Consumer medicine information

Pfizer (Australia) Methotrexate Injection

Methotrexate

BRAND INFORMATION

Brand name

Pfizer (Australia) Methotrexate Injection BP

Active ingredient

Methotrexate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pfizer (Australia) Methotrexate Injection.

SUMMARY CMI

Pfizer (Australia) Methotrexate Injection

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.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using Pfizer Methotrexate Injection?

Pfizer Methotrexate Injection contains the active ingredient methotrexate. Pfizer Methotrexate Injection is used to treat certain types of cancers and severe psoriasis when the condition does not improve with other medicines.
For more information, see Section 1. Why am I using Pfizer Methotrexate Injection? in the full CMI.

2. What should I know before I use Pfizer Methotrexate Injection?

Do not use if you have ever had an allergic reaction to Pfizer Methotrexate Injection 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 use Pfizer Methotrexate Injection? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Pfizer Methotrexate Injection and affect how it works.
A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Pfizer Methotrexate Injection?

  • The dose of medicine given to you will depend on the condition being treated, your medical condition, your age, your size and how well your kidneys and liver are working. More instructions can be found in Section 4. How do I use Pfizer Methotrexate Injection? in the full CMI.

5. What should I know while using Pfizer Methotrexate Injection?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Pfizer Methotrexate.
  • You and your partner must use a reliable method of contraception (birth control pills or condom) during treatment with Pfizer Methotrexate and for at least 3 months after you stop treatment for men and 6 months after you stop treatment for women.
  • Discuss with your doctor how much water or fluids you should have as not enough fluid intake can increase the side effects of this medicine.
  • Remind your doctor you are on Pfizer Methotrexate if you are about to receive any vaccination.
  • Tell your doctor if you think you may be getting an infection (fever, chills, achiness, sore throat).
Things you should not do
  • Do not go out in the sun without sunscreen and protective clothing. Do not use sun lamps.
  • Do not breastfeed while using Pfizer Methotrexate.
Driving or using machines
  • Do not drive or operate machinery until you know how Pfizer Methotrexate affects you. Pfizer Methotrexate may cause dizziness, drowsiness, blurred vision or tiredness, affecting alertness.
Drinking alcohol
  • You must not drink alcohol whilst you are being given this medicine. Alcohol may increase the side effects of Pfizer Methotrexate and cause liver damage.

For more information, see Section 5. What should I know while using Pfizer Methotrexate Injection? in the full CMI.

6. Are there any side effects?

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.

WARNING:
Pfizer Methotrexate Injection should only be used for severe disease and when diagnosis has been made. It is a toxic medicine which can cause severe reactions and death. You should be treated under the constant care and follow up of your doctor or specialist.
Methotrexate can cause blood disorders such as low numbers of red blood cells, white blood cells or platelets. At high or repeated doses, methotrexate may be toxic to your liver. Your doctor will need to do tests to check your liver regularly, before and during treatment. Avoid alcohol while be treated with methotrexate.
Tell your doctor if you have cancer of the lymphatic system as methotrexate can affect the treatment of this condition.
Serious infections, leading to death may occur with methotrexate treatment.
Methotrexate can cause birth defects, harm the unborn child or cause miscarriage. Methotrexate should not be used in pregnant women or women who plan to become pregnant.
Methotrexate should not be started until it is confirmed you are not pregnant. If you become pregnant during treatment or think you might be pregnant, speak to your doctor as soon as possible. Your doctor will provide advice regarding the risk of harmful effects on the child through treatment.
You must avoid becoming pregnant or avoid fathering a child during treatment and for at least three months after the end of treatment for men and six months after the end of treatment for women. Both you and your partner must use a reliable method of contraception (birth control pills or condom) during this period.
Women should not breastfeed while being treated with methotrexate.
Methotrexate should not be used if you have severe kidney problems.
Tell your doctor if you take medicines to relieve pain, swelling of inflammation (nonsteroidal anti-inflammatory drugs - NSAIDs) as this can result in serious side effects when being treated with methotrexate. It can affect your blood, stomach or gut and may lead to death.
Tell your doctor if you develop a dry, non-productive cough or shortness of breath. Your doctor will stop treatment and monitor you closely as these may be signs of damage to the lungs.
Use of methotrexate for non-cancer conditions in children has not been well established.
Methotrexate should only be used once a week to treat certain conditions. Using methotrexate more frequently than once a week for these conditions may cause serious reactions and death.
Tell your doctor if you are to have radiotherapy (also known as radiation therapy) while on methotrexate as this can cause damage to tissue and bone.
Tell your doctor if you are to have any vaccinations while on methotrexate as this may lead to serious infections or death.



FULL CMI

Pfizer (Australia) Methotrexate Injection

Active ingredient(s): methotrexate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Pfizer Methotrexate Injection. 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 Pfizer Methotrexate Injection.

Where to find information in this leaflet:

1. Why am I using Pfizer Methotrexate Injection?
2. What should I know before I use Pfizer Methotrexate Injection?
3. What if I am taking other medicines?
4. How do I use Pfizer Methotrexate Injection?
5. What should I know while using Pfizer Methotrexate Injection?
6. Are there any side effects?
7. Product details

1. Why am I using Pfizer Methotrexate Injection?

Pfizer Methotrexate Injection contains the active ingredient methotrexate.

Pfizer Methotrexate Injection is an antineoplastic or cytotoxic medicine. It may also be called a chemotherapy medicine.

Pfizer Methotrexate Injection is used to treat certain types of cancers. It may also be used in severe psoriasis when the condition does not improve with other medicines.

The medicine works by blocking an enzyme needed by the body's cells to live. This interferes with the growth of some cells that are growing rapidly in psoriasis and cancer.

2. What should I know before I use Pfizer Methotrexate Injection?

Warnings

Do not use Pfizer Methotrexate Injection if:

  1. you are allergic to methotrexate, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine
  2. you are pregnant
  3. you are breastfeeding
  4. you have severe kidney problems
  5. you have severe liver problems
  6. are an alcoholic
  7. you have lowered immunity due to diseases or due to other treatments
  8. have bone marrow disease
  9. have any blood disorders, or conditions which cause a low number of red blood cells, white blood cells, or platelets
  10. have low iron in the blood (anaemia)
  11. have infectious disease or severe infections
  12. you are receiving a live vaccine
  13. you are taking vitamin A derivatives (such as acitretin), medicines used to treat psoriasis and other skin conditions
  14. you are receiving radiatiotherapy (radiation therapy) e.g. x-rays, ultra violet radiotherapy

Do not use Pfizer Methotrexate Injection to treat psoriasis if you:

  • have stomach ulcers (peptic ulcer disease)
  • have a condition where your large bowel is inflamed and has ulcers (ulcerative colitis)

Check with your doctor if you:

  • have any other medical conditions
    - kidney problems
    - liver problems, including hepatitis B or hepatitis C
    - lung problems
    - diabetes
    - low folate levels
    - blood disorders including abnormal blood cell count
    - immune system disorder
    - infection or high temperature
    - stomach ulcer or ulcerative colitis (bleeding from your bowel)

Before treatment is started your doctor may carry out blood tests to check the levels of cells in your blood, and also to check how well your kidneys and liver are working. You may also have a chest x-ray. Further tests may also be done during and after 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?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

The medicine may harm the unborn child, cause birth defects and miscarriage if either you or your partner is using it. Both you and your partner must use a reliable method of contraception (birth control pills or condom) during treatment with Pfizer Methotrexate Injection and for at least three months after you stop treatment for men and at least six months after stopping treatment for women. Your doctor will discuss with you what forms of contraception are suitable and when it is safe to stop using contraception if you wish to do so.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

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

Children and elderly

Special care will also be taken in children, the elderly and in those who are in poor physical condition.

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 may interfere with Pfizer Methotrexate Injection and affect how it works.

These include:

  • some antibiotics
  • sulphonylureas, medicines used to treat diabetes
  • para-aminobenzoic acid, a medicine used to treat skin and autoimmune disorders
  • diuretics, medicines to remove fluid or water from the body
  • phenytoin, a medicine used to treat epilepsy
  • ciclosporin and azathioprine, medicines used to prevent transplant organ rejection
  • vitamin supplements that contain folic acid or folinic acid
  • non-steroidal anti-inflammatory medicines (NSAIDs) and salicylates (e.g. aspirin), medicines used to relieve pain, swelling and inflammation
  • disease modifying antirheumatic drugs (DMARDs), medicines used to slow down progression of rheumatoid arthritis disease
  • allopurinol and probenecid, medicines used to treat gout
  • theophylline, a medicine used to relieve asthma
  • cholestyramine, a medicine used to lower high cholesterol
  • amiodarone, a medicine used to treat heart disorders
  • certain other medicines used to treat cancer
  • 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, medicines used to treat stomach ulcers and reflux
  • methoxsalen, a medicine used with ultraviolet light in PUVA therapy for conditions such as severe psoriasis

Pfizer Methotrexate Injection can also be affected by, or interfere with the following:

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

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

4. How do I use Pfizer Methotrexate Injection?

How much and when is it given

Your doctor will decide what dose, how often and how long you will receive it. This depends on your condition and other factors, such as your weight, age, blood tests, how well your kidneys and liver are working, and whether or not other medicines are being given at the same time.

Methotrexate should only be used once a week to treat certain conditions. Using methotrexate more frequently than once a week for these conditions may cause serious reactions and death.

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.

How Pfizer Methotrexate Injection is given

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

Pfizer Methotrexate Injection must only be given by a doctor or nurse.

If you use too much Pfizer Methotrexate Injection

As Pfizer Methotrexate Injection will most likely be given to you in hospital or under the supervision of your doctor, it is very unlikely that you will receive an overdose.

If you think that you have been given too much Pfizer Methotrexate Injection or experience severe side effects, you may need urgent medical attention.

Symptoms of a Pfizer Methotrexate Injection overdose may include the side effects listed in section 6, but are usually of a more severe nature. They may include blood in your bowel motions (black tarry stools), bleeding, nausea, vomiting, mouth ulcers and severe infections.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Pfizer Methotrexate Injection?

Things you should do

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

Tell any other doctors, dentists, and pharmacists who are treating you that you are being given this medicine.

If you are going to have surgery, tell the surgeon, anaesthetist or dentist that you are taking this medicine. It may affect other medicines used during surgery.

If you are about to be given an immunisation, remind your doctor that you are using this medicine.

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.

Tell your doctor immediately if you are spitting or coughing up blood when using Pfizer Methotrexate Injection.

Some patients have reported acute bleeding in the lungs when using Pfizer Methotrexate Injection to treat certain conditions.

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

Methotrexate can cause problems with your blood, liver and kidneys. Your doctor may do blood tests to check for these problems or may ask you to have an operation to have a small sample of your liver removed. There may also be a chest x-ray and a physical examination to check for swelling of your lymph nodes (glands in your neck, armpits and groin).

Things you should not do

Do not go out in the sun without wearing protective clothing (hat and shirt) and using a sunscreen with a high protection factor. Avoid exposure to sunlamps.

Pfizer Methotrexate Injection can increase your sensitivity to sunlight and cause severe reactions, increasing the risk of skin cancer (non-melanoma and melanoma). Symptoms may include a skin rash, itching, swelling, redness, blistering or a severe sunburn.

Things to be careful of

Pfizer Methotrexate Injection 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.

Pfizer Methotrexate Injection may be excreted in body fluids and waste, including blood, urine, faeces, vomit and semen. In general, precautions to protect other people should be taken while you are receiving Pfizer Methotrexate Injection 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.

