Consumer medicine information

DBL Methotrexate Injection

Methotrexate

BRAND INFORMATION

Brand name

DBL Methotrexate Injection

Active ingredient

Methotrexate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Methotrexate Injection.

SUMMARY CMI

DBL™ 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 DBL Methotrexate Injection?

DBL Methotrexate Injection contains the active ingredient methotrexate. DBL Methotrexate Injection is used to treat certain types of cancers, severe psoriasis or rheumatoid arthritis when the condition does not improve with other medicines.

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

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

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

3. What if I am taking other medicines?

Some medicines may interfere with DBL 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 DBL 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 DBL Methotrexate Injection? in the full CMI.

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

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using DBL Methotrexate.
  • You and your partner must use a reliable method of contraception (birth control pills or condom) during treatment with DBL 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 DBL 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 DBL Methotrexate.
Driving or using machines
  • Do not drive or operate machinery until you know how DBL Methotrexate affects you. DBL 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 DBL Methotrexate and cause liver damage.

For more information, see Section 5. What should I know while using DBL 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. DBL 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:
DBL 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 3 months after the end of treatment for men and 6 months after the end of treatment for women.
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 psoriasis 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

DBL™ Methotrexate Injection

Active ingredient(s): methotrexate


Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using DBL Methotrexate Injection?

DBL Methotrexate Injection contains the active ingredient methotrexate.

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

DBL Methotrexate Injection is used to treat certain types of cancers. It may also be used in severe psoriasis or rheumatoid arthritis 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. In rheumatoid arthritis, this medicine reduces the overactivity of the immune system leading to less pain, swelling and damage to the joints.

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

Warnings

Do not use DBL 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 have severe kidney problems
  3. you have lowered immunity due to diseases or due to other treatments
  4. you are breastfeeding
  5. you are taking vitamin A derivatives (such as acitretin), medicines used to treat psoriasis and other skin conditions
  6. you are receiving radiotherapy (radiation therapy) e.g. x-rays, ultra violet radiotherapy
  7. you are receiving a live vaccine

Do not use DBL Methotrexate Injection to treat psoriasis or rheumatoid arthritis if you:

  1. are pregnant
  2. have poor nutrition
  3. have any blood disorders, or conditions which cause a low number of red blood cells, white blood cells, or platelets
  4. have bone marrow disease
  5. have low iron in the blood (anaemia)
  6. have liver or severe kidney problems
  7. are an alcoholic
  8. have infectious disease or severe infections
  9. have stomach ulcers (peptic ulcer disease)
  10. 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 DBL Methotrexate Injection and for at least 3 months after you stop treatment for men and at least 6 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.

DBL 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 DBL 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

DBL 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 DBL Methotrexate Injection.

4. How do I use DBL 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 DBL Methotrexate Injection is given

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

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

If you use too much DBL Methotrexate Injection

As DBL 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 DBL Methotrexate Injection or experience severe side effects, you may need urgent medical attention.

Symptoms of a DBL 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 DBL 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 DBL 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 DBL Methotrexate Injection.

Some patients have reported acute bleeding in the lungs when using DBL Methotrexate Injection to treat rheumatoid arthritis and other related diseases.

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.

DBL 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

DBL 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.

DBL 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 DBL 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 DBL Methotrexate Injection affects you.

DBL 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 DBL Methotrexate Injection and cause liver damage.

Looking after your medicine

DBL 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)
Speak to your doctor if you have any of these side effects and they worry you.
Side effectsWhat to do
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)
Eye related
  • temporary blindness
Lung related
  • persistent dry, non-productive cough
  • shortness of breath, wheezing, difficulty breathing or chest pain (may be due to accumulation of fluid in the lungs called pulmonary oedema)
  • spitting or coughing blood
Nervous system related
  • fits, seizures or convulsions
  • difficulty speaking, writing or understanding language
  • weakness in the legs that spreads to the upper limbs and the face, which may result in paralysis
  • headache, dizziness, vomiting, loss of coordination or confusion (may be due to accumulation of fluid in the brain called brain oedema).
Infection related
  • fever and chills, sore throat, sweats, body aches or feel generally unwell
  • sore mouth (mouth ulcers, blisters), difficulty swallowing, cold sores, swollen glands
Severe skin reaction related
  • skin redness/rash, pinpoint red spots, ulceration, blistering; hives or itchy skin
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals (Stevens-Johnson syndrome)
  • dark red or black patches of skin around the injection site
Bleeding related
  • blood in urine, vomit or bowel motion (e.g. black tarry stools, black vomit)
  • bleeding or bruising more easily than usual (e.g. bleeding gums, broken blood vessels)
Kidney related
  • swelling of hands, ankles or feet
  • frequent or painful urination, difficulty urinating, blood in urine, lower back or side pain
Liver related
  • yellowing of the skin and eyes, nausea, vomiting, loss of appetite, feeling generally unwell, fever, itchy or lighter patches on the skin, pale coloured stools, dark coloured urine
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

