appearance or worsening of neurological symptoms, such as general muscle weakness, vision changes, changes in thinking, 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).

Skin

Methotrexate can make your skin sensitive to sunlight, so you should avoid prolonged exposure to the sun.

You should also not visit a tanning salon without consulting your doctor.

Methotrexate can 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.

Changes in the skin caused by psoriasis may worsen during treatment with Bertanel if exposure to UV radiation occurs at the same time.

If you have experienced skin problems after radiation therapy (radiation dermatitis) and sunburns, these conditions may recur under methotrexate therapy (memory effect).

There have been reports of severe skin reactions, sometimes fatal, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell syndrome) after single or continuous use of methotrexate (please see section 4).

Gastrointestinal system

Treatment with methotrexate can lead to severe complications in your gastrointestinal system. In this case, treatment with methotrexate should be interrupted.

Contact your doctor immediately if you experience any problems in your gastrointestinal system (please see section 4).

Infections

Treatment with methotrexate can lead to infections, which can be fatal in some cases.

Contact your doctor immediately if you experience signs of infection (please see section 4).

Lung function

Treatment with methotrexate can lead to severe lung complications. In this case, treatment with methotrexate should be interrupted.

Contact your doctor immediately if you experience any respiratory problems or lung problems (please see section 4).

Pulmonary hemorrhage has been reported with methotrexate in patients with underlying rheumatic disease. If you experience symptoms of coughing or bleeding, contact your doctor immediately.

Tumors

A rare cancer in the lymph nodes (malignant lymphoma) may occur in patients receiving low doses of methotrexate, which in some cases may have resolved after interrupting treatment; therefore, no cytotoxic treatment was required. If a lymphoma occurs, treatment with methotrexate should be interrupted; and only if the lymphoma does not disappear, appropriate cytotoxic treatment should be initiated.

Methotrexate temporarily affects the production of sperm and eggs, which is reversible in most cases.

Methotrexate can cause miscarriages and severe congenital defects. If you are a woman, you should avoid becoming pregnant while using methotrexate and for at least six months after stopping treatment.If you are a man, you should avoid fathering a child while taking methotrexate and for at least three months after stopping treatment.See also the section “Pregnancy, breastfeeding and fertility”.

Follow-up examinations and recommended precautions:

Although Bertanel is administered at low doses, severe adverse effects can occur. To diagnose them as soon as possible, your doctor should perform follow-up examinations 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 and hepatitis will also be checked in your blood. In addition, your serum albumin (a blood protein) will be checked, as well as your liver state (hepatic infection) and renal function. Your doctor may also decide to perform other liver tests, some of which may be images 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 tests:

-oral cavity and pharynx 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 monitor liver function

-imaging tests to monitor liver function

-taking a small sample of liver tissue for closer examination

-blood test to monitor renal function

-lung function 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 accordingly.

Do not miss any of your scheduled tests.

If the results of any of these tests are abnormal, your doctor will take the necessary measures.

Elderly patients

Elderly patients treated with methotrexate should be under close medical supervision to detect possible adverse effects as soon as possible. The deterioration of liver and kidney function associated with age, as well as having low folate reserves in old age, require the administration of a relatively low dose of methotrexate.

Children and adolescents

The use is not recommended in children under 3 years due to lack of experience in this age group.

Children treated with methotrexate should be maintained under particularly close medical supervision by specialists in this area to identify possible adverse effects as soon as possible.

Other medications and Bertanel

Inform your doctor or pharmacist if you are using, have used recently, or may need to use other medications, including over-the-counter medications, such as herbal remedies or vitamins.

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

• medications that can damage the liver such as:

• azathioprine (used to prevent rejection after organ transplantation)
• leflunomide (for rheumatoid arthritis)
• retinoids (used to treat psoriasis and other skin disorders)
• sulfasalazine (used for rheumatoid arthritis and ulcerative colitis)

