Consumer medicine information

Methotrexate Ebewe

Methotrexate

BRAND INFORMATION

Brand name

Methotrexate Ebewe

Active ingredient

Methotrexate

Schedule

What is in this leaflet

This leaflet answers some common questions about Methotrexate Ebewe. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Methotrexate Ebewe against the benefits this medicine is expected to have for you.

This medicine is likely to be used while you are at the clinic or in hospital. If possible, please read this leaflet carefully before this medicine is given to you. In some cases this leaflet may be given to you after the medicine has been used.

If you have any concerns about taking this medicine, ask your doctor or pharmacist. For any further information please see your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What Methotrexate Ebewe is used for

Methotrexate Ebewe belongs to a group of anticancer drugs known as antineoplastics. Methotrexate Ebewe works by preventing the growth of certain cells. It is used for different types of cancer and also severe psoriasis (a skin condition).

Methotrexate Ebewe may be used for the treatment of other conditions that are not mentioned above. Your doctor will be able to tell you about the specific condition for which you have been prescribed Methotrexate Ebewe.

This medicine is available only with a doctor's prescription.

Methotrexate is not recommended for use in children, as there is not enough information on its effects in children.

Before you are given Methotrexate Ebewe

When you must not be given it

Do not use Methotrexate Ebewe if:

you have an allergy to Methotrexate Ebewe or any of the ingredients listed at the end of this leaflet
you have kidney disease or poor kidney function
you have liver disease or poor liver function
you are pregnant or planning to get pregnant
you are breastfeeding
you have a problem with your immune system such as severe or repeated infections
you have a problem with your blood such as anaemia
you are receiving radiotherapy e.g. X-rays, ultra violet radiotherapy
you have a stomach ulcer or ulcerative colitis (bleeding from your bowel)
bone marrow disease
you are an alcoholic
you have an infection

If you are not sure whether any of these apply to you, check with your doctor.

Do not use this medicine if you are taking acitretin or etretinate, a medicine used to treat psoriasis and other skin conditions.

Do not use live vaccine while you are using Methotrexate Ebewe.

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you are given it

The medicine may cause birth defects if either you or your partner is taking it. Both you and your partner must use a reliable method of contraception (birth control or condom) using treatment with Methotrexate Ebewe and for at least 6 months after you stop treatment. Your doctor will discuss with you what forms of contraception are suitable and when it is safe to stop using contraception if you wish to do so.

Tell your doctor if:

you have any allergies to:

any other medicine
any other substances, such as foods, preservatives or dyes

if you are pregnant or intend to become pregnant.

Methotrexate Ebewe may affect your developing baby if you take/use it during pregnancy. If it is necessary for you to be given it, your doctor or pharmacist will discuss the risks and benefits of taking/using it during pregnancy.

you are breastfeeding or plan to breastfeed

Methotrexate Ebewe passes into breast milk and should not be used when breastfeeding.

you have or have had any medical conditions, especially the following:

any sort of infection or immune system disorder e.g. sinusitis, tooth abscess etc
stomach ulcer or ulcerative colitis (bleeding from your bowel)
fluid or swelling in your abdomen or stomach
fever, chills, sore throat or mouth ulcers
bleeding or bruising more than usual
tiredness, headaches, shortness of breath, dizziness, looking pale
diabetes
cancer
folate deficiency

If you have not told your doctor or pharmacist about any of the above, tell them before you are given Methotrexate Ebewe.

Your carer will also need to take some precautions, such as wearing of gloves, when handling the injection.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

If your doctor tells you to take folic acid, do not take it on the same day as methotrexate.

Some medicines and Methotrexate Ebewe may interfere with each other. These include:

other anticancer drugs such as cisplatin, cytarabine, mercaptopurine or asparaginase
antibiotics or antimalarial drugs including tetracyclines, penicillins, sulphonamides, trimethoprim and chloramphenicol, pyrimethamine
aspirin and other pain killers
medicines to relieve swelling or inflammation including medicines for arthritis
non-steroidal anti-inflammatory drugs, used to help with pain relief, such as azapropazone, diclofenac, indomethacin and ketoprofen
triamterene, a medicine to remove fluid or water from the body
medicines for epilepsy such as phenytoin
corticosteroids such as hydrocortisone and prednisolone
medicines for diabetes such as sulphonylureas
medicines that reduce cholesterol such as cholestyramine
medicines for gout such as probenecid and allopurinol
vitamin preparations that contain folic acid
medicines for psoriasis such as etretinate
medicines for heart problems such as amiodarone
medicines used to treat asthma and related compounds such as theophylline
azathioprine, a medicine used to prevent transplant organ rejection
retinoids (acitretin or etretinate) medicines used to treat skin conditions
proton pump inhibitors, such as omeprazole, esomeprazole or pantoprazole

Methotrexate Ebewe can also be affected by the following:

blood transfusions
nitrous oxide anaesthetics
vaccinations
alcohol
radiation e.g. X-rays, radiotherapy

Your doctor will advise you about continuing to take other medicines while you are receiving methotrexate.

You may need different amounts of your medicines, or you may need to take/use different medicines. Your doctor or pharmacist will advise you.

You should not receive certain vaccinations while being treated with methotrexate.

How Methotrexate Ebewe is given

How much is given

Your doctor will decide what dose of Methotrexate Ebewe you will receive. This depends on your condition and other factors, such as your weight, and other medicines you are being given. This medicine may be given alone or in combination with other drugs. It may be given as a short course or on an ongoing basis. Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any unwanted effects have been controlled. For cancer treatment, several courses of Methotrexate Ebewe therapy may be needed depending on your response to treatment. For the treatment of psoriasis, Methotrexate Ebewe therapy is usually required on an ongoing basis.

Ask your doctor if you want to know more about the dose of Methotrexate Ebewe you receive.

How it is given

Methotrexate Ebewe may be given as an injection into a vein. Methotrexate Ebewe must only be given by a doctor or nurse.

If you are given too much (overdose)

This rarely happens as Methotrexate Ebewe is administered under the care of a highly trained doctor.

However, if you are given too much methotrexate, you may experience some of the effects listed under "Side effects" below.

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26 in Australia or call 0800 764 766 in New Zealand) for advice, or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have given you too much Methotrexate. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Your doctor has information on how to recognise and treat an overdose.

Ask your doctor if you have any concerns.

While you are being treated with Methotrexate Ebewe

Things you must do

Tell your other doctors, dentists, and pharmacists if you are taking any other medicines.
Drink plenty of water on the day you take the medicine.
The recommended daily intake is 8 glasses per day. Inadequate fluid intake can increase the side effects of the medicine. Keep all of your doctor’s appointments so that your progress can be checked.
You will need to have regular blood and urine tests. Regular blood tests will show any abnormal effects of methotrexate on the blood cells and the liver. As you may not get symptoms of these problems you must have regular blood checks. Your doctor may also want you to have some other tests.
Both you and your partner must use a reliable method of contraception (birth control) during and for at least 6 months after treatment with Methotrexate Ebewe. Your doctor will discuss with you what forms of contraception are suitable and when it is safe to stop using contraception if you wish to do so.
This is because methotrexate can cause damage to the baby during pregnancy and can also cause genetic problems if the baby is conceived while you are taking methotrexate.

If you are going to have surgery, tell the surgeon, anaesthetist or dentist that you are taking this medicine.

