Methotrexate-ebewe

Standard text – January 22, 2004 / June, 2005

Package leaflet: Information for the user

Methotrexat-Ebewe, 10 mg/ml, solution for injection
Methotrexatum
Please read all of this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm them even if their symptoms are the same.
• If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Contents of the leaflet:

1. What Methotrexat-Ebewe is and what it is used for
2. Important information before using Methotrexat-Ebewe
3. How to use Methotrexat-Ebewe
4. Possible side effects
5. How to store Methotrexat-Ebewe
6. Contents of the pack and other information

1. What Methotrexat-Ebewe is and what it is used for

Methotrexat-Ebewe is an antineoplastic agent belonging to the group of antimetabolites. Tissues with rapidly dividing cells—such as tumor tissue, bone marrow, fetal cells, the mucous membranes of the oral cavity and intestines, and cells of the urinary bladder—are particularly sensitive to the action of this drug. The mechanism of action of the medicine consists in inhibiting tumor growth. If cellular proliferation in tumor tissue is more intense than in normal tissues, methotrexate may suppress tumor growth without causing significant harm to healthy tissues.

In patients with psoriasis, the rate of epidermal cell proliferation is considerably higher than in healthy individuals; this characteristic forms the basis for using methotrexate in severe forms of psoriasis.

Therapeutic indications:

• Malignant neoplasms, e.g. acute lymphoblastic leukemia (ALL), including meningeal leukemia, non-Hodgkin’s lymphoma (NHL), breast cancer, testicular cancer, ovarian cancer, head and neck cancers, small cell lung cancer, malignant choriocarcinoma, and bone sarcomas;
• Psoriasis refractory to other treatments.

2. Important information before using Methotrexat-Ebewe

When not to use Methotrexat-Ebewe

• if the patient is allergic to the active substance or to any of the other ingredients of this medicine (listed in section 6);
• if the patient has impaired liver function;
• if the patient has severe kidney dysfunction (when using low doses of methotrexate (<100 mg/m² BSA)) or moderate kidney dysfunction (when using medium or high doses of methotrexate (>100 mg/m² BSA));
• if the patient has disorders of the blood-forming system (e.g. after previous radiotherapy or chemotherapy);
• if the patient has severe and/or active acute infections;
• if the patient abuses alcohol;

Standard text – January 22, 2004 / June, 2005

• if the patient has disorders of the immune system;
• if the patient has oral inflammation or active peptic ulcer disease of the stomach or duodenum;
• during breastfeeding and additionally during pregnancy, if the patient is using the medicine for non-oncological indications (in the treatment of non-malignant disease) (see section "Pregnancy, breastfeeding and fertility").

Warnings and precautions
Before starting treatment with Methotrexat-Ebewe, discuss with your doctor if:

• the patient has diabetes and is being treated with insulin;
• the patient has inactive, chronic infections (e.g. tuberculosis, hepatitis B or C, shingles);
• the patient has or has had kidney or liver disease in the past;
• the patient has impaired lung function;
• the patient has significant overweight;
• fluid accumulates in the abdominal cavity or in the space between the lungs and the chest wall (ascites, pleural effusion);
• the patient is dehydrated or has conditions leading to dehydration (vomiting, diarrhoea, mucositis).

During treatment with methotrexate, recurrence of radiation-induced skin inflammation (radiation dermatitis) or sunburn ("recall reaction") may occur.
Exposure to UV radiation during therapy with Methotrexat-Ebewe may exacerbate skin changes associated with psoriasis.
Methotrexate may increase skin sensitivity to sunlight. Intense sun exposure should be avoided, and use of solariums or tanning lamps should not be undertaken without consulting a doctor.
To protect the skin from intense sunlight, appropriate clothing should be worn or a high-protection sunscreen filter should be used.
Cases of acute pulmonary haemorrhage have been reported in patients with underlying rheumatological disease during methotrexate treatment. If the patient develops haemoptysis, i.e. coughing up blood-tinged sputum, medical advice should be sought immediately.
If the patient, their partner or caregiver notice new onset or worsening of neurological symptoms, including general muscle weakness, visual disturbances, changes in thinking, memory and orientation leading to disorientation and personality changes, immediate contact with a doctor is necessary, as these may be symptoms of a very rare, serious brain infection called progressive multifocal leukoencephalopathy (PML).