• other treatments for rheumatoid arthritis or psoriasis, such as gold, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, and cyclosporine (to suppress the immune system)
• medications for pain relief and/or inflammation (non-steroidal anti-inflammatory drugs or salicylates, such as ibuprofen, indomethacin, phenylbutazone, amidopyrine derivatives, and acetylsalicylic acid, including salicylic acid). This also applies to over-the-counter medications
• some cancer treatments (cytotoxics such as doxorubicin, mercaptopurine, procarbazine, cisplatin, L-asparaginase, vincristine, cytarabine, and 5-fluorouracil)
• antibiotics (e.g., penicillin, sulfonamides, trimethoprim/sulfamethoxazole, tetracyclines, ciprofloxacin, pristinamicin, chloramphenicol)
• metamizole (synonyms novaminsulfon and dipirona) (medication for intense pain and/or fever)
• penicillins may reduce methotrexate excretion, potentially increasing the risk of adverse effects
• tranquilizers (e.g., benzodiazepines, such as lorazepam, alprazolam)
• medications for high blood sugar levels (tolbutamide, glipizide, glimepiride)
• para-aminobenzoic acid (treatment for skin problems)
• oral contraceptives
• triamterene (treatment for high blood pressure)
• anticonvulsants, such as phenytoin, levetiracetam (prevent seizures) and barbiturates (also used as injections for sleep)
• probenecid (for gout)
• amino hippuric acid (substance to check renal function)
• pyrimethamine (used to prevent and treat malaria)
• medications used to treat severe stomach acid or ulcers (e.g., proton pump inhibitors, such as omeprazole, pantoprazole, lansoprazole)
• theophylline (used to treat asthma and other lung diseases)
• amiodarone (for heart rhythm disorders)
• anesthesia based on nitrous oxide (consult your doctor if you have a planned surgery)
• vitamin preparations containing folic acid, folinic acid, or any derivative

You should not receive a simultaneous vaccination with live vaccines during treatment with methotrexate. If you are unsure, consult your doctor.

There have been reports of skin cancer in some patients with psoriasis who received methotrexate and PUVA treatment (treatment with ultraviolet light).

Treatment with radiation during methotrexate treatment may increase the risk of necrosis (tissue damage due to cell death) in soft tissue or bone tissue.

Bertanel with food and alcohol

During treatment with Bertanel, you should avoid consuming alcohol, as this may increase toxicity (especially liver toxicity). You should also avoid excessive consumption of coffee, caffeine-containing beverages, and black tea.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, or if you think you may be 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, damage the fetus, or cause miscarriages. It is associated with skull, facial, heart, and blood vessel malformations, brain, and limb malformations. Therefore, methotrexate should not be administered 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 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 about the risk of harm to 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.

Breastfeeding

You should not breastfeed your child during treatment, as methotrexate passes into breast milk. If your doctor considers that treatment with methotrexate is absolutely necessary, breastfeeding should be interrupted.

Male fertility

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 treatment with Bertanel, you may experience adverse effects that affect the central nervous system, such as fatigue, drowsiness, and dizziness. Therefore, in some cases, your ability to drive vehicles and/or operate machines may be affected. If you feel tired or dizzy, do not drive or operate tools or machines. This applies to a greater extent if you take it with alcohol.

Bertanel contains sodium

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

Follow exactly the administration instructions for Bertanel indicated by your doctor. Consult your doctor or pharmacist if you are unsure.

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

Bertanel is administeredonly once a weekAlong with your doctor, you can decide on a suitable day of the week, each week that you receive your injection.

Incorrect administration of Bertanel may cause severe adverse effects, including potentially fatal adverse effects.

The recommended dose is:

Dosage in patients with rheumatoid arthritis

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

If this is not sufficient and if you tolerate the medication well, the initial dose of Bertanel can be gradually increased by 2.5 mg. Alternatively, a higher starting dose can be used. The average weekly dose is 15-20 mg. In general, a weekly dose of more than 20 mg of Bertanel should not be exceeded. Once the desired therapeutic effect is achieved, if possible, the dose should be gradually reduced to the lowest effective maintenance dose.

The response to treatment is expected within 4-8 weeks. After suspension of treatment with Bertanel, symptoms may reappear.

Use in children (over 3 years) and adolescents

Dosage in children (over 3 years) and adolescents with polyarticular forms of idiopathic juvenile arthritis

The recommended dose is 10-15 mg/m2of body surface areaper week. In cases of inadequate response, the weekly dose can be increased to 20 mg/m2of body surface area per week. However, more frequent monitoring should be performed.

Adults with severe forms of psoriasis vulgar or psoriatic arthritis

Initial recommended dose (relative to an adult of 70 kg body weight): A single test dose of 2.5-5 mg is recommended for evaluation of toxicity.

If laboratory parameters do not change, treatment can be continued with approximately 7.5 mg 1 week later. The dose can be gradually increased (in increments of 5-7.5 mg per week) while laboratory parameters are monitored, until the desired optimal result is achieved. In general, a weekly dose of more than 25 mg of methotrexate should not be exceeded.

Once the desired effect is achieved, the maintenance dose should be gradually reduced to the lowest effective dose possible in the patient.

The response to treatment occurs, in general, within 4-8 weeks. From then on, treatment will be continued or suspended depending on the clinical situation and changes in laboratory parameters.