It may affect other medicines used during surgery.

Try to stay out of the sun and do not use sunlamps.
Methotrexate Ebewe can increase your sensitivity to sunlight and cause severe reactions and increase risk of skin cancer (non-melanoma and melanoma). Some signs are:
- redness
- itching
- swelling
- blistering
- rash
If you need to be in the sun, use a 30+ sunscreen and wear a hat and shirt to protect your skin from the sun.
Do not drink any alcohol while you are being treated with Methotrexate Ebewe, as this may cause permanent liver damage.
Do not drive or operate machinery until you know how Methotrexate Ebewe affects you.
Methotrexate Ebewe may cause dizziness or tiredness in some people and therefore may affect alertness.
If you can, avoid people with infections.
Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain or find it painful or difficult to urinate.
Be careful when using a toothbrush, toothpick or dental floss.
Be careful not to cut yourself
Wear disposable gloves when cleaning, especially when cleaning up body fluid or waste
Dispose of gloves, rags or other items safely in a sealed plastic bag.
Carers and other people who handle the injection should wear disposable gloves to avoid direct contact with the injection fluid.
Pregnant women should not handle the medicine at all.
Be careful not to drip the solution on any surfaces.
If you do, wipe up the area with paper towels and throw them into the ‘Sharps Bin’. Clean the area with lots of soap and water.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being given Methotrexate Ebewe. Like other medicines, methotrexate can cause some side effects. If they occur, most are likely to be minor or temporary. However, some may be serious and need medical attention.

Ask your doctor or nurse to answer any questions that you may have. Do not be alarmed by this list of possible side effects. You may not experience any of them.

If any of the following happen, tell your doctor or nurse immediately or go to Accident and Emergency at your nearest hospital:

severe abdominal pain, upset stomach, or diarrhoea
nausea or vomiting, especially vomiting blood, loss of appetite
mild dizziness
mild chills
mild headache
sore eyes
an increased tendency to bleed, unusual bruising or get infections
swelling of the face, lips or tongue or other parts of the body e.g. hands ankles or feet
rash, redness, hives, itching, pinpoint red spots or painful blistering resulting in peeling of layers of the skin
lighter patches on the skin, yellowing of the skin/eyes (jaundice)
severe blisters and bleeding in the lips, eyes, mouth, nose and genitals (Stevens-Johnson syndrome)
high fever, chills, headache, confusion and rapid breathing (serious blood infection)

These are very serious side effects. You may need urgent medical attention or hospitalisation.

All of these side effects are very rare.

Tell your doctor or nurse immediately if you notice any of the following:

infection of hair roots or hair loss, especially of the scalp
frequent or painful urination (cystitis/dysuria), or blood in the urine, or bowel motions
changes in the menstrual cycle (periods)
bleeding gums, sore mouth, difficulty swallowing, cold sores, mouth ulcers, swollen glands (lymph nodes)
coughing, wheezing, difficulty breathing, chest pain
black tarry stools or blood in the stools
fits, seizures or convulsions

These may be serious side effects. You may need urgent medical attention.

Tell your doctor or nurse if you notice any of the following and they worry you:

blurred vision, short term blindness
ringing in the ears
conjunctivitis (itchy eyes and crusty eyelids)
fever and chills, sore throat, sweats or feel generally unwell
tiredness, headaches, shortness of breath, dizziness, looking pale
sensitivity to the sun
acne or boils or skin ulcers
lack of appetite or weight loss
difficulty speaking, writing etc
drowsiness
weakness, numbness or paralysis, muscle cramps, spasms
feeling thirsty
irritability, depression, confusion or mood changes
changes in the toenails or fingernails or skin around the nails
impotence or loss of interest in sex
painful muscles and joints
back pain
stiff neck

These are the more common side effects of methotrexate.

Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your doctor. Other side effects may be only seen by blood urine or other tests. Your doctor will carry out any necessary tests. Some side effects of methotrexate may occur after you stop taking it.

Storage

Methotrexate Ebewe will be stored in the pharmacy, doctor’s surgery or on the ward. The injection is kept in a cool dry place, protected from light, where the temperature stays below 25°C. Do not freeze.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Product Description

What it looks like

Methotrexate Ebewe is a clear yellow liquid in glass vials.

Ingredients

Methotrexate Ebewe contains Methotrexate as the active ingredient. It also contains:

water for injections
sodium hydroxide

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Methotrexate Ebewe comes in the following strengths and pack sizes:

500 mg in 5 mL vial - AUST R 98546

1000 mg in 10 mL vial - AUST R 98547

5000 mg in 50 mL vial - AUST R 120618

Manufacturer

EBEWE Pharma Ges.m.b.H. Nfg. KG
A-4866 Unterach
Austria

Sponsor

Methotrexate Ebewe is distributed in Australia by:

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park
Australia
Tel: 1800 634 500

Methotrexate Ebewe is distributed in New Zealand by:

Novartis New Zealand Ltd
PO Box 99102
Newmarket
Auckland 1149
Tel: 0800 354 335

This leaflet was updated in November 2021.

Published by MIMS December 2021

BRAND INFORMATION

Brand name

Methotrexate Ebewe

Active ingredient

Methotrexate

Schedule

1 Name of Medicine

Methotrexate.

2 Qualitative and Quantitative Composition

Methotrexate Ebewe 500 mg/5 mL concentrated injection contains 500 mg methotrexate.
Methotrexate Ebewe 1000 mg/10 mL concentrated injection contains 1000 mg methotrexate.
Methotrexate Ebewe 5000 mg/50 mL concentrated injection contains 5000 mg methotrexate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Methotrexate Ebewe concentrated injection is a clear yellow solution in a glass vial.

4 Clinical Particulars

4.1 Therapeutic Indications

Antineoplastic chemotherapy.

Methotrexate has a broad spectrum of antineoplastic activity. It is indicated for the treatment of breast cancer and the palliation of acute and subacute lymphocytic leukaemia (greatest effect has been observed in palliation of acute lymphoblastic (stem cell) leukaemias). Methotrexate is now most commonly used for the maintenance of medicine induced remissions.

High dose therapy.

In high dose schedules, methotrexate may be effective, alone or in combination therapy, in the treatment of epidermoid cancers of the head and neck, osteogenic sarcoma and bronchogenic carcinoma. Calcium folinate (leucovorin calcium) must be used in conjunction with high dose methotrexate therapy.

Psoriasis chemotherapy.

(See Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use). Methotrexate may be of value in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of treatment. However, due to the high risk associated with its use, methotrexate should be used after the diagnosis has been definitely established, as by biopsy and/or after dermatological consultation.

4.2 Dose and Method of Administration

Dosage.

Because of its potential to cause severe toxicity, methotrexate therapy requires close supervision with particular caution to distinguish between daily and weekly dosage regimens. Weekly dosage prescriptions should specify a particular day of the week.
Antineoplastic chemotherapy.

Breast carcinoma.

Prolonged cyclic combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil has given good results when used as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. Methotrexate dosage was 40 mg/m² intravenously on only the first and eighth days.

Maintenance therapy for leukaemia.

