Bertanel 7.5 mg/0.75 ml solution for injection in pre-filled syringe

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Bertanel 7.5 mg/0.75 ml solution for injection in pre-filled syringe

Bertanel 10 mg/1 ml solution for injection in pre-filled syringe

Bertanel 15 mg/1.5 ml solution for injection in pre-filled syringe

methotrexate

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

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others, even if they have the same symptoms as yours, as it may harm them.
• If you experience any side effects, talk to your doctor or pharmacist, even if they are side effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

1. What Bertanel is and what it is used for

Bertanel is a medicine containing methotrexate. Methotrexate is a substance that has the following properties:

• interferes with the growth of certain rapidly dividing cells in the body (antitumour agent)
• reduces unwanted reactions of the body's own defence system (immunosuppressant)

and

• has anti-inflammatory effects.

Bertanel is used in patients with:

• active rheumatoid arthritis (RA) in adults
• polyarticular forms (when five or more joints are involved) of active and severe juvenile idiopathic arthritis (JIA) in children over 3 years of age, when response to non-steroidal anti-inflammatory drugs (NSAIDs) has been inadequate
• severe, disabling, recalcitrant psoriasis that does not respond adequately to other treatments such as phototherapy, PUVA, and retinoids, and severe psoriasis affecting the joints (psoriatic arthritis) in adult patients.

2. What you need to know before using Bertanel

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

Do not use Bertanel

• if you are allergic (hypersensitive) to methotrexate or to any of the other components of this medicine (listed in section 6)
• if you have an existing or severe infection
• if you have inflammation of the mouth or active peptic ulcers
• if you have significant kidney disease (your doctor determines the severity of the disease)
• if you have significant liver disease (your doctor determines the severity of your condition)
• if you have disorders of the blood-forming system (your doctor determines the severity of your condition)
• if you have increased alcohol consumption (if you have alcohol-induced liver disease or another chronic liver disease)
• if your immune system is impaired (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 per week.

Always use Bertanel exactly as your doctor has instructed.

Incorrect dosing of methotrexate may cause serious adverse effects, including fatal outcomes. Please read section 3 of this leaflet carefully.

Talk to your doctor before using Bertanel.

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

Methotrexate should only be prescribed by physicians with sufficient experience in treating diseases with methotrexate.

Your doctor will inform you about the potential benefits and risks (including early 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 early as possible.

If you notice symptoms of intoxication (please refer to section 4 "Possible side effects"), contact your doctor immediately. Your doctor will decide whether monitoring and treatment of intoxication symptoms are necessary and will inform you of additional measures.

Consult your doctor or pharmacist before using Bertanel if you:

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

Liver function

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

Kidney function

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

Blood-forming system and immune system

Treatment with Bertanel could damage your bone marrow (bone marrow suppression). This may lead to serious infections and/or bleeding and anemia.

Your doctor will perform blood tests so these conditions can be treated as early as possible.

Contact your doctor if you experience fever, sore throat, mouth ulcers, flu-like symptoms, exhaustion, bruising, or bleeding.

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

Nervous system

Certain brain disorders (encephalitis/encephalopathy), which could be fatal, have been reported with intravenous methotrexate. Cases of leukoencephalopathy have been reported in patients treated with oral methotrexate. If you, your partner, or caregiver notice the onset or worsening of neurological symptoms such as general muscle weakness, vision disturbances, changes in thinking, memory, and orientation causing confusion and personality changes, contact your doctor immediately, as these may be symptoms of a rare but serious brain infection called progressive multifocal leukoencephalopathy (PML).

Skin

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

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

Methotrexate can increase skin sensitivity 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 appropriate clothing or use a sunscreen with a high protection factor.

Skin changes caused by psoriasis may worsen during treatment with Bertanel if exposure to UV radiation occurs simultaneously.

If you have experienced skin problems after radiotherapy (radiation-induced dermatitis) or sunburns, these conditions may reappear under methotrexate therapy (memory effect).

