Consumer medicine information

Methotrexate Accord

Methotrexate

BRAND INFORMATION

Brand name

Methotrexate Accord

Active ingredient

Methotrexate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Methotrexate Accord.

SUMMARY CMI

METHOTREXATE ACCORD

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being given Methotrexate Accord?

Methotrexate Accord contains the active ingredient methotrexate. Methotrexate Accord belongs to a group of medicines known as antineoplastic or cytotoxic agents.

Methotrexate Accord is used to treat some types of cancers. It may also be used in severe psoriasis when these conditions do not improve with other medicines.

For more information, see Section 1. Why am I using Methotrexate Accord? in the full CMI.

2. What should I know before I am given Methotrexate Accord?

Do not use if you have ever had an allergic reaction to methotrexate or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given Methotrexate Accord? in the full CMI.

3. What if I am taking other medicines?

Some medicines and methotrexate may interfere with each other and may affect how well each medicine works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How will I be given Methotrexate Accord?

Methotrexate Accord will be given to you by a doctor or a nurse as an injection into a muscle, a vein, an artery or into the spine.

More instructions can be found in Section 4. How will I be given Methotrexate Accord? in the full CMI.

5. What should I know while being given Methotrexate Accord?

Things you should do
  • Be sure to keep all your doctor's appointments
  • Use an effective method of birth control while you are being treated with methotrexate or for at least 6 months after stopping treatment
  • If you or your partner becomes pregnant while you are being treated with methotrexate, or for up to 6 months afterwards, tell you doctor immediately
  • Tell your doctor if you have an infection or high temperature
  • Protect your skin when you are in the sun. Avoid exposure to sunlamps
  • Discuss with your doctor how much water or fluids you should have whilst you are being given it
  • Remind your doctor if you are about to receive any vaccination
Things you should not do
  • Do not breast-feed if you are being treated with Methotrexate Accord
  • Do not drink alcohol whilst you are being given this medicine
Driving or using machinesBe careful driving or operating machinery until you know how Methotrexate Accord affects you. Methotrexate Accord may cause dizziness, drowsiness or tiredness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

For more information, see Section 5. What should I know while being given Methotrexate Accord? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Side effects include nausea, stomach pain, sore mouth (mouth ulcers, blisters), fatigue, generally feeling unwell, dizziness, drowsiness, blurred vision, sore eyes, ringing in ears and low numbers of blood cell counts. Pfizer Methotrexate Injection can cause serious side effects including severe allergic reaction; sore throat, fever, chills, achiness; severe skin rash with blistering; injection site reactions, persistent cough, pain or difficulty breathing, or becoming breathless; spitting or coughing blood; skin rash and fever with swollen glands; swelling of the hands, ankles, or feet; yellowing of the skin and eyes; loss of coordination, ability to speak or understand speech, weakness and inability to move one side of the body or the whole body, convulsions or fits

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

METHOTREXATE ACCORD

Active ingredient(s): Methotrexate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Methotrexate Accord. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Methotrexate Accord.

Where to find information in this leaflet:

1. Why am I being given Methotrexate Accord?
2. What should I know before I am given Methotrexate Accord?
3. What if I am taking other medicines?
4. How will I be given Methotrexate Accord?
5. What should I know while being given Methotrexate Accord?
6. Are there any side effects?
7. Product details

1. Why am I being given Methotrexate Accord?

Methotrexate Accord contains the active ingredient methotrexate. Methotrexate Accord belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines. This medicine works by blocking an enzyme needed by body cells to live. This interferes with the growth of some cells that are growing rapidly, such as skin cells in psoriasis and cancer cells.

Methotrexate Accord is used to treat some types of cancers. It may also be used in severe psoriasis when these conditions do not improve with other medicines.

Your doctor, however, may prescribe Methotrexate Accord for another purpose.

2. What should I know before I am given Methotrexate Accord?

Warnings

You must not be given Methotrexate Accord if:

  • you have an allergy to methotrexate or any of the ingredients listed at the end of this leaflet
  • you have/have had severe kidney problems
  • you have/have had lowered immunity due to diseases such as HIV/AIDS, or lowered immunity due to other treatments
  • you are going to be vaccinated with a live vaccine

You must not be given this medicine to treat psoriasis if you have or have had any of the following:

  • any blood disorders, or conditions which cause a reduced number of red blood cells, white blood cells, or platelets
  • bone marrow disease
  • anaemia (low iron in the blood)
  • liver problems
  • stomach ulcers (peptic ulcer disease)
  • ulcerative colitis, a condition where your colon (large bowel) is inflamed and has ulcers
  • alcoholism

Tell your doctor if you have or have had:

  • allergies to any other medicines, foods, preservatives or dyes
  • kidney problems
  • lung problems
  • diabetes
  • folate deficiency

If you are taking this medicine to treat cancer, tell your doctor if you have or have had:

  • any blood disorders, or conditions that cause a reduced number of red blood cells, white blood cells, or platelets
  • bone marrow disease
  • anaemia (low iron in the blood)
  • stomach ulcers (peptic ulcer disease)
  • liver problems
  • ulcerative colitis, a condition where your colon (large bowel) is inflamed and has ulcers

Pregnancy and breastfeeding

Do not use Methotrexate Accord if you are pregnant. Like most cytotoxic medicines methotrexate is not recommended for use during pregnancy. If there is any need to consider methotrexate during your pregnancy, your doctor or pharmacist will discuss with you the benefits and risks of using it.

Methotrexate may cause birth defects if either the male or female is using it at the time of conception. It is recommended that you use a barrier method of birth control while you are using methotrexate and for at least6 months after you stop treatment. Your doctor will discuss this with you.