Acute lymphatic (lymphoblastic) leukaemia in children and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common. In chronic lymphatic leukaemia, the prognosis for adequate response is less encouraging. Methotrexate alone, or in combination with other agents, appears to be the medicine of choice for securing maintenance of medicine induced remissions. Methotrexate has been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen. Various experts have recently introduced a variety of dosage schedules for both induction and maintenance of remission with various combinations of alkylating and antifolate agents. Multiple medicine therapy with several agents, including methotrexate given concomitantly, is gaining increasing support in both the acute and chronic forms of leukaemia.
The prescriber should consult the appropriate scientific literature.
Acute granulocytic leukaemia is rare in children but common in adults. This form of leukaemia responds poorly to chemotherapy, and remissions are short with relapses common and resistance to therapy develops rapidly.
High dose therapy (see Section 4.4 Special Warnings and Precautions for Use). Dosage regimens have varied considerably in different studies; the nature and severity of the disease and the previous experience of the investigator are some of the factors influencing the choice of dosage and the duration of therapy. It must be emphasised that high dosages should be used only by qualified specialists and in hospitals where the necessary facilities are available.
Psoriasis chemotherapy. The patient should be fully informed of the risks involved and should be under constant supervision of the physician.
Assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests (such as full blood count, urinalysis, serum creatinine, liver function studies and liver biopsy if indicated) before beginning methotrexate, periodically during methotrexate therapy and before reinstituting methotrexate therapy after a rest period. Appropriate steps should be taken to avoid conception during and for at least 6 months following methotrexate therapy.
The commonly used injectable dosage schedule is by weekly parenteral intermittent large doses.
All schedule should be continually tailored to the individual patient. Dose schedules cited below pertain to an average 70 kg adult. An initial test dose one week prior to initiation of therapy is recommended to detect any idiosyncrasy. A suggested dose range is 5 to 10 mg parenterally.

Recommended starting dose.

Weekly single intravenous dose schedules: 10 to 25 mg per week until adequate response is achieved. With this dosage schedule, 50 mg per week should ordinarily not be exceeded.
Dosage may be gradually adjusted to achieve optimal clinical response, but not to exceed the maximum stated for each schedule. Once optimal clinical response has been achieved the dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.

Dosage adjustment.

Renal impairment.

Methotrexate is excreted primarily by the kidneys. In patients with renal impairment the dose may need to be adjusted to prevent accumulation of drug (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Method of administration.

Methotrexate Ebewe is suitable only for intravenous use. It should be diluted prior to administration. It is not suitable for intrathecal administration.
For conversion of mg/kg bodyweight to mg/m² of body surface area or the reverse, a ratio of 1:30 is given as a guideline. The conversion factor varies between 1:20 and 1:40 depending on age and body build.

Instructions for handling.

As with all antineoplastic agents, trained personnel should prepare Methotrexate Ebewe. This should be performed in a designated area (preferably a cytotoxic laminar flow cabinet). Protective gown, mask, gloves and appropriate eye protection should be worn when handling methotrexate. Where solution accidentally contacts skin or mucosa, the affected area should be immediately washed thoroughly with soap and water. It is recommended that pregnant personnel not handle cytotoxic agents such as methotrexate.
Luer-Lok fitting syringes are recommended. Large bore needles are recommended to minimise pressure and possible formation of aerosols. Aerosols may also be reduced by using a venting needle during preparation.
Items used to prepare Methotrexate Ebewe, or articles associated with body waste, should be disposed of by placing in a double sealed polythene bag and incinerating at 1100°C.

Spills and disposal.

If spills occur, restrict access to the affected area. Wear two pairs of gloves (latex rubber), a respirator mask, a protective gown and safety glasses. Limit the spread of the spill by covering with absorbent material such as absorbent towel or adsorbent granules. Collect up the towel of absorbent/adsorbent material and other debris from spill and place in a leak proof plastic container and label accordingly. Cytotoxic waste should be regarded as hazardous or toxic and should be clearly labelled 'Cytotoxic waste for incineration at 1100°C'. Waste material should be incinerated at 1100°C for at least 1 second. Cleanse the remaining spill area with copious amounts of water. Single use only. Discard unused portion.

4.3 Contraindications

Methotrexate should not be given to:
Patients with a known hypersensitivity to methotrexate or to any of the excipients.
Pregnant women (see Section 4.6 Fertility, Pregnancy and Lactation).
Breast-feeding women (see Section 4.6 Fertility, Pregnancy and Lactation).
Patients with severe hepatic impairment.
Patients with severe renal impairment.
Patients with alcoholism or alcoholic liver disease.
Patients who have overt or laboratory evidence of immunodeficiency syndromes.
Patients with pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or anaemia.
Patients with severe acute or chronic infections.
Psoriasis patients with peptic ulcer disease or ulcerative colitis.
During methotrexate therapy concurrent vaccination with live vaccines must not be carried out.
An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Therefore, the combination of methotrexate with retinoids such as acitretin is also contraindicated.

4.4 Special Warnings and Precautions for Use

Methotrexate Ebewe (methotrexate 100 mg/mL) is recommended for intravenous administration only.

Use with caution in the following circumstances.

Methotrexate must only be used by physicians experienced in antimetabolite chemotherapy or, in the case of nononcological conditions, by a specialist physician.
Patients should be fully informed of the risk of fatal or severe toxic reactions involved with the administration of methotrexate and should be under constant supervision of the physician. Close monitoring for toxicity throughout treatment is mandatory, particularly in high dose therapy, or where drug elimination could be impaired (renal impairment, pleural effusion, ascites).
Methotrexate exits slowly from the third space compartments (e.g. pleural effusions or ascites) which may lead to prolonged terminal phase half-life and unexpected toxicity. In patients with significant third space accumulation, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels. Such patients require especially careful monitoring for toxicity, and require dose reduction, or in some cases, discontinuation of methotrexate administration (see Pulmonary).
Deaths have been reported with use of methotrexate in the treatment of malignancy and psoriasis.
In the treatment of psoriasis, methotrexate should be restricted to severe, recalcitrant, disabling disease, which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after appropriate consultation.
Methotrexate should be used with extreme caution in the presence of debility and in extreme youth or old age (see Paediatric use and Use in the elderly).
Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. These lymphomas may regress following withdrawal of methotrexate without requiring treatment. Failure of the lymphoma to show signs of spontaneous regression requires initiation of cytotoxic therapy.
Methotrexate, like other cytotoxic drugs may trigger tumour lysis syndrome in patients with rapidly growing tumours.
Methotrexate has the potential for serious toxicity. Toxic effects may be related in frequency and severity to dose or frequency of administration, but have been seen at all doses. Because the toxic effects can occur at any time during therapy, it is necessary to follow the patients on methotrexate therapy very closely.
When considering the use of methotrexate for chemotherapy, clinicians must evaluate the need and potential value of the drug against the risks, adverse effects or toxic effects. Most adverse effects are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If methotrexate therapy is reinstituted, it should be carried out with utmost caution, with adequate consideration of further need for the drug, and with increased alertness as to possible recurrence of toxicity.
Both the physician and the pharmacist should emphasise to the patient the importance of the weekly dosage regimens; mistaken daily use may cause serious and sometimes life-threatening or fatal toxicity (see Boxed Warnings).
Concomitant use of hepatotoxic or haematotoxic DMARDs (disease-modifying antirheumatic drugs, e.g. leflunomide) is not advisable.

Folinic acid deficiency.