Recommended monitoring and precautions
Even after administration of low doses of Methotrexat-Ebewe, severe adverse reactions may occur. To detect these reactions as early as possible, the doctor must perform regular check-ups and laboratory tests.

Before starting treatment
Before starting treatment, the doctor will order blood tests to check blood cell counts, liver function and to detect hepatitis. Serum albumin levels (a blood protein), tests for liver inflammation and kidney function tests will be performed. The doctor may also recommend additional liver tests – imaging studies or tests requiring a small sample of liver tissue for more detailed examination. A chest X-ray or lung function tests may also be recommended to check whether the patient has tuberculosis. Further tests may also be performed during and after completion of treatment.

Standard text – January 22, 2004 / June, 2005

During treatment:
The doctor may order the following tests:

• examination of the mouth and throat to rule out mucosal lesions such as inflammation or ulceration;
• blood tests and/or complete blood count with assessment of the number of different types of blood cells and measurement of methotrexate serum concentration;
• blood tests to monitor liver function;
• imaging tests to monitor liver status;
• liver biopsy (taking a small tissue sample) for detailed examination;
• blood tests to monitor kidney function;
• monitoring of respiratory function and, if necessary, lung function tests.

Patients must attend all scheduled blood tests and other examinations recommended by the doctor.
If any of these test results are abnormal, treatment will be resumed only after all parameters have returned to normal.

Children and adolescents
Treatment with methotrexate in children and adolescents should be initiated and monitored by a specialist experienced in diagnosing and treating diseases for which the medicine is indicated.
During treatment with Methotrexat-Ebewe, the doctor will carefully monitor the child's condition to detect any adverse reactions as early as possible.

Elderly patients
During treatment with Methotrexat-Ebewe, elderly patients should be monitored particularly carefully to detect any adverse reactions as early as possible.
Doses used in elderly patients should be relatively low, due to age-related impairment of liver and kidney function and low body stores of folic acid.

Special precautions for the use of Methotrexat-Ebewe
Methotrexate temporarily interferes with the production of sperm and egg cells. Methotrexate may cause miscarriage and severe congenital malformations. The patient should avoid becoming pregnant during methotrexate treatment and for at least 6 months after completion of treatment. Men should avoid fathering a child during methotrexate treatment and for at least 3 months after completion of treatment. See also section "Pregnancy, breastfeeding and fertility".

Methotrexat-Ebewe and other medicines
Inform your doctor or pharmacist about all medicines currently taken or recently used, including those obtained without a prescription, herbal medicines or natural remedies. If a doctor prescribes another medicine, inform them about the use of Methotrexat-Ebewe.

It is particularly important to inform the doctor about the use of the following medicines:
cholestyramine, salicylates, sulfonamides, phenytoin, antibiotics (such as tetracycline, chloramphenicol, ciprofloxacin, penicillin, pristinamycin), sulfasalazine, doxorubicin, cyclophosphamide, barbiturates, probenecid, Vinca alkaloids, folic acid-containing medicines, vitamin preparations and oral iron supplements containing folic acid, disease-modifying agents (such as gold salts, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine), cytarabine, leflunomide, pyrimethamine, cotrimoxazole, proton pump inhibitors (e.g. omeprazole, pantoprazole), sulfonylurea antidiabetic drugs, triamterene, levetiracetam, amiodarone, non-steroidal anti-inflammatory drugs (NSAIDs), metamizole (synonyms: novaminsulfone and dipyrone) [a potent analgesic and/or antipyretic], folate antagonists (trimethoprim/sulfamethoxazole), etretinate, phenytoin, sedatives, oral contraceptives, medicines toxic to kidneys and liver, medicines excreted by the kidneys, and live vaccines.

Penicillins may reduce methotrexate excretion, potentially increasing the risk of adverse reactions.

During methotrexate treatment, the immune response to concomitant vaccination may be reduced.

Concomitant use of methotrexate and non-steroidal anti-inflammatory drugs (NSAIDs) is not recommended in the presence of risk factors such as kidney impairment, including mild kidney impairment.

Pregnancy, breastfeeding and fertility
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to have a child, she should consult a doctor or pharmacist before using this medicine.