Other side effects not listed 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 DBL Methotrexate Injection contains

Active ingredient
(main ingredient)
methotrexate
Other ingredients
(inactive ingredients)

water for injections

sodium chloride (except for 1 g/10 mL)

sodium hydroxide

hydrochloric acid (as pH-adjustment agent)

sodium hydroxide (as pH-adjustment agent)

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

What DBL Methotrexate Injection looks like

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

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

  • 5 mg/2 mL vial x 5 AUST R 16313
  • 50 mg/2 mL vial x 5 AUST R 16314
  • 500 mg/20 mL vial x 1 AUST R 47252
  • 1 g/10 mL vial x 1 AUST R 16312

Who distributes DBL Methotrexate Injection

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

This leaflet was prepared in August 2023

Published by MIMS October 2023

BRAND INFORMATION

Brand name

DBL Methotrexate Injection

Active ingredient

Methotrexate

Schedule

S4

 

1 Name of Medicine

Methotrexate BP.

2 Qualitative and Quantitative Composition

DBL Methotrexate Injection 5 mg/2 mL.

Each 2 mL vial contains 5 mg methotrexate.

DBL Methotrexate Injection 50 mg/2 mL.

Each 2 mL vial contains 50 mg methotrexate.

DBL Methotrexate Injection 500 mg/20 mL.

Each 20 mL vial contains 500 mg methotrexate.

DBL Methotrexate Injection 1 g/10 mL.

Each 10 mL vial contains 1 g methotrexate.
Sodium chloride is included for isotonicity except in the 1 g/10 mL vial.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
DBL Methotrexate Injection is a clear yellow solution. DBL Methotrexate Injection is preservative-free. DBL Methotrexate Injection has a pH of 7.5 to 9.0.

4 Clinical Particulars

4.1 Therapeutic Indications

Antineoplastic chemotherapy.

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

High dose therapy.

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

Psoriasis chemotherapy (see Boxed Warnings).

Methotrexate may be of value in the symptomatic control of severe, recalcitrant, disabling psoriasis which is not adequately responsive to other forms of treatment. However, due to the high risk associated with its use, methotrexate should be used after the diagnosis has been definitely established, as by biopsy and/or after dermatologic consultation.

Rheumatoid arthritis chemotherapy (see Boxed Warnings).

Management of severe, recalcitrant, active rheumatoid arthritis in adults not responding to, or intolerant of, an adequate trial of NSAIDs and one or more disease modifying drugs.
Aspirin, NSAIDs and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylate has not been fully explored.
Steroids may be reduced gradually in patients who respond to methotrexate.
Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine or cytotoxic agents has not been studied and may increase the incidence of adverse effects. Rest and physiotherapy as indicated should be continued.

4.2 Dose and Method of Administration

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

Dosage.

(a) Antineoplastic chemotherapy.

Trophoblastic neoplasms.

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

Breast carcinoma.

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

Leukaemia.

Acute lymphatic (lymphoblastic) leukaemia in children and young adolescents is the most responsive to present day chemotherapy. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common. In chronic lymphatic leukaemia, the prognosis for adequate response is less encouraging.
Methotrexate in doses of 3.3 mg/m2 orally in combination with prednisolone 60 mg/m2 daily has been given for induction of remission of lymphoblastic leukaemia. When remission and general clinical improvement have been attained, a maintenance dosage of methotrexate 30 mg/m2 IM twice weekly may be given. This treatment is expected to produce remission in 50% of patients treated, usually within 4 to 6 weeks.
Alternatively, 2.5 mg/kg IV every 14 days may be given. Should relapse occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen. A variety of dosage schedules for both induction and maintenance of remission with various combinations of alkylating and antifolic agents have recently been introduced. Multiple drug therapy with several agents, including methotrexate given concomitantly, appears to be gaining increasing support in both the acute and chronic forms of leukaemia.
Acute granulocytic leukaemia is rare in children but common in adults. This form of leukaemia responds poorly to chemotherapy and remissions are short with relapses common. Resistance to therapy also develops rapidly.

Meningeal leukaemia.

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

Lymphomas.

The usual dosage of methotrexate for the treatment of stage I or II of Burkitt's lymphoma is 10 to 25 mg per day orally for 4 to 8 days. In stage III, methotrexate is commonly given concomitantly with other antineoplastic agents. In all stages, several courses of drug therapy are usually administered interposed with 7 to 10 day rest periods. Lymphosarcomas in stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 mg to 2.5 mg/kg daily.
Methotrexate is of no value in the treatment of Hodgkin's disease.

Mycosis fungoides.

Methotrexate has been given IM (intramuscularly) in doses of 50 mg once weekly or 25 mg twice weekly. Initial dosage and dosage adjustment are determined by patient response and haematologic monitoring.
Methotrexate appears to produce clinical remissions in 50% of the cases treated.
(b) High-dosage therapy. (See Section 4.4 Special Warnings and Precautions for Use).
Recent published literature should be consulted for details; dosage regimens have varied considerably in different studies depending upon the nature and severity of the disease, the experience of the investigator, etc. It must be emphasised that high dosages should be only used by qualified specialists and in hospitals where the necessary facilities are available.
In order to prevent precipitation of methotrexate in the renal tubules, the patients should maintain an adequate urine flow by drinking plenty of fluids for 2 days after a high dose injection (greater than 200 mg), and keep the urine alkaline by using sodium bicarbonate continuously for at least 24 hours afterwards.
(c) Psoriasis chemotherapy. The patient should be fully informed of the risks involved and should be under constant supervision of the physician.
Assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests (such as haemogram, urinalysis, serum creatinine, liver function studies and liver biopsy if indicated) before beginning methotrexate, periodically during methotrexate therapy and before reinstituting methotrexate therapy after a rest period. Appropriate steps should be taken to avoid conception for at least 12 weeks following methotrexate therapy.
The commonly used injectable dosage schedule is weekly parenteral intermittent large doses.
All schedules should be continually tailored to the individual patient. A single test dose of 5 to 10 mg parenterally one week prior to initiation of therapy is recommended to detect any idiosyncratic reaction.

Recommended dose schedules for a 70 kg adult.

Weekly single dose schedule: 10 to 25 mg IM or IV per week until adequate response is achieved. Weekly dosage should not exceed 50 mg.
Dosage may be gradually adjusted to achieve optimal clinical response, but not to exceed the maximum stated. After optimal response has been achieved, each dosage schedule should be reduced to the lowest possible dose with the largest possible rest period. Conventional topical therapy should be resumed as soon as possible.
(d) Rheumatoid arthritis chemotherapy. The patient should be fully informed of the risks involved and should be under constant supervision of the doctor.
Assessment of haematological, hepatic, renal and pulmonary function should be made by history, physical examination and laboratory tests before beginning, periodically during and before reinstituting methotrexate therapy. Appropriate steps should be taken in men and women to avoid conception during methotrexate therapy.
Both the doctor 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.
All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects. Complete blood count with platelets should be evaluated seven to ten days later.
Therapeutic response usually begins within three to six weeks and the patient may continue to improve for another twelve weeks or more. The dosage in each schedule may be increased to 15 mg/week after six weeks in non-responsive patients. If necessary, dosage may be gradually increased further to achieve optimal response, but not ordinarily to exceed a total weekly dosage of 20 mg. Once response has been achieved, each schedule should be reduced, if possible, to the lowest possible amount of drug and with the longest rest period.
The optimal duration of therapy is unknown. Limited data available from long-term studies indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within three to six weeks.

Method of administration.

DBL Methotrexate Injection products suitable for IV, IM, intra-arterial or intrathecal use.

DBL Methotrexate 5 mg/2 mL injection vial.
DBL Methotrexate 50 mg/2 mL injection BP vial.
DBL Methotrexate 500 mg/20 mL injection BP vial.

DBL Methotrexate Injection products suitable for IV use only. Not for intrathecal use as the solution is hypertonic.

DBL Methotrexate 1 g/10 mL injection vial (Hypertonic).
A guideline of a ratio of 1:30 is given for the conversion of mg/kg bodyweight to mg/m2 body surface area. The conversion factor varies between 1:20 and 1:40 depending on age and body build.
Instructions for handling. The following protective recommendations are given due to the toxic nature of this substance:
Personnel should be trained in good handling technique.
Pregnant staff should be excluded from working with this drug.
Personnel handling injectable methotrexate should wear protective clothing including goggles, gowns and disposable gloves and masks.
A designated area should be assigned for preparation (preferably under a laminar flow system), with the work surface protected by disposable, plastic backed, absorbent paper.
All items used for administration or cleaning, including gloves, should be placed in high risk, waste disposal bags for high temperature incineration.
Accidental contact with the skin or eyes should be treated immediately by copious lavage with water or sodium bicarbonate solution; medical attention should be sought.
Caution.

Pharmacist.

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

4.3 Contraindications

Methotrexate is contraindicated in patients with severe renal impairment.
In the treatment of psoriasis and rheumatoid arthritis, methotrexate is contraindicated in pregnant women and in patients with poor nutritional status, bone marrow depression, hepatic disorders or in those with pre-existing blood dyscrasias, such as bone marrow hypoplasia, leucopenia, thrombocytopenia or anaemia.
Methotrexate is contraindicated in patients with overt or laboratory evidence of immunodeficiency syndrome(s).
Breastfeeding is contraindicated in women taking methotrexate.
Methotrexate is contraindicated in rheumatoid arthritis patients with active, infectious disease or psoriasis patients with serious infections, and in psoriasis and rheumatoid arthritis patients with peptic ulcer disease or ulcerative colitis. Methotrexate is contraindicated in psoriatic and rheumatoid arthritis patients suffering severe renal disorders, alcoholism or hepatic disorders including alcoholic liver disease or other chronic liver disease.
Methotrexate is contraindicated in patients with a known hypersensitivity to it or to any of the excipients.
During methotrexate therapy, concurrent vaccination with live vaccines must not be carried out.
Radiotherapy to the central nervous system should not be given concurrently with intrathecal methotrexate.
An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Therefore, the combination of methotrexate and acitretin is also contraindicated.

4.4 Special Warnings and Precautions for Use

(See Boxed Warnings.)

General.

Methotrexate must only be used by physicians experienced in antimetabolite chemotherapy or, in the case of non-oncological conditions, by a specialist physician.
Because of the possibility of serious toxic reactions (which can be fatal), methotrexate should be used only in neoplastic diseases (as indicated), or in patients with severe, recalcitrant, disabling psoriasis or rheumatoid arthritis that is not adequately responsive to other forms of therapy. The patient should be informed by the physician of the risks involved and should be under a physician's constant supervision.
Methotrexate has a high potential for toxicity, which is usually dose-related. The physician should be familiar with the various characteristics of the drug and its established clinical usage. Because the toxic effects can occur at any time during methotrexate therapy, patients must be kept under appropriate supervision so that signs or symptoms of possible toxicity or adverse effects may be detected as early as possible. This is especially important in patients undergoing high dose therapy or in those where drug elimination could be impaired (renal impairment, pleural effusion, ascites).
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 dosage should be reduced or drug discontinued and appropriate corrective measures taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent haemodialysis with a high-flux dialyser. Caution should be exercised when reinstituting methotrexate therapy and adequate consideration given to the need for further drug administration and alertness to the possible recurrence of toxicity.
Methotrexate exits slowly from the third-space compartments (e.g. pleural effusions or ascites). This results in a prolonged terminal phase half-life and unexpected toxicity. In patients with significant third-space accumulation, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels.
Methotrexate should be used with extreme caution in the presence of peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age.
Methotrexate should be used with extreme caution in the presence of active infection, and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes.
Like other cytotoxic drugs, methotrexate may induce "tumour lysis syndrome" in patients with rapidly growing tumours. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.
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).

Haematologic.

Pretreatment and periodic haematologic evaluations are essential to the use of methotrexate in chemotherapy because of its haematopoietic suppressive effects, manifesting as anaemia, aplastic anaemia, pancytopenia, leucopenia, neutropenia and/or thrombocytopenia. This may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates immediate cessation of the drug and appropriate therapy. Methotrexate should be used with caution, if at all, in patients with malignant disease who have pre-existing bone marrow aplasia, leucopenia, thrombocytopenia, or anaemia.
In the treatment of neoplastic diseases, methotrexate should be continued only if the potential benefit outweighs the risk of severe myelosuppression. In psoriasis and rheumatoid arthritis, methotrexate should be stopped immediately if there is a significant drop in blood cell counts.

Gastrointestinal.

If vomiting, diarrhoea or stomatitis occur, resulting in dehydration, supportive therapy should be instituted and methotrexate discontinued until recovery occurs.

Pulmonary.

Acute or chronic interstitial pneumonitis and pleural effusion, often associated with blood eosinophilia, may occur and deaths have been reported. Rheumatoid arthritis patients are at risk to develop rheumatoid lung disease, which is often associated with interstitial pulmonary disease. Methotrexate may exacerbate this underlying lung disease.
Methotrexate has been associated with pulmonary toxicity, which is potentially fatal. Patients should be closely monitored for pulmonary symptoms at each follow-up visit. Methotrexate should be discontinued and careful clinical evaluation should be performed in patients developing pulmonary manifestations (especially a dry, non-productive cough). Although clinically variable, the typical patient with methotrexate-induced lung disease presents with fever, cough, chest pain, dyspnoea, hypoxaemia and an infiltrate on X-ray; infection needs to be excluded. This lesion can occur at all dosages (see Boxed Warnings). Infection (including pneumonia) needs to be excluded.
If methotrexate-induced lung disease is suspected, treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.
Methotrexate-induced pulmonary toxicity may occur at any time during therapy and may not be fully reversible.
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.

Laboratory test monitoring of patients.

The following laboratory tests should be carried out as part of the essential clinical evaluation and appropriate monitoring of patients on methotrexate therapy; complete haemogram; haematocrit; urinalysis; renal and liver function tests. A chest X-ray is recommended. The tests should be performed prior to, during and after therapy.
During therapy for psoriasis, monitoring of the following parameters is recommended: haematology at least monthly, liver and renal function every one to three months. More frequent monitoring is usually indicated during antineoplastic therapy. It is important to perform liver biopsy or bone marrow aspiration studies where high dose or long-term therapy is being followed. Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available.
During therapy of rheumatoid arthritis and psoriasis, monitoring of the following parameters is recommended: haematology at least monthly, hepatic enzyme levels and renal function every 1 to 2 months. More frequent monitoring is usually indicated during antineoplastic 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.

Hepatic.

Methotrexate causes hepatotoxicity, liver fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic and do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histological 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. Periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
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 risk of developing acute hepatitis and chronic hepatotoxicity in psoriatic patients seems to be correlated not only to the cumulative dose of methotrexate 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 g.

Psoriasis.

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

Rheumatoid arthritis.

In rheumatoid arthritis, age at first use of methotrexate and duration of therapy has been reported as risk factors for hepatotoxicity. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid population. Liver function tests should be performed at baseline and at 4-8 week intervals in patients receiving methotrexate for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values, or chronic hepatitis B or C infection. During therapy, liver biopsy should be performed if there are persistent liver function test abnormalities, or there is a decrease in serum albumin below the normal range (in the setting of well controlled rheumatoid arthritis).
If the results of a liver biopsy show mild changes (Roenigk grades I, II, IIIa), methotrexate may be continued and the patient monitored according to the recommendations listed above. Methotrexate should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy, or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV).

Musculoskeletal.

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

Infection or immunologic states.

Methotrexate therapy has immunosuppressive activity, which can potentially lead to serious or even fatal infections. Bacterial infection may occur or be a threat if profound leucopenia occurs during therapy. In this instance, the drug should be discontinued and appropriate antibiotic therapy instituted. If severe bone marrow depression occurs, blood or platelet transfusions may be required.
Pneumonia (in some cases leading to respiratory failure) may occur. Potentially fatal opportunistic infections, especially Pneumocystis jirovecii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis jirovecii pneumonia should be considered.

Immunisation.

Immunisation may be ineffective when given during methotrexate therapy. Immunisation with live virus vaccines is contraindicated during therapy (see Section 4.3 Contraindications). There have been reports of disseminated vaccinia infections after smallpox immunisation in patients receiving methotrexate therapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Skin.

Severe, occasionally fatal, skin reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis (Lyell's syndrome), and erythema multiforme have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of intramuscular, intravenous or intrathecal administration. Recovery has been reported with discontinuation of therapy.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration has been reported in psoriatic patients. Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.
Patients receiving immunosuppressive therapy, including methotrexate, are at an increased risk of developing skin cancer (melanoma and non-melanoma). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Periodic skin examination is recommended for all patients who are at increased risk for skin cancer and exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Folinic acid deficiency.

Folate deficiency states may increase methotrexate toxicity.
If acute methotrexate toxicity occurs, patients may require folinic acid. In patients with rheumatoid arthritis or psoriasis, folic acid or folinic acid may reduce methotrexate toxicities such as gastrointestinal symptoms, stomatitis, alopecia, and elevated liver enzymes.
Before taking a folate supplement, it is advisable to check B12 levels, since folate administration can mask symptoms of B12 deficiency.

High dose therapy.

Methotrexate has been used in very high dosage followed by leucovorin rescue in the experimental treatment of certain neoplastic disease. This procedure is investigational and hazardous. It should not be attempted outside of facilities where the necessary expertise and resources have been assembled. The recent published literature should be consulted. Large doses should not be used in patients with impaired renal function or a third-space reservoir such as ascites or large pleural effusion. Renal function and serum levels should be carefully monitored in order to reveal potential toxicity. Administration of calcium folinate is mandatory in high-dose methotrexate therapy. The administration of calcium folinate, hydration and alkalinisation of the urine should be carried out with constant monitoring of the toxic effects and the elimination of methotrexate in order to prevent renal precipitation in acidic urine.
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. Transient acute neurologic syndrome has been observed in patients treated with high dose regimens of methotrexate. Manifestations of this neurologic syndrome may include behavioural abnormalities, focal sensorimotor signs, including transient blindness and abnormal reflexes. The exact cause is unknown.

Neurologic.

There have been reports of leucoencephalopathy following IV administration of methotrexate in high doses to patients who have had craniospinal irradiation. Symptomatic patients were commonly noted to have leucoencephalopathy, encephalopathy and/or microangiopathic calcifications on diagnostic imaging studies.
Chronic leucoencephalopathy has also been reported in patients who received repeated doses of high-dose methotrexate with folinic acid rescue even without cranial irradiation.
Discontinuation of methotrexate does not always result in complete recovery.
After the intrathecal or high dose use of methotrexate, central nervous system toxicity may occur and can be classified as follows:
1) acute chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity and fever;
2) sub-acute myelopathy usually transient, characterised by e.g. paraparesis/ paraplegia and increased CSF pressure associated with involvement with one or more spinal nerve roots;
3) a delayed syndrome occurring months to years after treatment characterised by necrotising leucoencephalopathy and manifested by confusion, irritability, somnolence, ataxia, dementia, occasionally convulsions and, rarely, death. The effects are dose-related and occur particularly when intrathecal methotrexate is given at doses greater than 50 mg in combination with cranial irradiation and systemic methotrexate therapy.
Central nervous system toxicity can be progressive and even fatal. There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leucoencephalopathy. Signs of neurotoxicity (meningeal irritation, transient or permanent paresis, encephalopathy) should be monitored following intrathecal administration of methotrexate.
Intrathecal and intravenous administration of methotrexate may also result in acute encephalitis and acute encephalopathy with fatal outcome.
There have been reports of patients with periventricular CNS lymphoma who developed cerebral herniation with the administration of intrathecal methotrexate.
Cases of severe neurological adverse reactions ranging from headache to paralysis, coma and stroke-like episodes have been reported mostly in juveniles and adolescents given intrathecal methotrexate in combination with intravenous cytarabine. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Instructions to patients.

1. Patients should be informed of the potential benefit and risk in the use of methotrexate. The risk of effects on reproduction should be discussed with both male and female patients taking methotrexate.
2. Patients should be informed of the early signs and symptoms of toxicity, of the need to see their doctor promptly if they occur, and the need for close follow-up, including periodic laboratory tests to monitor toxicity. Baseline assessment should include a complete blood count with differential and platelet counts; hepatic enzymes; hepatitis B or C infection testing, renal function tests; and a chest X-ray.
3. 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).

Use in hepatic impairment.

Transient abnormalities of liver function tests (elevated transaminases) are observed frequently but persistent abnormalities and/or significant decreases in serum albumin may indicate serious liver toxicity and require evaluation. Liver biopsy is currently believed to be the only reliable measure of methotrexate-induced hepatotoxicity.
When to perform a liver biopsy in rheumatoid arthritis patients has not been established, either in terms of cumulative methotrexate dose or duration of therapy. There is a combined reported experience in 217 patients with rheumatoid arthritis with liver biopsy both before and during treatment (after a cumulative dose of at least 1500 mg) and in 714 patients with a biopsy only during treatment. There were 64 (7%) cases of fibrosis and only one (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks. When methotrexate is discontinued, a "flare" of arthritis usually occurs within three to six weeks.

Use in renal impairment.

As methotrexate is excreted primarily by the kidney, its use in the presence of impaired renal function may lead to drug accumulation with resultant toxicity or even additional renal damage. The renal status of the patient should be determined prior to and periodically during methotrexate therapy. Caution should be exercised if significant renal impairment is present because impairment of renal function will decrease methotrexate elimination. Drug dosage should be reduced or discontinued until renal function is improved or restored. The urine should be kept alkaline throughout therapy with methotrexate (methotrexate is a weak acid and tends to precipitate at urine pH below 6.0).
Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function including adequate hydration, urine alkalinisation and measurement of serum methotrexate and renal function are recommended.
Concomitant use of proton pump inhibitors (PPIs) and high dose methotrexate should be avoided, especially in patients with renal impairment (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Proton pump inhibitors).

Methotrexate level.

Serum methotrexate level monitoring can significantly reduce toxicity and mortality by allowing the adjustment of methotrexate dosing and the implementation of appropriate rescue measures.
Patients subject to the following conditions are predisposed to developing elevated or prolonged methotrexate levels and benefit from routine monitoring of levels: e.g. pleural effusion, ascites, gastrointestinal tract obstruction, previous cisplatin therapy, dehydration, aciduria, impaired renal function.
Some patients may have delayed methotrexate clearance in the absence of these features. It is important that 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 of methotrexate concentrations should include determination of a methotrexate level at 24, 48 or 72 hours, and assessment of the rate of decline in methotrexate concentrations (to determine how long to continue folinic acid rescue).

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.

Serious neurotoxicity, frequently manifested as generalised or focal seizures, has been reported with unexpectedly increased frequency among paediatric patients with acute lymphoblastic leukaemia who were treated with intermediate-dose intravenous methotrexate (1 g/m2).
Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis.
Overdose by intravenous and intrathecal miscalculation of dosage (particularly in juveniles) have occurred. Special attention must be given to dose calculation (see Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs highly bound to plasma proteins.

As methotrexate is partly bound to serum proteins, its toxicity may be increased as a result of displacement by certain drugs such as salicylates, phenylbutazone, sulphonamides, sulphonylureas, phenytoin, para-aminobenzoic acid, some antibiotics such as penicillins, tetracycline, pristinamycin, probenecid, and chloramphenicol. These drugs, particularly salicylates and sulphonamides, should not be given concurrently until the significance of these findings is established.

Probenecid.

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

Antibiotics.

Ciprofloxacin.

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

Penicillins and sulfonamides.

Penicillins and sulfonamides may reduce the renal clearance of methotrexate; haematologic and gastrointestinal toxicity has been observed in combination with high- and low-dose methotrexate.
The excretion of methotrexate from the body can be markedly reduced by the concurrent use of penicillins and sulfonamides. There is a considerable risk of methotrexate toxicity. 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 alone and sulfamethoxazole/ trimethoprim have been reported rarely to increase the toxic effects (e.g. bone marrow suppression) of methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. Increased toxic effects (e.g. bone marrow suppression) have also been reported in patients receiving methotrexate and pyrimethamine.

Hypolipidaemic compounds.

Hypolipidaemic compounds such as cholestyramine provided preferential binding sites compared to serum proteins when given in combination with methotrexate. This may lead to decreased methotrexate serum levels.

Vitamins.

In inflammatory arthritis, such as rheumatoid arthritis, concomitant treatment with folinic acid or folic acid may decrease the incidence or severity of adverse effects from methotrexate therapy. It is not known whether these medications may decrease the efficacy of methotrexate in treating arthritis. Because vitamin preparations containing folic acid or folinic acid may decrease the effectiveness or alter the responses to methotrexate these should not be given to patients taking methotrexate for conditions other than arthritis, including in the treatment of neoplastic disease. 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.

Disease-modifying antirheumatic drug (DMARD) and nonsteroidal anti-inflammatory drugs (NSAIDs).

Oncology indications.

NSAIDs should not be administered prior to or concomitantly with high doses of methotrexate such as used in the treatment of osteosarcoma. NSAIDs elevate and prolong serum methotrexate levels, resulting in deaths from severe haematologic (including bone marrow suppression and aplastic anaemia) and gastrointestinal toxicity. These unexpectedly severe toxicities have been reported with concomitant administration of methotrexate and aspirin, 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.
Caution should be used when NSAIDs or salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity.

Non-oncology indications.

In treating rheumatoid arthritis with methotrexate, aspirin, NSAIDs, and/or low dose steroids may be continued. Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and the larger doses could lead to unexpected toxicity. Therefore, until more is known about the NSAID/methotrexate interaction, it is recommended that methotrexate dosage be carefully controlled during treatment with NSAIDs.
Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, has not been studied and may increase the incidence of adverse effects.

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.

Chemotherapeutic agents.

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 effects of methotrexate.

Mercaptopurine.

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

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 performed 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.

Nitrous oxide anesthesia.

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, 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.

Hepatotoxic agents.

An increased risk of hepatotoxicity has been reported when methotrexate and etretinate are given concurrently (see Section 4.3 Contraindications).
The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g. leflunomide, azathioprine, retinoids, sulfasalazine and alcohol) should be closely monitored for possible increased risk of hepatotoxicity.

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.

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).

Proton pump inhibitors.

A potential interaction may exist between methotrexate and proton pump inhibitors (e.g. omeprazole, pantoprazole).
Use caution when administering high dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydromethotrexate, possibly leading to methotrexate toxicities.
Concomitant use of PPIs and high dose methotrexate should therefore be avoided, especially in patients with 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 lose 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 3 months following discontinuation of methotrexate.
The possible risks of effects on reproduction should be discussed with patients of childbearing potential.
(Category D)
In the treatment of psoriasis and rheumatoid arthritis, use of methotrexate is contraindicated throughout pregnancy (see Section 4.3 Contraindications).
Methotrexate has been shown to be teratogenic. Methotrexate has caused embryotoxicity, abortion, 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 while 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.
Methotrexate has been detected in human breast milk and is contraindicated during breastfeeding. Women should be advised not to breastfeed while being treated with methotrexate.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

The major toxic effects of methotrexate occur on normal, rapidly proliferating tissues, particularly the bone marrow and gastrointestinal tract. Ulcerations of the oral mucosa are usually the earliest signs of toxicity.
Ulcerative stomatitis, leucopenia, nausea and abdominal distress are the most common adverse effects. Others reported include malaise, undue fatigue, chills and fever, dizziness, drowsiness, tinnitus, blurred vision, eye discomfort and decreased resistance to infection. The incidence and severity of side effects generally appear to be dose and frequency related. Adverse effects have been reported for the various systems:

Skin.

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

Blood and lymphatic system.

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

Cardiovascular system.

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

Alimentary system.

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

Urogenital system.

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

Pulmonary system.

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

Central nervous system.

Paresthesia, encephalopathy/leucoencephalopathy, headaches, dizziness, drowsiness, blurred vision, speech impairment including dysarthria and aphasia, cranial nerve disorder/palsies, coma and brain oedema. Aphasia, hemiparesis and convulsions have occurred possibly related to haemorrhage or to complications from intra-arterial catheterisation. Convulsion, paresis, Guillain-Barre syndrome and increased cerebrospinal fluid pressures have followed intrathecal administration. Following low doses, occasional patients have reported transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations. Cognitive impairment has been recorded in children who received intrathecal methotrexate together with cranial irradiation. Other side effects include: neurotoxicity, arachnoiditis, paraplegia, stupor, ataxia, dementia, motor dysfunction, depression, confusional state and irritability.

Ophthalmic.

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

Ear and labyrinth disorders.

Tinnitus.

Infections.

There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis jirovecii pneumonia was the most common infection. Other reported infections include pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, herpes zoster, H. simplex hepatitis, disseminated H. simplex, fatal sepsis and cytomegalovirus, including cytomegaloviral pneumonia, reactivation of hepatitis B infection, worsening of hepatitis C infection, respiratory tract infection, cutaneous bacterial infections.

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

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

Other.

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

General disorders and administration site conditions.

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

Reporting suspected adverse effects.

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

4.9 Overdose

Discontinue methotrexate at the first sign of ulceration or bleeding, diarrhoea or marked depression of the haematopoietic system.
Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacological doses, particularly haematological and gastrointestinal reactions. For example, leucopenia, thrombocytopenia, anaemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following overdose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic anaemia were also reported.
Symptoms following injectable overdosage would be expected to produce effects which are an extension of the pharmacological effects. The toxic reactions expected would include those listed under Section 4.8 Adverse Effects (Undesirable Effects).
Calcium folinate (leucovorin calcium) is a potent agent for neutralising the immediate toxic effects of methotrexate on the haematopoietic system. In general, when overdosage is suspected, the dose of calcium folinate should be equal to or higher than the offending dose of methotrexate, and should be given as soon as possible, preferably within the first hour, after which it is much less effective. Calcium folinate may be administered by IV infusion in doses of up to 75 mg within 12 hours, followed by 12 mg IM every 6 hours for 4 doses. When average doses of methotrexate appear to have an adverse effect, 6 to 12 mg of calcium folinate may be given IM every 6 hours for 4 doses.
Concomitant hydration and alkalinisation of the urine with sodium bicarbonate is recommended to prevent precipitation of methotrexate or its metabolite in the renal tubules. Patients undergoing methotrexate therapy should be advised to increase fluid intake. Neither standard haemodialysis nor peritoneal dialysis 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 dialyzer.
Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinisation, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent haemodialysis with a high-flux dialyzer may also be beneficial in these patients.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Methotrexate is an antimetabolite antineoplastic agent, which exerts its cytotoxic effect through competitive inhibition of dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolic acid results in interference with DNA synthesis and cellular reproduction.
Tissues with high rates of cellular proliferation, e.g. malignant cells, bone marrow, fetal cells, dermal epithelium, buccal and intestinal mucosa and cells of the urinary bladder are generally more sensitive to this effect of methotrexate.
In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in reproductive rates provides the basis for use of methotrexate to control the psoriatic process.
In patients with rheumatoid arthritis, effects of methotrexate on articular swelling and tenderness can be seen as early as three to six weeks. Although methotrexate clearly ameliorates symptoms of inflammation (pain, swelling, stiffness) there is no evidence that it reduces remission of rheumatoid arthritis nor has a beneficial effect been demonstrated on bone erosion and other radiological changes which result in impaired joint use, functional disability and deformity. Most studies of methotrexate in patients with rheumatoid arthritis are relatively short term (three to six months). Data from long-term studies indicate that an initial clinical improvement is maintained for at least two years with continued therapy.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Peak serum levels may be achieved within 0.5 to 2 hours following intravenous (IV) or intramuscular (IM) administration.
Approximately 50% of the absorbed methotrexate is reversibly bound to serum proteins. Methotrexate is widely distributed into body tissues and concentrates in the kidneys, liver and gastrointestinal tract. It also distributes into third space accumulation of fluid, e.g. ascites or pleural effusions. Methotrexate does not reach therapeutic concentrations in the cerebrospinal fluid (CSF) when given orally or parenterally. High concentrations of the drug, when needed, may be attained by intrathecal injection.
Methotrexate does not appear to be appreciably metabolised. Methotrexate is predominantly excreted by the kidneys and small amounts appear in the faeces. Excretion of methotrexate is reduced in the presence of impaired renal function.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

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.

Reproductive and developmental toxicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Water for Injections BP, Sodium Chloride BP (except for 1 g/10 mL), Sodium Hydroxide BP, Hydrochloric acid (as pH-adjustment agent), Sodium hydroxide (as pH-adjustment agent).

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

The liquid vials are preservative-free and should therefore be used once only and discarded.
DBL Methotrexate Injection, when diluted to a concentration of 1 mg/mL with sodium chloride 0.9% injection, glucose 5% injection, Hartmann's Injection, Ringer's Injection and 5% glucose in 0.9% sodium chloride injection, retains its potency for 24 hours when stored at room temperature in the presence and absence of fluorescent light.
However, because of microbiological contamination hazards, infusion of the admixed solutions should commence as soon as possible after preparation, and in any case, should be completed within 24 hours. Storage of admixed solutions should be at 2 to 8°C.
Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

DBL Methotrexate Injection is available in the following presentations:
DBL Methotrexate Injection 5 mg/2 mL clear glass vials, packs of 5.
DBL Methotrexate Injection 50 mg/2 mL clear glass vials, packs of 5.
DBL Methotrexate Injection 500 mg/20 mL clear glass vials, single packs.
DBL Methotrexate Injection 1 g/10 mL clear glass vials, single packs.

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

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