Folate deficiency states may increase methotrexate toxicity.
Adequate folinic acid (calcium folinate) protection is indicated in high-dose methotrexate therapy. The administration of calcium folinate, hydration, and urine alkalisation should be carried out with constant monitoring of the toxic effects and the elimination of methotrexate. Appropriate calcium folinate administration can be discontinued when the serum methotrexate concentration level is below 10^-8 M (see Section 4.9 Overdose).
If acute methotrexate toxicity occurs, patients may require folinic acid. In patients with psoriasis, folic acid or folinic acid may reduce methotrexate toxicities such as gastrointestinal symptoms, stomatitis, alopecia, and elevated liver enzymes.
Before taking a folate supplement, it is advisable to check B12 levels, since folate administration can mask symptoms of B12 deficiency.

High dose therapy.

Methotrexate has been used in very high dosage followed by folinic acid rescue in the experimental treatment of certain neoplastic disease. High dosing regimens for other neoplastic diseases are investigational, hazardous and a therapeutic advantage has not been established. These procedures should not be attempted outside of facilities where the necessary expertise and resources have been assembled. The recent published literature should be consulted. Large doses should not be used in patients with impaired renal function or a third space reservoir such as ascites or large pleural effusion, because rapid drug excretion is important in limiting toxicity. Careful monitoring of renal function and methotrexate serum levels is required in order to reveal impending toxicity. Administration of calcium folinate is mandatory in high dose methotrexate therapy. The administration of calcium folinate, hydration and urine alkalinisation should be carried out with constant monitoring of the toxic effects and the elimination of methotrexate.
The use of methotrexate high-dose regimens (≥ 500 mg/m²) recommended for osteosarcoma requires meticulous care. High doses of methotrexate used in the treatment of osteosarcoma may cause renal damage leading to acute renal failure. Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, using alkalinisation and measurement of serum methotrexate and creatinine levels are essential for safe administration.
Systemic high doses of methotrexate may cause significant CNS toxicity. Patients should be closely monitored for neurologic symptoms and if these occur treatment should be discontinued and appropriate therapy instituted (see Section 4.9 Overdose).

Organ system toxicity.

Gastrointestinal.

Methotrexate should be used with extreme caution in the presence of peptic ulcer and ulcerative colitis. Methotrexate is contraindicated in psoriasis patients with peptic ulcer disease or ulcerative colitis (see Section 4.3 Contraindications).
Gastrointestinal disorders frequently require dosage adjustment. Vomiting, diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy; otherwise haemorrhagic enteritis and death from intestinal perforation may occur. Supportive therapy (including preventing dehydration) should be instituted until recovery occurs.
In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon.

Haematologic.

Methotrexate may produce marked depression of bone marrow, and cause anaemia, aplastic anaemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia and bleeding. Clinical sequelae such as fever, infections, haemorrhage from various sites and septicaemia may be expected.
Methotrexate should not be used in patients with pre-existing haematopoietic impairment (see Section 4.3 Contraindications).
Pre-treatment and periodic haematologic studies are essential to the use of methotrexate in chemotherapy because of the common effects of haematopoietic suppression. These effects may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates that methotrexate should be immediately discontinued and appropriate therapy instituted.
If profound leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow depression, blood or platelet transfusions may be necessary.
In the treatment of neoplastic diseases, methotrexate should be continued only if the potential benefit outweighs the risk of severe myelosuppression. In psoriasis, methotrexate should be stopped immediately if there is a significant drop in blood cell counts.
Folate supplementation may permit continuation of methotrexate therapy with resolution of anaemia.
Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Antibiotics, Oral antibiotics).
Megaloblastic anaemia has also been reported, mainly in elderly patients receiving long-term methotrexate therapy.

Musculoskeletal.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Infection or immunologic states.

Any infections should be attended to before initiation of methotrexate therapy. Methotrexate should be used with extreme caution in the presence of active infections, and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Methotrexate therapy has immunosuppressive activity, which can potentially lead to serious or even fatal infections. This factor must be taken into consideration in evaluating the use of the drug where immune responses in a patient may be important or essential.
Pneumonia (in some cases leading to respiratory failure) may occur. Potentially fatal opportunistic infections, especially Pneumocystis jirovecii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis jirovecii pneumonia should be considered.
In addition, pulmonary alveolar haemorrhage has been reported with methotrexate used in rheumatologic and related indications. This even may also be associated with vasculitis and other comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage is suspected to confirm the diagnosis.
Special attention should be paid in cases of inactive chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) because of their potential for re-activation.
Patients receiving immunosuppressive therapy, including methotrexate, are at an increased risk of developing skin cancer (melanoma and non-melanoma). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Periodic skin examination is recommended for all patients who are at increased risk for skin cancer and exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Immunisation.

Methotrexate has some immunosuppressive activity and immunisation may be ineffective when given during methotrexate therapy. Immunisation with live virus vaccines is contraindicated during therapy (see Section 4.3 Contraindications). There have been reports of disseminated vaccinia infections after smallpox immunisation in patients receiving methotrexate therapy.

Neurologic.

There have been reports of leukoencephalopathy following intravenous administration of methotrexate in high doses to patients who have had craniospinal irradiation (see Paediatric use). Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies.
Chronic leukoencephalopathy has also been reported in patients who received repeated doses of high-dose methotrexate with folinic acid rescue even without cranial irradiation. There are also reports of leukoencephalopathy in patients who received oral methotrexate.
Discontinuation of methotrexate does not always result in complete recovery.
A transient acute neurologic syndrome has been observed in patients treated with high dosing regimens. Manifestations may include behavioural abnormalities, focal sensorimotor signs, including transient blindness and abnormal reflexes. The exact cause is unknown.
Patients with leukaemia are subject to leukaemic invasion of the central nervous system. This may manifest characteristic signs or symptoms or may remain silent and be diagnosed only by examination of the cerebrospinal fluid, which contains leukaemic cells in such cases. Therefore, the CSF should be examined in all leukaemic patients. Since passage of methotrexate from blood serum to the cerebrospinal fluid is minimal, for adequate therapy methotrexate is administered intrathecally. Methotrexate Ebewe is not suitable for intrathecal administration. If intrathecal methotrexate therapy is indicated, a suitable alternative formulation should be used.
After high dose use of methotrexate, the central nervous system toxicity, which may occur, can be classified as follows:
1. acute chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity and fever;
2. sub-acute myelopathy, usually transient, characterised by e.g. paraparesis/paraplegia and increased CSF pressure associated with involvement with one or more spinal roots;
3. a delayed syndrome occurring months to years after treatment characterised by chronic leucoencephalopathy and manifested by confusion, irritability, somnolence, ataxia, dementia, occasionally major convulsions, and coma. This central nervous system toxicity can be progressive and even fatal. The effects are dose related and occur particularly when intrathecal methotrexate is given at doses greater than 50 mg in combination with cranial irradiation and systemic methotrexate therapy.
Intravenous administration of methotrexate may also result in acute encephalitis and acute encephalopathy with fatal outcome.

Pulmonary.