Serious, sometimes fatal, skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome) have been reported after single or continuous use of methotrexate (please refer to section 4).

Gastrointestinal system

Treatment with methotrexate may lead to serious complications in your gastrointestinal system. In such cases, methotrexate treatment must be discontinued.

Contact your doctor immediately if you experience any gastrointestinal problems (please refer to section 4).

Infections

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

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

Lung function

Treatment with methotrexate may lead to serious pulmonary complications. In such cases, methotrexate treatment must be discontinued.

Contact your doctor immediately if you experience any breathing problems or lung issues (please refer to section 4).

Acute lung hemorrhage has been reported with methotrexate in patients with underlying rheumatological disease. If you experience symptoms of coughing up or spitting blood, contact your doctor immediately.

Tumors

A rare cancer of the lymph nodes (malignant lymphoma) may occur in patients receiving low-dose methotrexate, which in some cases resolved after discontinuation of treatment; therefore, cytotoxic treatment was not required. If lymphoma occurs, methotrexate therapy should be stopped; and only if the lymphoma does not resolve should appropriate cytostatic treatment be initiated.

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

Methotrexate may cause miscarriages and severe congenital defects. If you are a woman, you must avoid becoming pregnant while taking methotrexate and for at least six months after stopping treatment. If you are a man, you must avoid fathering a child while being treated with methotrexate and for at least 3 months after completing treatment. See also the section “Pregnancy, breastfeeding and fertility”.

Follow-up monitoring and recommended precautions:

Although Bertanel is administered at low doses, serious adverse effects may occur. To detect them as early as possible, your doctor must perform follow-up examinations and laboratory tests.

Before starting treatment:

Before starting treatment, you will have a blood test to check whether you have sufficient blood cells. Your liver function and whether you have hepatitis will also be checked in your blood. Additionally, serum albumin (a blood protein), hepatitis status (liver infection), and kidney function will be assessed. Your doctor may decide to perform additional liver tests, some of which could include imaging of your liver and others may require a small tissue sample from your liver for closer examination. Your doctor may also check whether you have tuberculosis and may order a chest X-ray or a lung function test.

During treatment:

Your doctor may perform the following tests:

• examination of the oral cavity and pharynx to detect changes in the mucous membrane, such as inflammation or ulcers
• blood tests/blood counts, including blood cell count and measurement of serum methotrexate levels
• blood tests to monitor liver function
• imaging tests to monitor liver function
• taking a small tissue sample from the liver for closer examination
• blood tests to monitor kidney function
• monitoring of the respiratory tract and, if necessary, lung function tests

It is very important that you attend these scheduled tests.

If any of these test results 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 not normal, your doctor will take appropriate measures.

Elderly patients

Elderly patients receiving methotrexate must be under close medical supervision so that possible adverse effects can be detected as early as possible. Age-related decline in liver and kidney function, as well as low folic acid reserves in older age, require administration of a relatively low dose of methotrexate.

Children and adolescents

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

Children treated with methotrexate should be under particularly close medical supervision by specialists in this field to identify possible side effects as early as possible.

Other medicines and Bertanel

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

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

• medicines that may damage the liver such as:

• azathioprine (used to prevent organ transplant rejection)

• 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)

• medicines for pain and/or inflammation (non-steroidal anti-inflammatory drugs or salicylates, such as ibuprofen, indomethacin, phenylbutazone, amidopyrine derivatives and acetylsalicylic acid derivatives, including salicylic acid). This also applies to medicines available without a prescription

• some cancer treatments (cytotoxic agents such as doxorubicin, mercaptopurine, procarbazine, cisplatin, L-asparaginase, vincristine, cytarabine, and 5-fluorouracil)

• antibiotics (e.g., penicillin, sulfonamides, trimethoprim/sulfamethoxazole, tetracyclines, ciprofloxacin, pristinamycin, chloramphenicol)