Pregnancy
Do not use Methotrexat-Ebewe during pregnancy unless prescribed by a doctor for oncological indications. Methotrexate may cause congenital malformations, harm the unborn child or cause miscarriage. This is associated with developmental defects of the skull, face, heart and blood vessels, brain and limbs. Therefore, it is extremely important that women who are pregnant or planning pregnancy do not take methotrexate, except for oncological indications.

If the patient is of childbearing age, pregnancy must be ruled out before starting treatment for non-oncological indications, e.g. by performing a pregnancy test. Do not use Methotrexat-Ebewe if the patient is pregnant or trying to become pregnant. The patient must strictly avoid becoming pregnant during methotrexate treatment and for at least 6 months after its completion. Effective contraception must be used throughout this period (see also section "Warnings and precautions").

If the patient becomes pregnant during treatment or suspects she may be pregnant, she should consult a doctor as soon as possible. If pregnancy occurs during treatment, advice should be sought regarding the potential harmful effects of treatment on the child.

If the patient plans to become pregnant, she should consult her treating doctor, who may refer her to a specialist for advice before planned initiation of treatment.

Breastfeeding
Breastfeeding should not be undertaken during treatment, as methotrexate passes into breast milk. If the treating doctor considers methotrexate treatment absolutely necessary during this time, breastfeeding must be discontinued.

Male fertility
Available evidence does not indicate an increased risk of developmental defects or miscarriages after paternal exposure to methotrexate at doses below 30 mg/week. However, the risk cannot be completely ruled out, and there is no information regarding higher doses of methotrexate. Methotrexate may be genotoxic, meaning it may cause genetic mutations. Methotrexate may affect sperm production, which may lead to congenital malformations.

The patient should avoid impregnating his partner and donating semen during methotrexate treatment and for at least 3 months after its completion. Since treatment with higher doses of methotrexate, typically used in cancer therapy, may cause infertility and genetic mutations, sperm cryopreservation before starting treatment may be recommended for men receiving methotrexate doses above 30 mg/week (see also section "Warnings and precautions").

Standard text – January 22, 2004 / June, 2005

Driving and operating machinery
During treatment with Methotrexat-Ebewe, adverse reactions affecting the central nervous system may occur, such as fatigue and dizziness. In some cases, these may impair the ability to drive or operate machinery. If the patient experiences fatigue or dizziness, he or she should not drive or operate machinery.

Methotrexat-Ebewe contains sodium
The medicine contains approximately 3.74 mg of sodium (main component of table salt) in the 1 ml vial. This corresponds to 0.19% of the maximum recommended daily dietary sodium intake for adults.
The medicine contains 18.7 mg of sodium (main component of table salt) in the 5 ml vial. This corresponds to 0.95% of the maximum recommended daily dietary sodium intake for adults.
The medicine may be diluted in 0.9% sodium chloride solution. The sodium content originating from the diluent should be taken into account when calculating the total sodium content in the prepared diluted solution. For accurate information on the sodium content of the solution used to dilute the medicine, refer to the patient leaflet of the diluent used.

3. How to use Methotrexat-Ebewe

Methotrexat-Ebewe may only be prescribed by physicians familiar with the properties of this medicinal product and its mode of action.
Methotrexat-Ebewe must always be used exactly as directed by the physician. If in doubt, consult your physician, pharmacist, or nurse.
Depending on the indication and treatment regimen used, the dose of Methotrexat-Ebewe may vary within very wide limits; therefore, it is extremely important that treatment is supervised by qualified medical personnel.
Methotrexat-Ebewe is usually administered either directly or after dilution in physiological saline or 5% glucose solution. It may be given intravenously (bolus or infusion), intramuscularly, intra-arterially, or intrathecally.
The medicinal product can be administered either as a rapid injection (bolus) or as a prolonged infusion. Prolonged infusions are used when high doses of Methotrexat-Ebewe are administered.
The physician will determine the dose based on the diagnosis, body surface area or body weight of the patient, route of administration (monotherapy or combination with other cytostatic agents), and organ function (bone marrow, liver, kidneys). The exception is intrathecal administration, for which the maximum recommended dose is 15 mg and the recommended maximum concentration is 5 mg/ml.
In patients with impaired liver, kidney, or bone marrow function, the dose should be reduced.

Malignant tumours and acute leukaemias:
Low (single dose not exceeding 100 mg/m² BSA), medium (single dose from 100 mg/m² BSA to 1000 mg/m² BSA), or high (single dose exceeding 1000 mg/m² BSA) doses of methotrexate are used, depending on the multi-agent chemotherapy regimen employed.

