Methotrexate

Package leaflet: Information for the user

METHOTREXATE 2.5 mg tablets, 5 mg powder for injectable solution, 7.5 mg/ml injectable solution, 10 mg/1.33 ml injectable solution, 15 mg/2 ml injectable solution, 20 mg/2.66 ml injectable solution

Methotrexate
Please read all of this leaflet carefully before you start using this medicine, as 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 the doctor treating your child or your pharmacist.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, please inform your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Methotrexate is and what it is used for

Methotrexate contains the active substance methotrexate, which belongs to a group of medicines called
antineoplastic and antirheumatic agents.
Methotrexate is used to treat:

• acute leukaemia (blood cancer) in adults and children;
• choriocarcinoma, a tumour that develops during pregnancy;
• rheumatoid arthritis (inflammation of the joints) in adults;
• juvenile polyarticular arthritis (inflammation of the joints affecting children);
• psoriasis (a chronic skin disease characterised by red patches covered with dry, thick, silvery scales that are difficult to remove), in adults;
• psoriatic arthritis (inflammation of the joints associated with psoriasis)

2. What you need to know before using Methotrexate

Do not use Methotrexate if:

• you are allergic to methotrexate or to any of the other ingredients of this medicine (listed in section 6);
• you are alcohol-dependent;
• you have severe liver problems (liver disease due to alcoholism, chronic liver diseases of other types);
• you have immunodeficiency syndromes (severe impairment of the immune system);
• you have blood disorders: bone marrow hypoplasia (inadequate bone marrow activity), leucopenia (reduced number of white blood cells), thrombocytopenia (reduced number of platelets), or significant anaemia (reduced number of red blood cells);
• you are breastfeeding, and, in addition, for non-oncological indications (treatment not related to cancer), if you are pregnant (see section “Pregnancy, breastfeeding and fertility”);
• you are planning a pregnancy. In this case, neither partner should be undergoing treatment with this medicine (see section “Pregnancy, breastfeeding and fertility”).

Warnings and precautions
Talk to your doctor or pharmacist before using Methotrexate.
During treatment with Methotrexate, you will be closely monitored by your doctor.
Inform your doctor if:

• you have a stomach ulcer (lesion) or bleeding in the stomach or part of the intestine (duodenum), or suffer from chronic inflammatory bowel disease (ulcerative colitis);
• you have chronic liver infections (e.g. hepatitis B or C). These may reactivate, worsen, or lead to death;
• you are dehydrated or suffer from conditions that may cause dehydration (vomiting, diarrhoea, and stomatitis);
• you are very elderly or very young and/or debilitated;
• you have tumour lysis syndrome, i.e. disturbances due to rapid death of tumour cells;
• you have folic acid deficiency (a vitamin) or deficiencies in similar substances;
• you have recently undergone or are currently undergoing radiotherapy;
• you are experiencing patchy hair loss (alopecia);
• you have diabetes;
• you are severely overweight;
• you have bone marrow problems leading to reduced numbers of white blood cells, red blood cells, and platelets in the blood;
• you have or have had liver or kidney problems;
• you have signs or symptoms of an ongoing infection (e.g. fever);
• you have abnormal accumulation of fluid in the abdomen or pleura (the cavity between the lungs and the chest wall);
• you have lung problems;
• you experience headache (cephalalgia), back pain, neck stiffness, fever, epileptic seizures, paralysis, loss of muscle coordination (ataxia), irritability, confusion, drowsiness, dementia, coma, or any other sign of brain problems;
• you develop skin rashes, lesions, peeling, skin and mucosal necrosis;
• you experience swollen lymph nodes. This may be a symptom of lymphoma development, which usually resolves after discontinuation of Methotrexate treatment.

Methotrexate temporarily affects sperm and egg production. Methotrexate may cause miscarriage and severe birth defects. If you are a woman, you must avoid pregnancy or conception during treatment with methotrexate and for at least six months after treatment ends. If you are a man, you must avoid fathering a child during treatment with methotrexate and for at least three months after treatment ends. See also section "Pregnancy, breastfeeding and fertility".
Diarrhoea and ulcerative stomatitis (mouth mucosa infection characterised by lesions) are side effects of Methotrexate that may require treatment interruption. Inform your doctor if you experience diarrhoea. Additionally, during treatment with Methotrexate, your doctor will regularly examine your mouth and throat to check for mucosal lesions.
Methotrexate may reduce the immune system's response and thereby affect vaccinations. Vaccination may be less effective. Moreover, during treatment with this medicine, it is preferable not to receive live vaccines, as you may develop infections.
If you have previously experienced skin problems following exposure to radiation or sunlight, these may reappear during treatment with this medicine. If you are using Methotrexate for the treatment of psoriasis, avoid exposure to UV light, as your condition may worsen.
Cases of acute pulmonary haemorrhage have been reported in patients with rheumatological disease treated with methotrexate. If you notice blood in your saliva or after coughing, contact your doctor immediately.
If you, your partner, or caregiver notice the onset or worsening of neurological symptoms, including generalised muscle weakness, vision disturbances, changes in thinking, memory, and orientation, leading to confusion and personality changes, contact your doctor immediately, as these may be symptoms of a very rare and serious brain infection called progressive multifocal leukoencephalopathy (PML).

Recommended monitoring and precautions
Even when methotrexate is used at low doses, serious adverse effects may occur. To detect them early, your doctor must perform monitoring tests and laboratory examinations.

Before starting therapy:
Before starting treatment, your blood will be tested to ensure you have sufficient blood cell counts. Your blood will also be analysed to check liver function and to detect hepatitis. In addition, serum albumin (a blood protein), hepatitis status (liver infection), and kidney function will be evaluated. Your doctor may also decide to perform further liver tests, some of which may involve imaging of your liver, while others may require taking a small tissue sample from your liver for closer examination. Your doctor may also check for tuberculosis and may perform a chest X-ray or lung function test.

During treatment:
Your doctor may perform the following tests:

• examination of the oral cavity and pharynx for mucosal changes such as inflammation or ulceration;
• blood tests / full blood count with blood cell counts and measurement of serum methotrexate levels;
• blood tests to monitor liver function;
• imaging to monitor liver condition;
• liver tissue biopsy for closer examination;
• blood tests to monitor kidney function;
• respiratory monitoring and, if necessary, lung function tests.

It is very important that you attend these scheduled tests.
If any of these tests yield significant results, your doctor will adjust your treatment accordingly.

Children
Children must be carefully monitored to determine the optimal dose of this medicine and to detect possible side effects early.

Elderly patients
Elderly patients receiving methotrexate must be closely monitored by a doctor so that possible adverse effects can be detected as early as possible.
Age-related impairment of liver and kidney function, as well as low body reserves of folic acid vitamin in older age, require a relatively low dose of methotrexate.
Fatal toxicities due to incorrect daily instead of weekly administration have been reported, particularly in elderly patients.