Older patients

A dose reduction should be considered in older patients due to decreased renal and hepatic function, as well as the decrease in folate reserves that occurs with advancing age.

Patients with renal insufficiency

Patients with renal insufficiency may require lower doses.

Method and duration of administration

Your 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 as an injection under the skin, into muscle or into a vein; in children and adolescents, it should not be administered intravenously.

Treatment with Bertanel for rheumatoid arthritis, idiopathic juvenile arthritis, psoriasis vulgar, and psoriatic arthritis is long-term treatment.

Rheumatoid arthritis

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

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

Generally, the response to treatment can be expected within 4-8 weeks. Depending on the clinical situation and changes in laboratory parameters, treatment will be continued or 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. Under 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 administration instructions indicated by your doctor. Do not change the dose on your own.

If you suspect that you (or someone else) has administered too much Bertanel, contact your doctor or go to the nearest hospital immediately or consult the Toxicology Information Service, phone 91 562 04 20. They will decide what measures to take based on the severity of the overdose.

A methotrexate overdose can cause severe toxic reactions, including a fatal outcome. Symptoms of overdose may include bleeding or bruising, unusual weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood or coffee ground-like vomit, and decreased urine production. See section 4.

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

The antidote for overdose is folic acid calcium.

If you forget to use Bertanel

If you miss a dose, administer it within 24 hours of the specified day. If a longer delay occurs, consult your doctor first. Do not take a double dose to compensate for missed doses, continue using the prescribed dose. If you have doubts, consult your doctor.

If you interrupt treatment with Bertanel

You should not discontinue treatment with Bertanel unless your doctor has instructed you to do so. If you suspect severe 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.

The side effects generally depend on the dose level and duration of treatment with methotrexate.

Severe side effects can also occur at lower doses, which may lead to the interruption or termination of therapy.

Side effects can appear at any time during treatment.

Most side effects are reversible if recognized in time. The end of treatment does not always completely resolve all side effects.

However, some of the severe side effects listed below may cause sudden death in very rare cases.

Some side effects may occur after treatment has ended.

Please talk to your doctor.

If you develop any of the following side effects, contact your doctor immediately, as they may be signs of potentially fatal side effects that need to be treated immediately. Your doctor may decide to reduce the dose or discontinue treatment.

Severe side effects

• Allergic symptoms such as hives or itching (especially affecting the entire body), swelling of the hands, feet, ankles, eyelids, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing), sudden wheezing, difficulty breathing, and feeling like you are going to faint (these may be signs of severe allergic reactions or anaphylactic shock) (may affect up to 1 in 100 patients)

• Pulmonary problems (symptoms may include, generally, discomfort, irritating and dry cough, difficulty breathing, feeling of lack of air at rest, chest pain, or fever), which may be signs of pneumonia, interstitial pneumonitis, or alveolitis (may affect up to 1 in 10 patients)
• Coughing up or spitting blood
• Symptoms of liver failure such as yellowing of the skin (jaundice) and the white of the eyes, dark urine, nausea, vomiting, loss of appetite, pain in the right side of the abdomen, and itching (may affect up to 1 in 100 patients)
• Symptoms of kidney failure such as swelling of the hands, ankles, or feet, or changes in urination frequency or decreased or absent urination (may affect up to 1 in 100 patients)
• Symptoms of an infection such as fever, chills, pain, or sore throat. Methotrexate may decrease your resistance to infections; severe infections such as a special type of pneumonia (Pneumocystis jirovecii pneumonia) (may affect up to 1 in 10,000 patients) or blood poisoning (may affect up to 1 in 1,000 patients)
• Fever, sore throat, mouth ulcers, general feeling of discomfort, and fatigue, nasal bleeding, and small red spots on the skin may be symptoms of bone marrow damage (may affect up to 1 in 10 patients)
• Mouth and throat ulcers (may affect more than 1 in 10 patients)
• Abdominal pain, nausea, vomiting, and fever, as these may be signs of pancreatitis (may affect up to 1 in 100 patients)
• Severe abdominal pain, fever, nausea, vomiting, severe diarrhea, black or tar-like stools, or changes in bowel habits, as these may be symptoms of gastrointestinal tract complications, such as ulcers (may affect up to 1 in 100 patients) or intestinal perforation (unknown frequency)
• Severe toxic skin reactions, such as vesicle formation and skin layer detachment (Stevens-Johnson syndrome, toxic epidermal necrolysis/Lyell syndrome). Skin reactions are associated with severe general condition and fever. The skin reaction may be potentially fatal (may affect up to 1 in 100 patients)
• Symptoms of thrombosis (blood clot) such as chest pain, pain in the arms, back, neck, or jaw, shortness of breath, numbness or weakness in one half of the body, speech disturbances, headache, or drowsiness (may affect up to 1 in 1,000 patients)
• Cough, chest pain, sudden shortness of breath, or coughing up blood; these may be symptoms of a pulmonary embolism (blood clot in the lung) (may affect up to 1 in 1,000 patients)