Standard text – January 22, 2004 / June, 2005

Psoriasis:
Important warning regarding dosing of Methotrexat-Ebewe (methotrexate):
In the treatment of psoriasis resistant to other therapies, Methotrexat-Ebewe must be administered once weekly only. Administration of more frequent doses of Methotrexat-Ebewe (methotrexate) may result in death. Please read section 3 of this leaflet carefully. If you have any questions, consult your physician or pharmacist before taking the medicinal product.

Recommended dose
The recommended initial dose in psoriasis is 7.5 mg once weekly.
The usual optimal weekly dose ranges from 10 to 25 mg.

Administration of a higher than recommended dose of Methotrexat-Ebewe
Calcium folinate is a specific antidote that reduces the toxic effects of Methotrexat-Ebewe. It may be administered orally, intramuscularly, or intravenously as a bolus or prolonged infusion. In case of overdose, calcium folinate should be administered within one hour in a dose equal to or greater than the methotrexate dose administered, followed by continued administration until a safe methotrexate level is achieved.
Patients who have overdosed on Methotrexat-Ebewe may also require haemodialysis or blood transfusion.

Missed dose of Methotrexat-Ebewe
Do not take a double dose to make up for a missed dose. Continue with the next scheduled dose as prescribed. Consult your physician for advice.

Discontinuation of Methotrexat-Ebewe
Do not interrupt or stop treatment with Methotrexat-Ebewe without consulting your physician. If you suspect serious adverse reactions, seek immediate medical advice.

If you have any further questions or doubts about the use of this medicinal product, consult your physician or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can have adverse reactions, although not everyone will experience them.
You should immediately inform the doctor if the patient suddenly develops wheezing,
difficulty breathing, swelling of the eyelids, face or lips, rash or itching (especially
affecting the whole body).
Serious adverse reactions
You should contact the doctor immediately if any of the following adverse reactions occur:

• Pulmonary disorders (symptoms may include general malaise; dry, irritating cough; shortness of breath, dyspnea at rest, chest pain or fever);
• Severe peeling of the skin or formation of blisters on the skin;
• Unexplained bleeding (including vomiting blood) or bruising;
• Severe diarrhoea;
• Mucosal ulceration of the oral cavity;
• Black or tarry stools;
• Blood in the urine or faeces;
• Small red spots on the skin;
• Fever;

Standard text – January 22, 2004 / June, 2005

• Yellowing of the skin (jaundice);
• Pain or difficulty passing urine;
• Excessive thirst and/or frequent urination;
• Seizures (fits);
• Loss of consciousness;
• Blurred vision or visual disturbances;
• Haemoptysis, i.e. coughing up blood-stained sputum (reported during methotrexate use in patients with underlying rheumatological disease).

Other possible adverse reactions
Very common (may affect more than 1 in 10 people):

• Decreased resistance to infections
• Sore throat
• Reduced platelet count (thrombocytopenia), reduced white blood cell count (leukopenia)
• Headache, dizziness
• Cough
• Loss of appetite
• Diarrhoea, abdominal pain, nausea, vomiting
• Ulcerative stomatitis
• Increased liver enzyme activity (AspAT, AlAT), alkaline phosphatase
• Increased blood bilirubin concentration
• Decreased creatinine clearance
• Hair loss
• Fatigue, malaise

Common (may affect less than 1 in 10 people):

• Herpes zoster
• Anaemia, (reduced number of red blood cells, white blood cells and platelets (pancytopenia), complete or almost complete absence of granulocytes (agranulocytosis)
• Bone marrow suppression
• Somnolence
• Numbness or tingling sensation, or reduced response to stimuli
• Conjunctivitis
• Pulmonary complications due to interstitial pneumonitis, alveolitis (may lead to death), acute pulmonary oedema
• Rash, erythema, itching, skin ulceration
• Photosensitivity

Uncommon (may affect less than 1 in 100 people):

• Opportunistic infections (life-threatening)
• Malignant lymphoma
• Allergic reactions up to anaphylactic shock
• Immunosuppression
• Diabetes mellitus
• Hemiparesis
• Confusion
• Seizures
• Encephalopathy/leukoencephalopathy
• Vasculitis, allergic vasculitis
• Pulmonary fibrosis, pleural effusion
• Gastric and intestinal mucosal ulceration
• Haemorrhage
• Pancreatitis
• Hepatotoxicity