• metamizole (synonyms novaminsulfone and dipyrone) (medicine for severe pain and/or fever)

• penicillins may reduce methotrexate excretion, potentially increasing adverse effects

• tranquilizers (e.g., benzodiazepines such as lorazepam, alprazolam)

• medicines for high blood sugar levels (tolbutamide, glipizide, glimepiride)

• para-aminobenzoic acid (treatment for skin problems)

• oral contraceptives

• triamterene (treatment for high blood pressure)

• anticonvulsant medicines, such as phenytoin, levetiracetam (prevent seizures) and barbiturates (also used as sleep-inducing injections)

• probenecid (for gout)

• hippuric acid (substance to check kidney function)

• pyrimethamine (used to prevent and treat malaria)

• medicines used to treat severe stomach acidity or ulcers (e.g., proton pump inhibitors such as omeprazole, pantoprazole, lansoprazole)

• theophylline (used to treat asthma and other lung diseases)

• amiodarone (to treat heart rhythm disorders)

• anesthesia based on nitrous oxide (talk to your doctor if you have a planned surgery)

• vitamin preparations containing folic acid, folinic acid, or any derivative

You must not receive live vaccinations simultaneously with methotrexate treatment. If you are unsure, consult your doctor.

Development of skin cancer has been reported in some patients with psoriasis who received methotrexate and PUVA treatment (ultraviolet light therapy).

Radiation therapy during methotrexate treatment could increase the risk of necrosis (damaged tissue due to cell death) in soft tissue or bone.

Bertanel with food and alcohol

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

Pregnancy, breastfeeding 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 medicine.

Pregnancy

Do not use Bertanel during pregnancy or if you are trying to become pregnant. Methotrexate may cause birth defects, harm the fetus, or cause miscarriages. It is associated with malformations of the skull, face, heart and blood vessels, brain, and limbs. Therefore, it is very important that methotrexate is not administered to pregnant patients or those planning to become pregnant. In women of childbearing potential, pregnancy must be ruled out by appropriate measures, for example, a pregnancy test before starting treatment. You must avoid becoming pregnant while taking methotrexate and for at least 6 months after stopping treatment, using reliable contraceptive methods throughout this period (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 should be provided with information about the risk of harmful effects on the child during treatment.

If you wish to become pregnant, consult your doctor, who may refer you to a specialist for counseling before the planned start of treatment.

Breastfeeding

You must not breastfeed during treatment, as methotrexate passes into breast milk. If your doctor considers methotrexate treatment absolutely necessary, breastfeeding must be discontinued.

Male fertility

Available data do not indicate an increased risk of malformations or miscarriages if the father takes a methotrexate dose below 30 mg/week. However, this risk cannot be completely ruled out. Methotrexate may be genotoxic, meaning it may cause genetic mutations. Methotrexate may affect sperm production and cause birth defects. Therefore, you must avoid fathering a child or donating semen while taking methotrexate and for at least 3 months after stopping treatment.

Driving and using machines

During treatment with Bertanel, adverse effects affecting the central nervous system such as fatigue, drowsiness, and dizziness may occur. Therefore, in some cases, your ability to drive vehicles and/or operate machinery may be impaired. If you feel tired or dizzy, do not drive or operate tools or machinery. This is especially important if taken with alcohol.

Bertanel contains sodium

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

3. How to use Bertanel

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

Important warning regarding the dose of Bertanel (methotrexate)

Use Bertanel only once a week for the treatment of rheumatoid arthritis, polyarticular forms of juvenile idiopathic arthritis, or psoriasis. Overuse of Bertanel (methotrexate) can be fatal. Please read section 3 of this leaflet very carefully. If you have any doubts, consult your doctor or pharmacist before using this medicine.

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

Bertanel is administered only once a week. Together with your doctor, you can decide on a suitable day of the week each week to receive your injection.

Incorrect administration of Bertanel may lead to serious adverse effects, including potentially life-threatening adverse effects.