Other medicines and Methotrexate
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
It is particularly important that you inform your doctor if you are taking the following medicines:

• para-aminobenzoic acid (an amino acid);
• phenytoin (a medicine used to treat epileptic seizures);
• antibiotics (e.g. neomycin, aminoglycosides, tetracyclines, penicillins, pristinamycin, chloramphenicol, ciprofloxacin, sulfonamides, trimethoprim/sulfamethoxazole, and gastrointestinal antibiotics);
• probenecid (used for gout);
• non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. aspirin, phenylbutazone) and salicylates (medicines used for pain and inflammation);
• steroids (medicines used against inflammation);
• leflunomide (a medicine used for rheumatoid arthritis and psoriasis);
• cisplatin, mercaptopurine, cytarabine, and L-asparaginase (medicines used for certain types of cancer);
• azathioprine (a medicine used to prevent organ transplant rejection);
• retinoids (a medicine used to treat skin diseases);
• sulfasalazine (a medicine used for rheumatoid arthritis and colitis);
• pyrimethamine (a medicine used to treat and prevent malaria);
• leucovorin (folinic acid) and vitamin preparations containing folic acid;
• proton pump inhibitors (a medicine used to treat ulcers and severe heartburn);
• theophylline (a medicine used to treat asthma);
• triamterene (a medicine used to increase urine production);
• amiodarone (a medicine used for heart rhythm disorders).

The effects of penicillamine (a medicine for inflammation), hydroxychloroquine (a medicine for malaria and rheumatic diseases), and gold salts (for rheumatic diseases) when taken together with Methotrexate are unknown. Therefore, it is recommended not to use Methotrexate together with these medicines.
Inform your doctor if you have recently received a transfusion of concentrated erythrocytes (red blood cells), if you are undergoing radiotherapy, or if you are receiving psoriasis treatment involving xanthotoxin (a medicine) and ultraviolet radiation.
If you are scheduled for anaesthesia with nitrous oxide, inform your doctor that you are being treated with Methotrexate.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.

Pregnancy
Do not use Methotrexate during pregnancy unless prescribed by your doctor for oncological treatment. Methotrexate may cause birth defects, harm the foetus, or lead to miscarriage. It is associated with malformations of the skull, face, heart and blood vessels, brain, and limbs. Therefore, it is very important that pregnant women or those planning a pregnancy are not treated with methotrexate, unless it is used for oncological treatment.
For non-oncological indications, pregnancy must be ruled out in women of childbearing age before starting treatment, for example by performing a pregnancy test.
Do not use Methotrexate if you are trying to become pregnant. During treatment with methotrexate and for at least six months after treatment ends, you must avoid pregnancy by using an effective contraceptive method throughout this entire period (see also section “Warnings and precautions”).
If you become pregnant during treatment or suspect you are pregnant, contact your doctor immediately. If you become pregnant during treatment, you will be counselled regarding the risk of harmful effects on the baby due to the treatment.
If you wish to become pregnant, you should consult your doctor, who will refer you to a specialist before the planned start of treatment.

Breastfeeding
Methotrexate passes into breast milk and may cause serious adverse effects in the infant. Discontinue breastfeeding if you need to start treatment with this medicine.

Fertility
Methotrexate may impair fertility in men, causing oligospermia (reduced sperm count), and in women (menstrual dysfunction).

Male fertility
Available evidence does not indicate an increased risk of birth defects or miscarriage if the father takes a methotrexate dose below 30 mg/week. However, the risk cannot be completely excluded, and there is no information regarding higher doses of methotrexate. Methotrexate may have a genotoxic effect. That is, this medicine may cause genetic mutations. Methotrexate may affect sperm production, which is associated with the possibility of birth defects.
During treatment with methotrexate and for at least three months after treatment ends, you must avoid fathering a child or donating semen. Since treatment with higher doses of methotrexate commonly used in cancer treatment may cause infertility and genetic mutations, male patients receiving methotrexate doses above 30 mg/week may wish to consider sperm preservation before starting treatment (see also section “Warnings and precautions”).

Driving and using machines
Methotrexate may cause dizziness and fatigue, which may affect your ability to drive or operate machinery.

Methotrexate 2.5 mg tablets contain lactose
Methotrexate 2.5 mg tablets contain lactose. If your doctor has diagnosed you with an intolerance to certain sugars, contact him before taking this medicine.

Methotrexate 2.5 mg tablets contain sodium
This medicine contains less than 1 mmol (23 mg) of sodium per tablet, i.e. essentially "sodium-free".

Methotrexate 5 mg powder for injectable solution contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e. essentially "sodium-free".

Methotrexate 7.5 mg/ml injectable solution contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per pre-filled syringe, i.e. essentially "sodium-free".

Methotrexate 10 mg/1.33 ml injectable solution contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per pre-filled syringe, i.e. essentially "sodium-free".

Methotrexate 15 mg/2 ml injectable solution contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per pre-filled syringe, i.e. essentially "sodium-free".

Methotrexate 20 mg/2.66 ml injectable solution contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per pre-filled syringe, i.e. essentially "sodium-free".

3. How to use Methotrexate

Important warning about Methotrexate dosage:
In the treatment of rheumatoid arthritis, polyarticular juvenile arthritis, psoriatic arthritis, and psoriasis requiring a weekly dose, Methotrexate must be taken only once a week. Excessive use of Methotrexate can be fatal. Please read paragraph 3 of this leaflet very carefully. If in doubt, consult your doctor or pharmacist before taking this medicine.
Use this medicine exactly as directed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.
This medicine must be prescribed under the supervision of experienced physicians. If Methotrexate is to be administered by injection, it must be done in a hospital or clinic.
Administration may be oral, intramuscular (by deep injection into a muscle), intravenous (into a vein), intratumoral (into the tumor), intra-arterial (into an artery), or intrathecal (into the cerebrospinal fluid).
At the beginning of treatment, Methotrexate will be administered to you by medical personnel. However, your doctor may determine that you are able to learn how to self-administer Methotrexate injections. In such a case, you will receive adequate training. Under no circumstances should you attempt to self-inject without proper training.

Oncological indications
Treatment of acute leukemia and choriocarcinoma
Administration may be intramuscular (by deep injection into a muscle), intravenous (into a vein), intratumoral (into the tumor), intra-arterial (into an artery), or intrathecal (into the cerebrospinal fluid).
Recommended dose:

• for neonates: from 1.25 mg to 2.5 mg
• for children: from 2.5 mg to 5 mg
• for adults: from 5 mg to 10 mg

Doses should be administered 3 to 6 times per week. Your doctor will determine the dose and frequency of treatment based on the severity of the disease and your condition.

Non-oncological indications
Treatment of rheumatoid arthritis and psoriatic arthritis
This medicine must be taken only once a week, either orally or by intramuscular injection (by deep injection into a muscle).
Recommended oral dose:

• 7.5 mg per week

The maximum recommended oral dose is 20 mg per week.

Recommended dose for intramuscular injection:

• 5–15 mg per week. The maximum recommended dose is 20 mg per week. Subsequently, the dose may be gradually reduced to the lowest effective dose.

Treatment of polyarticular juvenile rheumatoid arthritis
This medicine must be taken only once a week, either orally or by intramuscular injection (by deep injection into a muscle).
The recommended initial dose is 10 mg per m² of body surface area, administered once weekly.
Your doctor will determine the total dose to be administered and whether this medicine should be taken orally or by intramuscular injection.

