Consumer medicine information

Methoblastin PFS

Methotrexate

BRAND INFORMATION

Brand name

Methoblastin PFS

Active ingredient

Methotrexate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Methoblastin PFS.

What is in this leaflet

This leaflet answers some common questions about METHOBLASTIN® PFS. 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 taking METHOBLASTIN® PFS against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What METHOBLASTIN® PFS is used for

This medicine is used to treat:

  • severe psoriasis (a skin condition)
  • severe rheumatoid arthritis (a chronic inflammatory condition)

when these conditions do not improve with other medicines.

The medicine contains methotrexate, which belongs to a family of medicines called antimetabolites. It may also be called a chemotherapy medicine.

The medicine works by blocking an enzyme needed by the body cells to live. This interferes with the growth of some cells that are growing rapidly in psoriasis. In rheumatoid arthritis, this medicine reduces the overactivity of the immune system leading to less pain, swelling and damage to the joints.

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/is not addictive.

It is only available with a doctor's prescription.

Before you use METHOBLASTIN® PFS

When you must not use it

Do not use the medicine 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.

Do not use the medicine if you have:

  • severe kidney problems
  • a problem with your immune system such as severe or repeated infections, e.g. tuberculosis or HIV /AIDS any blood disorders, or conditions which causes a reduced number of red or white blood cells or platelets
  • are receiving radiotherapy e.g. X-rays, ultraviolet radiotherapy
  • bone marrow disease
  • liver disease
  • poor nutritional status
  • stomach ulcers
  • ulcerative colitis, inflammation of the bowel
  • an infection
  • an alcohol dependence (alcoholism).

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

Do not use live vaccine while you are using METHOBLASTIN® PFS

Do not use the medicine if you are pregnant or trying to become pregnant.

Do not use the medicine if your partner is trying to become pregnant.

Do not use the medicine if you are breastfeeding.

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Do not take this medicine/it after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you start to use it

Tell your doctor if you, your partner or carer becomes pregnant while you are taking or just after you stop taking the medicine.

Tell your doctor if you plan to become pregnant. METHOBLASTIN® PFS is not recommended for use during pregnancy. The medicine may cause birth defects if either you or your partner is taking it. Use a reliable method of birth control, such as the contraceptive pill or a condom, while taking the medicine and for at least 12 weeks after you stop treatment. Your doctor will discuss with you what forms of contraception are suitable and when it is safe to stop using contraception if you wish to do so.

If there is any need to consider methotrexate during your pregnancy, your doctor or pharmacist will discuss with you the benefits and risks of using it.

Your carer should not be a person who is pregnant, or intends to become pregnant.

Tell your doctor if you are breastfeeding or plan to breastfeed. It passes into the breast milk and may affect your baby.

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

  • kidney problems
  • lung problems
  • liver problems
  • fluid or swelling in your abdomen or stomach
  • blood disorders
  • diabetes
  • folate deficiency.
  • cancer

Your doctor may do tests to check your blood, liver and kidneys.

Tell your doctor if you have an infection or high temperature. Your doctor may decide to delay your treatment until the infection has gone.

Tell your doctor if you will have a friend or relative care for you or help to give you the METHOBLASTIN® PFS Your carer will also need to take some precautions, such as wearing of gloves, when handling the injection.

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

If you have not told your doctor about any of the above, tell them before you start using the medicine.

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.

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

Folic acid is included in many multi-vitamin preparations. Folic acid and methotrexate interact with each other if you take them on the same day of the week. It is all right to take these medicines on another day of the week.

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

  • aspirin and other pain relievers or anti-inflammatory medicines
  • non-steroidal anti-inflammatory drugs, used to help with pain relief, such as azapropazone, diclofenac, indomethacin and ketoprofen
  • some antibiotics, including tetracyclines, penicillins, sulphonamides, trimethoprim and chloramphenicol
  • phenytoin, a medicine used to treat epilepsy
  • sulfonylurea medicines used to treat diabetes
  • allopurinol and probenecid, medicines used to treat gout
  • pyrimethamine, a medicine used to prevent malaria
  • cholestyramine, a medicine used to lower blood cholesterol levels
  • theophylline, a medicine used to treat asthma
  • azathioprine, a medicine used to prevent transplant organ rejection
  • amiodarone, a medicine used to treat heart disorders
  • leflunomide, a medicine used to treat rheumatoid arthritis
  • sulfasalazine, a medicine used to treat Crohn's disease, ulcerative colitis and rheumatoid arthritis
  • retinoids (acitretin or e-tretinate), medicines used to treat skin conditions
  • some medicines used to treat cancers (such as asparaginase and mercaptopurine)
  • methoxsalen, a medicine used with UV light for the treatment of skin conditions, such as severe psoriasis
  • proton pump inhibitors, such as omeprazole, esomeprazole or pantoprazole
  • nitrous oxide anaesthesia
  • radiation e.g. X-rays, radiotherapy