The recommended dosage is:

Dosage in patients with rheumatoid arthritis

The recommended initial dose is 7.5 mg of methotrexate once weekly.

If this is not sufficient and if you tolerate the medicine well, the initial dose of Bertanel may be gradually increased by 2.5 mg. Alternatively, a higher starting dose may be used. The average weekly dose is 15–20 mg. Generally, a weekly dose of 20 mg of Bertanel should not be exceeded. Once the desired therapeutic effect has been achieved, the dose should be gradually reduced, if possible, to the lowest effective maintenance dose.

A response to treatment is expected after 4–8 weeks. After discontinuation 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 juvenile idiopathic arthritis

The recommended dose is 10–15 mg/m² of body surface area per week. In cases of inadequate response, the weekly dose may be increased up to 20 mg/m² of body surface area per week. However, more frequent periodic monitoring should be performed.

Adults with severe forms of psoriasis vulgaris or psoriatic arthritis

Recommended initial dose (relative to an average adult weighing 70 kg): A single test dose of 2.5–5 mg is recommended to assess toxicity.

If laboratory parameters do not change, treatment may continue approximately 1 week later with a dose of about 7.5 mg. The dose should be gradually increased (in increments of 5–7.5 mg per week) while monitoring laboratory parameters until the expected optimal response is achieved. In general, a weekly dose of 25 mg of methotrexate should not be exceeded.

Once the desired response has been achieved, the maintenance dose should be gradually reduced, as far as possible, to the lowest effective dose for the patient.

The response to treatment generally occurs after 4–8 weeks. Thereafter, treatment will be continued or discontinued based on the clinical situation and changes in laboratory parameters.

Elderly patients

A dose reduction should be considered in elderly patients due to decreased renal and hepatic function, as well as declining folate reserves with advancing age.

Patients with renal impairment

Patients with renal impairment may require lower doses.

Method and duration of administration

Your doctor will determine the duration of treatment. Bertanel is injected once a week! It is recommended to designate a specific day of the week as the “injection day.”

Bertanel is administered by subcutaneous, intramuscular, or intravenous injection; in children and adolescents, intravenous administration should not be used.

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

Rheumatoid arthritis

Improvement in symptoms can generally be expected within 4–8 weeks of treatment. Symptoms may reappear after discontinuation of Bertanel treatment.

Severe forms of psoriasis vulgaris and psoriatic arthritis (psoriatic arthropathy)

Generally, a response to treatment can be expected within 4–8 weeks. Depending on the clinical picture and changes in laboratory parameters, treatment will be continued or discontinued.

At the beginning of treatment, Bertanel may be administered by medical personnel. However, your doctor may decide that you can learn to self-inject Bertanel. You will receive appropriate training for this. Under no circumstances should you attempt to self-inject unless you have been properly instructed to do so.

If you use more Bertanel than you should

Follow the administration instructions provided by your doctor. Do not change the dose on your own.

If you suspect that you (or someone else) have administered too much Bertanel, contact your doctor or go immediately to the nearest hospital or contact the Toxicology Information Service at telephone number 91 562 04 20. They will determine which measures to take based on the severity of the poisoning.

An overdose of methotrexate may cause severe toxic reactions, including fatal outcomes. Symptoms of overdose may include bleeding or bruising, unusual weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood, or vomiting that looks like coffee grounds, and decreased urine output. See section 4.

Take the medicine with you if you go to the doctor or hospital.

The antidote in case of overdose is calcium folinate.

If you forget to use Bertanel

If you miss a dose, take it within 24 hours of the scheduled day. If the delay is longer, consult your doctor first. Do not take a double dose to make up for missed doses; continue with the prescribed dose. If you have any doubts, consult your doctor.

If you stop treatment with Bertanel

Do not stop treatment with Bertanel unless instructed by your doctor. If you suspect serious adverse effects, consult your doctor immediately.

