January 22, 2004 / June, 2005

Package leaflet: Information for the user

Methotrexat-Ebewe, 100 mg/ml, concentrate for solution for infusion
Methotrexatum
Please read all of this leaflet carefully before using this medicine because it contains important information for you.

Keep this leaflet as you may need to read it again.
If you have any 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 side effects, including any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Leaflet contents:

What Methotrexat-Ebewe is and what it is used for
Important information before using Methotrexat-Ebewe
How to use Methotrexat-Ebewe
Possible side effects
How to store Methotrexat-Ebewe
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 antimetabolite group. Tissues with rapid cell division, such as tumour tissue, bone marrow, fetal cells, oral and intestinal mucosa, and cells of the urinary bladder, are particularly sensitive to the action of this drug. The mechanism of action of the drug consists of inhibiting tumour growth. If cell proliferation in tumour tissue is stronger than in normal tissues, methotrexate may inhibit tumour growth without harmful effects on healthy tissues.

Cell proliferation in the skin epithelium is significantly higher in patients with psoriasis than in healthy individuals; this forms the basis for using methotrexate in severe forms of psoriasis.

Indications:

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

2. 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 renal impairment (when administering low-dose methotrexate (<100 mg/m² body surface area)) or moderate renal impairment (when administering medium or high doses of methotrexate (>100 mg/m² body surface area));
if the patient has disorders of the haematopoietic system (e.g. following previous radiotherapy or chemotherapy);
if the patient has severe and/or active acute infections;
if the patient abuses alcohol;
if the patient has immune system disorders;
if the patient has stomatitis or active peptic ulcer disease of the stomach or duodenum;
January 22, 2004 / June, 2005
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 lesions associated with psoriasis.
Methotrexate may increase skin sensitivity to sunlight. Intense sun exposure should be avoided, and use of solariums or tanning lamps is not recommended without prior consultation with a doctor.
To protect the skin from intense sunlight, wear appropriate clothing or use a high-protection sunscreen filter.
During methotrexate treatment, cases of acute pulmonary haemorrhage have been reported in patients with underlying rheumatic disease. If the patient develops haemoptysis, i.e. coughing up sputum containing blood, medical advice should be sought immediately.
If the patient, their partner or caregiver notice new onset or worsening of neurological symptoms, including generalised muscle weakness, visual disturbances, changes in thinking, memory and orientation leading to disorientation and personality changes, immediate contact with a doctor is required, as these may be symptoms of a very rare but serious brain infection called progressive multifocal leukoencephalopathy (PML).

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

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

During treatment:
The doctor may order the following tests:

January 22, 2004 / June, 2005
examination of the mouth and throat to rule out mucosal lesions such as inflammation or ulceration;
blood tests and/or complete blood count to assess the number of different types of blood cells and serum methotrexate concentration;
blood tests to monitor liver function;
imaging tests to monitor liver status;
liver biopsy to obtain a detailed examination;
blood tests to monitor kidney function;
monitoring of respiratory function and, if necessary, lung function tests.

It is essential to attend all scheduled blood tests and other examinations recommended by the doctor.
If any of these test results are abnormal, treatment will only be resumed once 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 the conditions for which the medicine is indicated.
During treatment with Methotrexat-Ebewe, the doctor will closely monitor the child's condition to detect any adverse effects as early as possible.

Elderly patients
During treatment with Methotrexat-Ebewe, elderly patients should be monitored particularly closely to detect any adverse effects 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 impairs the production of sperm and oocytes. Methotrexate may cause miscarriage and severe congenital malformations. Female patients should avoid becoming pregnant during methotrexate treatment and for at least 6 months after completion of therapy. Men should avoid fathering a child during methotrexate treatment and for at least 3 months after completion of therapy. 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 available without prescription, herbal remedies or natural products. If your doctor prescribes any other medicines, 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 supplements and oral iron preparations containing folic acid, disease-modifying drugs (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, nephrotoxic and hepatotoxic drugs, drugs excreted by the kidneys, and live vaccines.

January 22, 2004 / June, 2005

Penicillins may reduce methotrexate excretion, potentially increasing the risk of adverse effects.
During methotrexate treatment, the immune response to concomitant vaccination may be weakened.
Concomitant use of methotrexate and non-steroidal anti-inflammatory drugs (NSAIDs) is not recommended in the presence of risk factors such as renal impairment, including mild renal impairment.