Also, the following side effects have been reported:

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

• Reduction of blood cell formation with decreased white blood cells and/or platelets (leucopenia, thrombocytopenia)
• Headache, dizziness
• Cough
• Loss of appetite, nausea (feeling of discomfort), vomiting, diarrhea (particularly during the 24-48 hours after the first administration of methotrexate), abdominal pain
• Inflammation and ulcers in the mouth and throat (particularly during the 24-48 hours after the first administration of methotrexate)
• Increased liver enzymes in blood tests
• Hair loss
• Decreased creatinine clearance (your doctor may determine it through a blood test and it is a sign of worsening kidney function)
• Feeling of weakness

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

• Herpes (herpes zoster)
• Anemia
• Decreased number of red blood cells, white blood cells, and platelets, sudden drop in certain white blood cells (agranulocytosis), disorders in blood cell formation (pancytopenia)
• Fatigue, drowsiness
• Tickling, tingling, pinching (paresthesia)
• Redness, itching, burning of the skin, rash, inflammation
• Ulcers on the skin
• Red eyes (conjunctivitis)

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

• Opportunistic infections (due to inadequate immune function) that may be fatal in some cases
• Lymphoma, see section 2
• Immune system dysfunction, leading to a higher likelihood of infections/inflammations
• Diabetes
• Depression
• Weakness of the entire right or left side of the body (hemiparesis)
• Dizziness, confusion
• Seizures
• Brain damage (encephalopathy/leucoencephalopathy)
• Severe inflammation of blood vessels (vasculitis)
• Allergic vasculitis
• Formation of scar tissue in the lungs (pulmonary fibrosis), fluid around the lungs
• Ulcers and bleeding in the digestive tract
• Inflammation of the pancreas
• Chronic liver damage (cirrhosis)
• Decreased serum albumin
• Urticaria (hives), skin darkening
• Increased rheumatoid nodules
• Painful psoriasis
• Lesions on the skin similar to herpes
• Reactions similar to sunburn due to increased skin sensitivity to sunlight
• Muscle or joint pain
• Osteoporosis (reduction of bone mass)
• Inflammation and ulceration of the bladder (possibly with blood in the urine), problems emptying the bladder, absence of urination, painful or reduced urination
• Birth defects
• Inflammation and ulcers of the vagina
• Fever

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

• Very large red blood cells (megaloblastic anemia)
• Mood fluctuations
• Temporary perception problems
• Weakness of voluntary movement in the entire body
• Speech problems (aphasia/disarthria)
• Severe visual disturbances (blurred or cloudy vision), blood clots in the retina
• Low blood pressure
• Blood clots (thromboembolic episodes)
• Sore throat
• Interruption of breathing
• Inflammation of the digestive tract, bloody stools
• Swollen eyelids
• Acute hepatitis (inflammation of the liver)
• Change in nail color, nail loss
• Acne, red or purple spots due to blood vessel bleeding
• Erythema multiforme, red skin rash
• Fracture due to excessive force
• Electrolyte disturbances, increased urea, creatinine, and uric acid in the blood (azotemia)
• Abortion
• Defective sperm formation (returns to normal after treatment ends)
• Menstrual disorders (returns to normal after treatment ends)

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

• Heatitis caused by herpes viruses (herpes simplex hepatitis), infections caused by fungi (histoplasmosis, cryptococcosis), bacteria (nocardiosis), or viruses (cytomegalovirus infections, including pneumonia)
• Herpes simplex fever
• Anemia caused by inadequate red blood cell formation (aplastic anemia), increased eosinophils in the blood (eosinophilia), decreased neutrophils in the blood (neutropenia), inflammation of lymph nodes in the head and neck, axilla, and groin (partially reversible), uncontrolled proliferation of lymphocytes (partially reversible)
• Immunodeficiency (hypogammaglobulinemia)
• Heatitis
• Muscle and joint pain
• Changes in taste (metallic taste)
• Inflammation of the meninges that causes paralysis or vomiting
• Swelling around the eyes, inflammation of the eyelids, tearing, increased sensitivity to light, transient blindness, vision deterioration
• Inflammation of the sac around the heart (pericarditis), cardiac filling obstruction due to pericardial effusion (cardiac tamponade), fluid accumulation between the pericardial layers (pericardial effusion)
• Abnormal pulmonary function test results, difficulty breathing, and cough
• Vomiting blood
• Death of liver cells (necrosis), acute liver degeneration, liver failure
• Deep follicular infection (folliculitis), permanent capillary enlargement visible on the skin (telangiectasia), acute inflammation of the nail bed
• Blood and/or protein in the urine
• Fetal death
• Problems with ovum formation (women) and sperm formation (men)
• Menstrual cycle disorders
• Loss of libido
• Difficulty achieving an erection
• Male breast enlargement
• Vaginal discharge
• Infertility
• Reduced sensitivity to stimuli