Standard text – January 22, 2004 / June, 2005

• Hepatic steatosis
• Chronic fibrosis and cirrhosis of the liver
• Decreased serum albumin concentration
• Skin eruptions, herpes-like skin lesions
• Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome)
• Urticaria
• Increased skin pigmentation
• Sunburn-like reactions due to increased skin sensitivity to sunlight
• Pseudotumors related to methotrexate
• Impaired wound healing
• Pain in psoriatic lesions
• Joint pain, muscle pain
• Osteoporosis
• Nephropathy, renal failure
• Cystitis and bladder ulceration
• Haematuria
• Urinary disorders, painful urination, oliguria, anuria
• Congenital malformations in the foetus
• Vaginitis and vaginal ulceration
• Fever

Rare (may affect less than 1 in 1,000 people):

• Sepsis (including fatal cases)
• Megaloblastic anaemia
• Mood changes, transient perception disturbances
• Paralysis
• Speech disorders, including dysarthria and aphasia
• Myelopathy (after intrathecal administration)
• Visual disturbances (including severe)
• Severe retinal vessel thrombosis
• Hypotension
• Thromboembolic events (including arterial and cerebral vessel thrombosis, phlebitis, deep vein thrombosis)
• Pharyngitis
• Respiratory arrest
• Pulmonary embolism
• Enteritis
• Gingivitis
• Tarry stools
• Acute hepatitis
• Acne
• Purpura
• Erythema multiforme
• Erythematous skin rashes
• Worsening of nail pigmentation changes, nail plate separation
• Stress fractures
• Increased serum uric acid, urea and creatinine concentrations, azotemia

Very rare (may affect less than 1 in 10,000 people):

• Hepatitis caused by herpes simplex virus
• Cryptococcosis, histoplasmosis, nocardiosis
• Infections caused by cytomegalovirus (including pneumonia)
• Disseminated herpes simplex virus infection
• Pneumonia caused by Pneumocystis jirovecii
• Tumour lysis syndrome (in patients treated for neoplastic disease)
• Aplastic anaemia

Standard text – January 22, 2004 / June, 2005

• Eosinophilia, neutropenia
• Lymphadenopathy
• Lymphoproliferative disorders (excessive white blood cell production)
• Hypogammaglobulinaemia
• Myasthenia
• Limb pain
• Taste disturbances (metallic taste)
• Acute aseptic meningitis with meningeal reaction
• Meningitis-like symptoms without infection (paralysis, vomiting)
• Cranial nerve disorders
• Periorbital oedema
• Blepharitis
• Epiphora due to inadequate tear film drainage
• Photophobia
• Transient blindness, vision loss
• Pericarditis, pericardial tamponade, pericardial effusion
• Chronic obstructive pulmonary disease
• Asthma-like reactions with cough, dyspnoea and changes in pulmonary function tests
• Vomiting blood
• Acute liver necrosis, acute liver degeneration, liver failure
• Raynaud's phenomenon, telangiectasia, acute onychia
• Haematuria, proteinuria
• Foetal death
• Sperm production disorders, oocyte production disorders
• Infertility
• Menstrual cycle disturbances
• Loss of libido
• Impotence
• Vaginal discharge
• Gynaecomastia
• Chills

Frequency unknown (frequency cannot be estimated from available data):

• Pneumonia
• Reactivation of hepatitis B virus infection
• Exacerbation of hepatitis C virus infection
• Neurotoxicity
• Adhesive arachnoiditis
• Transverse myelitis
• Stupor
• Ataxia
• Dementia
• Increased intracranial pressure
• Chest pain
• Hypoxia
• Alveolar haemorrhage (reported during methotrexate use in patients with underlying rheumatological disease)
• Non-infectious peritonitis
• Intestinal perforation
• Glossitis
• Acute megacolon
• Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Dermatitis
• Redness and peeling of the skin
• Worsening of psoriatic lesions following concomitant exposure to UV radiation
• Skin ulceration (in patients with psoriasis)

Standard text – January 22, 2004 / June, 2005

• Oedema
• Osteonecrosis
• Jaw osteonecrosis (due to excessive white blood cell production)
• Skin cancer (in patients treated for psoriasis)
• Retinopathy
• Urinary and genital system disorders
• Tissue necrosis at injection site

If the patient develops diarrhoea or ulceration in the mouth or throat, this should be reported to the doctor immediately, as treatment may need to be discontinued due to the risk of gastrointestinal perforation or haemorrhagic enteritis.
Methotrexate use may cause recurrence of radiation-induced skin inflammation and skin burns (so-called "recall reactions").
After intramuscular administration, adverse reactions may occur at the injection site (burning sensation) or tissue damage (formation of sterile abscess, fatty tissue damage).