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

4. Possible adverse effects

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

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

Serious adverse effects may also occur at lower doses, which may lead to interruption or discontinuation of therapy.

Adverse effects may appear at any time during treatment.

Most adverse effects are reversible if recognized promptly. However, stopping treatment does not always completely resolve all adverse effects.

Nevertheless, some of the serious adverse effects listed below may, in very rare cases, lead to sudden death.

Some adverse effects may occur after treatment has ended.

Please speak with your doctor.

If you develop any of the following adverse effects, contact your doctor immediately, as they could be signs of potentially life-threatening adverse effects requiring immediate treatment. Your doctor may decide to reduce the dose or discontinue treatment.

Serious adverse effects

• Allergic symptoms such as rash or itching (especially affecting the whole 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 faint (these may be signs of severe allergic reactions or anaphylactic shock) (may affect up to 1 in 100 patients)

• Lung problems (symptoms may generally include discomfort, irritating dry cough, difficulty breathing, shortness of breath 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 coughing blood

• Symptoms of liver failure such as yellowing of the skin (jaundice) and whites 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, reduced or absent urine output (may affect up to 1 in 100 patients)

• Signs of infection such as fever, chills, pain, sore throat. Methotrexate may reduce your resistance to infections; serious infections may occur, such as a specific type of pneumonia (Pneumocystis jirovecii pneumonia) (may affect up to 1 in 10,000 patients) or blood poisoning (sepsis) (may affect up to 1 in 1,000 patients)

• Fever, sore throat, mouth ulcers, general malaise and fatigue, nosebleeds, 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 tarry stools, or changes in bowel habits, which could be symptoms of gastrointestinal complications such as ulcers (may affect up to 1 in 100 patients) or intestinal perforation (frequency not known)

• Severe toxic skin reactions, such as blistering and peeling of the top layer of skin (Stevens-Johnson syndrome, toxic epidermal necrolysis/Lyell’s syndrome). Skin reactions are associated with severe general illness 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 or pressure, arm, back, neck or jaw pain, shortness of breath, numbness or weakness on one side 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 pulmonary embolism (blood clot in the lung) (may affect up to 1 in 1,000 patients)

The following adverse effects have also been reported:

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

• Reduced blood cell formation with decreased white blood cells and/or platelets (leucopenia, thrombocytopenia)
• Headache, dizziness
• Cough
• Loss of appetite, nausea (feeling unwell), vomiting, diarrhea (particularly within the first 24–48 hours after initial methotrexate administration), stomach pain
• Inflammation and ulcers in the mouth and throat (particularly within the first 24–48 hours after initial methotrexate administration)
• Increased liver enzymes in blood tests
• Hair loss
• Decreased creatinine clearance (your doctor may detect this in a blood test and it indicates 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
• Tingling, prickling, pins and needles (paresthesia)
• Burning sensation of the skin, rash, skin redness, itching
• Skin ulcers
• Red eyes (conjunctivitis)