Pregnancy, breastfeeding and fertility
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to become pregnant, 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 induce miscarriage. These effects are associated with developmental abnormalities of the skull, face, heart and blood vessels, brain and limbs. Therefore, it is extremely important that female patients who are pregnant or planning pregnancy do not take methotrexate unless for oncological indications.
If the patient is of childbearing potential, pregnancy should 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 absolutely 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 immediately. If pregnancy occurs during treatment, advice should be sought regarding the potential harmful effects of treatment on the foetus.
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 continued during treatment, as methotrexate passes into breast milk. If the treating doctor considers methotrexate treatment absolutely necessary during this period, breastfeeding must be discontinued.

Male fertility
Available evidence does not indicate an increased risk of developmental abnormalities or miscarriages following paternal exposure to methotrexate at doses below 30 mg/week. However, the risk cannot be completely excluded; there is also 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 abnormalities.
The patient should avoid impregnating a partner and donating sperm during methotrexate treatment and for at least 3 months after its completion. Given that treatment with higher doses of methotrexate, typically used in cancer therapy, may cause infertility and genetic mutations, sperm cryopreservation prior to treatment initiation is recommended for men receiving methotrexate doses exceeding 30 mg/week (see also section “Warnings and precautions”).

January 22, 2004 / June, 2005 Driving and operating machinery During treatment with Methotrexat-Ebewe, adverse effects on the central nervous system such as fatigue and dizziness may occur. In some cases, these may impair the ability to drive or operate machinery. If the patient experiences fatigue or dizziness, driving vehicles or operating machinery should be avoided.

Methotrexat-Ebewe contains sodium
The medicine contains approximately 11.15 mg of sodium per 1 ml of concentrate.
The medicine contains sodium (the main component of table salt) in the following amounts:

55.75 mg of sodium in the 5 ml vial (equivalent to 2.8% of the maximum recommended daily dietary sodium intake for adults);
111.5 mg of sodium in the 10 ml vial (equivalent to 5.6% of the maximum recommended daily dietary sodium intake for adults);
557.5 mg of sodium in the 50 ml vial (equivalent to 27.9% of the maximum recommended daily dietary sodium intake for adults).

The concentrate may be diluted with 0.9% sodium chloride solution. The sodium content 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 in 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 medicine and its mode of action.
Methotrexat-Ebewe must always be used exactly as directed by the physician. If in doubt, consult your doctor, pharmacist, or nurse.
Depending on the indication and treatment regimen used, the dose of Methotrexat-Ebewe may vary widely; therefore, it is extremely important that treatment is supervised by qualified medical personnel.
Methotrexat-Ebewe is usually administered directly or after dissolution in physiological saline or 5% glucose solution. It may be given intravenously (bolus or infusion), intramuscularly, intra-arterially, or intrathecally.
The medicine can be administered either as a rapid injection (bolus) or as a prolonged infusion. Prolonged infusions are used when administering high doses of Methotrexat-Ebewe.
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 also 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.
In patients with impaired liver, kidney, or bone marrow function, the dose should be reduced.

Malignant tumors and acute leukemias:
Small (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 commonly used, depending on the multi-agent chemotherapy regimen employed.

January 22, 2004 / June, 2005 Psoriasis:

Important warning regarding the dosing of Methotrexat-Ebewe (methotrexate):
In the treatment of psoriasis resistant to other therapies, Methotrexat-Ebewe must be used only once weekly.
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 doctor or pharmacist before taking the medicine.

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

Overdose of Methotrexat-Ebewe
Calcium folinate is a specific antidote that reduces the toxic effects of Methotrexat-Ebewe. It can 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, followed by continued administration until methotrexate levels reach a safe range.
Patients who have overdosed on Methotrexat-Ebewe may also require renal dialysis 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 doctor for advice.

Stopping Methotrexat-Ebewe treatment
Do not interrupt or discontinue treatment with Methotrexat-Ebewe without consulting your doctor. If you suspect severe adverse reactions, seek immediate medical advice.

If you have any further questions or uncertainties regarding the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can have adverse effects, although not everyone will experience them.
You must immediately inform the doctor if the patient suddenly develops wheezing,
difficulty breathing, swelling of the eyelids, face or lips, rash or itching (especially
if affecting the entire body).
Serious adverse effects
You should contact the doctor immediately if any of the following adverse effects 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 development of bruises;
Severe diarrhea;
Ulceration of the oral mucosa;
Black or tarry stools;
Blood in the urine or feces;
Small red spots on the skin;
Fever;
January 22 , 2004 / June, 2005
Yellowing of the skin (jaundice);
Pain or difficulty urinating;
Feeling thirsty and/or frequent urination;
Seizures (convulsions);
Loss of consciousness;
Blurred vision or visual disturbances;
Hemoptysis, i.e. coughing up sputum containing blood (reported during methotrexate use in patients with underlying rheumatic disease).