Tell your doctor or pharmacist if you or your partner are pregnant or intend to become pregnant.

Do not breast-feed if you are being treated with this medicine. Methotrexate passes into breast milk and there is a possibility that your baby may be affected.

General

You must not be given this medicine if you are taking acitretin (a medicine to treat psoriasis and other skin disorders).

Tell your doctor if you have an infection or high temperature.

Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

3. What if I am taking other medicines?

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

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

  • some antibiotics, including tetracyclines, penicillins, sulphonamides, trimethoprim, chloramphenicol, pristinamycin and ciprofloxacin
  • sulphonylureas, a group of medicines used to treat diabetes
  • para-aminobenzoic acid, a medicine used to treat skin and autoimmune disorders
  • phenytoin, a medicine used to treat epilepsy
  • ciclosporin and azathioprine, medicines used to prevent transplant organ rejection
  • corticosteroids such as hydrocortisone and prednisolone
  • folic acid or folinic acid (which may be present in multi-vitamin preparations)
  • non-steroidal anti-inflammatory medicines (NSAIDs) and salicylates, medicines used to relieve pain, swelling and other symptoms of inflammation (such as aspirin, diclofenac, indomethacin, ketoprofen, naproxen, phenylbutazone)
  • disease modifying antirheumatic drugs (DMARDs), medicines used to slow down progression of rheumatoid arthritis disease
  • allopurinol and probenecid, medicines used to treat gout
  • medicines for psoriasis such as etretinate
  • theophylline, a medicine used to relieve asthma
  • fluid tablets
  • cholestyramine, a medicine used to lower high cholesterol
  • amiodarone, a medicine used to treat heart disorders
  • other medicines used to treat cancer (such as cisplatin, asparaginase, mercaptopurine)
  • sulfasalazine, a medicine used to treat Crohn's disease, ulcerative colitis and rheumatoid arthritis
  • other medicines that may cause damage to your liver
  • retinoids, medicines used to treat skin conditions such as acitretin
  • pyrimethamine, a medicine used for malaria
  • proton pump inhibitors, such as omeprazole, pantoprazole
  • methoxsalen (a medicine used with ultraviolet light in PUVA therapy for conditions such as severe psoriasis)

Methotrexate Accord can also be affected by the following:

  • blood transfusions
  • nitrous oxide anaesthetics
  • vaccines
  • alcohol
  • radiotherapy (radiation therapy) e.g. x-rays, ultraviolet radiotherapy

These medicines may be affected by methotrexate, or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor or pharmacist will advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Methotrexate Accord.

4. How will I be given Methotrexate Accord?

How much will be given

Your doctor will decide what dose of methotrexate 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 therapy may be needed depending on your response to treatment.

For the treatment of psoriasis, methotrexate therapy is usually required long term.

How it is given

Methotrexate Accord may be given as an injection into a muscle, a vein, an artery or into the spine.

If you receive too much Methotrexate Accord

Since Methotrexate Accord is usually given to you in hospital under the supervision of your doctor or nurse, it is very unlikely that you will be given too much of the medicine. If you think that you have been given too much Methotrexate Accord.

You should immediately:

  • contact your doctor or nurse
  • phone the Poisons Information Centre (by calling 13 11 26)

5. What should I know while being given Methotrexate Accord?

Things you must do

Keep all of your doctor's appointments so your progress can be checked.

Your doctor may want to check your blood pressure and do some blood and other tests from time to time to check on your progress and to check for any unwanted side effects.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given Methotrexate Accord.

Tell any other doctors, dentists, and pharmacists who treat you that you are being given Methotrexate Accord.

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

A barrier method of birth control, such as a condom, should be used while you are being treated with methotrexate and for at least 6 months after stopping treatment. Your doctor will tell you what forms of contraception are suitable and when it is safe to stop using contraception if you wish to do so.

If you or your partner becomes pregnant while you are being treated with methotrexate, or for up to 6 months afterwards, tell your doctor immediately.

Protect your skin when you are in the sun, especially between 10am and 3pm. If outdoors, wear protective clothing and use a 15+ (minimum) sunscreen. Avoid exposure to sunlamps. Methotrexate may cause your skin to be much more sensitive to sunlight than it is normally and there is an increased risk of skin cancer (melanoma and non-melanoma). Exposure to sunlight may cause a skin rash, itching, redness, or a severe sunburn.

Discuss with your doctor how much water or fluids you should have whilst you are being given this medicine. Inadequate fluid intake can increase the side effects of this medicine.

Ask your doctor if there are any precautions you need to take to prevent your urine becoming too acidic. Acidic urine can increase the side effects of this medicine.

Methotrexate can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding. The following precautions should be taken to reduce your risk of infection or bleeding:

  • Avoid people who have 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. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work
  • Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters.
  • Avoid contact sports or other situations where you may bruise or get injured

Methotrexate may be excreted in body fluids and waste, including blood, urine, faeces, vomitus and semen. In general, precautions to protect other people should be taken while you are receiving methotrexate and for one week after the treatment period by:

  • Flushing the toilet twice to dispose of any body fluids and waste
  • Wearing gloves to clean any spill of body fluid or waste. Use paper towels or old rags, a strong solution of non-bleaching detergent and large amounts of water to mop up the spill. Discard the towels or rags into a separate waste bag and dispose of fluids in the toilet
  • Washing linen or clothing that is heavily contaminated by body fluids or waste separately from other items. Use a strong solution of non-bleaching detergent and large amounts of water
  • Placing soiled disposable nappies and other pads in a plastic bag, seal and dispose into the garbage
  • For sexual intercourse, use a barrier method such as a condom

Things you must not do

You must not drink alcohol whilst you are being given this medicine.