Carers and other people who handle the injection should wear disposable gloves to avoid direct contact with the injection fluid. Pregnant women should not handle the medicine at all.

Driving or using machines

Be careful before you drive, use any machines or tools or do anything else that could be dangerous until you know how Pfizer Methotrexate Injection affects you.

Pfizer Methotrexate Injection may cause dizziness, drowsiness, blurred vision or tiredness in some people and therefore may affect alertness.

Drinking alcohol

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

Alcohol may increase the side effects of Pfizer Methotrexate Injection and cause liver damage.

Looking after your medicine

Pfizer Methotrexate Injection is usually stored in the pharmacy, doctor's surgery or on the ward. It is kept in a cool dry place, protected from light, where the temperature stays below 25°C.

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.

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.
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 heart beats, 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
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
  • headache, dizziness, vomiting, loss of coordination or confusion (may be due to buildup of fluid in the brain called brain oedema).
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 here 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.

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.

What Pfizer Methotrexate Injection contains

Active ingredient
(main ingredient)		methotrexate
Other ingredients
(inactive ingredients)		water for injections
sodium chloride (only for 50 mg/2 mL and 500 mg/20 mL)
sodium hydroxide
hydrochloric acid

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

What Pfizer Methotrexate Injection looks like

Pfizer Methotrexate Injection is a clear yellow liquid in clear glass vials.

Pfizer Methotrexate Injection is available in the following strengths and pack sizes:

  • 50 mg/2 mL vial x 5 AUST R 10777
  • 1000 mg/10 mL vial x 1 AUST R 10778

Who distributes Pfizer Methotrexate Injection

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedicalinformation.com.au

This leaflet was prepared in October 2023.

Published by MIMS November 2023

BRAND INFORMATION

Brand name

Pfizer (Australia) Methotrexate Injection BP

Active ingredient

Methotrexate

Schedule

S4

 

1 Name of Medicine

Methotrexate.

2 Qualitative and Quantitative Composition

Each vial of Methotrexate Injection BP contains methotrexate 50 mg/2 mL, 500 mg/20 mL and 1000 mg/10 mL.
Sodium chloride is added to the 50 mg in 2 mL and 500 mg in 20 mL presentations to render them isotonic. Methotrexate Injection BP 1000 mg in 10 mL is hypertonic.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Methotrexate Injection BP is a sterile, preservative-free yellow to orange solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Antineoplastic chemotherapy.

Treatment of breast cancer, gestational choriocarcinoma, and in patients with chorioadenoma destruens and hydatidiform mole. Palliation of acute and subacute lymphocytic and meningeal leukaemia. Greatest effect has been observed in palliation of acute lymphoblastic (stem cell) leukaemias. In combination with corticosteroids, methotrexate may be used for induction of remission. The drug is now most commonly used for the maintenance of induced remissions. Methotrexate is also effective in the treatment of the advanced stages (III and IV, Peters staging system) of lymphosarcoma, particularly in children and in advanced cases of mycosis fungoides.

High dose therapy.

The use of very high doses is made possible by vials for injection containing 500 mg and 1000 mg (see Section 4.4 Special Warnings and Precautions for Use). Diseases treated with these doses administered in the form of single drug or combination therapy include osteogenic sarcoma, acute leukaemia, bronchogenic carcinoma and epidermoid carcinoma of the head and neck.

Psoriasis chemotherapy (see Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use).

Because of the high risk attending to its use, Methotrexate Injection is only indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultations.

4.2 Dose and Method of Administration

Dosage.

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

Breast carcinoma.

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

Choriocarcinoma and similar trophoblastic diseases.

Methotrexate is administered intramuscularly in doses of 15 mg to 30 mg daily for a five day course. Such courses are usually repeated three to five times as required with a rest period of one or more weeks interposed between courses, until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin hormone (β-hCG), which should return to normal or less than 50 units/24 hour usually after the 3rd or 4th course and usually followed by a complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of methotrexate after normalisation of β-hCG is usually recommended. Before each course of the drug, careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other antitumour drugs has been reported as being useful. Since hydatidiform mole may precede or be followed by 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 choriocarcinoma.