Adverse reactions particularly associated with intrathecal administration
Severe: chemically induced meningitis, manifesting as headache, back, arm or shoulder pain, neck stiffness and fever.
Subacute: may include paralysis (usually transient), paralysis of lower limbs, nerve paralysis, cerebellar disturbances.
Chronic: leukoencephalopathy presenting with irritability, confusion, disorientation, spasticity and sometimes seizures, dementia, somnolence, coma, and rarely death. It has been demonstrated that concomitant cranial irradiation and intrathecal methotrexate administration increases the frequency of leukoencephalopathy.

Other additional reactions with proven or probable association with methotrexate use have been described, such as osteoporosis, abnormal red blood cell morphology (usually "megaloblastic"), diabetes mellitus, other metabolic changes and sudden death.

Carcinogenic, mutagenic and fertility-impairing effects
Methotrexate has been shown to cause chromosomal damage in somatic animal cells and human bone marrow cells, an effect which was transient and reversible. In patients treated with methotrexate, these properties may increase the risk of developing tumours (usually lymphoma, typically reversible), although there is insufficient evidence to draw definitive conclusions. It has been observed that methotrexate causes fertility disorders, oligospermia, menstrual cycle disturbances and amenorrhea in humans during treatment and for a short period after discontinuation of the drug.
Furthermore, methotrexate has harmful effects on the embryo, leading to miscarriages and congenital malformations. Therefore, patients of reproductive age should be informed about the potential harmful effects on fertility.

Reporting of adverse reactions
If any adverse symptoms occur, including any adverse symptoms not listed in this leaflet, the patient should inform the doctor, pharmacist or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions at the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw
Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps to gather more information on the safety of the medicine.
Standard text – January 22, 2004 / June, 2005

5. How to store Methotrexat-Ebewe

Keep this medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and vial after EXP.
The expiry date refers to the last day of the stated month.
Store below 25°C and protect from light.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist
how to dispose of medicines no longer required. These measures will help protect the
environment.

6. Contents of the pack and other information

What Methotrexat-Ebewe contains
The active substance is methotrexate. 1 ml of injection solution contains 10 mg of methotrexate.
A 1 ml vial contains 10 mg of methotrexate.
A 5 ml vial contains 50 mg of methotrexate.
The other ingredients are: sodium chloride, sodium hydroxide (for pH adjustment) and water for injections.

What Methotrexat-Ebewe looks like and contents of the pack
Methotrexat-Ebewe is a clear, yellowish injection solution.
The pack contains either 1 or 5 vials of 50 mg methotrexate in 5 ml or 10 vials of 10 mg methotrexate in 1 ml.
Vials may be placed in protective plastic packaging (ONKO-Safe or Sleeving).

Marketing Authorisation Holder and Manufacturer
Ebewe Pharma Ges.m.b.H. Nfg. KG
Mondseestrasse 11
A-4866 Unterach, Austria

Manufacturer
Fareva Unterach GmbH
Mondseestraße 11
4866 Unterach
Austria

For further information, please contact:
Sandoz Polska Sp. z o.o.
ul. Domaniewska 50 C
02-672 Warszawa
tel. 22 209 70 00
Standard text – January 22, 2004 / June, 2005

Information for healthcare professionals only

■ Shelf life
After opening
The product should be drawn up immediately before use. From a microbiological point of view, the product should be used immediately. Otherwise, the responsibility for storage conditions and duration after opening lies with the user. After first withdrawal, any remaining product should not be stored for longer than 24 hours at room temperature unless the withdrawal was performed under controlled and verified aseptic conditions. When stored in the refrigerator or at room temperature protected from light, the product maintains its physico-chemical stability for up to 28 days.
The medicinal product Methotrexat-Ebewe 10 mg/ml maintains physico-chemical stability for up to 7 days at room temperature with exposure to light.