Alcohol may increase the side effects of methotrexate.

Driving or using machines

Be careful driving or operating machinery or doing jobs that require you to be alert until you know how Methotrexate Accord affects you.

Methotrexate Accord may cause dizziness, drowsiness or tiredness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Looking after your medicine

The hospital will store Methotrexate Accord under the correct conditions.

Getting rid of any unwanted medicine

Your doctor or pharmacist will dispose of any Methotrexate Accord that may be left over.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

If you are over 65 years of age you may have an increased chance of getting side effects.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Side effects

Side effectsWhat to do
Stomach or gut related
  • nausea, vomiting, diarrhoea
  • upset stomach or stomach pains
  • lack of appetite or weight loss
Nervous system related
  • dizziness, drowsiness, headaches
  • numbness, weakness, tingling, burning or cold sensations
  • irritability, depression, confusion or mood changes
Skin and nails related
  • skin rash, itchiness
  • sensitivity or increased burning of the skin from sun exposure
  • acne or boils or skin ulcers
  • infection of hair roots or hair loss, especially of the scalp
  • changes in the toenails/fingernails or skin around the nails
Eye and ear related
  • conjunctivitis (itchy eyes and crusty eyelids)
  • sore eyes, blurred vision
  • ringing in the ears
Blood related
  • tiredness, headaches, shortness of breath, dizziness, looking pale (signs of anaemia)
Other
  • unusual or excessive thirst
  • changes in menstrual cycle (periods), unusual vaginal discharge
  • enlarged breast
  • impotence or loss of interest in sex
  • back pain, stiff neck
  • painful joints or muscles
  • muscle cramps or spasms
  • brittle bones
  • injection site reactions
Speak to your doctor if you have any of these side effects and they worry you

The above list includes side effects which are usually mild or short-lived.

Serious side effects

Serious side effectsWhat to do
Allergic reaction related
  • signs of an allergic reaction such as shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching, or hives on the skin
Heart and blood related
  • chest pain, shortness of breath, fast or irregular heartbeats, weakness or fatigue
  • pain, swelling, redness and warmth in the leg (signs of a blood clot in the leg)
  • weakness or paralysis on one side of the body or face, difficulty speaking or swallowing, headache, loss of balance or vision (signs of stroke)
  • rapid weight gain, fluid retention, swollen ankles
Eye related
  • temporary blindness
Lung related
  • persistent dry, non-productive cough
  • wheezing, difficulty breathing, chest pain
  • shortness of breath which may be worse when lying down, cough, spitting or coughing up blood or pinkish mucus (may be due to buildup of fluid in the lungs called pulmonary oedema).
Nervous system related
  • fits, seizures or convulsions
  • difficulty speaking, writing or understanding language
  • weakness in the legs that spreads to the upper limbs and the face, which may result in paralysis
  • headache, dizziness, vomiting, loss of coordination or confusion (may be due to buildup of fluid in the brain called brain oedema).
Infection related
  • fever and chills, sore throat, sweats, body aches or feel generally unwell
  • sore mouth (mouth ulcers, blisters), difficulty swallowing, cold sores, swollen glands
Severe skin reaction related
  • skin redness/rash, pinpoint red spots, ulceration, blistering; hives or itchy skin
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals (Stevens-Johnson syndrome)
  • dark red or black patches of skin around the injection site
Bleeding related
  • blood in urine, vomit or bowel motion (e.g. black tarry stools, black vomit)
  • bleeding or bruising more easily than usual (e.g. bleeding gums, broken blood vessels)
Kidney related
  • Swelling of hands, ankles or feet
  • frequent or painful urination, difficulty urinating, blood in urine, lower back or side pain
Liver related
  • yellowing of the skin and eyes, nausea, vomiting, loss of appetite, feeling generally unwell, fever, itchy or lighter patches on the skin, pale coloured stools, dark coloured urine
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed above may occur in some people. Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

The benefits and side effects of methotrexate may take some time to occur. Therefore, even after you have finished your methotrexate treatment you should tell your doctor immediately if you notice any of the side effects listed in this section.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

Methotrexate Accord does not contain gluten, sucrose, lactose, tartrazine or any other azo dyes.

It is not addictive.

What Methotrexate Accord contains

Active ingredient
(main ingredient)		methotrexate
Other ingredients
(inactive ingredients)		sodium hydroxide
water for injections
sodium chloride (only in the 50 mg/2 mL strength)

Do not take this medicine if you are allergic to any of these ingredients.

What Methotrexate Accord looks like

Methotrexate Accord is a clear yellow to orange solution in glass vials.

(50 mg/2 mL: AUST R 213736, 1000 mg/10 mL:
AUST R 213737)

Who distributes Methotrexate Accord

Accord Healthcare Pty Ltd
Level 24, 570 Bourke Street
Melbourne, VIC, 3000
Australia

This leaflet was prepared in January 2024.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Methotrexate Accord

Active ingredient

Methotrexate

Schedule

S4

 

1 Name of Medicine

Methotrexate.

2 Qualitative and Quantitative Composition

1 mL contains 25 mg methotrexate,
1 vial of 2 mL solution for injection contains 50 mg methotrexate; or
1 mL contains 100 mg methotrexate,
1 vial of 10 mL solution for injection contains 1000 mg methotrexate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Methotrexate Accord is a sterile yellow to orange solution for injection.