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

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

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

Tell your doctor if you drink alcohol. Alcohol may affect how well the methotrexate works. Your doctor has more information on medicines to be careful with or avoid while using this medicine.

Talk to your doctor if you are not sure whether you should be taking this medicine.

How to use METHOBLASTIN® PFS

Important Dosage Instructions

Always read the pharmacist's label to check the exact dose and how often to use it. The dose depends on the condition this medicine is being used for.

Make sure that you understand how often your doctor wants you to use methotrexate to treat your medical condition. There are different doses for rheumatoid arthritis or psoriasis. It is important not to use methotrexate more often or in higher doses than your doctor has prescribed for your condition. You should only use one dose of METHOBLASTIN® PFS per week as directed by your doctor. Overdoses of methotrexate may cause serious illness or death.

If you are unsure about the dosage, ask your doctor or pharmacist.

Never use it more often than your doctor has told you to. Your doctor will tell you how much to use and when to use it.

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
  • it is important that you and your caregiver wear disposable gloves when handling methotrexate injection
  • Accidental contact with the skin or eyes should be treated immediately with copious lavage with water or sodium bicarbonate solution; medical attention should be sought.

How to use it

Your doctor or nurse will show you or your carer how to use the METHOBLASTIN® PFS.

Do not inject the methotrexate until you are confident you can do it on your own.

METHOBLASTIN® PFS should be given subcutaneously (under the skin) around the tummy area or in the thigh (see figure below).

Give the injection a few centimetres away from the belly button area.

Each week, you should use METHOBLASTIN® PFS in a different area.

Alternate between tummy and thigh, and between right and left sides.

Never inject into skin that is tender, bruised, red, hard, scarred or where you have stretch marks, psoriatic patches or lesions.

If you weigh more than 100kg, you should only inject METHOBLASTIN® PFS in your upper thigh and NOT in your abdomen.

This is the best place for the injection.

Injecting the solution:

  1. Remove the pre-filled syringe from the packaging at room temperature.
  2. Warm the syringe gently in your hands before injecting to avoid pain.
  3. Choose an injection site and disinfect it with the alcohol swab provided. Allow at least 60 seconds for the alcohol to dry.

  1. Carefully remove the protective plastic cap by pulling it straight off the syringe. If the cap is very stiff, turn it slightly with a pulling movement. Important: Do not touch the needle of the pre-filled syringe.

  1. Using two fingers, pinch up a fold of skin and quickly insert the needle into the skin at a 90-degree angle.

  1. Insert the needle fully into the fold of skin. Slowly push the plunger down completely to inject the liquid underneath your skin. Hold the skin securely until the injection is completed. Carefully pull the needle straight out.

If you are given the injection by a carer, they should wear protective clothing and ensure they wash their hands before and after giving the injection.

You should use or be given the entire dose in the syringe.

Use METHOBLASTIN® PFS once a week on the same day each week for rheumatoid arthritis and psoriasis. Only use your injection on the day agreed with your doctor or pharmacist.

Do not use METHOBLASTIN® PFS every day. If you have any questions about how to use the injection, speak to your doctor or a nurse.

How long to use it

Continue taking the medicine for as long as your doctor tells you to.

Ask your doctor if you are not sure how long to use it.

If you forget to use it

If you forget to use a dose, ask your doctor or pharmacist for advice.

Never use a double dose to make up for the dose that you missed. This may increase the chance of you getting unwanted side effects.

If you find it hard to remember how to give the injection, ask your doctor or nurse for help.

If you use too much (overdose)

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

While you are using METHOBLASTIN® PFS

Things you must do

Tell your doctor or pharmacist if you are taking any other medicines.

Check your injection very carefully each time you collect them from your pharmacist.