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

Reduced resistance to infections
Sore throat
Decreased platelet count (thrombocytopenia), decreased white blood cell count (leukopenia)
Headache, dizziness
Cough
Loss of appetite
Diarrhea, abdominal pain, nausea, vomiting
Ulcerative inflammation of the oral mucosa
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
Anemia, (decreased red blood cells, white blood cells and platelets (pancytopenia), complete or near-complete absence of granulocytes (agranulocytosis)
Bone marrow suppression
Drowsiness
Numbness or tingling sensation or reduced response to stimuli
Conjunctivitis
Pulmonary complications due to interstitial pneumonitis, alveolitis (may lead to death), acute pulmonary edema
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
Suppression of immune system function
Diabetes
Hemiparesis
Confusion
Seizures
Encephalopathy/leukoencephalopathy
Vasculitis, allergic vasculitis
Pulmonary fibrosis, pleural effusion
Ulceration of gastric and intestinal mucosa
Hemorrhage
Pancreatitis
Hepatotoxic effects
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 of methotrexate
Impaired wound healing
Pain in psoriatic lesions
Joint pain, muscle pain
Osteoporosis
Nephropathy, renal failure
Cystitis and bladder ulceration
Hematuria
Urinary disorders, painful urination, oliguria, anuria
Congenital malformations in the fetus
Vaginitis and ulceration of the vagina
Fever

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

Sepsis (including fatal cases)
Megaloblastic anemia
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)
Sore throat
Respiratory arrest
Pulmonary embolism
Enteritis
Gingivitis
Tarry stools
Acute hepatitis
Acne
Petechiae
Erythema multiforme
Erythematous skin rashes
Intensification of nail pigmentation changes, nail plate separation
Stress fractures
Increased serum uric acid, urea and creatinine levels, 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
Tumor lysis syndrome (in patients treated for malignant disease)
Aplastic anemia
January 22 , 2004 / June, 2005
Eosinophilia, neutropenia
Lymphadenopathy
Lymphoproliferative disorders (overproduction of white blood cells)
Hypogammaglobulinemia
Myasthenia
Limb pain
Taste disturbances (metallic taste)
Acute aseptic meningitis with meningeal reaction
Meningitis-like symptoms without infection (paralysis, vomiting)
Cranial nerve disorders
Periorbital edema
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, dyspnea and changes visible in lung function tests
Vomiting blood
Acute liver necrosis, acute liver degeneration, liver failure
Acrocyanosis, telangiectasia, acute paronychia
Hematuria, proteinuria
Fetal death
Sperm production disorders, oocyte production disorders
Infertility
Menstrual cycle disturbances
Loss of libido
Impotence
Vaginal discharge
Gynecomastia
Chills

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

Pneumonitis
Reactivation of hepatitis B virus infection
Exacerbation of hepatitis C virus infection
Neurotoxicity
Adhesive arachnoiditis
Transverse myelitis
Stupor
Ataxia
Dementia
Increased cerebrospinal fluid pressure
Chest pain
Hypoxia
Alveolar hemorrhage (reported during methotrexate use in patients with underlying rheumatic disease)
Non-infectious peritonitis
Intestinal perforation
Glossitis
Acute colonic dilation
Drug reaction with eosinophilia and systemic symptoms (DRESS)
Dermatitis
Redness and peeling of the skin
Worsening of psoriatic lesions after concomitant exposure to UV radiation
Skin ulceration (in patients with psoriasis)
January 22 , 2004 / June, 2005
Edema
Bone necrosis
Osteonecrosis of the jaw (due to overproduction of white blood cells)
Skin cancer (in patients treated for psoriasis)
Retinopathy
Urinary and genital disorders
Tissue necrosis at injection site