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

• Opportunistic infections (due to impaired immune system function), which may be fatal in some cases
• Cancer of lymphatic tissue (lymphoma), see also section 2
• Immune system dysfunction, leading to increased risk of infections/inflammations
• Diabetes
• Weakness affecting the entire right or left side of the body (hemiparesis)
• Dizziness, confusion
• Seizures
• Brain damage (encephalopathy/leukoencephalopathy)
• Inflammation of blood vessels (vasculitis)
• Allergic vasculitis
• Scarring tissue formation in the lung (pulmonary fibrosis), fluid around the lungs
• Ulcers and bleeding in the digestive tract
• Inflammation of the pancreas
• Liver damage, liver enlargement, scarring tissue formation in the liver (hepatic fibrosis), chronic liver damage (liver cirrhosis)
• Decrease in serum albumin
• Hives (alone), skin darkening
• Increase in rheumatoid nodules
• Painful psoriasis
• Skin lesions resembling herpes
• Sunburn-like reactions due to increased skin sensitivity to sunlight
• Muscle or joint pain
• Osteoporosis (reduced bone mass)
• Inflammation and ulceration of the bladder (possibly with blood in urine), difficulty emptying the bladder, absence of urination, painful or reduced urination
• Fetal malformations
• Vaginal inflammation and ulcers
• 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 throughout the body
• Speech difficulties (aphasia/dysarthria)
• Severe visual disturbances (blurred or cloudy vision), blood clots in the retina
• Low blood pressure
• Blood clots (thromboembolic episodes)
• Sore throat
• Breathing interruption
• Inflammation of the digestive tract, bloody stools
• Swollen gums
• Acute hepatitis (liver inflammation)
• Nail discoloration, nail loss
• Acne, red or purple spots due to bleeding from blood vessels
• Erythema multiforme, red skin rash
• Stress fracture
• Electrolyte imbalances, increased blood urea, creatinine, and uric acid (azotemia)
• Abortion
• Defective sperm formation (returns to normal after treatment ends)
• Menstrual disorders (return to normal after treatment ends)

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

• Hepatitis caused by herpes viruses (herpes simplex virus hepatitis), fungal infections (histoplasmosis, cryptococcosis), bacterial infections (nocardiosis), viral infections (cytomegalovirus infections, including pneumonia)
• Fevers (simplex herpes)
• Anemia due to inadequate red blood cell formation (aplastic anemia), increased eosinophils in blood (eosinophilia), reduced neutrophil granulocytes in blood (neutropenia), inflammation of lymph nodes in the head and neck, armpits, and groin (partially reversible), uncontrolled lymphocyte proliferation (partially reversible)
• Immunodeficiency (hypogammaglobulinemia)
• Hepatitis
• Muscle pain and weakness in limbs
• Changes in taste sensation (metallic taste)
• Inflammation of the brain lining causing paralysis or vomiting
• Swelling around the eyes, eyelid inflammation, tearing, increased light sensitivity, transient blindness, vision deterioration
• Inflammation of the sac around the heart (pericarditis), impaired heart filling due to pericardial effusion (cardiac tamponade), fluid accumulation between pericardial layers (pericardial effusion)
• Abnormal lung function test results, with difficulty breathing and cough
• Vomiting blood
• Liver cell death (hepatic necrosis), acute liver degeneration, liver failure
• Deep infection of hair follicles (furunculosis), permanent enlargement of capillaries visible on the skin (telangiectasia), acute inflammation of the nail bed
• Blood and/or protein in urine
• Fetal death
• Problems in egg (female) and sperm (male) formation
• Menstrual cycle disorders
• Loss of sexual desire
• Erectile dysfunction
• Enlargement of male breasts
• Vaginal discharge
• Infertility
• Numbness or tingling sensation/reduced sensitivity to stimuli

Not known (frequency cannot be estimated from available data):

• Pneumonia
• Reactivation of hepatitis B infection or worsening of hepatitis C infection
• Bleeding from the lungs
• Skin cancer (see also section 2)
• Increased cerebrospinal fluid pressure with symptoms such as headache, nausea, vomiting, increased blood pressure, confusion; nervous system damage (neurotoxicity), inflammation of the brain lining (arachnoiditis), leg paralysis (paraplegia), stupor, movement coordination problems (ataxia), dementia
• Non-inflammatory eye disorder (retinopathy)
• Hypoxia (lack of oxygen in organs)
• Non-infectious inflammation of the abdominal lining characterized by stomach pain and tenderness to pressure (peritonitis)
• Toxic megacolon (a severe complication due to massive colon enlargement combined with intense pain), intestinal perforation
• Tongue inflammation
• Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Dermatitis
• Generalized and jaw bone damage (secondary to excessive white blood cell growth)
• Urogenital dysfunction
• Chest pain, chills, tissue destruction at the injection site
• Skin redness and peeling
• Swelling

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

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

Reporting of adverse effects

If you experience any adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicines: www.notificaRAM.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Bertanel

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

Do not use this medicine after the expiry date stated on the label of the prefilled syringe and on the outer packaging, after "CAD". The expiry date refers to the last day of the month indicated.