Acute or chronic interstitial pneumonitis and pleural effusion, often associated with blood eosinophilia, may occur and deaths have been reported.
Pulmonary symptoms (especially a dry non-productive cough) or a non-specific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Methotrexate has been associated with pulmonary toxicity, which is potentially fatal. Patient should be closely monitored for pulmonary symptoms. The medicine should be discontinued and careful clinical evaluation should be performed in patients developing pulmonary manifestations (especially a dry, non-productive cough). Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, chest pain, dyspnoea, hypoxaemia and an infiltrate on chest X-ray. Pulmonary lesions can occur at all dosages. Infection (including pneumonia) needs to be excluded in patients presenting with symptoms of pulmonary toxicity.
If methotrexate-induced lung disease is suspected, treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.
Patients should be closely monitored for pulmonary signs and symptoms at each follow-up visit.
Methotrexate-induced pulmonary toxicity may occur at any time during therapy and may not be fully reversible.

Skin.

Severe, occasionally fatal, dermatological reactions, including toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, exfoliative dermatitis, skin ulceration/necrosis and erythema multiforme, have been reported in children and adults within days of methotrexate administration. Reactions were noted after single or multiple doses of methotrexate in patients with neoplastic and non-neoplastic diseases.
Burning and erythema may appear in psoriatic areas for 1 to 2 days following each dose. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration has been reported in psoriatic patients and a few cases of anaphylactoid reactions have been reported. Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.

Laboratory monitoring.

In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving methotrexate therapy: a complete blood count (with differential and platelet counts); haematocrit; urinalysis; renal function tests; hepatitis B or C infection testing; liver function tests and a chest X-ray. The tests should be performed prior to, at appropriate periods during therapy and after termination of therapy. During initial or change in dosing or during periods of increased risk of elevated methotrexate blood levels (e.g. dehydration), more frequent monitoring may also be indicated.
During therapy for psoriasis, monitoring of the following parameters is recommended: haematology at least monthly, and hepatic enzyme levels and renal function every 1 to 2 months. More frequent monitoring is usually indicated during antineoplastic therapy. It may be important to perform liver biopsy or bone marrow aspiration studies where high dose or long-term therapy is being followed.

Pulmonary function tests.

Pulmonary function tests may be useful if lung disease (e.g. interstitial pneumonitis) is suspected, especially if baseline measurements are available (see Pulmonary).

Methotrexate level.

Monitoring methotrexate serum levels, adjusting dose and implementing rescue measures as appropriate can significantly reduce toxicity and mortality.
Patients with pleural effusion, ascites, gastrointestinal tract obstruction, previous cisplatin therapy, dehydration, aciduria or impaired renal function are predisposed to developing elevated or prolonged methotrexate levels. Therefore, routine monitoring of methotrexate levels should be carried out in these patients.
Delayed methotrexate clearance can also occur in the absence of these conditions.
It is important that the patients with raised methotrexate levels are identified within 42 hours and that folinic acid rescue therapy is given to avoid irreversible methotrexate toxicity.
Monitoring should include determination of a methotrexate level at 24, 48, or 72 hours, and assessment of the rate of decline in methotrexate concentrations (to determine how long to continue folinic acid rescue).

Psoriasis.

Liver damage and function tests, including serum albumin and prothrombin time, should be performed several times prior to dosing. Liver function tests are often normal in developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. It is recommended to obtain a liver biopsy at the following points: 1) before start of therapy or shortly after initiation of therapy (2 to 4 months); 2) after a total cumulative dose of 1.5 grams; and 3) after each additional 1.0 to 1.5 grams.
In case of moderate fibrosis or any cirrhosis, discontinue the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder histologic findings such as fatty change and low-grade portal inflammation are relatively common before the start of therapy. Although these mild changes are normally not a reason to avoid or discontinue methotrexate therapy, the drug should be used with caution.

Information for patients.

Patients should be informed of the risks in the use of methotrexate (including the early signs and symptoms of toxicity), the need to see their physician promptly if they occur, and of the need for close follow-up, including periodic laboratory tests to monitor toxicity.
Patients should be advised to report all symptoms or signs suggestive of infection.
Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop a persistent cough or dyspnoea.
Patients should be informed of the potential benefit and risk in the use of methotrexate. The risk of effects on reproduction should be discussed with both male and female patients taking methotrexate.
Patients receiving methotrexate should avoid excessive unprotected exposure to sun or sunlamps because of possible photosensitivity reactions and increased risk of skin cancer (non-melanoma and melanoma).
Patients should be advised that adverse reactions to methotrexate, such as dizziness and fatigue, may affect their ability to drive or operate machinery.

Use in hepatic impairment.

Temporary increases in transaminases to twice or three times of the upper limit of normal have been reported. With interruption of methotrexate therapy, abnormalities of liver function tests or liver biopsy should return to normal within two weeks after which treatment may be recommenced at the discretion of the physician.
In the case of unresolving elevation of liver enzymes, a reduction of the dose or discontinuation of therapy should be considered. Closer monitoring of liver enzymes is necessary in patients taking other hepatotoxic or haematotoxic medicinal products (e.g. leflunomide).
Check liver function more frequently during initiation of methotrexate therapy, any time the dose is increased, and any time there is a risk of increased methotrexate exposure (e.g. dehydration, impaired renal function, additional or elevated dose of medicines administered concomitantly, such as NSAIDs).
Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. The need for liver biopsy should be evaluated case by case and national recommendations should be followed. Periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment.
Methotrexate may cause acute and chronic hepatotoxicity, particularly at high dosage or with prolonged therapy, including liver atrophy, necrosis, hepatic cirrhosis, acute hepatitis, fatty changes and periportal fibrosis. Transient and asymptomatic liver enzyme elevations are frequently seen after methotrexate administration and are usually not a reason for modification of methotrexate therapy or predictive of subsequent hepatic disease.
Persistent liver abnormalities, and/or decrease of serum albumin may be indicators of serious liver toxicity.
Particular attention should be given to the appearance of liver toxicity, since changes may occur without previous signs of gastrointestinal or haematologic toxicity. It is imperative that liver function be determined prior to initiation of treatment and monitored regularly throughout therapy (see Laboratory monitoring). Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function.
Methotrexate has caused reactivation of hepatitis B infection or worsening of hepatitis C infections, in some cases resulting in death. Some cases of hepatitis B reactivation have occurred after discontinuation of methotrexate. Clinical and laboratory evaluation should be performed to evaluate pre-existing liver disease in patients with prior hepatitis B or C infections. Based on these evaluations, treatment with methotrexate may not be appropriate for some patients.
If the results of a liver biopsy show mild changes (Roenigk grades I, II, IIIa), methotrexate may be continued and the patient monitored according to the recommendations listed above. Methotrexate should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy, or in any patient whose liver biopsy shows moderate to severe changes, (Roenigk grade IIIb or IV).
The primary risk factors for severe liver damage, due to methotrexate hepatotoxicity, include: previous liver disease, repeatedly abnormal liver function tests, alcohol consumption/abuse, hepatopathy (including chronic hepatitis B or C), and a family history of hepatopathy. Secondary risk factors include diabetes mellitus (in patients treated with insulin), obesity and exposure to hepatotoxic medicines or chemicals. Additional hepatotoxic medicinal products should not be taken during treatment with methotrexate unless clearly necessary and the consumption of alcohol should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In studies in psoriatic patients, hepatotoxicity appeared to be correlated not only to the cumulative dose of the drug but also to the presence of concurrent conditions such as alcoholism, obesity, diabetes, advanced age and arsenical compounds. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally 2 years or more) and after a total cumulative dose of at least 1.5 grams.

Use in renal impairment.