Wash your hands immediately after taking the medicine.

Drink plenty of water on the day you take the medicine.

The recommended daily intake is 8 glasses per day. Inadequate fluid intake can increase the side effects of the medicine.Keep all of your doctor's appointments so that your progress can be checked.

You will need to have regular blood and urine tests. Regular blood tests will show any abnormal effects of methotrexate on the blood cells and the liver. As you may not get symptoms of these problems you must have regular blood checks. Your doctor may also want you to have some other tests.

Both you and your partner must use a reliable method of birth control, such as the contraceptive pill or a condom, while taking the medicine and for at least 12 weeks after stopping treatment. Your doctor will discuss with you what forms of contraception are suitable and when it is safe to stop using contraception if you wish to do so. The medicine may cause birth defects if either you or your partner is taking it.

If you become pregnant while using this medicine, tell your doctor immediately.

Tell any other doctors, dentists, or pharmacists who treat you that you are taking this medicine.

If you are about to be started on any new medicine, remind your doctor, dentist or pharmacist that you are taking this medicine.

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

Things you must not do

Do not go out in the sun if possible. If you need to be in the sun, use a 30+ sunscreen and wear a hat and shirt to protect your skin from the sun.

This medicine may make your skin more sensitive to sunlight and increase risk of skin cancer (non-melanoma and melanoma). This means your skin may burn more quickly than usual. Some signs are:

  • redness
  • itching
  • swelling
  • blistering
  • rash.

Do not use sun lamps.

Do not drink alcohol while taking the medicine. Alcohol may increase the side effects of the medicine.

Do not stop taking the medicine, or change the dose, unless your doctor tells you to.

Do not start to take any other medicine before talking to your doctor or pharmacist.

Do not use this medicine to treat any other conditions unless your doctor tells you to.

Do not allow pregnant women to handle this medicine.

Do not give your medicine to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how the medicine affects you. It may cause dizziness, drowsiness or tiredness in some people. Make sure you know how you react to the medicine before you drive a car, operate machinery, or do anything that could be dangerous.

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. This medicine may cause harm to the unborn baby.

Be careful not to drip the solution on any surfaces. If you do, wipe up the area with paper towels and throw them into the ‘Sharps Bin’. Clean the area with lots of soap and water.

Because this medicine can reduce the ability of your immune system to fight infections, try to reduce the risk of infection. Maintain good hygiene. Some ways you can do this are:

  • avoid people with infections if possible
  • be careful when using a tooth brush, toothpick or dental floss
  • be careful not to cut yourself
  • avoid activities where you might be injured or bruised
  • wear disposable gloves when cleaning, especially when cleaning up body fluid or waste
  • dispose of gloves, rags or other items safely in a sealed plastic bag.

Side effects

Be aware that taking more than the exact prescribed dose can be dangerous.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using this medicine. This medicine may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

Ask your doctor to answer any questions you may have.

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

  • upset stomach, stomach pain, vomiting, nausea, loss of appetite
  • mild dizziness
  • mild chills
  • mild headaches
  • hair loss
  • mood changes or confusion
  • ringing in the ears
  • sore eyes
  • increased sensitivity to sunlight
  • unexplained weight loss or loss of appetite
  • tiredness or drowsiness
  • weakness
  • unusual or excessive thirst
  • inflamed gums or sore mouth
  • impotence or loss of interest in sex
  • painful muscles and joints
  • changes in menstrual cycle or unusual vaginal discharge.

The above list includes side effects that are usually mild or only last for a short time

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

  • vomiting
  • back pain
  • stiff neck
  • headaches, shortness of breath when exercising, dizziness, looking pale - signs of anaemia
  • bleeding or bruising more easily than usual
  • seizures, fits or convulsions
  • muscle cramps, spasms, weakness or paralysis
  • blurred vision, short term blindness
  • difficulty speaking, writing or understanding language.

The above list includes serious side effects that may require medical attention. Serious side effects are rare

If any of the following happen, tell your doctor 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
  • skin disorders, such as rash, ulceration or hives; itchy skin
  • swollen glands (lymph nodes), mouth ulcers, sore throat and fever
  • persistent diarrhoea
  • chest pain
  • dry non-productive cough
  • swelling of the face, lips, tongue or other parts of the body (e.g. hands ankles or feet)
  • fever, sore throat or chills - signs of infection
  • pain or difficulty urinating, lower back or side pain - signs of a possible kidney disorder
  • yellowing of the skin or eyes, light coloured bowel motions, dark coloured urine, generally feeling unwell - signs of possible liver disease
  • blood in urine or bowel motions, black tarry bowel motions, black vomit, pin-point red spots on the skin - signs of internal bleeding or other bleeding disorders.