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, gestational choriocarcinoma, and in patients with chorioadenoma destruens and hydatidiform mole.
Methotrexate may be used in combination with other chemotherapeutic agents for the palliative treatment of acute leukaemias, particularly acute lymphoblastic leukaemia. It may also be used in the treatment of Burkitt's lymphoma, advanced stages (III and IV, Peters' staging system) of lymphosarcoma, especially in children, and in advanced cases of mycosis fungoides.

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).

Methotrexate may be of value in the symptomatic control of severe, recalcitrant, disabling psoriasis which 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 dermatologic consultation.

4.2 Dose and Method of Administration

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.

Method of administration.

Methotrexate Accord product suitable for IV, IM, intra-arterial or intrathecal use: Methotrexate Accord 50 mg/2 mL injection vial.
Methotrexate Accord product suitable for IV use only. Not for intrathecal use as the solution is hypertonic:
Methotrexate Accord 1000 mg/10 mL injection vial (hypertonic).
For intrathecal injection, Methotrexate Accord should be diluted to a strength of 1 mg/mL with an appropriate preservative free medium such as 0.9% Sodium Chloride Injection.
A guideline of a ratio of 1:30 is given for the conversion of mg/kg body weight to mg/m2 body surface area. The conversion factor varies between 1:20 and 1:40 depending on age and body build.
(a) Antineoplastic chemotherapy.

Trophoblastic neoplasms.

The usual dosage is 15 to 30 mg IM for 5 days. A repeat course may be given after a period of one or more weeks provided all signs of toxicity have disappeared. Three to five courses of therapy are usually employed. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin hormone (CGH) which should return to normal or less than 50 IU/24 hours, usually after the 3rd or 4th course. Complete resolution of measurable lesions usually occurs 4 to 6 weeks later. One to two courses of methotrexate after normalization of CGH are usually recommended. Before each course of the drug, careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antineoplastic drugs has been reported as being useful.
Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended. Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in doses similar to those recommended for trophoblastic neoplasms.

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 the first and eighth days.

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 in doses of 3.3 mg/m2 orally in combination with prednisolone 60 mg/m2 daily has been given for induction of remission of lymphoblastic leukaemia. When remission and general clinical improvement have been attained, a maintenance dosage of methotrexate 30 mg/m2 IM twice weekly may be given. This treatment is expected to produce remission in 50% of patients treated, usually within 4 to 6 weeks.
Alternatively, 2.5 mg/kg IV every 14 days may be given. Should relapse occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen. A variety of dosage schedules for both induction and maintenance of remission with various combinations of alkylating and antifolic agents have recently been introduced. Multiple drug therapy with several agents, including methotrexate given concomitantly, appears to be gaining increasing support in both the acute and chronic forms of leukaemia.
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. Resistance to therapy also develops rapidly.

Meningeal leukaemia.

Patients with leukaemia are subject to leukaemic invasion of the central nervous system. This may manifest characteristic signs or symptoms or remain silent and be diagnosed only by examination of the cerebrospinal fluid (CSF), 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 CSF is minimal, for adequate therapy the drug is administered intrathecally. Only preservative-free methotrexate should be used for intrathecal administration.
It is now common practice to administer methotrexate intrathecally as prophylaxis in all cases of acute lymphocytic leukaemia.
By intrathecal injection the distribution of methotrexate is in the CSF, the volume of which is dependent upon age and not body surface area. The CSF is at 40% of adult volume at birth and reaches adult volume in several years. The recommended dose by age is shown in Table 1.
There is some indication that infants less than 4 months and adults 70 years of age or older may have increased acute toxicity with the doses recommended and dose reduction may be indicated.
For the treatment of meningeal leukaemia, intrathecal methotrexate may be given at intervals of 2 to 5 days, however there is some indication that doses given at intervals of less than one week may result in increased toxicity.
Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal, then one additional dose of the drug is administered.
For prophylaxis against meningeal leukaemia, the dosage is the same as for treatment except for the intervals of administration. On this subject, it is advisable for the physician to consult the medical literature.
Large doses may cause convulsions. Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character.
Methotrexate given by the intrathecal route appears in significant concentrations in the systemic circulation and may cause systemic methotrexate toxicity. Therefore systemic antileukaemic therapy with the drug should be appropriately adjusted, reduced or discontinued. Focal leukaemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

Lymphomas.

In stage III methotrexate is commonly given concomitantly with other antineoplastic agents. In all stages, several courses of drug therapy are usually administered interposed with 7 to 10 day rest periods. Lymphosarcomas in stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 mg to 2.5 mg/kg daily.
Methotrexate is of no value in the treatment of Hodgkin's disease.

Mycosis fungoides.

Methotrexate has also been given IM in doses of 50 mg once weekly or 25 mg twice weekly.
Methotrexate appears to produce clinical remissions in 50% of the cases treated.
(b) High-dosage therapy. Recent published literature should be consulted for details; dosage regimens have varied considerably in different studies depending upon the nature and severity of the disease, the experience of the investigator etc. It must be emphasised that high dosages should be only used by qualified specialists and in hospitals where the necessary facilities are available.
In order to prevent precipitation of methotrexate in the renal tubules, the patients should maintain an adequate urine flow by drinking plenty of fluids for 2 days after a high dose injection (greater than 200 mg), and keep the urine alkaline by using sodium bicarbonate continuously for at least 24 hours afterwards.
(c) 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 haemogram, 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 for at least 12 weeks following methotrexate therapy.
Weekly parenteral intermittent large doses: All schedules should be continually tailored to the individual patient. A single test dose of 5 to 10 mg parenterally one week prior to initiation of therapy is recommended to detect any idiosyncratic reaction.