Treatment of psoriasis
This medicine must be taken only once a week.
The recommended initial dose, administered orally (by mouth), intramuscularly (by deep injection into a muscle), or intravenously (into a vein), is:

• 10 mg to 25 mg once a week. The maximum recommended dose is 30 mg per week.

Duration of treatment
The duration of treatment will be determined by your doctor.

If you use more Methotrexate than you should
If you use more Methotrexate than prescribed, contact your doctor or hospital emergency department immediately. Taking an excessive dose of this medicine by mouth may cause serious side effects. Symptoms of overdose may include: reduced number of white blood cells (leucopenia), platelets (thrombocytopenia), red blood cells (anemia), or all blood cells (pancytopenia), reduced bone marrow activity (myelodepression), inflammation of the mouth (stomatitis), nausea, vomiting, stomach and intestinal ulcers and bleeding, widespread infection (sepsis and septic shock), kidney problems (renal failure), and inadequate blood cell production by the bone marrow (aplastic anemia). In severe cases, overdose may lead to death. Overdose administered intrathecally (into the head) may cause the following symptoms: headache (cephalalgia), nausea, vomiting, seizures, epileptic crisis, inflammation of the brain (toxic acute encephalopathy), cerebellar herniation, increased pressure in the head (increased intracranial pressure), and death.

If you forget to use Methotrexate
Do not take a double dose to make up for the missed dose.

If you stop using Methotrexate
Do not stop treatment with Methotrexate without consulting your doctor.

If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop treatment with Methotrexate and contact your doctor immediately if you experience any of the following side effects:

• widespread systemic infection (sepsis)
• reactivation of pre-existing hepatitis B infection
• worsening of pre-existing hepatitis C infection
• lymphoma (blood cancer)
• severe allergic reactions (anaphylactoid reactions)
• paralysis of one side of the body (hemiparesis), of a group of muscles (paresis), or of the lower part of the body (paraplegia)
• brain diseases (encephalopathy/leukoencephalopathy, arachnoiditis)
• temporary blindness or loss of vision, severe visual disturbances
• interstitial pneumonia (a severe form of pneumonia)
• blood in saliva or after coughing (side effect reported in patients with rheumatological disease treated with methotrexate)
• stomach and intestinal ulcers and bleeding, intestinal perforation
• non-infectious peritonitis (inflammation of the membrane lining the abdominal organs)
• acute inflammation of the liver (acute hepatitis)
• severe skin reactions such as rash and skin ulceration, redness, blisters, pustules, necrosis or skin peeling (Stevens-Johnson syndrome, toxic epidermal necrolysis, cutaneous ulceration)
• increased risk of bone fractures, death of bone tissue (osteonecrosis)
• fetal malformations or fetal death, miscarriage.

Contact your doctor if you experience any of the following side effects:
Common (may affect up to 1 in 10 people):

• sensation of numbness and tingling, reduced sensitivity to stimulation (paresthesia)*.

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

• reduced activity of the bone marrow producing blood cells (bone marrow failure), reduced number of red blood cells (anemia) and platelets (thrombocytopenia)
• headache (cephalalgia), seizures
• accumulation of fluid in the cavity between the lungs and the inner chest wall (pleural effusion)
• inflammation of the pancreas (pancreatitis)
• decreased appetite
• vomiting, diarrhea
• inflammation of the mouth (stomatitis)
• changes in certain blood laboratory tests assessing liver function (increased liver enzymes)
• patchy hair loss (alopecia)
• kidney failure, kidney damage (nephropathy).

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

• diabetes
• mood changes
• language disorder (aphasia)
• transient disturbances in intellectual function
• speech disorders (dysarthria)
• drowsiness
• blurred vision
• decrease in blood pressure (hypotension)
• formation of blood clots in arteries and veins affecting various organs (e.g. brain, lungs, eyes, and lower limbs)
• progressive decline in lung function (pulmonary fibrosis)
• inflammation of the throat (pharyngitis)
• blood in the stool (melena), inflammation of the intestine (enteritis), inflammation of the gums (gingivitis)
• decline in liver function (chronic cirrhosis and fibrosis), liver damage (hepatotoxicity)
• skin rashes (erythema multiforme, erythematous rash), painful shedding of psoriatic plaques, increased sensitivity to light (photosensitivity), skin rash (urticaria), itching, acne, bruising (ecchymosis), skin pigmentation changes
• muscle pain (myalgia) and joint pain (arthralgia)
• bone fragility (osteoporosis)
• difficulty urinating (dysuria)
• menstrual dysfunction
• nodule formation.

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

• disorders caused by rapid death of tumor cells
• anemia due to insufficient production of blood cells by the bone marrow (aplastic anemia)
• reduction in certain antibodies called "gamma-globulins"
• cranial nerve disorders
• eye inflammation
• lymphoproliferative disorders (excessive growth of white blood cells)
• accumulation of fluid or inflammation of the membrane surrounding the heart (pericardium)
• inflammation of blood vessels (vasculitis)
• vomiting with blood (hematemesis)
• reduced levels of albumin in the blood
• boils, dilation of small blood vessels in the skin (telangiectasia)
• presence of blood in urine (hematuria), urinary tract infection (cystitis)
• changes in a laboratory test (azotemia)
• disturbances in egg cell formation (oogenesis) or sperm cell formation (spermatogenesis), transient reduction in sperm count (oligospermia), infertility
• impotence, loss of sexual desire (libido)
• vaginal discharge
• sudden death.

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

• infections caused by various microorganisms (e.g. bacteria, viruses, fungi) affecting different organs (e.g. lungs, liver)
• decrease in the number of a type of white blood cells called granulocytes (agranulocytosis) or of all blood cells (pancytopenia), decrease in a type of white blood cells called neutrophils (neutropenia), damage to lymph nodes (lymphadenopathy and lymphoproliferative disorders), increase in the number of a type of white blood cells (eosinophils) in the blood (eosinophilia), reduction in red blood cells (megaloblastic anemia)
• increased pressure of the fluid surrounding the brain and spinal cord, brain damage, inflammation of the membranes surrounding the brain (meningitis)
• bone damage in the jaw (secondary to excessive growth of blood cells)
• lack of response to stimuli (stupor), movement coordination disorders (ataxia), dementia, dizziness
• inflammation of lung alveoli (alveolitis) and of their surrounding tissue (chronic interstitial pneumopathy), difficulty breathing (dyspnea), chest pain, lack of oxygen in the body (hypoxia), cough
• pulmonary hemorrhage (side effect reported in patients with rheumatological disease treated with methotrexate)
• inflammation of the tongue
• nausea
• liver problems (liver failure)
• drug reaction with increase in a type of white blood cells (eosinophilia), skin irritation (dermatitis), red spots on the skin (petechiae)
• presence of protein in urine (proteinuria)
• genital and urinary tract problems (urogenital dysfunction)
• fever, chills
• malaise, fatigue
• reaction at the injection site**
• tissue destruction at the injection site (necrosis at the injection site)**
• swelling
• skin redness and peeling

*very rare frequency for low-dose methotrexate.
**for parenteral administration only

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist.
You can also report side effects directly via the national reporting system at: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Methotrexate