Unknown (frequency cannot be estimated from available data):

• Pneumonia
• Reactivation of hepatitis B infection or worsening of hepatitis C infection
• Pulmonary hemorrhage
• Skin cancer (see also section 2)
• Increased cerebrospinal fluid pressure with symptoms such as headache, nausea, vomiting, increased blood pressure, confusion; brain damage (neurotoxicity), inflammation of the meninges (arachnoiditis), paralysis of the legs (paraplegia), stupor, coordination problems (ataxia), dementia
• Non-inflammatory eye disorder (retinopathy)
• Hypoxia (lack of oxygen in organs)
• Non-infectious inflammation of the abdominal lining characterized by abdominal pain and sensitivity to pressure (peritonitis)
• Toxic megacolon (a severe complication due to massive colon enlargement combined with intense pain), intestinal perforation
• Inflammation of the tongue
• Medication reaction with eosinophilia and systemic symptoms (DRESS)
• Dermatitis
• General and mandibular bone damage (secondary to excessive growth of white blood cells)
• Urogenital dysfunction
• Chest pain, chills, tissue destruction at the injection site
• Redness and peeling of the skin
• Swelling

When methotrexate is administered intramuscularly, local side effects (burning sensation) or damage (sterile abscesses, fat tissue destruction) may occur at the injection site.

Subcutaneous administration of methotrexate is well tolerated locally. Only mild local skin reactions were observed, decreasing during treatment.

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 leaflet. You can also report them directly through theSistema Español de Farmacovigilancia de Medicamentos de Uso Humano: www.notificaRAM.es.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 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. Do not freeze.

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!

Medications should not be disposed of through drains or trash. Deposit the containers and medications you no longer need at the SIGRE collection point at the pharmacy. If in doubt, 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 Bertanel

The active principle is methotrexate.

Each milliliter of injectable solution contains 10 mg of methotrexate (equivalent to 10.97 mg of methotrexate disodium).

Each preloaded syringe with 0.75 ml of injectable solution contains 7.5 mg of methotrexate.

Each preloaded syringe with 1 ml of injectable solution contains 10 mg of methotrexate.

Each preloaded syringe with 1.5 ml of injectable solution contains 15 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 preloaded syringes contain a clear, yellow, and particle-free injectable solution.

Bertanel is available in colorless glass syringes (type I according to Ph. Eur.) with a capacity of 1.25 ml, 2.25 ml, or 3.00 ml, with a rubber stopper and a rubber plunger.

Package size:

1 x 0.75 ml, 4 x 0.75 ml, 5 x 0.75 ml

1 x 1.0 ml, 4 x 1.0 ml, 5 x 1.0 ml

1 x 1.5 ml, 4 x 1.5 ml, 5 x 1.5 ml

1 x 2.0 ml, 4 x 2.0 ml, 5 x 2.0 ml

Single-use injection needles and alcohol swabs.

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

Fareva Unterach GmbH

Mondseestraße 11

4866 Unterach

Austria

Local Representative

Laboratorios Farmacéuticos ROVI, S.A.

Julián Camarillo, 35

28037 Madrid

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

AT/H/0192/01/MR

Last review date of this leaflet:September 2024

This information is intended solely for medical professionals or healthcare professionals:

Instructions for use, handling, and disposal

The solution must be clear and particle-free.

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 is pregnant, she must not handle and/or administer Bertanel.

For single use. Dispose of any unused solution.

The disposal of unused medicinal product or waste materials will be carried out in accordance with local regulations for cytotoxic agents.

Incompatibilities

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

Special precautions for storage

Store in the original packaging to protect it from light.

Do not store above 25°C.

Do not freeze.

Step-by-step instructions for subcutaneous injection:

Step 1:

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

Figure 1.

Step 2:

• Place the syringe back in the inner packaging. The yellow-colored 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 swab. 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:

• Remove the cannula carefully and wipe the injection site with a swab. Do not rub, as this may irritate the injection site.

• Dispose of the used syringe in a sharp object container.