If the patient develops diarrhea or ulceration in the mouth or throat, this must be reported immediately
to the doctor, as treatment may need to be discontinued due to the risk of gastrointestinal perforation
or hemorrhagic enteritis.
Methotrexate use may cause recurrence of skin inflammation and radiation-induced skin burns
(so-called "recall reactions").
After intramuscular administration, adverse effects at the injection site (burning sensation) or tissue
damage (formation of sterile abscess, fatty tissue damage) may occur.
Adverse effects particularly associated with intrathecal administration
Severe: chemically-induced meningitis, manifested by headache, back, arm pain, neck stiffness and
fever.
Subacute: may include paresis (usually transient), paralysis of lower limbs, nerve paralysis, cerebellar
disturbances.
Chronic: leukodystrophy presenting with irritability, confusion, disorientation, spasticity and sometimes
seizures, dementia, drowsiness, coma, and rarely death. It has been demonstrated that concomitant
cranial irradiation and intrathecal methotrexate administration increases the frequency of leukodystrophy.
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, other metabolic changes and sudden death.
Carcinogenic, mutagenic effects and effects on fertility
It has been shown that methotrexate causes chromosomal damage in somatic cells of animals and in human bone marrow cells, and this effect was transient and reversible. In patients treated with methotrexate, these properties may increase the risk of developing tumors (usually lymphoma, usually reversible), but there is insufficient evidence to draw definitive conclusions. It has been established that methotrexate causes fertility disorders, oligospermia, menstrual disturbances and amenorrhea during treatment and for a short period after discontinuation in humans.
Furthermore, methotrexate has harmful effects on the embryo, leading to miscarriages and fetal malformations. Therefore, patients of reproductive age should be informed about the potential harmful effects on reproduction.
Reporting of adverse effects
If any adverse symptoms occur, including any adverse effects not listed in this leaflet, you should inform your doctor, pharmacist or nurse. Adverse effects can be reported directly to the Department of Monitoring Adverse Drug Reactions of 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 effects can also be reported to the marketing authorization holder.
Reporting adverse effects allows more information on the safety of the medicine to be collected.

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 following EXP.
The expiry date refers to the last day of the stated month.
Store below 25°C and protect from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures help protect the environment.

6. Contents of the package and other information

What Methotrexat-Ebewe contains
The active substance is methotrexate.
1 ml of concentrate for solution for infusion contains 100 mg of methotrexate.
A 5 ml vial contains 500 mg of methotrexate.
A 10 ml vial contains 1000 mg of methotrexate.
A 50 ml vial contains 5000 mg of methotrexate.
The other ingredients are: sodium hydroxide (for pH adjustment) and water for injections.

What Methotrexat-Ebewe looks like and contents of the pack
Methotrexat-Ebewe is a clear, yellow concentrate for solution for infusion.
The pack contains:

1 or 5 vials of 500 mg methotrexate in 5 ml
1 vial of 1000 mg methotrexate in 10 ml
1 vial of 5000 mg methotrexate in 50 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, contact:
Sandoz Polska Sp. z o.o.
ul. Domaniewska 50 C
02-672 Warszawa
tel. 22 209 70 00

January 22, 2004 / June, 2005 ___________________________________________________________________________ Information exclusively for healthcare professionals Expiry date After opening: Draw up immediately before use. From a microbiological point of view, the product should be used immediately. Otherwise, the responsibility for storage conditions and duration lies with the user. After first withdrawal, the 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 refrigerated or at room temperature protected from light, the product maintains its physico-chemical stability for up to 28 days.

The medicinal product Methotrexat-Ebewe 100 mg/ml maintains physico-chemical stability for 28 days at room temperature with exposure to light.

After dilution
From a microbiological standpoint, the product should be used immediately. Otherwise, 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 performed under controlled and verified aseptic conditions.

Physical and chemical stability has been demonstrated for 28 days for Methotrexat-Ebewe 100 mg/ml solution diluted to concentrations of 5 mg/ml and 20 mg/ml in 0.9% sodium chloride solution or 5% glucose solution, when stored refrigerated or at room temperature protected from light, and for 7 days at room temperature with exposure to light.

For the 5 mg/ml solution diluted in 0.9% sodium chloride solution, physical and chemical stability has also been demonstrated for 28 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 route. The solution should be diluted with 0.9% sodium chloride or 5% glucose solution.

Due to the various proposed dosing regimens, the use of this medicinal product is recommended only 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 organ function (bone marrow, 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 methotrexate dose administered. Usually, up to 150 mg is given in divided doses over 12–24 hours by intramuscular injection, intravenous bolus, 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 should begin 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 bolus injection.

High-dose methotrexate may cause precipitation of methotrexate or its metabolites in renal tubules. As a preventive measure, significant fluid intake and urine alkalization to pH 6.5–7.0 are recommended, achieved 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 exceeding 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, 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 should begin 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 does not exhibit corrosive properties 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; no specific recommendations exist regarding incineration temperature.

Follow guidelines applicable to cytotoxic substances.

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

Methotrexate-ebewe