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton, blister, vial, or prefilled syringe after "Expiry". The expiry date refers to the last day of that month.
Methotrexate 2.5 mg tablets
Methotrexate 5 mg powder for injectable solution
Do not store above 25°C. Keep in the original packaging to protect the medicine from light and moisture.
Methotrexate 7.5 mg/ml, 10 mg/1.33 ml, 15 mg/2 ml and 20 mg/2.66 ml injectable solution
Do not store above 25°C. Keep in the original packaging to protect the medicine from light. Do not freeze.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Methotrexate contains
The active substance is methotrexate (as methotrexate sodium salt).
Methotrexate 2.5 mg tablets
Each tablet contains 5.484 mg of methotrexate sodium salt, equivalent to 2.5 mg of methotrexate.
The other components are: starch, lactose monohydrate and magnesium stearate.
Methotrexate 5 mg powder for injectable solution
One vial of powder contains 5.484 mg of methotrexate sodium salt, equivalent to 5 mg of methotrexate.
The other components are: sodium chloride and sodium hydroxide.
Methotrexate 7.5 mg/ml injectable solution
One pre-filled syringe contains 8.226 mg of methotrexate sodium salt, equivalent to 7.5 mg of methotrexate.
The other components are: sodium chloride, sodium hydrate and water for injections.
Methotrexate 10 mg/1.33 ml injectable solution
One pre-filled syringe contains 10.968 mg of methotrexate sodium salt, equivalent to 10 mg of methotrexate.
The other components are: sodium chloride, sodium hydrate and water for injections.
Methotrexate 15 mg/2 ml injectable solution
One pre-filled syringe contains 16.452 mg of methotrexate sodium salt, equivalent to 15 mg of methotrexate.
The other components are: sodium chloride, sodium hydrate and water for injections.
Methotrexate 20 mg/2.66 ml injectable solution
One pre-filled syringe contains 21.936 mg of methotrexate sodium salt, equivalent to 20 mg of methotrexate.
The other components are: sodium chloride, sodium hydrate and water for injections.

Description of the appearance of Methotrexate and package contents
Methotrexate 2.5 mg tablets
The tablets are available in PVC/aluminum blisters in packages containing 25 and 100 tablets.
Methotrexate 5 mg powder for injectable solution
The lyophilized powder is available in 5 mg glass vials with rubber stopper and aluminum seal. The package contains 1 vial.
Methotrexate 7.5 mg/ml injectable solution
Methotrexate 10 mg/1.33 ml injectable solution
Methotrexate 15 mg/2 ml injectable solution
Methotrexate 20 mg/2.66 ml injectable solution
Each package contains 4 single-use glass pre-filled syringes with sterile needle and plunger made of polypropylene.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Pfizer Italia S.r.l.
Via Isonzo, 71
04100 Latina
Italy

Manufacturer
Methotrexate 2.5 mg tablets
Haupt Pharma Wolfratshausen GmbH
Pfafferieder Strasse 5,
82515 Wolfratshausen (Germany)
Excella GmbH & Co. KG
Nuernberger Strasse 12,
90537 Feucht (Germany)

Methotrexate 5 mg powder for injectable solution
Wyeth Lederle s.r.l.
Via F. Gorgone n.6 Z.I.
Catania (Italy)

Methotrexate 7.5 mg/ml injectable solution
Methotrexate 10 mg/1.33 ml injectable solution
Methotrexate 15 mg/2 ml injectable solution
Methotrexate 20 mg/2.66 ml injectable solution
Wyeth Lederle s.r.l.
Via F. Gorgone n.6 Z.I.
Catania (Italy)

The following information is intended for healthcare professionals only

METHOTREXATE 2.5 mg tablets
METHOTREXATE 5 mg powder for injectable solution
METHOTREXATE 7.5 mg/ml injectable solution
METHOTREXATE 10 mg/1.33 ml injectable solution
METHOTREXATE 15 mg/2 ml injectable solution
METHOTREXATE 20 mg/2.66 ml injectable solution
Methotrexate
INSTRUCTIONS FOR USE

Methotrexate 5 mg powder for injectable solution

Preparation of the solution:
Methotrexate powder for injectable solution must be reconstituted immediately before use with
water for injections, using 2 ml of water for the 5 mg vial. The resulting solution contains 2.5 mg
per ml.
Vials must be used only once.
If a precipitate forms, the solution must be discarded.
Do not administer Methotrexate with other drugs in the same infusion.

Methotrexate 7.5 mg/ml injectable solution
Methotrexate 10 mg/1.33 ml injectable solution
Methotrexate 15 mg/2 ml injectable solution
Methotrexate 20 mg/2.66 ml injectable solution

Dispose of pre-filled syringes after use in designated containers for pharmaceutical waste.
Do not use any residual solution.
Do not use if the solution appears cloudy or contains deposits.
Do not use if the packaging containing the syringe and accessories is damaged or not intact.
To open the individual blister packs containing the syringes, it is recommended to separate the two compartments
before use, then remove the peelable paper covering each blister pack at the time of actual use.
Avoid contact of the solution with skin or mucous membranes.
In case of accidental contact, wash the affected area thoroughly with abundant water.

Persons who handle or work in areas where cytotoxic drugs are used may be exposed to these agents either through airborne contact or direct contact with contaminated objects. Potential health risks can be reduced by adhering to institutional procedures, published guidelines, and local regulations regarding the preparation, administration, transport, and disposal of hazardous drugs. There is no general agreement that all recommended procedures in the guidelines are necessary and appropriate.

Intramuscular administration
Methotrexate must be administered by deep intramuscular injection.

Intrathecal administration
Adults
Dilute preservative-free methotrexate to a concentration of 1 mg/ml in an appropriate sterile, preservative-free vehicle, such as 0.9% Sodium Chloride injectable solution.
The following recommendations for intrathecal administration are provided and may be modified according to specific treatment protocols, taking into account individual patient needs.
Remove a volume of cerebrospinal fluid equivalent to the volume of methotrexate to be administered.
The maximum recommended single dose is 15 mg.
Administer 10 to 15 mg intrathecally twice weekly until the cerebrospinal fluid is clear, followed by weekly doses for 2 to 3 weeks, then monthly doses.
Alternatively, administer a dose of 12 mg/m² (but not exceeding the absolute maximum dose of 15 mg) at intervals of 2 to 7 days until the cerebrospinal fluid cell count returns to normal. One or more additional doses may be administered weekly for two weeks, then monthly.
The standard dose of methotrexate is 12 mg.

Pediatrics
The following dosing regimen is based on patient age rather than body surface area, since, unlike body surface area, cerebrospinal fluid volume in pediatric patients approaches that of adults.
A fixed dose should be administered to the child as follows:

• Under one year of age: 6 mg
• One year of age: 8 mg
• Two years of age: 10 mg
• Three years of age or older: 12 mg

INCOMPATIBILITIES
Methotrexate is compatible with: dextrose in lactated Ringer's, dextrose in Ringer's solution, dextrose in sodium chloride, dextrose in water, lactated Ringer's, sodium chloride.
Methotrexate must not be administered with other drugs in the same infusion.