Methotrexate is contraindicated in patients with severe renal impairment (see Section 4.3 Contraindications).
Methotrexate may cause renal damage that may lead to acute renal failure. Close attention should be given to renal function including adequate hydration and urine alkalinisation. Measurement of serum methotrexate and renal function are recommended.
Methotrexate is excreted principally by the kidneys. Renal function should be closely monitored before, during and after methotrexate therapy. Impaired renal function may result in methotrexate accumulation of toxic amounts or even additional renal damage. Methotrexate therapy should be undertaken with caution in patients with renal impairment.
Drug dosage should be reduced or discontinued until renal function is improved or restored. A high fluid throughput and alkalinisation of the urine to pH 6.5 - 7.0 throughout therapy with methotrexate is recommended as a preventative measure (methotrexate is a weak acid and tends to precipitate at urine pH below 6.0).
Concomitant use of proton pump inhibitors (PPIs) and high dose methotrexate should be avoided, especially in patients with renal impairment (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

Due to diminished hepatic and renal functions as well as decreased folate states in elderly patients, relatively low doses should be considered and these patients should be closely monitored.

Paediatric use.

Aside from its established use in cancer chemotherapy, the safety and efficacy of using methotrexate in children has not been fully elucidated.
Serious neurotoxicity (often manifested by generalised or focal seizures) has been reported with unexpectedly high frequency among paediatric patients with acute lymphoblastic leukaemia who were treated with intravenous methotrexate (1 g/m²).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Chemotherapeutic agents.

Enhancement of nephrotoxicity may be seen if high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g. cisplatin).
In the treatment of patients with osteosarcoma, caution must be exercised if high dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g. cisplatin).

L-asparaginase.

The administration of L-asparaginase has been reported to antagonise the effect of methotrexate.

Mercaptopurine.

Methotrexate increases the plasma levels of mercaptopurine. Combination of methotrexate and mercaptopurine may therefore require dose adjustment.

Drug highly bound to plasma proteins.

Methotrexate is bound in part to serum albumin after absorption and toxicity may be increased because of displacement by other highly bound drugs such as salicylates, sulfonamides, sulfonylureas, phenylbutazone, phenytoin, and some antibacterials such as penicillins, tetracycline, chloramphenicol, pristinamycin, probenecid and para-aminobenzoic acid. When methotrexate is used concurrently with these drugs, its toxicity may be increased.

Hypolipidaemic compounds.

Hypolipidaemic compounds such as cholestyramine proved preferential binding substrates compared to serum proteins when given in combination with methotrexate. These drugs, especially salicylates and sulfonamides, whether antibacterial, hypoglycaemic or diuretic, should not be given concurrently until the significance of these findings is established.

Probenecid and drugs reducing tubular secretion.

Since probenecid and weak organic acids, such as "loop-diuretics", as well as pyrazoles reduce tubular secretion, great caution should be exercised when these medicinal products are coadministered with methotrexate.

Non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs should not be administered prior to or concomitantly with high dose methotrexate, for example as used in the treatment of osteosarcoma. Concomitant administration of NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe haematological and gastrointestinal toxicity.
Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce tubular secretion of methotrexate in an animal model and may enhance its toxicity by increasing methotrexate levels.
Unexpectedly severe (sometimes fatal) marrow suppression, aplastic anaemia and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high doses) with NSAIDs including aspirin and other salicylates, azapropazone, diclofenac, indomethacin and ketoprofen. Naproxen has been reported not to affect the pharmacokinetics of methotrexate but a fatal interaction has been reported.

Antibiotics.

Ciprofloxacin.

Renal tubular transport is diminished by ciprofloxacin; use of methotrexate with this drug should be carefully monitored.

Penicillins and sulfonamides.

Penicillins and sulfonamides may reduce renal clearance of methotrexate, thereby increasing serum concentrations of methotrexate. There is a considerable risk of methotrexate toxicity. Haematologic and gastrointestinal toxicity have been observed in combination with high- and low-dose methotrexate. Use of methotrexate with penicillins and sulfonamides should be carefully monitored.

Oral antibiotics.

Oral antibiotics such as tetracycline, chloramphenicol and non-absorbable broad-spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.
Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive anti-folate effect.
Concurrent use of the anti-protozoal pyrimethamine may increase the toxic effects of methotrexate because of an additive anti-folate effect. Increased bone marrow suppression has been reported in patients receiving methotrexate and pyrimethamine.

Vitamins.

Vitamin preparations containing folic acid or its derivatives may decrease response to methotrexate and should not be given concomitantly. Folate deficiency states may increase methotrexate toxicity.

Assay for folate.

Methotrexate may inhibit the organism used in the assay and interfere with detection of folic acid deficiency.

Other cytotoxic drugs.

Methotrexate is often used in combination with other cytotoxic drugs. Additive toxicity may be expected in chemotherapy regimens, which combine drugs with similar pharmacologic effects, and special monitoring should be made with regard to bone marrow depression, renal, gastrointestinal and pulmonary toxicity. The dosage of methotrexate should be adjusted if it is used in combination with other chemotherapeutic agents with overlapping toxicities.

Hepatotoxic agents.

Concurrent use of other potentially hepatotoxic agents (e.g. leflunomide, sulfasalazine and alcohol) should be avoided due to an increased risk of hepatotoxicity. Special caution should be exercised when azathioprine is given concurrently with methotrexate. The combination of methotrexate with retinoids, such as acitretin, is contraindicated (see Section 4.3 Contraindications).

Allopurinol.

Concomitant use of allopurinol with methotrexate may result in an increased incidence of cytotoxic-induced bone marrow depression.

Leflunomide.

Methotrexate in combination with leflunomide may also increase the risk of pancytopenia and interstitial pneumonitis.

Nitrous oxide anaesthesia.

The use of nitrous oxide anaesthesia potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression and stomatitis. Whilst this effect can be reduced by the use of folinic acid rescue (see Section 4.9 Overdose), avoid concomitant use of nitrous oxide in patients receiving methotrexate. Use caution when administering methotrexate after a recent history of nitrous oxide administration.

Amiodarone.

Amiodarone administration to patients receiving methotrexate treatment for psoriasis has induced ulcerative skin lesions.

Psoralen plus ultraviolet light (PUVA) therapy.

Skin cancer has been reported in a few patients with psoriasis or mycosis fungoides (a cutaneous T-cell lymphoma) receiving concomitant treatment with methotrexate plus PUVA therapy (methoxsalen and ultraviolet light).

Packed red blood cells.

Care should be exercised whenever packed red blood cells and methotrexate are given concurrently. Patients receiving 24-hour methotrexate infusion and subsequent transfusions have showed enhanced toxicity probably resulting from prolonged serum methotrexate concentrations.

Vaccines.

Methotrexate is an immunosuppressant and may reduce immunological response to concurrent vaccination. Severe antigenic reactions may occur if a live vaccine is given concurrently.
Vaccination with a live vaccine in patients receiving chemotherapeutic agents may result in severe and fatal infections and are therefore contraindicated (see Section 4.3 Contraindications).

Theophylline.

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.

Diuretics.

Bone marrow suppression and decreased folate levels have been described in the concomitant administration of triamterene and methotrexate.

Proton pump inhibitors.