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

These side effects are very rare

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

Some of these side effects can only be found when your doctor does blood, urine or other tests from time to time to check your progress.

Tell your doctor immediately if you notice any of the side effects even after you have finished your treatment. Some side effects of methotrexate may occur after you stop taking it.

After using METHOBLASTIN® PFS

Storage

Keep METHOBLASTIN® PFS in the pack until it is time to use it.

Keep METHOBLASTIN® PFS in a cool dry place where the temperature stays below 25°C.

Do not store METHOBLASTIN® PFS or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

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

Only use each syringe once. Do not keep the syringe after it has been used, even if you don’t use all of the medicine. If any of the medicine is left over, you must still throw it away. It cannot be stored in the fridge for another day.

Disposal

After using METHOBLASTIN® PFS, throw the used syringe into a ‘Sharps Bin’.

The used syringe should be thrown into a special plastic bin (Sharps Bin) that you can get from your pharmacy or hospital.

Do not throw the used syringe into your normal rubbish bin.

Once the ‘Sharps Bin’ is full, return it to the pharmacy or hospital for disposal. They will dispose of it properly.

If your doctor tells you to stop using this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

METHOBLASTIN® PFS comes in a prefilled syringe with a needle.

Ingredients

METHOBLASTIN® PFS contains 25 mg of methotrexate, as the active ingredient, in each millilitre of injection. It also contains:

  • sodium chloride
  • sodium hydroxide
  • sterile water

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

Sponsor

Australian Sponsor:

Pfizer Australia Pty Ltd
Sydney, NSW
Toll Free number: 1800 675 229.
www.pfizer.com.au

This leaflet was revised in March2020.

7.5 mg/0.3mL AUST R 279543

10 mg/0.4mL AUST R 279544

15 mg/0.6mL AUST R 279551

20 mg/0.8mL AUST R 279552

25 mg/1.0 mL AUST R 279553

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Methoblastin PFS

Active ingredient

Methotrexate

Schedule

S4

 

1 Name of Medicine

Methotrexate.

2 Qualitative and Quantitative Composition

One mL of Methoblastin PFS contains 25 mg of methotrexate as methotrexate sodium, 4.90 mg of sodium chloride, approximately 5 mg of sodium hydroxide and water for injections to a total volume of 1 mL. Sodium chloride is included for isotonicity. Sodium hydroxide is included for pH adjustment.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection in pre-filled syringe.
Methoblastin PFS is a solution for subcutaneous injection, available in a pre-filled syringe. It is a sterile, clear, yellow brown solution of methotrexate sodium in water for injections, practically free from visible particles.
Methoblastin PFS has a pH of 7.0 to 9.0.

4 Clinical Particulars

4.1 Therapeutic Indications

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.
Methoblastin PFS is for subcutaneous use in one patient on one occasion only.
Methoblastin PFS should only be prescribed by physicians who are familiar with the various characteristics of the medicinal product and its mode of action. If the clinical situation permits the treating physician can delegate subcutaneous administration to the patient or caregiver. Methoblastin PFS is injected once weekly.
The patient is to be explicitly informed about the fact of administration once weekly. It is advisable to determine a fixed, appropriate weekday as the day of injection.

Dosage.

(a) 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 dosing schedule 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.

Weekly single dose schedule.

A weekly dose of 7.5 to 25 mg administered subcutaneously is recommended, depending on response and tolerability. The recommended initial dose is 7.5 mg of methotrexate once weekly, administered subcutaneously. The dose is to be increased gradually but should not exceed a weekly dose of 25 mg of methotrexate. Dosage should not ordinarily exceed 20 mg/week due to significant increase in toxicity, especially bone marrow suppression.
Response to treatment can generally be expected after approximately 2-6 weeks.
Upon achieving the therapeutically desired result, the dose should be reduced gradually to the lowest possible effective maintenance dose.
The 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.

(b) 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.
The dosing schedule 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.
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.

Weekly single dose schedule.