After dilution
From a microbiological standpoint, the solution should be used immediately. Otherwise, the responsibility for storage conditions and duration of the prepared solution lies with the user. Prepared solutions should not be stored for longer than 24 hours at a temperature of 2°C to 8°C, unless dilution was carried out under controlled and verified aseptic conditions.
Physical and chemical stability has been demonstrated for 28 days for Methotrexat-Ebewe 10 mg/ml solution diluted to concentrations of 0.10 mg/ml and 3 mg/ml in 0.9% sodium chloride solution or 5% glucose solution, when stored refrigerated or at room temperature protected from light.
For the 3 mg/ml solution, physical and chemical stability has also been demonstrated for up to 7 days at room temperature with exposure to light.

■ Instructions for preparation, administration and disposal of residual product:
Methotrexate may be administered by intravenous injection (bolus or infusion), intra-arterial, intramuscular or intrathecal injection. The solution should be diluted with 0.9% sodium chloride or 5% glucose solution.
Due to the various proposed dosing regimens, use of the drug should be under the supervision of a physician experienced in cytotoxic therapy.

The dose depends on the diagnosis, body surface area or body weight of the patient, route of administration (monotherapy or combination with other cytostatics), and on bone marrow and organ function (liver, kidneys). The exception is intrathecal administration, where the maximum recommended dose is 15 mg and the recommended maximum concentration is 5 mg/ml.

Folinic acid rescue regimens vary depending on the dose of methotrexate administered. Usually, up to 150 mg is given in divided doses over 12–24 hours by intramuscular injection, intravenous bolus injection, intravenous infusion or orally, followed by 12–25 mg intramuscularly or intravenously, or 15 mg orally (one capsule) every six hours for the next 48 hours. Rescue therapy is initiated 8 to 24 hours after the start of methotrexate infusion. If lower doses of methotrexate (less than 100 mg) are used, one capsule (15 mg) of folinic acid every six hours for 48 to 72 hours is sufficient.

In patients with impaired liver, kidney or bone marrow function, the dose should be reduced.
High doses of Methotrexat-Ebewe (greater than 100 mg) are usually administered by intravenous infusion not exceeding 24 hours. Part of the dose may be given as an initial rapid bolus injection.
Administration of high-dose methotrexate may cause precipitation of methotrexate or its metabolites in the renal tubules. As prophylaxis, it is recommended to administer large amounts of fluids and to alkalinize urine to pH 6.5–7.0 by oral or intravenous administration of sodium bicarbonate (5 tablets x 625 mg every three hours) or acetazolamide (500 mg orally four times daily).
When doses greater than 150 mg/m² are used, concomitant administration of folinic acid is necessary to reverse toxic effects on normal cells.

The method of folinic acid administration depends on the dose of Methotrexat-Ebewe. Usually, up to 150 mg is given in divided doses over 12–24 hours by intramuscular injection, intravenous bolus injection, intravenous infusion or orally, followed by 12–25 mg intramuscularly or intravenously, or 15 mg orally (one capsule) every six hours for the next 48 hours. Rescue therapy is initiated 8 to 24 hours after the start of methotrexate infusion. If lower doses of methotrexate (less than 100 mg) are used, one capsule (15 mg) of folinic acid every six hours for 48 to 72 hours is sufficient.

Due to the toxic properties of the substance, the following safety precautions must be observed:
■ Preparation, administration and disposal of residual product must be performed only by trained personnel; as with all cytostatic drugs, pregnant women should not be exposed to the drug;
■ Personnel preparing methotrexate should wear protective clothing: goggles, gowns, disposable gloves and disposable masks;
■ Methotrexate is not corrosive and should not cause skin damage upon contact; however, the preparation should be washed off immediately with water; in case of transient burning sensation, a mild cream may be applied. If there is a risk of systemic absorption of significant amounts of methotrexate via any route, folinic acid should be administered;
■ Unused or spilled residues should be disposed of by incineration; there are no specific recommendations regarding incineration temperature;
■ Handle in accordance with guidelines for cytotoxic substances.

■ Incompatibilities
Strong oxidizing agents and acids. Mixing with chlorpromazine hydrochloride, droperidol, idarubicin, metoclopramide hydrochloride, heparin solution, prednisolone phosphate sodium salt or promethazine hydrochloride causes precipitation or clouding of the solution.