Co-administration of proton pump inhibitors (e.g. omeprazole, pantoprazole) with methotrexate may decrease the clearance of methotrexate causing elevated methotrexate plasma levels with clinical signs and symptoms of methotrexate toxicity. Concomitant use of proton pump inhibitors and high dose methotrexate should therefore be avoided, especially in patients with renal impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Phenytoin.

Cytotoxic agents may impair absorption of phenytoin, which may decrease efficacy of phenytoin and increase the risk for exacerbation of convulsions. Risk of toxicity enhancement or loss of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin is possible.

Ciclosporin.

Ciclosporin may potentiate methotrexate efficacy and toxicity. There is a risk of excessive immunosuppression with risk of lymphoproliferation when the combination is used.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Methotrexate has been reported to cause impairment of fertility, defective oogenesis or spermatogenesis, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy.
Men treated with methotrexate should use contraception and not father a child during and for six months after treatment. Methotrexate may be genotoxic and has caused increased number of abnormal and immobile spermatozoa in clinical studies.
Since treatment with methotrexate can lead to severe and possibly irreversible disorders in spermatogenesis, men should seek advice about the possibility of sperm preservation before starting the therapy. Men should not donate semen during therapy or for six months following discontinuation of methotrexate.
The possible risks of effects on reproduction should be discussed with patients of childbearing potential.
(Category D)
Use of methotrexate is contraindicated throughout pregnancy (see Section 4.3 Contraindications).
Methotrexate has been shown to be teratogenic. Methotrexate has caused embryotoxicity, abortion, fetal death and/or congenital abnormalities when administered to pregnant women.
Methotrexate is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits are expected to outweigh the considered risks.
Women of childbearing potential should not be started on methotrexate until any existing pregnancy is excluded with certainty, e.g. by pregnancy test prior to initiating therapy.
Both male and female patients should be fully counselled on the serious risk to the fetus if pregnancy occurs whilst undergoing treatment.
Pregnancy should be avoided and reliable effective contraception used if either partner is receiving methotrexate, during and for a minimum of six months after therapy has ceased, although the optimal time interval between the cessation of methotrexate treatment of either partner, and pregnancy has not been clearly established.

Teratogenicity.

There is evidence of a teratogenic risk in humans (craniofacial, cardiovascular and extremital malformations) and in several animal species.
Methotrexate passes into breast milk and is contraindicated during breastfeeding (see Section 4.3 Contraindications). Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is contraindicated in nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

Central nervous system symptoms, such as fatigue and dizziness, can occur during treatment with methotrexate which may have minor or moderate influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

The major toxic effects of methotrexate occur on normal, rapidly proliferating tissues, particularly the bone marrow and gastrointestinal tract. Ulcerations of the oral mucosa are usually the earliest signs of toxicity.
When adverse reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. This includes use of folinic acid (calcium folinate) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.9 Overdose).
The most common adverse reactions of methotrexate are bone marrow suppression and mucosal damage which manifest as ulcerative stomatitis, leukopenia, nausea and other gastrointestinal disorders. Other reported adverse reactions include malaise, undue fatigue, chills and fever, headache, dizziness, drowsiness, tinnitus, blurred vision, eye discomfort and decreased resistance to infections.
In general, the incidence and severity of side effects are related to dose, dosing frequency, method of administration and duration of exposure. Adverse reactions are most common when using high and repeated doses of methotrexate in the treatment of malignant neoplasms.
Adverse reactions as reported for the various organ systems are as follows:

Immune system disorders.

Anaphylactoid reaction, anaphylactic reaction, hypogammaglobulinaemia.

Skin and subcutaneous tissue disorders.

Toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, exfoliative dermatitis, painful erosion of psoriatic plaques, skin ulceration, skin necrosis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), dermatitis, erythematous rashes, pruritus, urticaria, photosensitivity, pigmentation disorder (depigmentation/hyperpigmentation), alopecia, petechiae, ecchymosis, telangiectasia, acne, folliculitis, furunculosis, nail disorder, nail hyperpigmentation, acute paronychia.

Blood and lymphatic system disorders.

Bone marrow failure, leukopenia, neutropenia, thrombocytopenia, anaemia, aplastic anaemia, megaloblastic anaemia, eosinophilia, pancytopenia, agranulocytosis, lymphadenopathy, lymphoproliferative disorders (including reversible), haemorrhage (from various sites), septicaemia.

Gastrointestinal disorders.

Mucositis, gingivitis, stomatitis, glossitis, decreased appetite (anorexia), nausea, vomiting, diarrhoea, abdominal distress, haematemesis, melaena, gastrointestinal ulceration and bleeding, pancreatitis, intestinal perforation, non-infectious peritonitis, toxic megacolon, malabsorption, enteritis.

Hepatobiliary disorders.

Hepatic failure, acute and chronic hepatotoxicity, acute liver atrophy, necrosis, fatty metamorphosis, chronic fibrosis, acute hepatitis, periportal fibrosis, hepatic cirrhosis, liver enzyme elevations, increased transaminases, blood lactate dehydrogenase increased, decreased serum albumin. Alteration of liver function tests (increases in transaminases and LDH levels) is commonly reported but usually resolves within one month after cessation of therapy.

Renal and urinary disorders.

Renal failure, severe nephropathy, dysuria, azotaemia, cystitis, haematuria, proteinuria, urogenital dysfunction.

Pregnancy, puerperium and perinatal conditions.

Abortion, fetal defects, fetal death.

Reproductive system disorders.

Defective oogenesis/spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, vaginal bleeding, vaginal ulceration, vaginitis, vaginal discharge, gynaecomastia, loss of libido, impotence.

Cardiac disorders.

Pericarditis, pericardial effusion, pericardial tamponade, pulmonary oedema.

Vascular disorders.

Vasculitis, hypotension, thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis and pulmonary embolism).

Nervous system disorders.

Paraesthesia, headaches, dizziness, drowsiness, convulsions, aphasia, hemiparesis, speech impairment, paresis, dysarthria, lethargy, motor dysfunction, cranial nerve disorder, cranial nerve palsies, leukoencephalopathy, encephalopathy, CSF pressure increased, neurotoxicity, arachnoiditis, coma, paraplegia, stupor, ataxia, dementia, unusual cranial sensations, Guillain-Barre syndrome, brain oedema.

Psychiatric disorders.

Depression, confusional state, irritability, transient cognitive dysfunction, mood altered.

Respiratory, thoracic and mediastinal disorders.

Pneumonitis, interstitial pneumonitis (including fatalities), respiratory failure, respiratory fibrosis, interstitial pulmonary fibrosis, reversible eosinophilic pulmonary infiltrates, chronic interstitial pulmonary disease, pharyngitis, alveolitis, pleural effusion, pleurisy, dyspnoea, chest pain, hypoxia, cough (especially dry and non-productive). Pulmonary alveolar haemorrhage has been reported for methotrexate used in rheumatologic and related indications.

Eye disorders.

Conjunctivitis, blurred vision, eye discomfort, serious visual changes, transient blindness/vision loss.

Ear and labyrinth disorders.

Tinnitus.

Infections and infestations.

Infections (including fatal sepsis), decreased resistance to infection, opportunistic infections (sometimes fatal in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases), Pneumocystis jirovecii pneumonia (most common infection), respiratory tract infection, cutaneous bacterial infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, herpes zoster, herpes simplex hepatitis, disseminated herpes simplex, cytomegalovirus infection (including cytomegaloviral pneumonia), reactivation of hepatitis B infection, worsening of hepatitis C infection.

Neoplasms benign, malignant, and unspecified (including cysts and polyps).

Lymphoma (including reversible lymphoma), tumour lysis syndrome, melanoma and non-melanoma skin cancer.

Metabolism and nutrition disorders.

Diabetes mellitus, metabolic disorder.

Musculoskeletal, connective tissue and bone disorders.

Osteoporosis, osteonecrosis (aseptic necrosis of the femoral head), soft tissue necrosis, abnormal tissue cell changes, arthralgia/myalgia, stress fracture, back pain, nuchal rigidity.

General disorders and administration site conditions.

Sudden death, nodule, pyrexia, chills, malaise, fatigue, oedema, peripheral oedema, injection site reactions, injection site necrosis.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.9 Overdose

Signs and symptoms.

In post-marketing experience, overdose with methotrexate has been reported.
Discontinue methotrexate at the first sign of ulceration or bleeding, diarrhoea or marked depression of the haematopoietic system.
Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacological doses, particularly haematological and gastrointestinal reactions. These signs and symptoms include leukopenia, thrombocytopenia, anaemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding, anorexia, progressive weight loss and bloody diarrhoea. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anaemia were also reported.

Treatment.

Folinic acid (calcium folinate) neutralises effectively the immediate toxic effects of methotrexate. After an inadvertent overdosage of methotrexate, calcium folinate should be given as soon as possible and preferably started within 1 hour after the administration of methotrexate. As the time interval between methotrexate administration and folinic acid initiation increases, the effectiveness of folinic acid in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with folinic acid.
Calcium folinate should be given at 10 mg/m² IV or IM every 6 hours until the serum methotrexate levels are below 10^-8 M. In the presence of gastric stasis or obstruction, calcium folinate should be administered parenterally. Concomitant hydration (3 L/d) and urinary alkalinisation with sodium bicarbonate should be employed. The bicarbonate dose should be adjusted to maintain a urinary pH at 7 or greater. Serum samples should be assayed for creatinine levels and methotrexate levels at 24 hour intervals. If the 24 hour serum creatinine level has increased 50% over baseline or if the 24 hour methotrexate level is > 5 x 10^-6 M or the 48 hour methotrexate level is 9 x 10^-7 M or higher, the doses of calcium folinate should be increased to 100 mg/m² IV every 3 hours until the methotrexate level is < 10^-8 M. The infusion rate of calcium folinate should not exceed 16.0 mL (160 mg calcium folinate) per minute. Patients with significant third space accumulations should be considered high risk and closely monitored until serum methotrexate levels are < 10^-8 M regardless of their 24 hour serum concentration.
The above mentioned statements on calcium folinate dosage do not apply with high dosage methotrexate therapy. The dosages of calcium folinate have varied in different studies and the published literature on high dosage methotrexate should be consulted.
In cases of massive overdose, hydration and urinary alkalinisation may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither standard haemodialysis nor peritoneal dialysis have been shown to significantly improve methotrexate elimination. Some clearance of methotrexate may be obtained by haemodialysis if the patient is totally anuric and no other therapeutic options are available. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialysator.
There are published case reports of intravenous and intrathecal carboxypeptidase G2 treatment to hasten clearance of methotrexate in cases of overdose.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia) and 0800 POISON or 0800 764766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Methotrexate exerts its cytotoxic effect through competitive inhibition of dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolic acid results in interference with DNA synthesis and cellular reproduction.
Tissues with high rates of cellular proliferation, e.g. malignant cells, bone marrow, foetal cells, dermal epithelium, buccal and intestinal mucosa and cells of the urinary bladder are generally more sensitive to this effect of methotrexate.
In psoriasis, the rate of production of epithelial cells in the skin is greatly increased than in over normal skin. This differential in reproduction rates is the basis for the use of methotrexate to control the psoriatic process.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

After parenteral injection, peak serum levels are seen in about 0.5 - 2.0 hours.
Repeated daily doses result in more sustained serum levels and some retention of methotrexate over each 24-hour period, which may result in accumulation of the medicine within the tissues. The liver cells appear to retain certain amounts of the medicine for prolonged periods even after a single therapeutic dose. Methotrexate is retained in the presence of impaired renal function and may increase rapidly in the serum and in the tissue cells under such conditions.

Distribution.

Approximately one-half of absorbed methotrexate is reversibly bound to serum protein, but exchanges with body fluids easily and diffuses into the body tissue cells.
Methotrexate does not penetrate the blood cerebrospinal fluid barrier in therapeutic amounts when given parenterally. High concentrations of the drug when needed may be attained by direct intrathecal administration. However, Methotrexate Ebewe is not suitable for intrathecal administration.

Metabolism.

No data available.

Excretion.

Elimination is triphasic. The first phase probably describes distribution into organs; the second, renal excretion; and the third, passing of methotrexate into the enterohepatic circulation. Excretion occurs mainly through the kidneys. Approximately 41% of the dose is excreted unchanged in the urine during the first six hours, 90% within 24 hours.

5.3 Preclinical Safety Data

Genotoxicity.

Methotrexate is mutagenic in vivo and in vitro. There is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone marrow cells. In vitro, methotrexate caused chromosomal aberrations in Chinese hamster A(T1)C1-3 cells, induced morphological transformation in mouse C3H/10T1/_1/2 clone 8 cells and was associated with an increased incidence of large colony mutants at the tk locus in L5178Y/tk^± mouse lymphoma cells. In vivo, it caused an increased incidence of polychromatic erythrocytes in mice and a transient and reversible increase in chromosomal aberrations in human bone marrow cells. The clinical significance of these findings is uncertain.

Carcinogenicity.

No controlled human data exist regarding the risk of neoplasia with methotrexate.
Methotrexate has been evaluated in a number of animal studies for carcinogenic potential with inconclusive results.
Cytotoxic drugs have been reported to be associated with an increased risk of development of secondary tumours in humans. Reports of lymphoma, including reversible lymphomas and tumour lysis syndrome have been documented in patients treated with methotrexate.
Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires initiation of cytotoxic therapy.
Benefit should be weighed against this potential risk before using methotrexate alone or in combination with other drugs, especially in children or young adults.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium hydroxide, water for injections.

6.2 Incompatibilities

Methotrexate has been reported to be incompatible with cytarabine, fluorouracil and prednisolone.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.
Do not freeze.
Protect from light.

6.5 Nature and Contents of Container

Methotrexate Ebewe 500 mg/5 mL concentrated injection, glass vial. Pack of 1 vial.
Methotrexate Ebewe 1000 mg/10 mL concentrated injection, glass vial. Pack of 1 vial.
Methotrexate Ebewe 5000 mg/50 mL concentrated injection, glass vial. Pack of 1 vial.
Not all presentations may be marketed in Australia.
Vial stopper is not made with natural rubber latex.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Methotrexate is a yellow or orange, crystalline powder, practically insoluble in water, in alcohol, in ether and in methylene chloride. It dissolves in dilute solutions of mineral acids and in dilute solutions of alkali hydroxides and carbonates.

Chemical structure.

Chemical name: (2S)-2-[[4-[[(2,4-Diaminopteridin-6-yl)methyl] methylamino]benzoyl] amino]pentanedioic acid.
Molecular formula: C₂₀H₂₂N₈O₅.
Molecular weight: 454.4.

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