Package leaflet: Information for the user

METHOTREXATE 50 mg powder for injectable solution, 500 mg powder for injectable solution, 1 g powder for injectable solution, 50 mg/2 ml injectable solution, 500 mg/20 ml injectable solution, 1 g/10 ml injectable solution, 5 g/50 ml injectable solution

Methotrexate
Please read this leaflet carefully before this medicine is administered to you, as it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor, the doctor treating your child, or the nurse.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, consult your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Methotrexate is and what it is used for

Methotrexate contains the active substance methotrexate, which belongs to a group of medicines called
antineoplastic and antirheumatic agents.
Methotrexate is used in adults and children to treat:

• breast cancer;
• choriocarcinoma, a tumour that develops during pregnancy, and other similar tumours ( trophoblastic conditions );
• acute and subacute lymphatic and meningeal leukaemia, acute leukaemia, lymphosarcoma (blood or bone marrow cancers);
• mycosis fungoides (a cancer of the immune system);
• bone cancer ( osteogenic osteosarcoma );
• lung cancer ( bronchogenic carcinoma );
• head cancer ( epidermoid carcinoma of the head ) and neck.

2. What you need to know before Methotrexate is administered

Methotrexate must not be administered if:

• you are allergic to methotrexate or to any of the other ingredients of this medicine (listed in section 6);
• you are pregnant or breastfeeding (see section “Pregnancy, breastfeeding and fertility”);
• you are planning a pregnancy. In this case, neither partner should be treated with this medicine (see section “Pregnancy, breastfeeding and fertility”);
• you have severe kidney problems ( severe renal insufficiency ).

Warnings and precautions
Talk to your doctor or pharmacist before Methotrexate is administered.
During treatment with Methotrexate, you will be closely monitored by your doctor.
Inform your doctor if:

• you have a stomach ulcer (lesion) or bleeding in the stomach or intestine (duodenum), or suffer from chronic inflammation of the lower part of the intestine (ulcerative colitis);
• you have chronic liver infections (e.g. hepatitis B or C). These may reactivate, worsen, or lead to death;
• you are dehydrated or suffer from conditions that may cause dehydration (vomiting, diarrhoea, and stomatitis);
• you are very elderly or very young and/or debilitated;
• you have tumour lysis syndrome, i.e. disorders due to rapid death of tumour cells;
• you have folic acid deficiency (a vitamin) or deficiency of similar substances;
• you have recently undergone or are currently undergoing radiotherapy;
• you are experiencing patchy hair loss (alopecia);
• you have diabetes;
• you are severely overweight;
• you have bone marrow problems leading to reduced numbers of white blood cells, red blood cells, and platelets in the blood;
• you have or have had liver or kidney problems;
• you have signs or symptoms of an ongoing infection (e.g. fever);
• you have abnormal fluid accumulation in the abdomen or pleura (the cavity between the lungs and chest wall);
• you have lung problems;
• you experience headache (cephalalgia), back pain, neck stiffness, fever, seizures, paralysis, loss of muscle coordination (ataxia), irritability, confusion, drowsiness, dementia, coma, or any other sign of brain problems;
• you develop skin rashes, lesions, skin peeling, skin and mucosal necrosis;
• you experience swollen lymph nodes. This may be a symptom of lymphoma development, which usually resolves after discontinuation of Methotrexate treatment.

Methotrexate temporarily affects sperm and egg production. Methotrexate may cause miscarriage and severe birth defects. If you are a woman, you must avoid pregnancy or conception during treatment with methotrexate and for at least six months after treatment ends. If you are a man, you must avoid fathering a child during treatment with methotrexate and for at least three months after treatment ends.
See also the section "Pregnancy, breastfeeding and fertility".
Diarrhoea and ulcerative stomatitis (mouth mucosa infection characterised by lesions) are side effects of Methotrexate that may require discontinuation of treatment. Inform your doctor if you experience diarrhoea. Furthermore, during treatment with Methotrexate, your doctor will regularly examine your mouth and throat to check for mucosal lesions.
Methotrexate may reduce the immune system's response and thereby affect vaccinations. Vaccination may be less effective. In addition, during treatment with this medicine, vaccination with live vaccines is not recommended, as you may develop infections.
Cases of acute pulmonary haemorrhage have been reported in patients with rheumatological disease treated with methotrexate.
If you, your partner, or your caregiver notice the onset or worsening of neurological symptoms, including generalised muscle weakness, vision disturbances, changes in thinking, memory, and orientation, leading to confusion and personality changes, contact your doctor immediately, as these may be symptoms of a very rare and serious brain infection called progressive multifocal leukoencephalopathy (PML).

Recommended monitoring tests and precautions
Even when methotrexate is used at low doses, serious side effects may occur. To detect them early, your doctor must perform monitoring examinations and laboratory tests.

Before starting treatment:
Before starting therapy, your blood will be tested to ensure you have an adequate number of blood cells. Your blood will also be analysed to check liver function and to determine whether you have hepatitis. In addition, serum albumin (a blood protein), hepatitis status (liver infection), and kidney function will be assessed. Your doctor may also decide to perform further liver tests, some of which may involve imaging of your liver, while others may require a small tissue sample from the liver for closer examination. Your doctor may also check for tuberculosis and may perform a chest X-ray or lung function tests.

During treatment:
Your doctor may perform the following tests:

• examination of the oral cavity and pharynx for changes in the mucous membrane such as inflammation or ulceration;
• blood tests / full blood count with blood cell count and measurement of serum methotrexate levels;
• blood test to monitor liver function;
• imaging to monitor liver condition;
• liver biopsy (removal of a small tissue sample from the liver for closer examination);
• blood test to monitor kidney function;
• respiratory monitoring and, if necessary, lung function tests.

It is very important that you attend these scheduled examinations.
If any of these tests yield significant results, your doctor will adjust your treatment accordingly.

Children
Children must be carefully monitored to determine the optimal dose of this medicine and to detect possible side effects early.

Elderly patients
Elderly patients receiving methotrexate must be closely monitored by a doctor so that possible side effects can be detected as early as possible.
Age-related impairment of liver and kidney function, as well as low body reserves of folic acid vitamin in older age, require a relatively low dose of methotrexate. Fatal toxicity due to accidental daily instead of weekly administration has been reported, particularly in elderly patients.

Other medicines and Methotrexate
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
It is particularly important that you inform your doctor if you are taking the following medicines:

• para-aminobenzoic acid (an amino acid);
• phenytoin (a medicine used to treat epileptic seizures);
• antibiotics (e.g. tetracyclines, penicillins, pristinamycin, chloramphenicol, ciprofloxacin, sulfonamides, trimethoprim/sulfamethoxazole, and gastrointestinal antibiotics);
• probenecid (used for gout);
• non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. aspirin, phenylbutazone) and salicylates (medicines used for pain and inflammation);
• leflunomide (a medicine used for rheumatoid arthritis and psoriasis);
• cisplatin, mercaptopurine, cytarabine, and L-asparaginase (medicines used for certain types of cancer);
• azathioprine (a medicine used to prevent organ transplant rejection);
• retinoids (a medicine used to treat skin diseases);
• sulfasalazine (a medicine used for rheumatoid arthritis and colitis);
• pyrimethamine (a medicine used to treat and prevent malaria);
• leucovorin (folinic acid) and vitamin preparations containing folic acid;
• proton pump inhibitors (a medicine used to treat ulcers and severe heartburn);
• theophylline (a medicine used to treat asthma);
• triamterene (a medicine used to increase urine production);
• amiodarone (a medicine used to treat heart rhythm abnormalities).

Inform your doctor if you have recently received a transfusion of concentrated red blood cells (erythrocytes), if you are undergoing radiotherapy, or if you are receiving treatment for psoriasis or mycosis fungoides involving xanthotoxin (a medicine) and ultraviolet radiation.
If you are scheduled to undergo anaesthesia with nitrous oxide, inform your doctor that you are being treated with Methotrexate.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or nurse before this medicine is administered.

Pregnancy
Do not use Methotrexate during pregnancy unless prescribed by your doctor for oncological treatment. Methotrexate may cause birth defects, harm the foetus, or cause miscarriage. It is associated with malformations of the skull, face, heart and blood vessels, brain, and limbs. Therefore, it is very important that patients who are pregnant or planning a pregnancy are not treated with methotrexate, unless it is used for oncological treatment.
For non-oncological indications, pregnancy must be ruled out in women of childbearing age, for example by performing pregnancy tests before starting treatment.
Do not use Methotrexate if you are trying to become pregnant. During treatment with methotrexate and for at least six months after treatment ends, you must avoid pregnancy by using an effective contraceptive method throughout this period (see also section “Warnings and precautions”).
If you become pregnant during treatment or suspect you are pregnant, contact your doctor immediately. If you become pregnant during treatment, you will receive counselling regarding the risk of harmful effects on the baby due to the treatment.
If you wish to become pregnant, you should consult your doctor, who will refer you to a specialist before the planned start of treatment.

Breastfeeding
Methotrexate passes into breast milk and may cause serious adverse effects in the infant. Discontinue breastfeeding if you need to start treatment with this medicine.

Fertility
Methotrexate may impair fertility in men, causing oligospermia (reduced number of sperm), and in women (menstrual dysfunction).

Male fertility
Available evidence does not indicate an increased risk of birth defects or miscarriage if the father takes a methotrexate dose below 30 mg/week. However, the risk cannot be completely excluded, and there is no information regarding higher doses of methotrexate. Methotrexate may have genotoxic effects; that is, this medicine may cause genetic mutations. Methotrexate may affect sperm production, which is associated with the possibility of birth defects.
During treatment with methotrexate and for at least three months after treatment ends, you must avoid fathering a child or donating semen. Since treatment with higher doses of methotrexate commonly used in cancer treatment may cause infertility and genetic mutations, male patients treated with methotrexate doses exceeding 30 mg/week may wish to consider sperm preservation before starting treatment (see also section “Warnings and precautions”).

Driving and using machines
Methotrexate may cause dizziness and fatigue, which may affect your ability to drive or operate machinery.

Methotrexate 50 mg powder for injectable solution contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e. essentially "sodium-free".

Methotrexate 500 mg powder for injectable solution contains sodium
This medicine contains 48.8 mg of sodium (main component of table salt) per vial. This corresponds to 2.44% of the maximum recommended daily sodium intake for an adult. Consult your doctor or pharmacist if you need 8 or more vials per day over a prolonged period, especially if you have been advised to follow a low-sodium diet.

Methotrexate 1 g powder for injectable solution contains sodium
This medicine contains 97 mg of sodium (main component of table salt) per vial. This corresponds to 4.9% of the maximum recommended daily sodium intake for an adult. Consult your doctor or pharmacist if you need 4 or more vials per day over a prolonged period, especially if you have been advised to follow a low-sodium diet.

Methotrexate 50 mg/2 ml injectable solution
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e. essentially "sodium-free".

Methotrexate 500 mg/20 ml injectable solution
This medicine contains 38,553 mg of sodium (main component of table salt) per vial. This corresponds to 1.927% of the maximum recommended daily sodium intake for an adult. Consult your doctor or pharmacist if you need 10 or more vials per day over a prolonged period, especially if you have been advised to follow a low-sodium diet.

Methotrexate 1 g/10 ml injectable solution
This medicine contains 114,958 mg of sodium (main component of table salt) per vial. This corresponds to 5.747% of the maximum recommended daily sodium intake for an adult. Consult your doctor or pharmacist if you need 3 or more vials per day over a prolonged period, especially if you have been advised to follow a low-sodium diet.

Methotrexate 5 g/50 ml injectable solution
This medicine contains 574.793 mg of sodium (main component of table salt) per vial. This corresponds to 28.739% of the maximum recommended daily sodium intake for an adult. Consult your doctor or pharmacist if you need 1 or more vials per day over a prolonged period, especially if you have been advised to follow a low-sodium diet.

3. How to use Methotrexate

Use this medicine exactly as instructed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.
This medicine must be administered in a hospital or clinic setting under the supervision of experienced physicians.
Administration may be given by intramuscular (into a muscle), intravenous (into a vein), intratumoral (into the tumour), or intrathecal (into the spinal fluid) routes.
Your doctor will determine the dose and frequency of administration based on the type and severity of the disease or your individual condition.
If high doses are administered, you will also receive calcium folinate (leucovorin) to help reduce the unwanted effects of Methotrexate.

If you use more Methotrexate than you should
This medicine will be administered by appropriately trained healthcare personnel.
Administration of an excessive dose of this medicine may cause serious adverse effects. Overdose administered intrathecally (into the spinal fluid) may cause the following symptoms: headache (cephalalgia), nausea, vomiting, seizures, epileptic convulsions, inflammation of the brain (acute toxic encephalopathy), displacement of the cerebellum (cerebellar herniation), increased pressure in the head (intracranial pressure), death.

If you forget to administer Methotrexate
This medicine will be administered by appropriately trained healthcare personnel. If you think that one or more doses of this medicine have been missed, consult your doctor or pharmacist.

If you stop treatment with Methotrexate
Do not stop treatment with Methotrexate without first consulting your doctor. If you have any questions about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
Stop treatment with Methotrexate and contact your doctor immediately if you or your child experience any of the following side effects:

• widespread infection affecting the whole body (sepsis)
• reactivation of pre-existing hepatitis B infection
• worsening of pre-existing hepatitis C infection
• lymphoma (blood cancer)
• severe allergic reactions (anaphylactoid reactions)
• paralysis affecting one side of the body (hemiparesis), a group of muscles (paresis), or the lower part of the body (paraplegia)
• brain disorders (encephalopathy/leukoencephalopathy, arachnoiditis)
• temporary blindness or loss of vision, severe visual disturbances
• interstitial pneumonia (a severe form of pneumonia)
• stomach and intestinal ulcers and bleeding, intestinal perforation
• non-infectious peritonitis (inflammation of the membrane lining the abdominal organs)
• acute inflammation of the liver (acute hepatitis)
• severe skin reactions such as rash and ulceration of the skin, redness, blisters, pustules, necrosis or peeling of the skin (Stevens-Johnson syndrome, toxic epidermal necrolysis, skin ulceration)
• increased risk of bone fractures, death of bone tissue (osteonecrosis)
• fetal malformations or fetal death, miscarriage.

Contact your doctor if you or your child experience any of the following side effects:
Common (may affect up to 1 in 10 people):

• sensation of numbness and tingling, reduced sensitivity to stimuli (paresthesia)*.

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

• reduced activity of the bone marrow producing blood cells (bone marrow failure), reduced number of red blood cells (anemia) and platelets in the blood (thrombocytopenia)
• headache (cephalalgia), seizures
• accumulation of fluid in the space between the lungs and the chest wall (pleural effusion)
• inflammation of the pancreas (pancreatitis)
• decreased appetite
• vomiting, diarrhea
• inflammation of the mouth (stomatitis)
• changes in blood laboratory tests assessing liver function (elevated liver enzymes)
• patchy hair loss (alopecia)
• kidney failure, kidney damage (nephropathy).

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

• diabetes
• mood changes
• language disorder (aphasia)
• transient disturbances in intellectual function
• speech disorders (dysarthria)
• drowsiness
• blurred vision
• decreased blood pressure (hypotension)
• formation of blood clots in arteries and veins affecting various organs (e.g. brain, lungs, eyes, and lower limbs)
• progressive decline in lung function (pulmonary fibrosis)
• inflammation of the throat (pharyngitis)
• blood in the stool (melena), inflammation of the intestine (enteritis), inflammation of the gums (gingivitis)
• decline in liver function (chronic cirrhosis and fibrosis), liver damage (hepatotoxicity)
• skin rashes (erythema multiforme, erythematous rash), painful detachment of psoriatic plaques, increased sensitivity to light (photosensitivity), skin rash (urticaria), itching, acne, bruising (ecchymosis), changes in skin pigmentation
• muscle pain (myalgia) and joint pain (arthralgia)
• bone fragility (osteoporosis)
• difficulty urinating (dysuria)
• menstrual disorders
• nodule formation.

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

• disorders caused by rapid death of tumor cells
• anemia due to insufficient production of blood cells by the bone marrow (aplastic anemia)
• reduction in certain antibodies called "gamma-globulins"
• cranial nerve disorders
• eye inflammation
• lymphoproliferative disorders (excessive growth of white blood cells)
• accumulation of fluid or inflammation of the membrane surrounding the heart (pericardium)
• inflammation of blood vessels (vasculitis)
• vomiting with blood (hematemesis)
• reduced levels of albumin in the blood
• boils, dilation of small blood vessels in the skin (telangiectasia)
• presence of blood in the urine (hematuria), urinary tract infection (cystitis)
• changes in a laboratory test (azotemia)
• disturbances in egg (oogenesis) or sperm (spermatogenesis) formation, transient reduction in sperm concentration in semen (oligospermia), infertility
• impotence, loss of sexual desire (libido)
• vaginal discharge
• sudden death.

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

• infections caused by various microorganisms (e.g. bacteria, viruses, fungi) affecting different organs (e.g. lungs, liver)
• decreased number of a type of white blood cells in the blood called granulocytes (agranulocytosis) or of all blood cells (pancytopenia), decreased number of a type of white blood cells called neutrophils (neutropenia), lymph node damage (lymphadenopathy and lymphoproliferative disorders), increased number of a type of white blood cells (eosinophils) in the blood (eosinophilia), reduced red blood cells (megaloblastic anemia)
• increased pressure of the fluid surrounding the brain and spinal cord, brain damage, inflammation of the membranes surrounding the brain (meningitis)
• bone damage in the jaw/mandible (secondary to excessive blood cell growth)
• lack of response to stimuli (stupor), movement coordination disorders (ataxia), dementia, dizziness
• inflammation of lung alveoli (alveolitis) and their surrounding tissue (chronic interstitial pneumopathy), difficulty breathing (dyspnea), chest pain, lack of oxygen in the body (hypoxia), cough
• inflammation of the tongue
• nausea
• liver problems (liver failure)
• drug reaction with increased number of a type of white blood cells (eosinophilia), skin irritation (dermatitis), red spots on the skin (petechiae)
• presence of protein in the urine (proteinuria)
• problems with genital and urinary organs (urogenital dysfunction)
• fever, chills
• malaise, fatigue
• reaction at the injection site**
• tissue damage at the injection site (necrosis at the injection site)**
• redness and skin peeling.

*frequency not rare for low-dose methotrexate
**for parenteral administration only

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the national reporting system at: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Methotrexate

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and vial after "Expiry". The expiry date refers to the last day of that month.
Methotrexate 50 mg powder for injectable solution
Methotrexate 500 mg powder for injectable solution
Methotrexate 1 g powder for injectable solution
Do not store above 25°C. Keep in the original packaging to protect the medicine from light and moisture.
Use the product immediately after reconstitution. Discard any unused reconstituted solution.
Methotrexate 50 mg/2 ml solution for injection
Methotrexate 500 mg/20 ml solution for injection
Methotrexate 1 g/10 ml solution for injection
Methotrexate 5 g/50 ml solution for injection
Store between 15°C and 22°C. Keep in the original packaging to protect the medicine from light.
Use the medicine immediately after opening the vial. Discard any unused solution.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Methotrexate contains
The active substance is methotrexate (as methotrexate sodium salt).
Methotrexate 50 mg powder for injectable solution
One vial of powder contains 54.84 mg of methotrexate sodium salt equivalent to 50 mg of methotrexate.
The other components are: sodium chloride and sodium hydroxide.
Methotrexate 500 mg powder for injectable solution
One vial of powder contains 548.4 mg of methotrexate sodium salt equivalent to 500 mg of methotrexate.
The other component is: sodium hydroxide.
Methotrexate 1 g powder for injectable solution
One vial of powder contains 1.097 g of methotrexate sodium salt equivalent to 1 g of methotrexate.
The other component is: sodium hydroxide.
Methotrexate 50 mg/2 ml solution for injection
One vial of powder contains 54.84 mg of methotrexate sodium salt equivalent to 50 mg of methotrexate.
The other components are: sodium hydroxide, sodium chloride, and water for injections.
Methotrexate 500 mg/20 ml solution for injection
One vial of powder contains 548.4 mg of methotrexate sodium salt equivalent to 500 mg of methotrexate.
The other components are: sodium hydroxide, sodium chloride, and water for injections.
Methotrexate 1 g/10 ml solution for injection
One vial of powder contains 1.097 g of methotrexate sodium salt equivalent to 1 g of methotrexate.
The other components are: sodium hydroxide and water for injections.
Methotrexate 5 g/50 ml solution for injection
One vial of powder contains 5.484 g of methotrexate sodium salt equivalent to 5 g of methotrexate.
The other components are: sodium hydroxide and water for injections.

Description of the appearance of Methotrexate and contents of the pack
Methotrexate is available in glass vials with rubber stoppers and aluminium seals. Each pack contains 1 vial.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Pfizer Italia S.r.l.
Via Isonzo, 71
04100 Latina
Italy

Manufacturer
Methotrexate 50 mg powder for injectable solution
Methotrexate 500 mg powder for injectable solution
Methotrexate 1 g powder for injectable solution
Wyeth Lederle s.r.l.
Via F. Gorgone n.6
Catania
Italy

Methotrexate 50 mg/2 ml solution for injection
Methotrexate 500 mg/20 ml solution for injection
Methotrexate 1 g/10 ml solution for injection
Methotrexate 5 g/50 ml solution for injection
Haupt Pharma Wolfratshausen GmbH
Pfaffenrieder Strasse 5
82515 Wolfratshausen (Germany)

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The following information is intended exclusively for healthcare professionals

METHOTREXATE 50 mg powder for injectable solution
METHOTREXATE 500 mg powder for injectable solution
METHOTREXATE 1 g powder for injectable solution
METHOTREXATE 50 mg/2 ml injectable solution
METHOTREXATE 500 mg/20 ml injectable solution
METHOTREXATE 1 g/10 ml injectable solution
METHOTREXATE 5 g/50 ml injectable solution
Methotrexate

DOSAGE
GUIDELINES FOR HIGH-DOSE METHOTREXATE THERAPY ASSOCIATED WITH
LEUCOVORIN (FOLINIC ACID) RESCUE

1. Administration of Methotrexate must be delayed (until the parameters listed below return to normal ranges) if:

   • white blood cell count is less than 1,500 cells/microliter
   • neutrophil count is less than 200 cells/microliter
   • platelet count is less than 75,000/microliter
   • serum bilirubin level is greater than 1.2 mg/dL
   • SGPT level is greater than 450 U
   • mucositis is present (and until healing is clearly evident)
   • a persistent pleural effusion is present; such effusion must be aspirated prior to infusion

2. Adequate renal function must be documented:
   a) Serum creatinine must be within normal limits and creatinine clearance must be greater than 60 mL/min before starting therapy.
   b) Serum creatinine must be measured before each subsequent cycle of therapy. If serum creatinine increases by 50% or more compared to the previous value, creatinine clearance should be assessed and confirmed to be greater than 60 mL/min (even if serum creatinine remains within the normal range).

3. Patients must be well hydrated and treated with sodium bicarbonate to alkalinize the urine.
   a) Administer intravenously 1000 mL/m² of fluid over the 6 hours preceding the start of Methotrexate infusion. Continue hydration at a rate of 125 mL/m²/h (3 L/m²/day) during Methotrexate infusion and for two days following the infusion.
   b) Alkalinize the urine to maintain a pH above 7.0 during Methotrexate infusion and leucovorin therapy. This can be achieved by oral administration of sodium bicarbonate or by intravenous administration in a separate solution.

4. Measure serum creatinine and serum Methotrexate concentration 24 hours after the start of Methotrexate infusion and at least once daily until Methotrexate levels fall below 0.05 micromoles.

5. The following table provides general guidelines for leucovorin (folinic acid) dosing based on serum Methotrexate levels (see table below). Patients who exhibit delayed early elimination of Methotrexate are at increased risk of developing oliguric, irreversible renal failure. In addition to appropriate leucovorin therapy, these patients require continued hydration and urinary alkalinization, as well as close monitoring of fluid and electrolyte status, until serum Methotrexate levels fall below 0.05 micromoles and renal impairment has resolved. If necessary, intermittent hemodialysis using a high-flux dialyzer may be beneficial in these patients.

6. Some patients may exhibit abnormalities in Methotrexate elimination or in renal function after Methotrexate administration that are significant but less severe than those described in the table below. These abnormalities may or may not be associated with clinically significant toxicity. If clinically significant toxicity occurs, leucovorin rescue should be extended by an additional 24 hours (for a total of 14 doses over 84 hours) in subsequent treatment cycles. The possibility that the patient is taking other medications that interact with Methotrexate (e.g., drugs that may interfere with Methotrexate binding to serum albumin or its elimination) should always be considered when laboratory abnormalities or clinical toxicity are observed.

WARNING: DO NOT ADMINISTER LEUCOVORIN (FOLINIC ACID) BY INTRATHECAL ROUTE.
GUIDELINES FOR LEUCOVORIN (FOLINIC ACID) DOSING AS RESCUE THERAPY
FOLLOWING HIGH-DOSE METHOTREXATE ADMINISTRATION

Intrathecal administration
Adults
Dilute preservative-free methotrexate to a concentration of 1 mg/ml in an appropriate sterile, preservative-free vehicle, such as 0.9% Sodium Chloride injectable solution.
The following recommendations for intrathecal administration are provided and may be modified according to specific treatment protocols, taking into account individual patient needs.
Remove a volume of cerebrospinal fluid equivalent to the volume of methotrexate to be administered.
The maximum recommended single dose is 15 mg.
Administer 10 to 15 mg intrathecally twice weekly until the cerebrospinal fluid is clear, followed by weekly dosing for 2 to 3 weeks, then monthly dosing.
Alternatively, administer a dose of 12 mg/m² (but not exceeding the absolute maximum dose of 15 mg) at intervals of 2 to 7 days until the cerebrospinal fluid cell count returns to normal. One or more additional doses may be administered weekly for two weeks, followed by monthly administration.
The standard dose of methotrexate is 12 mg.

Pediatrics
The following dosing regimen is based on patient age rather than body surface area, since, unlike body surface area, cerebrospinal fluid volume in pediatric patients approaches that of adults.
A fixed dose should be administered to the child as follows:

• Under one year of age: 6 mg
• One year of age: 8 mg
• Two years of age: 10 mg
• Three years of age or older: 12 mg

INSTRUCTIONS FOR USE

Use each vial only once.
If a precipitate forms, the solution must be discarded.
Do not administer Methotrexate together with other drugs in the same infusion.
Persons who handle antineoplastic agents or work in areas where these drugs are used may be exposed to these agents either through airborne exposure or direct contact with contaminated objects. Potential health risks can be reduced by adhering to institutional procedures, published guidelines, and local regulations regarding the preparation, administration, transport, and disposal of hazardous drugs. There is no general agreement that all recommended procedures in the guidelines are necessary and appropriate.

Methotrexate powder for injectable solution:
Methotrexate 500 mg and Methotrexate 1 g powder for injectable solution must be reconstituted immediately before use with 10 ml and 20 ml, respectively, of Water for Injections or Sodium Chloride Solution or 5% Dextrose Solution, all preservative-free. To obtain a solution with a concentration of 50 mg/ml, reconstitute the vial containing 1 g of methotrexate with 19.4 ml of diluent.
Methotrexate 50 mg powder for injectable solution must be reconstituted immediately before use with 20 ml of Water for Injections.

When high doses of Methotrexate are administered by intravenous infusion, dilute the total dose in 5% Dextrose Solution.
For intrathecal administration, reconstitute to a concentration of 1 mg/ml using an appropriate sterile, preservative-free solution, such as for example Sodium Chloride Solution.

Methotrexate injectable solution
If necessary, the solution may be further diluted immediately before use with Sodium Chloride Solution or 5% Dextrose Solution, both preservative-free.

INCOMPATIBILITIES
Methotrexate is compatible with: Dextrose in Lactated Ringer's, Dextrose in Ringer's Solution, Dextrose in Sodium Chloride, Dextrose in Water, Lactated Ringer's, Sodium Chloride.
Methotrexate must not be administered with other drugs in the same infusion.