Leukaemia.

Acute lymphatic (lymphoblastic) leukaemia in children and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common. In chronic lymphatic leukaemia, the prognosis for adequate response is less encouraging. Methotrexate alone or in combination with steroids was used initially for induction of remission of lymphoblastic leukaemias. More recently, corticosteroid therapy in combination with other antileukaemic drugs or in cyclic combination therapy including methotrexate has produced rapid and effective remissions. When used for induction, in doses of 3.3 mg/m2 in combination with prednisolone 60 mg/m2 given daily, remission occurred in 50% of patients treated, usually within a period of 4 to 6 weeks.
Methotrexate alone, or in combination with other agents, appears to be the drug of choice for securing maintenance of drug induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated by administering methotrexate 2 times weekly intramuscularly in doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

Meningeal leukaemia.

Patients with leukaemia are subject to leukaemic invasion of the central nervous system. This may manifest characteristic signs or symptoms or may remain silent and be diagnosed only by examination of the cerebrospinal fluid, which contains leukaemic cells in such cases. Therefore, the CSF should be examined in all leukaemic patients. Since passage of methotrexate from blood serum to the cerebrospinal fluid is minimal, for adequate therapy the drug is administered intrathecally.
It is now common practice to administer methotrexate intrathecally as prophylaxis in all cases of lymphocytic leukaemia.
By intrathecal injection the distribution of methotrexate is in the CSF, the volume of which is dependent on 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 (see Table 1):
There is some indication that infants less than 4 months and adults ≥ 70 years may have increased acute toxicity with doses recommended and dose reduction may be indicated.
The solution is made in a strength of 1 mg/mL with an appropriate, sterile, preservative free medium such as 0.9% Sodium Chloride Injection BP. Remove a volume of cerebrospinal fluid equivalent to the volume of methotrexate being administered.
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. Do not exceed the maximum recommended single dose of 15 mg.
Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal. At this point, one additional dose is advisable.
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 intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukaemic therapy with drug should be appropriately adjusted, reduced or discontinued. Focal leukaemic involvement of the CNS may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

Lymphomas.

In Burkitt's tumour, stages I-II, methotrexate has produced prolonged remission in some cases. Recommended dosage is 10 to 25 mg per day orally for 4 to 8 days. In stage III, methotrexate is commonly given concomitantly with other antitumour agents. Treatment in all stages usually consists of several courses of the drug 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. Hodgkin's disease responds poorly to methotrexate and to most types of chemotherapy.

Mycosis fungoides.

As an alternative to oral therapy, methotrexate 50 mg intramuscularly weekly or 25 mg intramuscularly twice weekly may be given.
High dose therapy (see Section 4.4 Special Warnings and Precautions for Use). Dosage regimens have varied considerably in different studies; the nature and severity of the disease and the previous experience of the investigator are some of the factors influencing the choice of dosage and the duration of therapy. It must be emphasised that high dosages should be used only by qualified specialists and in hospitals where the necessary facilities are available.
Psoriasis chemotherapy. The patient should be fully informed of the risks involved and should be under constant supervision of the physician.
Assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests (such as full blood count, urinalysis, serum creatinine, liver function studies and liver biopsy if indicated) before beginning methotrexate, periodically during methotrexate therapy and before reinstituting methotrexate therapy after a rest period. Appropriate steps should be taken to avoid conception during and for at least 6 months following methotrexate therapy.
The commonly used injectable dosage schedule is by weekly parenteral intermittent large doses.
All schedules should be continually tailored to the individual patient. Dose schedules cited below pertain to an average 70 kg adult. An initial test dose one week prior to initiation of therapy is recommended to detect any idiosyncrasy. A suggested dose range is 5 mg to 10 mg parenterally.

Recommended starting dose schedules.

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

Dosage adjustment.

Renal impairment.

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

Method of administration.

Methotrexate Injection (BP) products suitable for IV, IM or intrathecal use.

Pfizer (Australia) Methotrexate 50 mg/2 mL injection BP, Pfizer (Australia) Methotrexate 500 mg/20 mL injection BP vial.

Methotrexate Injection (BP) Injection products suitable for IV use only.

Not for intrathecal use as the solution is hypertonic: Pfizer (Australia) Methotrexate 1000 mg/10 mL injection BP vial (hypertonic).
For intrathecal injection, Methotrexate Injection should be diluted to a strength of 1 mg/mL with an appropriate preservative-free medium such as 0.9% Sodium Chloride Injection.
For conversion of mg/kg bodyweight to mg/m2 of body surface area or the reverse, a ratio of 1:30 is given as a guideline. The conversion factor varies between 1:20 and 1:40 depending on age and body build.

Instructions for handling.

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

Spills and disposal.

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

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Use with caution in the following circumstances.

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

Folinic acid deficiency.

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

High dose therapy.

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

Organ system toxicity.

Gastrointestinal.

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

Haematologic.

Methotrexate may produce marked depression of bone marrow, and cause anaemia, aplastic anaemia, pancytopenia, 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 the common effects of haematopoietic suppression. These effects may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates that methotrexate should be immediately discontinued and appropriate therapy instituted.
If profound 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 radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Infection or immunologic states.

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

Immunisation.

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

Neurologic.

There have been reports of leucoencephalopathy following intravenous administration of methotrexate in high doses to patients who have had craniospinal irradiation (see Paediatric use). Symptomatic patients were commonly noted to have leucoencephalopathy 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 leucoencephalopathy 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 intrathecal or high dose use of methotrexate, the central nervous system toxicity which may occur can be classified as follows: (1) acute chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity, and fever; (2) subacute 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 chronic leucoencephalopathy and manifested by confusion, stupor, irritability, somnolence, ataxia, dementia, occasionally major convulsions, and coma. This central nervous system toxicity can be progressive and even fatal. The effects are dose related and occur particularly when intrathecal methotrexate is given at doses greater than 50 mg in combination with cranial irradiation and systemic methotrexate therapy. 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 that ranged 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, Cytarabine).

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 chest X-ray. Pulmonary lesions can occur at all dosages. Infection (including pneumonia) needs to be excluded in patients presenting with symptoms of pulmonary toxicity.
If methotrexate induced lung disease is suspected, treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.
Patients should be closely monitored for pulmonary signs and symptoms at each follow-up visit.
Methotrexate induced pulmonary toxicity may occur at any time during therapy and may not be fully reversible.

Skin.

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

Laboratory monitoring.

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

Pulmonary function tests.

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

Methotrexate level.

Monitoring methotrexate serum levels, adjusting dose and implementing rescue measures as appropriate can significantly reduce toxicity and mortality.
Patients with pleural effusion, ascites, gastrointestinal tract obstruction, previous cisplatin therapy, dehydration, aciduria or impaired renal function are predisposed to developing elevated or prolonged methotrexate levels. Therefore, routine monitoring of methotrexate levels should be carried out in these patients.
Delayed methotrexate clearance can also occur in the absence of these conditions.
It is important that patients be identified within 48 hours since methotrexate toxicity may not be reversible if adequate folinic acid rescue is delayed for more than 42 to 48 hours.
Monitoring should include determination of a methotrexate level at 24, 48, or 72 hours, and assessment of the rate of decline in methotrexate concentrations (to determine how long to continue folinic acid rescue).

Psoriasis.

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

Information for patients.

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

Use in hepatic impairment.

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

Use in renal impairment.

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

Use in the elderly.

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

Paediatric use.

Cases of overdose by 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).
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).
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.

Drug highly bound to plasma proteins.

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

Hypolipidaemic compounds.

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

Probenecid and drugs reducing tubular secretion.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs).

NSAIDs should not be administered prior to or concomitantly with high dose methotrexate, for example as used in the treatment of osteosarcoma. Concomitant administration of NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe haematological (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 NSAIDs including aspirin and other salicylates, azapropazone, diclofenac, indomethacin and ketoprofen. Naproxen has been reported not to affect the pharmacokinetics of methotrexate, but a fatal interaction has been reported.

Antibiotics.

Ciprofloxacin.

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

Penicillins and sulfonamides.

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

Oral antibiotics.

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

Vitamins.

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

Assay for folate.

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

Other cytotoxic drugs.

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

Hepatotoxic agents.

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

Allopurinol.

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

Leflunomide.

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

Nitrous oxide anaesthesia.

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

Amiodarone.

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

Psoralen plus ultraviolet light (PUVA) therapy.

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

Packed red blood cells.

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

Vaccines.

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

Theophylline.

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

Diuretics.

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

Proton pump inhibitors.

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

Teratogenicity.

There is evidence of a teratogenic risk in humans (craniofacial, cardiovascular and extremital malformations) and in several animal species.
 Methotrexate passes into breast milk and is contraindicated during breastfeeding (see Section 4.3 Contraindications). The highest breast milk to plasma concentration ratio reached was 0.08:1. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, it is contraindicated in nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

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

Immune system disorders.

Anaphylactoid reaction, anaphylactic reaction, hypogammaglobulinaemia.

Skin and subcutaneous tissue disorders.

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

Blood and lymphatic system disorders.

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

Gastrointestinal disorders.

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

Hepatobiliary disorders.

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

Renal and urinary disorders.

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

Pregnancy, puerperium and perinatal conditions.

Abortion, fetal defects, fetal death.

Reproductive system disorders.

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

Cardiac disorders.

Pericarditis, pericardial effusion, pericardial tamponade, pulmonary oedema.

Vascular disorders.

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

Nervous system disorders.

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

Psychiatric disorders.

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

Respiratory, thoracic and mediastinal disorders.

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

Eye disorders.

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

Ear and labyrinth disorders.

Tinnitus.

Infections and infestations.

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

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

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

Metabolism and nutrition disorders.

Diabetes mellitus, metabolic disorder.

Musculoskeletal, connective tissue and bone disorders.

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

General disorders and administration site conditions.

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

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

In postmarketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose has also been reported.
Discontinue methotrexate at the first sign of ulceration or bleeding, diarrhoea or marked depression of the haematopoietic system.
Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacological doses, particularly haematological and gastrointestinal reactions. These signs and symptoms include leucopenia, thrombocytopenia, anaemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding, anorexia, progressive weight loss and bloody diarrhoea. In some cases of overdose, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure and aplastic anaemia were also reported.
Symptoms of intrathecal overdose are generally central nervous system (CNS) symptoms, including headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms were reported. There have also been cases of fatal intrathecal overdose, in which cerebellar herniation associated with increased intracranial pressure and acute toxic encephalopathy were reported.

Treatment.

Folinic acid (calcium folinate) neutralises effectively the immediate toxic effects of methotrexate. After an inadvertent overdosage of methotrexate, calcium folinate should be given as soon as possible and preferably started within 1 hour after the administration of methotrexate. As the time interval between methotrexate administration and folinic acid initiation increases, the effectiveness of folinic acid in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with folinic acid.
Calcium folinate should be given at 10 mg/m2 IV or IM every 6 hours until the serum methotrexate levels are below 10-8 M. In the presence of gastric stasis or obstruction calcium folinate should be administered parenterally. Concomitant hydration (3 L/day) and urinary alkalinisation with sodium bicarbonate should be employed. The bicarbonate dose should be adjusted to maintain a urinary pH at 7 or greater. Serum samples should be assayed for creatinine levels and methotrexate levels at 24 hour intervals. If the 24 hour serum creatinine level has increased 50% over baseline or if the 24 hour methotrexate level is > 5 x 10-6 M or the 48 hour methotrexate level is 9 x 10-7 M or higher, the doses of calcium folinate should be increased to 100 mg/m2 IV every 3 hours until the methotrexate level is < 10-8 M. The infusion rate of calcium folinate should not exceed 16.0 mL (160 mg calcium folinate) per minute. Patients with significant third space accumulations should be considered high risk and closely monitored until serum methotrexate levels are < 10-8 M regardless of their 24 hour serum concentration.
The above-mentioned statements on calcium folinate dosage do not apply with high dosage methotrexate therapy. The dosages of calcium folinate have varied in different studies and the published literature on high dosage methotrexate should be consulted.
In cases of massive overdose, hydration and urinary alkalinisation may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither standard haemodialysis nor peritoneal dialysis have been shown to significantly improve methotrexate elimination. Some clearance of methotrexate may be obtained by haemodialysis if the patient is totally anuric and no other therapeutic options are available. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialysator.
Accidental intrathecal overdosage may require intensive systemic support, high dose systemic (intravenous) folinic acid, alkaline diuresis, and rapid CSF drainage and ventriculolumbar perfusion.
There are published case reports of intravenous and intrathecal carboxypeptidase G2 treatment to hasten clearance of methotrexate in cases of overdose.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Methotrexate has as its principal mechanism of action the competitive inhibition of the enzyme folic acid reductase. Folic acid must be reduced to tetrahydrofolic acid by this enzyme in the process of DNA synthesis and cellular replication. Methotrexate inhibits the reduction of folic acid and interferes with tissue cell reproduction. Methotrexate is a phase specific substance. Its main effect is directed to the S-phase of cell division. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, dermal epithelium, buccal and intestinal mucosa and cells of the urinary bladder are in general more sensitive to the effects of methotrexate. Cellular proliferation in malignant tissue is greater than in most normal tissue and thus methotrexate may impair malignant growth without irreversible damage to normal tissues.
In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over that in normal skin. This differential in reproduction rates is the basis for the use of methotrexate to control the psoriatic process.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

After parenteral injection, peak serum levels are seen in about 0.25-2.0 hours.

Distribution.

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

Metabolism.

Methotrexate does not appear to be appreciably metabolised. It is predominantly excreted by the kidneys and small amounts appear in the faeces. Approximately 10% of the administered methotrexate dose is metabolised intra-hepatically. The principal metabolite is 7-hydroxymethotrexate.

Excretion.

Elimination is triphasic. The first phase probably describes distribution into organs; the second, renal excretion; and the third, passing of methotrexate into the enterohepatic circulation. Excretion occurs mainly through the kidneys. Approximately 41% of the dose is excreted unchanged in the urine during the first six hours; 90% within 24 hours. Repeated daily doses result in more sustained serum levels and some retention of methotrexate over each 24 hour period which may result in accumulation of the drug within the tissues. The liver cells appear to retain certain amounts of the drug for prolonged periods even after a single therapeutic dose. Methotrexate is retained in the presence of impaired renal function and may increase rapidly in the serum and in the tissue cells under such conditions.

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/10T½ clone 8 cells and was associated with an increased incidence of large colony mutants at the tk locus in L5178Y/tk± mouse lymphoma cells. In vivo, it caused an increased incidence of polychromatic erythrocytes in mice and a transient and reversible increase in chromosomal aberrations in human bone marrow cells. The clinical significance of these findings is uncertain.

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium hydroxide, water for injections, sodium chloride (only for 50 mg/2 mL and 500 mg/20 mL).

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. Protect from light.

6.5 Nature and Contents of Container

Methotrexate Injection BP 50 mg/2 mL (sterile) plastic vial.
Methotrexate Injection BP 500 mg/20 mL (sterile) plastic vial.
Methotrexate Injection BP 1000 mg/10 mL (sterile) plastic vial.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

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

Chemical structure.


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

CAS number.

59-05-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes