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.

What is in this leaflet

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

All medicines have risks and benefits. Your doctor has weighed the risks of you being given methotrexate against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

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

What DBL™ Methotrexate Injection is used for

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

This medicine belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines.

This medicine works by blocking an enzyme needed by body cells to live. This interferes with the growth of some cells that are growing rapidly, such as skin cells in psoriasis and cancer cells.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

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

Before you are given DBL™ Methotrexate Injection

When you must not be given it

You must not be given DBL™ Methotrexate Injection if you have an allergy to:

  • any medicine containing methotrexate
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include 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.

Females: tell your doctor or pharmacist if you are pregnant or intend to become pregnant. Like most cytotoxic medicines DBL™ Methotrexate Injection is not recommended for use during pregnancy. If there is any need to consider DBL™ Methotrexate Injection during your pregnancy, your doctor or pharmacist will discuss with you the benefits and risks of using it.

Males: tell your doctor or pharmacist if your partner intends to become pregnant while you are being given DBL™ Methotrexate Injection or shortly after you have stopped treatment with DBL™ Methotrexate Injection.

DBL™ Methotrexate Injection may cause birth defects if either the male or female is using it at the time of conception. It is recommended that you use some kind of birth control while you are using DBL™ Methotrexate Injection and for at least 12 weeks after you stop treatment. A barrier method of birth control, such as a condom, should be used while you are being given DBL™ Methotrexate Injection and for the first week of this 12-week period. Your doctor will discuss this with you.

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

You must not be given this medicine if you have or have had any of the following medical conditions:

  • severe kidney problems
  • lowered immunity due to diseases such as HIV/AIDS, or lowered immunity due to other treatments.

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

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

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

Tell your doctor if you have an infection or high temperature. Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • kidney problems
  • lung problems
  • diabetes
  • folate deficiency.

If you are taking this medicine to treat cancer, tell your doctor if you have or have had any of the following medical conditions:

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

If you have not told your doctor about any of the above, tell him/her before you start being given DBL™ Methotrexate Injection.

Taking other medicines

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

Some medicines and DBL™ Methotrexate Injection may interfere with each other. These include:

  • some antibiotics, including tetracyclines, penicillins, sulphonamides, trimethoprim and chloramphenicol
  • sulphonylureas, a group of medicines used to treat diabetes
  • phenytoin, a medicine used to treat epilepsy
  • folic acid or folinic acid (which may be present in multi-vitamin preparations)
  • non-steroidal anti-inflammatory medicines (NSAIDs) and salicylates, medicines used to relieve pain, swelling and other symptoms of inflammation (such as aspirin, diclofenac, indomethacin, ketoprofen, naproxen, phenylbutazone)
  • 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
  • other medicines used to treat cancer (such as cisplatin, asparaginase, mercaptopurine)
  • medicines which can affect the liver such as azathioprine, leflunomide, retinoids or sulfasalazine
  • pyrimethamine, a medicine used for malaria
  • proton pump inhibitors, such as omeprazole, esomeprazole and pantoprazole
  • methoxsalen (a medicine used with ultraviolet light in PUVA therapy for conditions such as severe psoriasis).
  • Nitrous oxide, used as anaesthetic

These medicines may be affected by DBL™ Methotrexate Injection, or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Tell your doctor if you are due to receive any vaccinations. You should not receive certain vaccinations while being treated with DBL™ Methotrexate Injection.

Your doctor and pharmacist may have more information on medicines/vaccinations to be careful with or avoid while you are being treated with DBL™ Methotrexate Injection.

How DBL™ Methotrexate Injection is given

How much is given

Your doctor will decide what dose of DBL™ Methotrexate Injection you will receive. This depends on your condition and other factors, such as your weight, and other medicines you are being given.

This medicine may be given alone or in combination with other drugs. It may be given as a short course or on an ongoing basis.

Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any unwanted effects have been controlled.

For cancer treatment, several courses of DBL™ Methotrexate Injection therapy may be needed depending on your response to treatment.

For the treatment of psoriasis, DBL™ Methotrexate Injection therapy is usually required long term.

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

How it 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 1000 MG IN 10 ML SHOULD BE USED BY INTRAVENOUS INFUSION ONLY. IT SHOULD NOT BE USED INTRATHECALLY AS THE SOLUTION IS HYPERTONIC.

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

If you have too much (overdose)

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. However, if you experience severe side effects tell your doctor immediately, telephone your doctor or the Poisons Information Centre (telephone 13 11 26 in Australia, or call 0800 764 766 in New Zealand) for advice, or go to Accident and Emergency at the nearest hospital, or go to Accident and Emergency at the nearest hospital. You may need urgent medical attention.

Symptoms of a DBL™ Methotrexate Injection overdose may include the side effects listed below in the 'Side Effects' section, but are usually of a more severe nature. They may include blood in your bowel motions or black, tarry bowel motions, bleeding, nausea, vomiting, mouth ulcers and severe infections.

While you are being given DBL™ Methotrexate Injection

Things you must 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.

Keep all of your doctor's appointments so your progress can be checked. Your doctor may want to check your blood pressure and do some blood and other tests from time to time to check on your progress and to check for any unwanted side effects.

Be careful to use an effective method of birth control while you are being treated with DBL™ Methotrexate Injection and for at least 12 weeks after stopping treatment. A barrier method of birth control, such as a condom, should be used. Your doctor will tell you what forms of contraception are suitable and when it is safe to stop using contraception if you wish to do so.

If you or your partner becomes pregnant while you are being treated with DBL™ Methotrexate Injection, or for up to 12 weeks afterwards, tell your doctor immediately.

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

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

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

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.

Things you must not do

You must not drink alcohol whilst you are being given this medicine. Alcohol may increase the side effects of DBL™ Methotrexate Injection.

Things to be careful of

Be careful driving or operating machinery until you know how DBL™ Methotrexate Injection affects you. This medicine may cause dizziness, drowsiness or tiredness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being given DBL™ Methotrexate Injection.

This medicine may have unwanted side effects. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

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

  • mild nausea
  • stomach pains
  • mild tiredness
  • mild chills
  • mild dizziness
  • drowsiness
  • increased burning of the skin from sun exposure
  • hair loss (usually occurs only with high doses of methotrexate)
  • inflamed mouth gums
  • inflamed mucous membranes (mucositis) or sore mouth
  • loss of appetite
  • changes in menstrual cycle unusual vaginal discharge
  • mild headaches
  • ringing in the ears
  • eye discomfort.

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

Tell your doctor or nurse as soon as possible if you notice any of the following:

  • diarrhoea
  • vomiting
  • mouth ulcers
  • skin rash, itchiness
  • difficulty speaking
  • back pain
  • stiff neck
  • painful joints or muscles
  • irritability and confusion
  • altered conscious state
  • painful urination or difficulty urinating, lower back or side pain (these may be symptoms of kidney disease)
  • swelling of hands, ankles or feet
  • muscle cramps, spasms, weakness or paralysis
  • blurred vision or impaired vision.

The above list includes serious side effects, which may require medical attention.

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

  • 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.
  • swollen glands (lymph nodes)
  • dry, non-productive cough
  • signs of an infection (such as fever, chills, sore throat, cough)
  • tiredness, headaches, dizziness and looking pale
  • unusual bleeding or bruising (including blood in your stools or urine)
  • yellowing of the skin and eyes, nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, and dark coloured urine (these may be symptoms of a type of liver disease called hepatitis)
  • chest pain
  • seizures (fits)
  • skin ulceration or severe skin rash.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

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

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

After being given DBL ™ Methotrexate Injection

Storage

DBL™ Methotrexate Injection will be 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.

Product description

What it looks like

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

Ingredients

DBL™ Methotrexate Injection contains methotrexate as the active ingredient.

It also contains:

  • water for injections
  • sodium chloride.

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

Sponsor

Australian Sponsor:

Hospira Australia Pty Ltd
ABN 58 097 064 330
Level 3
500 Collins Street
Melbourne VIC 3000
Australia

DBL™ Methotrexate Injection comes in the following strengths and pack sizes:

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

This leaflet was updated in February 2020.

Published by MIMS May 2020

BRAND INFORMATION

Brand name

DBL Methotrexate Injection

Active ingredient

Methotrexate

Schedule

S4

 

Notes

Specialist physician only

1 Name of Medicine

Methotrexate BP.

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.

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.

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.

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.

No data available.

Carcinogenicity.

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

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.

4.3 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.
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.)
Methotrexate must only be used by physicians experienced in antimetabolite chemotherapy or, in the case of nononcological conditions, by a specialist physician.
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 such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If methotrexate therapy is reinstituted, it should be carried out with utmost caution, with adequate consideration of further need for the drug, and with increased alertness as to possible recurrence of toxicity.
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.
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.

Check the following before and during use.

If vomiting, diarrhoea or stomatitis occur, resulting in dehydration, methotrexate should be discontinued until recovery occurs.
Methotrexate has been associated with pulmonary toxicity which is potentially fatal. Patients should be closely monitored for pulmonary symptoms. Methotrexate should be discontinued and careful clinical evaluation should be performed in patients developing pulmonary manifestations (especially a dry, nonproductive 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.
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.
Methotrexate should be used with extreme caution in the presence of infection, 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.
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 causes hepatotoxicity, liver fibrosis and cirrhosis, but generally only after prolonged use. 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.
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.
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.
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).
Methotrexate therapy has immunosuppressive activity, which can potentially lead to serious or even fatal infections. Bacterial infection may occur or be a threat if profound leucopenia occurs during therapy. In this instance, the drug should be discontinued and appropriate antibiotic therapy instituted. If severe bone marrow depression occurs, blood or platelet transfusions may be required.
Pneumonia (in some cases leading to respiratory failure) may occur. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.
Immunisation may be ineffective when given during methotrexate therapy. Immunisation with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunisation in patients receiving methotrexate therapy (see Section 4.5).
Severe, occasionally fatal, skin reactions 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.
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.

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.
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 Section 4.4; Boxed Warnings).

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.
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. 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.

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.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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, tetracyclines, chloramphenicol and para-aminobenzoic acid. These drugs, particularly salicylates and sulphonamides, should not be given concurrently until the significance of these findings is established.
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.
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.
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.
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.
NSAIDs should not be administered prior to or concomitantly with high doses of methotrexate. NSAIDs elevate and prolong serum methotrexate levels, resulting in deaths from severe haematologic and gastrointestinal toxicity. These unexpectedly severe toxicities have been reported with concomitant administration of methotrexate and aspirin, other salicylates, asapropazone, 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.
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.
Probenecid may increase the methotrexate plasma half-life and thereby increase blood levels.
A potential interaction may exist between methotrexate and proton pump inhibitors (e.g. omeprazole, pantoprazole).
Concomitant use of allopurinol with methotrexate may result in an increased incidence of cytotoxic induced bone marrow depression.
Methotrexate in combination with leflunomide may also increase the risk of pancytopenia and interstitial pneumonitis.
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.
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.
Folate deficiency states may increase methotrexate toxicity. 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.
Assay for folate. Methotrexate may inhibit the organism used in the assay and interfere with detection of folic acid deficiency.
The use of nitrous oxide anaesthesia potentiates the effect of methotrexate on folate metabolism, yielding severe, unpredictable myelosuppression, stomatitis and neurotoxicity with intrathecal administration. Whilst this effect can be reduced by the use of folinic acid rescue, avoid concomitant use of nitrous oxide in patients receiving methotrexate. Use caution when administering methotrexate after a recent history of nitrous oxide administration.
Amiodarone administration to patients receiving methotrexate treatment for psoriasis has induced ulcerative skin lesions.
An increased risk of hepatotoxicity has been reported when methotrexate and etretinate are given concurrently (see Section 4.3).
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) should be closely monitored for possible increased risk of hepatotoxicity. Methotrexate in combination with leflunomide may also increase the risk of pancytopenia.
Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.
Methotrexate increases the plasma levels of mercaptopurine. Combination of methotrexate and mercaptopurine may therefore require dose adjustment.
The administration of asparaginase has been reported to antagonise the effects of methotrexate.
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).
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.
Methotrexate is an immunosuppressant and may reduce immunological response to concurrent vaccination. Severe antigenic reactions may occur if a live vaccine is given concurrently. 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Methotrexate has been reported to cause chromosome damage. Methotrexate may cause defective oogenesis and spermatogenesis. Therefore, in men and women of fertile age, steps should be taken to avoid conception during methotrexate therapy. The risk of genetic abnormalities may persist after discontinuing methotrexate therapy. Thus it is advised that both men and women avoid intercourse leading to conception for an indefinite period (at least 12 weeks) after discontinuing methotrexate, to ensure the re-establishment of normal germinal cells.
(Category D)
Methotrexate has caused fetal death and/or congenital abnormalities; therefore, it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant psoriatic or rheumatoid arthritis patients should not receive methotrexate. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counselled on the serious risk to the fetus should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate, during and for at least 12 weeks after cessation of therapy.
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.

4.8 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. Burning and erythema may appear in psoriatic areas for 1 to 2 days following each dose. Rarely, painful plaque erosions may appear. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration has been reported in psoriatic patients. Anaphylactic reactions and skin ulceration/necrosis consistent with toxic epidermal necrolysis, soft tissue necrosis and osteonecrosis have also been reported. Severe, occasionally fatal dermatologic reactions, including toxic epidermal necrolysis, 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 proliferative disorders 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, 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), anorexia, nausea, vomiting, diarrhoea, abdominal distress, haematemesis, melaena, gastrointestinal ulceration and bleeding, intestinal perforation, pancreatitis, enteritis, acute and chronic hepatic toxicity resulting in acute liver atrophy, necrosis, fatty metamorphosis, acute hepatitis, periportal fibrosis, or hepatic cirrhosis, elevated liver enzymes, decreased serum albumin 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.

Pulmonary system.

Interstitial pneumonitis, 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 nonproductive), dyspnoea, chest pain, hypoxaemia and/or radiological evidence of pulmonary infiltrates (usually diffuse and/or alveolar).

Central nervous system.

Headaches, drowsiness, blurred vision, speech impairment including dysarthria and aphasia, and coma. 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. There have been reports of leucoencephalopathy following IV administration of methotrexate in high doses to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalised or focal seizures, has been reported with unexpectedly increased frequency among paediatric patients with acute lymphoblastic leukaemia who were treated with intermediate dose intravenous methotrexate (1 g/m2). Symptomatic patients were commonly noted to have leukoencephalopathy, encephalopathy and/or microangiopathic calcifications on diagnostic imaging studies.
After the intrathecal or high dose use of methotrexate, the central nervous system toxicity which may occur can be classified as follows:
1) chemical arachnoiditis manifested by such symptoms as headache, back pain, nuchal rigidity and fever;
2) paresis, usually transient, manifested by paraplegia and increased CSF pressure associated with involvement with one or more spinal nerve roots;
3) a delayed syndrome occurring months to years after treatment characterised by necrotising leucoencephalopathy and manifested by confusion, irritability, somnolence, ataxia, dementia, occasionally convulsions and, rarely, death. The effects are dose related and occur particularly when intrathecal methotrexate is given at doses greater than 50 mg in combination with cranial irradiation and systemic methotrexate therapy.

Ophthalmic.

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

Infections.

There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common infection. Other reported infections include pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, herpes zoster, H. simplex hepatitis, disseminated H. simplex, fatal sepsis and cytomegalovirus, including cytomegaloviral pneumonia.
Other reactions related to or attributed to the use of methotrexate, such as metabolic changes, precipitation of diabetes, osteoporotic effects (including aseptic necrosis of the femoral head), abnormal changes in tissue cells, arthralgia/myalgia, proteinuria, nodulosis, stress fractures, loss of libido, impotence and even sudden death, have been reported.
Radiation dermatitis and sunburn may be "recalled". A few cases of anaphylactoid reactions have been reported.

Carcinogenicity.

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

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.

4.2 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.

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 nonresponsive 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.

Methotrexate may be administered by intramuscular, intravenous, intra-arterial or intrathecal injection. DBL Methotrexate Injection 1000 mg in 10 mL should be used by intravenous infusion only. It should not be used intrathecally as the solution is 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.

4.7 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.

4.9 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, 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, see Section 4.8.
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 dialyser may also be beneficial in these patients.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Water for Injections BP, Sodium Chloride BP (except for 1 g/10 mL), Sodium Hydroxide BP.

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.

Summary Table of Changes