Store in the original packaging to protect from light.

Do not store above 25°C. Do not freeze.

The product should be used immediately after opening the packaging.

Do not use Bertanel if the solution is not clear or contains particles.

For single use only. Discard any unused solution remaining!

Medicines must not be disposed of via wastewater or household waste. Dispose of empty containers and unused medicines at the SIGRE collection point at your pharmacy. If in doubt, ask your pharmacist how to dispose of unused containers and medicines. This will help protect the environment.

6. Contents of the container and other information

Composition of Bertanel

The active substance is methotrexate.

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

Each pre-filled syringe containing 0.75 ml of injectable solution contains 7.5 mg of methotrexate.

Each pre-filled syringe containing 1 ml of injectable solution contains 10 mg of methotrexate.

Each pre-filled syringe containing 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 injections.

Appearance of the medicinal product and contents of the container

Bertanel pre-filled syringes contain a clear, yellow, particle-free injectable solution.

Bertanel is available in colourless glass pre-filled syringes (type I according to Ph. Eur.) with a capacity of 1.25 ml, 2.25 ml or 3.00 ml, fitted with an elastomeric stopper and elastomeric plunger.

Pack sizes:

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 certain pack sizes may be marketed.

Marketing Authorization Holder

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

Mondseestrasse 11,

4866 Unterach, Austria

Manufacturer 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 under the following designation:

AT/H/0192/01/MR

Austria	Ebetrexat 10 mg/ml solution for injection in a prefilled syringe
Spain	Bertanel 7.5 mg/0.75 ml, solution for injection in a prefilled syringe Bertanel 10 mg/ml, solution for injection in a prefilled syringe Bertanel 15 mg/1.5 ml, solution for injection in a prefilled syringe
Netherlands	Metotrexate Sandoz 7.5 mg = 0.75 ml, solution for injection 10 mg/ml

Date of the most recent review of this leaflet: September 2024

This information is intended for healthcare professionals only:

Instructions for use, handling and disposal

The solution should be clear and free of particles.

Handling and disposal of this medicinal product must be carried out in the same manner as for other cytotoxic preparations and in accordance with local regulations. Pregnant healthcare personnel must not handle and/or administer Bertanel.

For single use only. Any unused solution must be discarded.

Disposal of unused medicinal product or waste materials must be performed in accordance with local regulations for cytotoxic agents.

Incompatibilities

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

Special storage precautions

Keep in the original container to protect from light.

Do not store above 25°C.

Do not freeze.

Step-by-step instructions for subcutaneous injection:

Step 1:

• Remove from the carton the inner package containing the pre-filled syringe, cannula, and needle.
• Open the inner package by pulling the tab at the corner. Remove the pre-filled syringe.
• Rotate 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 into the inner package. The yellow solution will not spill.
• Check the label on the plastic needle case. The label must be intact (see Figure 2).

Figure 2.

Step 3:

• Remove the cap from the plastic needle case by twisting and pulling. See Figure 3.1.
• Carefully screw the needle, together with the plastic case, onto the syringe until fully secured. See Figure 3.2.

Figure 3.1 Figure 3.2

Step 4:

• Select an injection site on the abdominal or thigh area and clean it with an alcohol-soaked cotton pad. Do not touch this area before injection (see Figures 4.1 and 4.2).

Figure 4.1 Figure 4.2

Step 5:

• Remove the cannula cover and set it aside.

• Do not touch the sterile cannula. If this occurs, consult your doctor or pharmacist about whether another cannula should be used. Using two fingers, pinch the skin to form a skin fold, 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 apply a cotton pad to the injection site. Do not rub, as this may irritate the injection site.

• To prevent injury, dispose of the used syringe in a sharps container.