Weekly dose of 7.5 to 25 mg administered subcutaneously is recommended, depending on response and tolerability. The recommended initial dose is 7.5 mg of methotrexate once weekly, administered subcutaneously. Depending on the individual activity of the disease and tolerability by the patient, the initial dose may be increased gradually by 2.5 mg per week. An alternative methotrexate product may be administered instead of Methoblastin PFS if doses of 12.5 mg, 17.5 mg or 22.5 mg are necessary during dose titration. A weekly dose of 25 mg should not be exceeded. Dosage should not ordinarily exceed 20 mg/week due to significant increase in toxicity, especially bone marrow suppression.
Response to treatment can be expected after approximately 4-8 weeks.
Upon achieving the therapeutically desired result, the dose should be reduced gradually to the lowest possible effective maintenance dose.

Method of administration.

Methoblastin PFS is for subcutaneous use in one patient on one occasion only.
Methoblastin PFS should only be prescribed by physicians who are familiar with the various characteristics of the medicinal product and its mode of action. If the clinical situation permits the treating physician can delegate subcutaneous administration to the patient or caregiver. Methoblastin PFS is injected once weekly.
The patient is to be explicitly informed about the fact of administration once weekly. It is advisable to determine a fixed, appropriate weekday as the day of injection.

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 appropriate personal protective equipment such as disposable gloves;
a designated area should be assigned for preparation, 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.

Dosage adjustment.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).
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. Additional monitoring may also be required when changing from oral to parental routes of administration. Appropriate steps should be taken to avoid conception for at least 12 weeks following methotrexate therapy.
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.
If changing the oral application to parental administration a reduction of the dose may be required due to the variable bioavailability of methotrexate after oral administration. Folic acid supplementation may be considered according to the current treatment guidelines.
No dose adjustment is necessary when switching from the intramuscular to the subcutaneous route or vice versa.
Methoblastin PFS contains no anti-microbial preservative. The volume of injection is sufficient to permit administration of the nominal volume declared on the label.
Methoblastin PFS does not contain any preservative, is for single use only and should be discarded after use in a sharps container.

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).
Breast feeding 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.
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

Methotrexate must only be used by physicians experienced in antimetabolite chemotherapy or, in the case of non-oncological conditions, by a specialist physician.
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 and hepatitis B or C infection testing (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment). 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 (e.g. interstitial pneumonitis) is suspected, especially if baseline measurements are available.
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, gastrointestinal tract obstruction, previous cisplatin therapy, dehydration, aciduria). 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.
Some patients may have delayed methotrexate clearance in the absence of these features.
Pre-treatment 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.

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).
4. It must be explicitly emphasised to the patient that the recommended dose is taken once a week in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led to fatal toxicity. It is advisable to determine an appropriate fixed day of the week for the injection. Patients should be cautioned not to change the dosage or the schedule of administration without medical consultation.
5. Patients should subcutaneously inject the solution in the side of the upper thigh or the abdomen, except around the navel. However, obese patients (i.e. patients with a body weight of more than 100 kg) should inject Methoblastin PFS solely in the upper thighs (not in the abdomen).
6. Appropriate instruction for a subcutaneous self-injection or injection by a caregiver should be provided. If a patient or caregiver is to administer Methoblastin PFS:
a. The physical and cognitive ability of the patient or caregiver should be assessed.
b. The patient or caregiver's ability to administer Methoblastin PFS should be assessed.
c. Patients or caregivers administering Methoblastin PFS should be advised to wear disposable gloves.
d. The patient or caregiver should be instructed in correct subcutaneous injection techniques.
e. The initial subcutaneous injection should be performed under the supervision of an appropriately qualified health care professional.
f. Patients or caregivers should be advised of rotating sites of injection with each dose, to minimize the likelihood of injection site reactions.
g. Patients or caregivers should be instructed on managing spills of the solution.
h. Patients or caregivers should be instructed in the correct technique and importance of proper disposal of the pre-filled syringe and be cautioned against reuse of the pre-filled syringe.

Check the following before and during use.

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. 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.
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 therapy has immunosuppressive activity, which can potentially lead to serious or even fatal infections. Bacterial infection may occur or be a threat if profound leucopenia occurs during therapy. In this instance, the drug should be discontinued and appropriate antibiotic therapy instituted. If severe bone marrow depression occurs, blood or platelet transfusions may be required.
Pneumonia (in some cases leading to respiratory failure) may occur. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.
In addition, pulmonary alveolar haemorrhage has been reported with methotrexate used in rheumatologic and related indications. This event may also be associated with vasculitis and other comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage is suspected to confirm the diagnosis.
Immunisation 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 Interactions with Other Medicines and Other Forms of Interactions).
Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal administration. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation.
Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.
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.
Folate deficiency states may increase methotrexate toxicity.

Neurologic.

Transient acute neurologic syndrome has been observed in patients treated with high dose regimens of methotrexate. Manifestations of this neurologic syndrome may include behavioral abnormalities, focal sensorimotor signs, including transient blindness, and abnormal reflexes. The exact cause is unknown.
After intrathecal 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 chronic leukoencephalopathy and manifested by confusion, stupor, irritability, somnolence, ataxia, dementia, occasionally major convulsions, and coma. 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 leukoencephalopathy. 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.

Use in hepatic impairment.

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.
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.
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 grams.
In psoriasis, liver damage and function tests, including serum albumin and prothrombin time, should be performed several times prior to dosing. Liver function tests are often normal in developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. It is recommended to obtain a liver biopsy at: 1) before start of therapy or shortly after initiation of therapy (2-4 months); 2) after a total cumulative dose of 1.5 grams; and 3) after each additional 1.0 to 1.5 grams. In case of moderate fibrosis or any cirrhosis, discontinue the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder histologic findings such as fatty change and low grade portal inflammation are relatively common before the start of therapy. Although these mild changes are usually not a reason to avoid or discontinue methotrexate therapy, 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).
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.
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; see Section 4.4 Special Warnings and Precautions for Use).

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.
If vomiting, diarrhoea or stomatitis occur, resulting in dehydration, methotrexate should be discontinued until recovery occurs.
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).

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.

Methoblastin PFS is not recommended for use in paediatric patients.

Effects on laboratory tests.

Assay for folate.

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

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, tetracyclines, chloramphenicol and 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.

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.

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.

Penicillins and sulfonamides.

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. Hematologic and gastrointestinal toxicity has been observed in combination with high- and low-dose methotrexate.

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.

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. NSAIDs elevate and prolong serum methotrexate levels, resulting in deaths from severe haematologic (including bone marrow suppression and aplastic anemia) 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.

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.

Diuretics.

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

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.

Asparaginase.

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

Nitrous oxide anethesia.

The use of nitrous oxide anaesthesia potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression and stomatitis and neurotoxicity with intrathecal administration. Whilst this effect can be reduced by administering folinic acid rescue (see Section 4.9 Overdose, treatment of overdosage, for information on 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) 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.

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.

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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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.
(Category D)
Methotrexate can cause fetal death, embryotoxicity, abortion, or teratogenic effects when administered to a pregnant woman.
Methotrexate has caused foetal 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 foetus 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 breast feed 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, acute paronychia, nail changes (nail hyperpigmentation), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Burning and erythema may appear in psoriatic areas for 1 to 2 days following each dose. Rarely, painful plaque erosions may appear. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration has been reported in psoriatic patients. Anaphylactic reactions and skin ulceration/necrosis consistent with toxic epidermal necrolysis, soft tissue necrosis and osteonecrosis have also been reported. Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, 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 (decreased appetite), nausea, non-infectious peritonitis, vomiting, diarrhoea, abdominal distress, haematemesis, melena, 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, blood lactate dehydrogenase increased, 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, vaginal bleeding, gynaecomastia.

Pulmonary system.

Interstitial pneumonitis, interstitial fibrosis, reversible eosinophilic pulmonary infiltrates, respiratory fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, alveolitis, death, pleural effusion, pleurisy. Manifestations of methotrexate-induced pulmonary toxicity commonly include fever, cough (especially dry and non-productive), dyspnoea, chest pain, 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.

Headaches, drowsiness, blurred vision, speech impairment including dysarthria and aphasia, and coma, paraesthesia, paresis, leukoencephalopathy, encephalopathy, CSF pressure increased, neurotoxicity, arachnoiditis, paraplegia, stupor, ataxia, dementia, Guillain Barre Syndrome, motor dysfunction, depression, confusional state, irritability. Aphasia, hemiparesis and convulsions have occurred possibly related to haemorrhage or to complications from intra-arterial catheterization. Following low doses, occasional patients have reported transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations.

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.

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, respiratory tract infection, cutaneous bacterial infections, reactivation of hepatitis B infection, worsening of hepatitis C infection.

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

Lymphoma (including reversible lymphoma), tumour lysis syndrome, melanoma and non-melanoma skin cancer.
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, back pain, nuchal rigidity, nodulosis, stress fractures, loss of libido, impotence and even sudden death, have been reported.
Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate. A few cases of anaphylactoid reactions have been reported.

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 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 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 non reversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinisation, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent haemodialysis with a high-flux dialyzer may also be beneficial in these patients.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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

Rheumatoid arthritis.

Subcutaneous use.

A double-blind, multicentric, randomised clinical trial (study no. MC-MTX.6/RH) was conducted to evaluate the efficacy of subcutaneously administered MTX in comparison with oral treatment in patients with active rheumatoid arthritis (RA). A total of 384 patients aged 18 to 75 years with active RA defined by a disease activity score (DAS) 28 ≥ 4, who have never been treated with MTX before and who were familiar with subcutaneous self-administration through confirmed practice phase were included into this trial.
Patients were randomised into an oral arm (A; n = 190) or a subcutaneous arm (B; n = 194). Patients within arm A received 2 tablets of MTX 7.5 mg and one dummy pre-filled syringe per week. Patients within arm B received one pre-filled syringe containing 15 mg MTX and two dummy tablets per week. The patients were treated for 24 weeks with a constant dose of 15 mg MTX, except for patients who had not achieved a 20% improvement according to American College of Rheumatology criteria (ACR20) at week 16. In this case the study medication of the patients was changed from 15 mg oral to 15 mg SC (Arm A) or from 15 mg SC to 20 mg SC (Arm B), respectively.
The primary endpoint for this trial was the demonstration of superiority of MTX after SC administration vs oral administration after 24 weeks based on the ACR20 response. Sample size was determined by assuming a 15% point increase in ACR20 response rate after 24 weeks (55% in the MTX oral arm vs 70% in the SC group) within the full-analysis-set. The two-tailed significance level was 5%. The power of the statistical test was fixed at 80%.
Of all patients, 78.2% in the SC group and 70.1% in the oral group were ACR20 responders at week 24. This difference was statistically significant (Cochran-Mantel-Haenszel test; P = 0.0412). The estimate of common relative risk was 1.12 (95% CI: 1.01-1.24). Furthermore, significantly more patients in the SC group were ACR70 responders compared to the oral group at week 24 (41 vs 33.2%; P = 0.03).
Time to initial ACR20 response was evaluated using Kaplan-Meier methods. No difference was seen between the two treatment groups. In both arms the median number of weeks to reach an ACR20 response for the first time was 6 weeks. A low rate of withdrawal was observed in both groups with approximately 10% of the patients. Less patients discontinued study for insufficient clinical response in the SC group than in the oral group (1.1% vs 2.1%) but more patients withdrew from the study due to adverse events in the SC group (9.6% vs 5.3%).
Methotrexate given subcutaneously was thus shown to be well tolerated and statistically more efficacious than when given orally in terms of percentage of patients with ACR20.

Psoriasis.

A favourable efficacy and safety profile has been established for MTX in a number of clinical trials, as well as in common practice. For the treatment of psoriasis, MTX is usually given once weekly either orally, intramuscularly or subcutaneously. The methotrexate start-dose in randomised controlled trials varied from 5 to 25 mg/week, most commonly being either 7.5 mg or 15 mg. Guidelines vary from 5 to 15 mg/week. The majority of studies have demonstrated a remission or an improvement in skin condition within 16-24 weeks after introducing methotrexate treatment. A higher starting dose (15 mg/week) in two studies has contributed to an achievement of maximum response after 8-12 weeks of treatment.

MC‐MTX.7/PH.

Study MC‐MTX.7/PH was an open‐label, single dose, 2‐period crossover phase 1 study comparing IM and SC doses of MTX 15 mg (using the 10 mg/mL injection solution). The primary objective of the study was to evaluate the PK characteristics, and the rate and extent of absorption of MTX 15 mg given by IM versus SC administration.
The primary PK results of study MC‐MTX.7/PH showed that the SC and IM routes of administration for MTX were bioequivalent in terms of the extent of drug exposure (based on AUC) but with higher peak plasma levels achieved from the IM injection (0.5 versus 1 hour). In addition, the mean Cmax for SC administration is approximately 60% of that seen following IM injection of MTX. See Table 1.
The secondary PK results for 7‐OH MTX showed a similar pattern to the primary PK observations. The mean AUC for 7‐OH MTX achieved following SC and IM administration were similar, and the geometric mean Cmax was also similar (44.84 microgram/L for SC and 52.85 microgram/L for IM administration).

MC-MTX.9/PH.

Trial MC-MTX.9/PH compared the pharmacokinetics of two different MTX concentrations (10 mg/mL versus 50 mg/mL) in 24 healthy volunteers where one treatment arm was given via the SC route and the other given via the IM route. Each treatment arm consisted of a unique set of patients with no cross-over. The results show an equal extent of absorption of MTX with both concentrations after both routes of administration. The rate of absorption expressed by Cmax was different with about 15-20% higher maximum MTX concentrations achieved after administration of the higher concentrated solution. No clinical consequences are anticipated as the total exposure to MTX was equivalent. Both formulations were equally well tolerated. See Table 2.
Using a cross group comparison, which does not permit extraction of variability due to subject differences or period effects, it appears the 50 mg/mL product has a higher Cmax and slightly lower AUC when given by i.m. injection compared to s.c. injection. This difference in the AUC after IM administration of the 10 mg/mL and 50 mg/mL is not expected to have any clinical consequence. The differences between the i.m. and s.c. routes for the two injection concentrations in the cross study arm comparisons are similar, suggesting there are population differences contributing to this finding.

Studies comparing oral with parenteral administration.

Four published studies in adult patients with RA have compared oral MTX 7.5-30 mg/week with equivalent doses administered by either IM or SC injection. The mean bioavailability in 15 adult patients with RA after oral MTX 30 mg/week, as demonstrated by Hoekstra et al (2004), was 0.64 (range 0.21-0.96) which was statistically significantly different to the SC administration of the same dose. Seideman et al (1993) reported the AUC in nine patients where IM and oral doses met bioequivalence criteria (90% CI 92-121% for the AUC ratio). In the study of 21 RA patients conducted by Hamilton et al (1997) the 24-hour AUC was significantly lower with oral versus IM therapy at a mean MTX dose of 17 mg/week (p = 0.027), but this was not seen at the lower 7.5 mg weekly dose of MTX. Auvinet et al (1992) observed a 10 mg/week oral dose that was 60% bioavailable relative to the same SC dose involving 8 adult patients with RA, which is consistent with the results reported by Hamilton and Hoekstra. Another study by Herman et al (1989) reported oral bioavailability of a 10 mg dose as 70% compared with the same dose given by IM injection in a study involving 41 RA patients. Overall, the published data indicates that a lower AUC is seen with oral therapy versus parenteral administration for doses of MTX as low as 10 mg, consistently when the dose is > 15 mg. (Also see Section 4.2 Dose and Method of Administration.)

5.2 Pharmacokinetic Properties

Absorption.

Methotrexate at low doses (< 25 mg/m2) is well absorbed from the gastrointestinal tract; at larger doses absorption may become erratic and incomplete. Absorption is significantly higher after intramuscular and subcutaneous administration with no differences between both routes. Peak serum levels may be achieved within 0.25 and 1 hour following intramuscular (IM) administration and 0.25 to 1.5 hours following subcutaneous (SC) administration. Peak serum levels may be achieved within 1 to 4 hours following oral administration, and within 0.5 to 2 hours following intravenous (IV) or intramuscular (IM) administration.

Distribution.

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

Metabolism.

Methotrexate does not appear to be appreciably metabolised.
Approx. 10% of the administered methotrexate dose is metabolised intrahepatically. The principal metabolite is 7-hydroxymethotrexate.

Excretion.

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 has been reported to cause chromosome damage. 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.

Carcinogenicity.

Methotrexate is considered to be carcinogenic. However, extensive epidemiologic studies are required to determine its carcinogenicity potential. Cytotoxic drugs have been reported to be associated with an increased risk of development of secondary tumours in humans. 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, sodium hydroxide, water for injections.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Methoblastin PFS is available in the following presentations. See Table 3.

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.


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