Recommended dose schedules for a 70 kg adult.

Weekly single dose schedule: 10 to 25 mg IM or IV per week until adequate response is achieved. Weekly dosage should not exceed 50 mg.
After optimal response has been achieved, dosage schedule should be reduced to the lowest possible dose with the largest possible rest period. Conventional topical therapy should be resumed as soon as possible.

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).

Instructions for handling.

The following protective recommendations are given due to the toxic nature of this substance:
personnel should be trained in good handling technique;
pregnant staff should be excluded from working with this drug;
personnel handling methotrexate injection should wear protective clothing including goggles, gowns and disposable gloves and masks;
a designated area should be assigned for preparation (preferably under a laminar flow system), with the work surface protected by disposable, plastic-backed, absorbent paper;
all items used for administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high temperature incineration;
accidental contact with the skin or eyes should be treated immediately by copious lavage with water or sodium bicarbonate solution; medical attention should be sought.

Stability.

The liquid vials are preservative-free and should therefore be used once only and discarded.
Methotrexate Injection, when diluted to a concentration of 1 mg/mL with sodium chloride 0.9% I.V. solution, glucose 5% I.V. solution, Hartmann's solution, Ringer's solution and an I.V. solution containing 0.9% sodium chloride and 5% glucose, retains its potency for 24 hours.
To reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary, hold at 2°C-8°C for not more than 24 hours.

Caution.

Pharmacist.

Because of its potential to cause severe toxicity, methotrexate therapy requires close supervision of the patient by the physician. Pharmacists should dispense no more than a seven (7) day supply of the drug at one time. Refill of such prescriptions should be by direct order (written or oral) of the physician only.

4.3 Contraindications

Methotrexate should not be given to:
Pregnant patients with psoriasis.
Nursing mothers.
Psoriasis patients with severe hepatic disorders.
Patients with severe renal impairment.
Psoriasis patients with poor nutritional status.
Psoriasis patients with alcoholism or alcoholic liver disease.
Patients who have overt or laboratory evidence of immunodeficiency.
Psoriasis patients with bone marrow depression or pre-existing blood dyscrasias, such as bone marrow hypoplasia, leucopenia, thrombocytopenia or anaemia.
Psoriasis patients with serious infections.
Patients with a known hypersensitivity to methotrexate or to any of the excipients.
Psoriasis patients with peptic ulcer disease or ulcerative colitis.
Radiotherapy to the central nervous system should not be given concurrently with intrathecal methotrexate.
Patients receiving etretinate, as an increased risk of hepatitis has been reported.
During methotrexate therapy concurrent vaccination with live vaccines must not be carried out.

4.4 Special Warnings and Precautions for Use

(See Boxed Warnings.)

Use in caution in the following circumstances.

Methotrexate must only be used by physicians experienced in antimetabolite chemotherapy or, in the case of non-oncological conditions, by a specialist physician.
Because of the possibility of fatal or severe toxic reactions the patient should be fully informed by the physician of the risks involved and should be under their constant supervision. Close monitoring for toxicity 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). This results in a 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 infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age.
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.
Like other cytotoxic drugs, methotrexate may induce tumour lysis syndrome in patients with rapidly growing tumours. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.
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 reactions or toxic effects. Most adverse reactions are reversible if detected early. When such reactions do occur, the dosage should be reduced or drug discontinued and appropriate corrective measures taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent haemodialysis with a high-flux dialyser. Caution should be exercised when reinstituting methotrexate therapy and adequate consideration given to the need for further drug administration and alertness to the 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 rheumatoid arthritis or 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 leucovorin 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. It 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 in order to prevent renal precipitation in acidic urine.
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 or intrathecal administration 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.

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, leucopenia, 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 its common effect of haematopoietic suppression. This may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates immediate stoppage of the drug and appropriate therapy. If profound leucopenia 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 radiation 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 infection, 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. Bacterial infection may occur or be a threat if profound leucopenia occurs during therapy. In this instance, the drug should be discontinued and appropriate antibiotic therapy instituted. If severe bone marrow depression occurs, blood or platelet transfusions may be required.
Pneumonia (in some cases leading to respiratory failure) may occur. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.
In addition, pulmonary alveolar haemorrhage has been reported with methotrexate used in rheumatologic and related indications. This event may also be associated with vasculitis and other comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage is suspected to confirm the diagnosis.

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 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Neurologic.

There have been reports of leucoencephalopathy following IV administration of methotrexate in high doses to patients who have had craniospinal irradiation. Symptomatic patients were commonly noted to have leucoencephalopathy, encephalopathy and/or microangiopathic calcifications on diagnostic imaging studies.
Chronic leucoencephalopathy 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.
After the intrathecal or high dose use of methotrexate, central nervous system toxicity may occur and 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 nerve roots;
3) a delayed syndrome occurring months to years after treatment characterised by necrotising leucoencephalopathy and manifested by confusion, stupor, irritability, somnolence, ataxia, dementia, occasionally major convulsions, coma and, rarely, death. 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.
Central nervous system toxicity can be progressive and even fatal. There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leucoencephalopathy. Signs of neurotoxicity (meningeal irritation, transient or permanent paresis, encephalopathy) should be monitored following intrathecal administration of methotrexate.
Intrathecal and intravenous administration of methotrexate may also result in acute encephalitis and acute encephalopathy with fatal outcome.
There have been reports of patients with periventricular CNS lymphoma who developed cerebral herniation with the administration of intrathecal methotrexate.
Cases of severe neurological adverse reactions ranging from headache to paralysis, coma and stroke-like episodes have been reported mostly in juveniles and adolescents given intrathecal methotrexate in combination with intravenous cytarabine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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. Although clinically variable, the typical patient with methotrexate-induced lung disease presents with fever, cough, chest pain, dyspnoea, hypoxaemia and an infiltrate on X-ray. This lesion 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 have occurred within days of, intramuscular, intravenous, or intrathecal administration. Recovery has been reported with discontinuation of therapy.
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.
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.

Laboratory test monitoring of patients.

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 full blood count, haematocrit; urinalysis; hepatitis B or C testing; renal and liver function tests. A chest X-ray is also recommended. The tests should be performed prior to therapy, at appropriate periods during therapy, and after termination of therapy. During initial or changing doses, 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 these parameters is recommended: haematology at least monthly, liver and renal function every one to two months. More frequent monitoring is usually indicated during antineoplastic therapy. It is important to perform liver biopsy or bone marrow aspiration studies where high dose or long term therapy is being followed. Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available.
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).

Methotrexate level.

Serum methotrexate level monitoring can significantly reduce toxicity and mortality by allowing the adjustment of methotrexate dosing and the implementation of appropriate rescue measures.
Patients subject to the following conditions are predisposed to developing elevated or prolonged methotrexate levels and benefit from routine monitoring of levels: e.g. pleural effusion, ascites, gastrointestinal tract obstruction, previous cisplatin therapy, dehydration, aciduria, impaired renal function.
Some patients may have delayed methotrexate clearance in the absence of these features.
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 of methotrexate concentrations 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.

In 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: 1) before start of therapy or shortly after initiation of therapy (2 - 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 usually not a reason to avoid or discontinue methotrexate therapy, the drug should be used with caution.

Instructions to patients.

1. 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.
2. Patients should be informed of the early signs and symptoms of toxicity, of the need to see their doctor promptly if they occur, and the need for close follow-up, including periodic laboratory tests to monitor toxicity. Baseline assessment should include a complete blood could with differential and platelet counts; hepatic enzymes; hepatitis B or C infection testing, renal function tests; and a chest X-ray.
3. Patients should be advised to report all symptoms or signs suggestive of infection.
4. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop a persistent cough or dyspnoea.
5. Patients receiving methotrexate should avoid excessive unprotected exposure to sun or sunlamps because of possible photosensitivity reactions and increased risk of skin cancer (melanoma and non-melanoma).
6. Adverse reactions to methotrexate, such as dizziness and fatigue may affect the 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 test monitoring of patients). 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.
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).
As methotrexate is excreted primarily by the kidney, its use in the presence of impaired renal function may lead to drug accumulation with resultant toxicity or even additional renal damage. The renal status of the patient should be determined prior to and periodically during methotrexate therapy. Caution should be exercised if significant renal impairment is present because impairment of renal function will decrease methotrexate elimination. Drug dosage should be reduced or discontinued until renal function is improved or restored. The urine should be kept alkaline throughout therapy with methotrexate (methotrexate is a weak acid and tends to precipitate at urine pH below 6.0).
Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function including adequate hydration, urine alkalinisation, and measurement of serum methotrexate and renal function are recommended.
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 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).
Overdose by intravenous and intrathecal miscalculation of dosage (particularly in juveniles) have occurred. Special attention must be given to dose calculation (see Section 4.2 Dose and Method of Administration).
Cognitive impairment has been recorded in children who received intrathecal methotrexate together with cranial irradiation.

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).

Cytarabine.

Intrathecal methotrexate given concomitantly with IV cytarabine may increase the risk of severe neurologic adverse events such as headache, paralysis, coma and stroke-like episodes.

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.

Drugs highly bound to plasma proteins.

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

Hypolipidaemic compounds.

Hypolipidemic compounds such as colestyramine 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.

Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored. Probenecid may increase the methotrexate plasma half-life and thereby increase blood levels.

Non-steroidal anti-inflammatory drugs (NSAIDs).

Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with the high dose methotrexate 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 (including bone marrow suppression and aplastic anaemia) 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 some nonsteroidal anti-inflammatory agents (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 the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant haematologic and gastrointestinal toxicity have been observed with 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 alone or in combination with sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. Increased bone marrow suppression has also been reported in patients receiving methotrexate and pyrimethamine.

Vitamins.

Conversely, multi-vitamin preparations including folic acid or its derivatives may alter responses 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 severe unpredictable myelosuppression, stomatitis and neurotoxicity with intrathecal administration. Whilst this effect can be reduced by the use of folinic acid rescue, 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.

Coadministration of proton pump inhibitors (PPIs) (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 chromosome damage. Methotrexate may cause defective oogenesis and spermatogenesis. Therefore, in men and women of fertile age, steps should be taken to avoid conception during methotrexate therapy. The risk of genetic abnormalities may persist after discontinuing methotrexate therapy. Therefore, it is advised that both men and women avoid intercourse leading to conception for an indefinite period (at least 6 months) after discontinuing methotrexate to ensure the re-establishment of normal germinal cells.
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. The possible risks of effects on reproduction should be discussed with patients of childbearing potential.
It has also been reported to cause menstrual dysfunction in humans, during and for a short period after cessation of therapy.
(Category D)
In the treatment of psoriasis and rheumatoid arthritis, use of methotrexate is contraindicated throughout pregnancy (see Section 4.3 Contraindications).
Methotrexate has been shown to be teratogenic. Methotrexate has caused embryotoxicity, abortion, foetal 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 foetus if pregnancy occurs while undergoing treatment. Pregnancy should be avoided and reliable effective contraception used if either partner is receiving methotrexate, during and for at least 6 months after cessation of therapy, although the optimal time interval between the cessation of methotrexate treatment of either partner, and pregnancy, has not been clearly established. Methotrexate passes into breast milk and is contraindicated during breastfeeding. The highest breast milk to plasma concentration ratio reached was 0.08:1. 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

Adverse reactions to methotrexate, such as dizziness and fatigue may affect the ability to drive or operate machinery.

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. The most common adverse reactions include ulcerative stomatitis, leucopenia, nausea and abdominal distress. Others reported are malaise, undue fatigue, chills and fever, pyrexia, headache, dizziness, drowsiness, tinnitus, blurred vision, eye discomfort and decreased resistance to infection. The incidence and severity of side effects generally appear to be dose- and frequency-related. Adverse reactions have been reported for the various systems:

Dermatological and hypersensitivity.

Dermatitis, erythematous rashes, pruritus, urticaria, photosensitivity, depigmentation/hyperpigmentation, alopecia, vasculitis, petechiae, ecchymosis, telangiectasia, acne, folliculitis, furunculosis, nail changes, nail hyperpigmentation, acute paronychia, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Burning and erythema may appear in psoriatic areas for 1 to 2 days following each dose. Rarely, painful plaque erosions may appear. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration has been reported in psoriatic patients. Anaphylactic reactions and skin ulceration/necrosis consistent with toxic epidermal necrolysis, soft tissue necrosis and osteonecrosis have also been reported.
Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) and erythema multiforme have been reported in children and adults within days of, intramuscular, intravenous or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases.

Haematological and lymphatic system.

Bone marrow depression, leucopenia, neutropenia, eosinophilia, pancytopenia, agranulocytosis, thrombocytopenia, anaemia (including aplastic anaemia), hypogammaglobulinaemia, decrease in serum albumin. Clinical sequelae such as fever, infections, haemorrhage from various sites, septicaemia, lymphadenopathy and lymphoproliferative disorders (including reversible) may be expected. Megaloblastic anaemia has also been reported, mainly in elderly patients receiving long-term methotrexate therapy. Folate supplementation may permit continuation of methotrexate therapy with resolution of anaemia.

Cardiovascular.

Pericarditis, vasculitis, pericardial effusion, pericardial tamponade, pulmonary oedema, hypotension and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis and pulmonary embolism have been reported with methotrexate therapy.

Gastrointestinal.

Mucositis (gingivitis, pharyngitis, stomatitis, glossitis), decreased appetite, anorexia, nausea, vomiting, diarrhoea, abdominal distress, haematemesis, melena, gastrointestinal ulceration and bleeding, intestinal perforation, noninfectious peritonitis, pancreatitis, enteritis, acute and chronic hepatic toxicity resulting in acute liver atrophy, necrosis, fatty metamorphosis, acute hepatitis, hepatotoxicity, periportal fibrosis, chronic fibrosis, hepatic cirrhosis, elevated liver enzymes, decreased serum albumin, increase of blood lactate dehydrogenase and hepatic failure. In rare cases, the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon. Alteration of liver function tests (increases in transaminases and LDH levels) is commonly reported but usually resolves within one month of cessation of therapy.

Urogenital.

Renal failure, dysuria, azotaemia, cystitis, haematuria, defective oogenesis or spermatogenesis, transient oligospermia, urogenital or menstrual dysfunction, infertility, abortion, foetal defects, foetal death, severe nephropathy, vaginal bleeding, vaginal ulceration, vaginitis, vaginal discharge, gynaecomastia.

Pulmonary.

Interstitial pneumonitis, pneumonitis, interstitial fibrosis and respiratory failure, reversible eosinophilic pulmonary infiltrates, respiratory fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, alveolitis, pharyngitis, pleural effusion, pleurisy death. Manifestations of methotrexate-induced pulmonary toxicity commonly include fever, cough (especially dry and non-productive), dyspnoea, chest pain, hypoxia, hypoxaemia and/or radiological evidence of pulmonary infiltrates (usually diffuse and/or alveolar). Pulmonary alveolar haemorrhage has been reported for methotrexate used in rheumatologic and related indications.

Neurological.

Headaches, drowsiness, dizziness, paraesthesia, blurred vision, speech impairment including dysarthria and aphasia, coma and brain oedema. Aphasia, hemiparesis, dysarthria, motor dysfunction, cranial nerve disorder, cranial nerve palsies, convulsions and coma have occurred possibly related to haemorrhage or to complications from intra-arterial catheterisation. Convulsion, paresis, Guillain-Barre syndrome and increased cerebrospinal fluid pressures have followed intrathecal administration. Following low doses, occasional patients have reported transient subtle cognitive dysfunction, depression, mood alteration, Guillain-Barre syndrome or unusual cranial sensations. Cognitive impairment has been recorded in children who received intrathecal methotrexate together with cranial irradiation. There have been reports of leucoencephalopathy following IV administration of methotrexate in high doses to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalised or focal seizures, has been reported with unexpectedly increased frequency among paediatric patients with acute lymphoblastic leukaemia who were treated with intermediate-dose intravenous methotrexate (1 gram/m2). Symptomatic patients were commonly noted to have leukoencephalopathy, encephalopathy and/or microangiopathic calcifications on diagnostic imaging studies.
After the intrathecal or high dose use of methotrexate, the central nervous system toxicity which may occur can be classified as follows.
1. 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 nerve roots;
3. A delayed syndrome occurring months to years after treatment characterised by necrotising leucoencephalopathy and manifested by confusion, irritability, somnolence, ataxia, dementia, occasionally convulsions and, rarely, death. 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.

Ophthalmic.

Conjunctivitis, eye discomfort, blurred vision and serious visual changes of unknown aetiology including transient blindness/ vision loss have been reported in patients receiving methotrexate.

Ear and labyrinth disorders.

Tinnitus.

Infections.

Infections, decreased resistance to infections, respiratory tract infection, cutaneous bacterial infections. There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common infection. Other reported infections include pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes Zoster, Herpes simplex hepatitis, disseminated Herpes simplex, fatal sepsis and cytomegalovirus, including cytomegaloviral pneumonia, reactivation of hepatitis B infection and worsening of hepatitis C infection, respiratory tract infection, cutaneous bacterial infections.
In the presence of active infection methotrexate should be used with extreme caution. Methotrexate is usually contraindicated for patients with overt or laboratory evidence of immunodeficiency syndromes.

Carcinogenicity.

Cytotoxic drugs have been reported to be associated with an increased risk of development of secondary tumours in humans. Evidence of chromosomal damage to animal somatic cells and human bone marrow cells has been reported with methotrexate. Reports of lymphoma (including reversible lymphomas), tumour lysis syndrome, melanoma and non-melanoma skin cancer have been documented in patients treated with methotrexate.

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

Reports of lymphoma, including reversible lymphomas and tumour lysis syndrome, melanoma and non-melanoma skin cancer have been documented in patients treated with methotrexate.

Other.

Other reactions related to or attributed to the use of methotrexate, such as metabolic changes, precipitation of diabetes, osteoporosis, osteonecrosis (including aseptic necrosis of the femoral head), abnormal changes in tissue cells, arthralgia/ myalgia, proteinuria, back pain, nuchal rigidity, nodulosis, stress fractures, loss of libido and impotence have been reported. A few cases of anaphylactoid reactions have been reported.

General disorders and administration site conditions.

Sudden death, nodule, pyrexia, chills, malaise, fatigue, oedema, oedema peripheral, 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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Discontinue methotrexate at the first sign of ulceration or bleeding, diarrhoea or marked depression of the haematopoietic system.
Symptoms following injectable overdosage would be expected to produce effects, which are an extension of the pharmacological effects. The toxic reactions expected would include those listed under Section 4.8 Adverse Effects (Undesirable Effects).
Calcium folinate (leucovorin calcium) is a potent agent for neutralising the immediate toxic effects of methotrexate on the haematopoietic system. In general, when overdosage is suspected, the dose of calcium folinate should be equal to or higher than the offending dose of methotrexate, and should be given as soon as possible, preferably within the first hour after which it is much less effective. Calcium folinate may be administered by IV infusion in doses of up to 75 mg within 12 hours, followed by 12 mg IM every 6 hours for 4 doses. When average doses of methotrexate appear to have an adverse effect, 6 to 12 mg of calcium folinate may be given IM every 6 hours for 4 doses.
Concomitant hydration and alkalinisation of the urine with sodium bicarbonate is recommended to prevent precipitation of methotrexate or its metabolite in the renal tubules. Patients undergoing methotrexate therapy should be advised to increase fluid intake. Neither standard haemodialysis nor peritoneal dialysis has 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 dialyzer.
Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinisation, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent haemodialysis with a high-flux dialyzer may also be beneficial in these patients.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Methotrexate is an antimetabolite antineoplastic agent, which 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 over normal skin. This differential in reproductive rates provides the basis for use of methotrexate to control the psoriatic process.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Methotrexate at low doses (< 25 mg/m2) is well absorbed from the gastrointestinal tract; at larger doses absorption may become erratic and incomplete. Peak serum levels may be achieved within 0.5 to 2 hours following intravenous (IV) or intramuscular (IM) administration.

Distribution.

Approximately 50% of the absorbed methotrexate is reversibly bound to serum proteins. Methotrexate is widely distributed into body tissues and concentrates in the kidneys, liver and gastrointestinal tract. It also distributes into third-space accumulation of fluid, e.g. ascites or pleural effusions. Methotrexate does not reach therapeutic concentrations in the cerebrospinal fluid (CSF) when parenterally. High concentrations of the drug, when needed, may be attained by intrathecal injection.

Metabolism and excretion.

Methotrexate does not appear to be appreciably metabolised. The drug is predominantly excreted by the kidneys and small amounts appear in the faeces. Excretion of methotrexate is reduced in the presence of impaired renal function.

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/10T1/2 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.

Methotrexate is considered to be carcinogenic. However, extensive epidemiologic studies are required to determine its carcinogenicity potential.
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.

Reproductive and developmental toxicity.

There is evidence of a teratogenic risk in humans (craniofacial, cardiovascular and extremital malformations) and in several animal species.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium hydroxide, sodium chloride (50 mg/2 mL presentation only), 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 and protect from light.

6.5 Nature and Contents of Container

Methotrexate Accord is available in two strengths: 50 mg/2 mL and 1000 mg/10 mL, in type I glass vials in packs of 1.

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 (S)-2-[4-[[(2,4-diaminopteridin-6-yl)methyl]methylamino]benzoylamino] pentanedioic acid. It is a yellow or orange, crystalline powder, practically insoluble in water, in alcohol, in ether and in ethylene chloride. It dissolves in dilute solutions of mineral acids and in dilute solutions of alkali hydroxides and carbonates.
Molecular formula: C20H22N8O5.
Molecular weight: 454.4.

Chemical structure.

The structural formula is represented below.

CAS number.

59-05-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes