Consumer medicine information

Trexject

Methotrexate

BRAND INFORMATION

Brand name

Trexject

Active ingredient

Methotrexate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Trexject.

SUMMARY CMI

TREXJECT®

Consumer Medicine Information (CMI) summary

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

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

1. Why am I using TREXJECT?

TREXJECT contains the active ingredient methotrexate (as sodium). TREXJECT is used to treat inflammatory conditions, including severe psoriasis, and severe rheumatoid arthritis.

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

2. What should I know before I use TREXJECT?

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

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

For more information, see Section 2. What should I know before I use TREXJECT? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TREXJECT and affect how it works.

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

4. How do I use TREXJECT

  • TREXJECT is given as a once weekly injection under the skin (subcutaneous)
  • You may decide together with your doctor on a suitable weekday each week to receive your injection

More instructions can be found in Section 4. How do I use TREXJECT? in the full CMI

5. What should I know while using TREXJECT?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using TREXJECT
  • Ensure you and your partner are using a reliable method of contraception during, and at least for six months after treatment with TREXJECT
  • Tell your doctor if you develop an infection or you notice new or changed spots on your skin
  • Discuss with your doctor, your water and fluid intake. Dehydration can increase the risk of side effects
  • Tell your doctor if you are scheduled for any vaccines
Things you should not do
  • You should not receive certain vaccinations while being treated with TREXJECT
  • You should not breastfeed while using TREXJECT
Driving or using machines
  • Do not drive or operate machinery until you know how TREXJECT affects you. TREXJECT may cause dizziness or tiredness in some people and therefore may affect alertness
Drinking alcohol
  • Avoid drinking alcohol while you are being treated with TREXJECT, as this may cause permanent liver damage
Looking after your medicine
  • Store below 25°C. Keep the syringes in the outer carton in order to protect from light
  • Keep it out of reach of children

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

6. Are there any side effects?

Side effects that require urgent medical attention include: Signs of an allergic reaction, such as chest tightness, difficulty breathing, swelling of face lips and tongue, rash; signs suggesting a blood disorder, such as persistent fever, bruising, bleeding, paleness, blood in stools, urine, or vomit; pinpoint red spots or painful blistering resulting in peeling of layers of skin, severe blisters, signs of infection such as fever, chills, sore throat, signs of liver problems such as yellowing of skin, eyes, loss of appetite, itching and dark coloured urine, chest pain, fits; signs of lung damage, such as a dry non-productive cough or shortness of breath.

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

WARNING

Use of TREXJECT is only for severe disease which is not treated adequately by other forms of therapy and only when diagnosis has been made. Due to the risk of fatal or severe reactions to methotrexate, you should be treated under supervision of your doctor or specialist.

Methotrexate can cause severe damage to blood, liver, kidneys, lungs and gastrointestinal system, and may increase your risk of bleeding. This is more likely when methotrexate is used at high or repeated doses. The risk of damage to these body systems will depend on several factors, including your health before starting methotrexate, and other medicines that you take. Serious and potentially fatal infections may occur with methotrexate therapy.

Your doctor will monitor your blood counts, liver function and kidney function while you are using methotrexate.

Tell your doctor immediately if you experience diarrhoea or stomach ulcers, as methotrexate may need to be paused to prevent further bleeding.

If you notice symptoms such as a dry non-productive cough or shortness of breath, stop using methotrexate and talk to your doctor.

Avoid alcohol while using methotrexate.

Tell your doctor if you are taking nonsteroidal anti-inflammatory drugs (NSAIDs), which are medicines used to relieve pain, swelling and inflammation.

Use of methotrexate to treat severe rheumatoid arthritis and psoriasis in children has not been well documented. Methotrexate has caused foetal death and/or congenital anomalies. It should not be used in pregnant women or in those who might become pregnant. Methotrexate should not be used in the treatment of psoriasis and rheumatoid arthritis in pregnant women. Methotrexate should not be started until it is confirmed you are not pregnant, and due to the serious risk to the foetus you should not become pregnant while undergoing treatment.

Pregnancy should be avoided if either partner is receiving methotrexate, during and for a minimum of 6 months after therapy has ceased.

TREXJECT should be used once a week on the same day each week. Taking TREXJECT more frequently than once each week may cause life-threatening or fatal toxicity. If you are unsure of how you should take TREXJECT, talk to your doctor or pharmacist.



FULL CMI

TREXJECT®

Active ingredient(s): methotrexate (as sodium)

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using TREXJECT?

TREXJECT contains the active ingredient methotrexate (as sodium). Methotrexate belongs to a group of medicines known as immunosuppressants. Methotrexate works by preventing the growth of certain cells.

TREXJECT is used to treat:

  • Severe Psoriasis (a skin disease with thickened patches of red skin, often with silver scales)
  • Severe Rheumatoid Arthritis (a disease mainly affecting the joints with pain and swelling)

2. What should I know before I use TREXJECT?

Warnings

Do not use TREXJECT if you:

  • are allergic to methotrexate, or any of the ingredients listed at the end of this leaflet
  • have liver disease or poor liver function
  • are an alcoholic
  • have kidney disease or poor kidney function
  • have any blood disorders, or conditions which cause a reduced number of red blood cells, white blood cells or platelets
  • have problems with your immune system such as severe or repeated infections, e.g. tuberculosis or HIV
  • have an infection
  • have a stomach ulcer or ulcerative colitis (bleeding from your bowel)
  • are pregnant, or if you or your partner are planning to get pregnant
  • are breastfeeding
  • have poor nutritional status, such as malnutrition
  • are about to have surgery that involves general anaesthetic
  • are taking a retinoid such as acitretin (a medicine used to treat skin conditions including psoriasis)

Do not receive a live vaccine while you are using TREXJECT.

Check with your doctor if you:

  • have any sort of infection or immune system disorder e.g. sinusitis, tooth abscess etc.
  • have a stomach ulcer or ulcerative colitis (bleeding from the bowel)
  • have fluid or swelling in your abdomen or stomach
  • have fever, chills, sore throat or mouth ulcers
  • have any increased or unusual bleeding or bruising
  • have kidney problems
  • have lung problems
  • have diabetes
  • have a folate deficiency
  • are experiencing tiredness, headaches, shortness of breath, dizziness, or if you are pale
  • are receiving radiotherapy e.g. X-rays, ultraviolet radiotherapy

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

Pregnancy and breastfeeding

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

If you wish to become pregnant you should consult your doctor, who may refer you for specialist advice before the planned start of treatment.

You and your partner must avoid becoming pregnant, and use a reliable method of contraception during, and for at least 6 months after treatment with TREXJECT.

The possibility of pregnancy must be excluded e.g. pregnancy test prior to starting treatment with TREXJECT.

TREXJECT passes into breast milk. Stop breast-feeding prior to, and during treatment with TREXJECT.

Use in liver impairment

  • Where possible, it is recommended that TREXJECT is not used where there is impaired liver function, or liver disorders, including where alcoholism is present.

Use in kidney impairment

  • Where possible, it is recommended that TREXJECT is not used where there is decreased kidney function.

Use in the elderly

  • Elderly patients are more likely to have decreased liver and kidney function, and decreased folate levels. Lower doses may need to be considered, and increased monitoring may be required.

Monitoring and follow up

To check you are receiving the correct dose, and to detect any severe side effects, your doctor may carry out checkups and laboratory tests from time to time. It is very important that you appear for these scheduled tests. If the results of any of these tests are conspicuous, your doctor will adjust your treatment accordingly.

These tests may include:

  • examinations of the mouth and throat for any changes in the mucosa
  • blood tests/ blood count with number of blood cells
  • blood tests to monitor liver function
  • imaging tests to monitor liver condition
  • small sample of tissue taken from the liver in order to examine it more closely (biopsy)
  • blood tests to monitor kidney function
  • lung function tests and respiratory tract monitoring

If you, your partner or your caregiver notice new onset or worsening of neurological symptoms including general muscle weakness, disturbance of vision, changes in thinking, memory and orientation leading to confusion and personality changes contact your doctor immediately because these may be symptoms of a very rare, serious brain infection called progressive multifocal leukoencephalopathy (PML).

3. What if I am taking other medicines?

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

The concurrent use of TREXJECT and some other medicines may interfere with each other, including (but not limited to):

  • retinoids such as acitretin (a medicine used to treat skin conditions including psoriasis)
  • medicines for gastric reflux such as omeprazole and pantoprazole
  • anticancer drugs such as cisplatin, mercaptopurine or asparaginase
  • antibiotics such as trimethoprim, tetracyclines and sulphonamides
  • non-steroidal anti-inflammatory drugs or salicylates (medicines used to relieve pain, swelling and inflammation such as aspirin, diclofenac and ibuprofen)
  • medicines for epilepsy such as phenytoin
  • corticosteroids such as hydrocortisone and prednisone
  • medicines for diabetes such as sulphonylureas
  • medicines that reduce cholesterol such as cholestyramine
  • medicines for gout such as allopurinol and probenecid
  • vitamin preparations that contain folic acid
  • other medicines for rheumatoid arthritis, such as leflunomide and sulfasalazine
  • other medicines for psoriasis such as etretinate
  • medicines for heart problems such as amiodarone
  • medicines used to treat asthma and related compounds such as theophylline
  • antimalarial medicine such as pyrimethamine
  • other immunosuppressive medication

TREXJECT may also be affected by, or interfere with, the following:

  • blood transfusions
  • nitrous oxide anaesthetics
  • vaccinations
  • alcohol
  • radiation e.g. X-rays, radiotherapy

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

4. How do I use TREXJECT?

How much to use

  • Your doctor will decide what dose you should be given, when it should be given, and for how long you will receive it. This depends on your condition and other factors, such as your weight, age, blood tests, how well your kidneys and liver are working, and whether other medicines are being given at the same time.
  • Response to TREXJECT treatment is usually seen after 4-8 weeks.
  • Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.
  • Too much TREXJECT may be fatal.

When to use TREXJECT

  • TREXJECT is given as a once weekly injection under the skin (subcutaneous) for the treatment of severe arthritis and severe psoriasis. You may decide together with your doctor on a suitable weekday each week to receive your injection.

How to use TREXJECT

  • TREXJECT is usually given by a doctor or nurse as a once weekly injection under the skin.
  • Your doctor may decide that you can administer the injection yourself under the skin (subcutaneously). If you will be self-administering TREXJECT, your doctor or nurse will give you detailed instructions on how to do this. Information is also provided below on how to self-administer the injection.

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 not handle or administer 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 by copious lavage with water or sodium bicarbonate solution; medical attention should be sought.

Carefully read the instructions below before starting your injection, and always use the injection technique advised by your doctor, pharmacist or nurse.

Preparation:

Select a clean, well-lit and flat working surface. Wash your hands carefully. Unpack the methotrexate prefilled syringe and read the package leaflet carefully.

Remove the pre-filled syringe from the packaging at room temperature. Before use, check the TREXJECT syringe for visual defects (or cracks).

Injection site:

The best sites for injection are the:

  • upper thighs, and
  • abdomen except around the navel

However, obese patients (i.e. patients with a body weight of more than 100 kg) should inject TREXJECT solely in the upper thighs (not in the abdomen).

If someone is helping you with the injection, he/she may also give the injection into the back of your arms, just below the shoulder.

Change the injection site with each injection. This may reduce the risk of developing irritations at the injection site.

Never inject into skin that is tender, bruised, red, hard, scarred or where you have stretch marks. If you have psoriasis, you should avoid injecting directly into any raised, thick, red or scaly skin patches or lesions.

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 clean the area
  4. Carefully remove the grey 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.

Note: Once you have removed the cap, perform the injection without delay.

  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. 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

Methotrexate should not come into contact with the surface of the skin or mucosa. In the event of contamination, the affected area must be rinsed immediately with plenty of water.

If you or someone around you is injured by the needle, consult your doctor immediately and do not use this pre-filled syringe.

Disposal and other handling:

Keep your syringes and syringe disposal unit out of reach of children; lock the supplies away if possible.

Never re-use syringes or needles.

Always use a sterile (aseptic) technique as described here. If in any doubt, discard needles, syringes or solution and start again.

Always place the used syringes in the appropriate disposal unit.

For further information of administration of TREXJECT, please visit www.trexject.com.au

If you forget to use TREXJECT

TREXJECT should be used once weekly at the same time each week. If you miss your dose at the usual time, do it as soon as you remember and then follow on with the next injection one week later.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

Ask your doctor if you are not sure what to do or have trouble remembering to inject your medicine.

If you use too much TREXJECT

If you think that you have used too much TREXJECT you may need urgent medical attention.

You should immediately:

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

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

5. What should I know while using TREXJECT?

Driving or using machines

Do not drive or operate machinery until you know how methotrexate affects you. Methotrexate may cause dizziness or tiredness in some people and therefore may affect alertness

Drinking alcohol

Avoid drinking alcohol while you are being treated with TREXJECT, as this may cause permanent liver damage

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

Store below 25°C in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Keep it where young children cannot reach it.

When to discard your medicine

TREXJECT is a single use injection for use in one patient on one occasion only. Once opened, use immediately.

Getting rid of any unwanted medicine

TREXJECT should NOT be placed in your household recycling bin, waste bin or public litter bin.

Always make sure your used TREXJECT syringes are secured in a strong plastic container, or a sharps bin before returning to your public hospital or participating pharmacy for disposal in a cytotoxic waste bin.

You should talk to your doctor, pharmacist or local council regarding disposal of these items.

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
Gut and digestion:
  • Inflammation of the mouth lining
  • Indigestion
  • Feeling sick
  • Loss of appetite or weight loss
  • Abdominal pain
Skin and nails:
  • Rash
  • Reddening of the skin
  • Itching
  • Sensitivity to the sun
  • Acne, boils or skin ulcers
  • Changes in the toenails or fingernails
Mental state:
  • Irritability
  • Depression
  • Confusion
  • Mood changes
Signs of anaemia such as:
  • Tiredness
  • Headache
  • Shortness of breath
  • Dizziness
  • Looking pale
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Gut and digestion:
  • Mouth ulcers
  • Diarrhoea
Signs of unusual bleeding such as:
  • Blood in stools or urine
  • Vomiting blood
  • An increased tendency to bleed
  • Unusual bruising
Signs of an allergic reaction such as:
  • Swelling of the face, lips or tongue
  • Rash
  • Redness
  • Hives
  • Itching
  • Shortness of breath, wheezing or difficulty breathing
Signs of a severe skin reaction such as:
  • Pinpoint red spots
  • Painful blistering resulting in peeling of layers of the skin
  • Severe blisters and bleeding in the lips, eyes, mouth, nose and genitals (Stevens Johnson syndrome)
Signs of infection such as:
  • Fever, chills, sweats
  • Sore throat, difficulty swallowing
  • Feeling generally unwell
  • Bleeding gums
  • Mouth ulcers, cold sores
Signs of liver problems (jaundice or hepatitis) such as:
  • Lighter patches on skin
  • Yellowing of the skin/eyes
  • Nausea, vomiting
  • Loss of appetite
  • Feeling generally unwell
  • Fever
  • Itching
  • Dark coloured urine
Signs of kidney problems such as:
  • Swelling of the hands, ankles, or feet
  • Changes to the frequency of urination
  • Absence of urination
Signs of lung problems such as:
  • Chest pain
  • Shortness of breath
  • Fever
  • Persistent dry non-productive cough
  • Spitting or coughing blood
Signs of a blood clot such as:
  • Weakness of one side of the body
  • Pain, swelling, redness and unusual warmth in one of your legs
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

Other side effects not listed here may occur in some people.

Reporting side effects

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

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

7. Product details

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

What TREXJECT contains

Active ingredient
(main ingredient)		methotrexate (as sodium)
Other ingredients
(inactive ingredients)		sodium chloride
sodium hydroxide
water for injections

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

What TREXJECT looks like

TREXJECT is a clear yellow-brown solution in a glass pre-filled syringe, packed in blisters. TREXJECT is available in the following presentations:

  • Syringe with 0.15 mL solution for injection, equivalent to 7.5 mg methotrexate. The syringe barrel is made of glass and has a red colour coded plastic backstop. (AUST R 233714)
  • Syringe with 0.20 mL solution for injection, equivalent to 10 mg methotrexate. The syringe barrel is made of glass and has a green colour coded plastic backstop. (AUST R 233715)
  • Syringe with 0.30 mL solution for injection, equivalent to 15 mg methotrexate. The syringe barrel is made of glass and has a purple colour coded plastic backstop. (AUST R 233717)
  • Syringe with 0.40 mL solution for injection, equivalent to 20 mg methotrexate. The syringe barrel is made of glass and has a dark red colour coded plastic backstop. (AUST R 233719)
  • Syringe with 0.50 mL solution for injection, equivalent to 25 mg methotrexate. The syringe barrel is made of glass and has a blue colour coded plastic backstop. (AUST R 233721)

You may notice an air bubble in the pre-filled syringe. The air bubble in the syringe guarantees dispensing of the full dose from the syringe and does not need to be removed. It will dissolve under the skin.

Who distributes TREXJECT

Link Medical Products Pty Ltd
5 Apollo Street
Warriewood NSW 2102

This leaflet was updated in April 2022.

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Trexject

Active ingredient

Methotrexate

Schedule

S4

 

1 Name of Medicine

Methotrexate.

2 Qualitative and Quantitative Composition

1 pre-filled syringe with 0.15 mL solution contains 7.5 mg methotrexate.
1 pre-filled syringe with 0.20 mL solution contains 10 mg methotrexate.
1 pre-filled syringe with 0.25 mL solution contains 12.5 mg methotrexate.
1 pre-filled syringe with 0.30 mL solution contains 15 mg methotrexate.
1 pre-filled syringe with 0.35 mL solution contains 17.5 mg methotrexate.
1 pre-filled syringe with 0.40 mL solution contains 20 mg methotrexate.
1 pre-filled syringe with 0.45 mL solution contains 22.5 mg methotrexate.
1 pre-filled syringe with 0.50 mL solution contains 25 mg methotrexate.
One mL of solution contains 50 mg of methotrexate as methotrexate sodium, 4 mg of sodium chloride, approximately 10 mg of sodium hydroxide and water for injections to a total volume of 1 mL. The volume of injection is sufficient to permit administration of the nominal volume declared on the label.
Methotrexate is (2S)-2-[(4-{[(2,4-diaminopteridin-6-yl) methyl] methylamino}benzoyl)amino] pentanedioic acid. It is a yellow to orange, crystalline powder, practically insoluble in water, alcohol, ether and ethylene chloride. It dissolves in dilute solutions of mineral acids and in dilute solutions of alkali hydroxides and carbonates.
Trexject is a sterile, clear, yellow-brown solution of methotrexate sodium in Water for Injections, practically free from visible particles. Sodium Chloride is included for isotonicity. Sodium Hydroxide is included for pH adjustment. Trexject Injection contains no anti-microbial preservative.
Trexject Injection has a pH of 7.5 to 9.0.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for subcutaneous injection, pre-filled syringe.

4 Clinical Particulars

4.1 Therapeutic Indications

Psoriasis therapy (see Boxed Warnings).

Trexject may be of value in the symptomatic control of severe, recalcitrant, disabling psoriasis in adults 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 therapy (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 or penicillamine, 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.
Trexject is for subcutaneous use only.
Trexject 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. Trexject 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.
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 parenteral routes of administration. Appropriate steps should be taken to avoid conception for at least 12 weeks following methotrexate therapy.
If changing the oral application to parenteral administration a reduction of the dose may be required due to the variable bioavailability of methotrexate after oral administration (also see Section 5.2 Pharmacokinetic Properties, Studies comparing oral with parenteral administration). Folic acid supplementation may be considered according to current treatment guidelines.
No dose adjustment is necessary when switching from the intramuscular to the subcutaneous route or vice versa.

Dosage of Trexject for adult patients with rheumatoid arthritis.

A weekly dose of 7.5 to 25 mg 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. 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.

Dosage of Trexject for patients with psoriasis vulgaris.

A weekly dose of 7.5 to 25 mg 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.

Patients with renal impairment.

Trexject should be used with caution in patients with impaired renal function. The dose should be adjusted as follows (see Table 1).

Patients with hepatic impairment.

Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol. If bilirubin is > 5 mg/dL (micromol/L), methotrexate is contraindicated.

Use in elderly patients.

Dose reduction should be considered in elderly patients due to reduced liver and kidney function as well as lower folate reserves which occur with increased age.

Use in patients with a third distribution space (pleural effusions, ascites).

As the half-life of methotrexate can be prolonged to 4 times the normal length in patients who possess a third distribution space dose reduction or, in some cases, discontinuation of methotrexate administration may be required.

Duration and method of administration.

Trexject is for subcutaneous use only.
The medicine is for single use only.
The overall duration of the treatment is decided by the physician.

Instructions for handling.

The following protective recommendations are given due to the toxic nature of this substance:
personnel should be trained in good handling technique;
pregnant staff should be excluded from working with this drug;
personnel handling methotrexate injection should wear disposable gloves;
all items used for administration or cleaning, including gloves, should be placed in high risk, waste disposal bags for disposal in a cytotoxic waste bin;
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.

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. It must be explicitly emphasised to the patient that the recommended dose is taken once a week only 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.
4. Patients should 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 Trexject solely in the upper thighs (not in the abdomen).
5. Appropriate instruction for self injection or injection by a caregiver should be provided. If a patient or caregiver is to administer Trexject:
the physical and cognitive ability of the patient or caregiver should be assessed;
the patient or caregiver's ability to administer Trexject should be assessed;
patients or caregivers administering methotrexate should be advised to wear disposable gloves whilst administering the treatment;
the patient or caregiver should be instructed in correct injection techniques;
the initial injection should be performed under the supervision of an appropriately qualified health care professional;
patients or caregivers should be advised of rotating sites of injection with each dose, to minimise the likelihood of injection site reactions;
patients or caregivers should be instructed on managing spills of the solution;
patients or caregivers should be instructed in the correct technique and importance of proper disposal of the prefilled syringe and be cautioned against reuse of the prefilled syringe.
6. Patients receiving methotrexate should avoid excessive unprotected exposure to sun or sunlamps because of possible photosensitivity reactions.
7. Adverse reactions to methotrexate, such as dizziness and fatigue may affect the ability to drive or operate machinery.

4.3 Contraindications

See Boxed Warnings.
Methotrexate is contraindicated in patients with:
hypersensitivity to methotrexate or to any of the excipients (see Section 6.1 List of Excipients);
alcoholism or hepatic disorders, including alcoholic liver disease or other chronic liver disease;
severe renal impairment (creatinine clearance less than 30 mL/min);
pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anaemia;
serious, acute or chronic infections such as tuberculosis, HIV or with overt or laboratory evidence of other immunodeficiency syndromes;
patients with peptic ulcer disease or ulcerative colitis and ulcers of the oral cavity;
pregnancy and breast-feeding (see Section 4.6 Fertility, Pregnancy and Lactation);
poor nutritional status;
concurrent vaccination with live vaccines.
Methotrexate is contraindicated in pregnancy and breastfeeding.
Trexject should not be used on the day of a surgery with anaesthesia.
An increased risk of hepatitis has been reported to result from combined use of methotrexate and retinoids like acitretin. Therefore, the combination of methotrexate and such medicinal products is also contraindicated.

4.4 Special Warnings and Precautions for Use

See Boxed Warnings.
Methotrexate must only be prescribed by physicians experienced in antimetabolic therapy and the treatment of severe rheumatoid arthritis or psoriasis.
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 reactions may be detected as early as possible. This is especially important in patients 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 the treatment of severe rheumatoid arthritis and psoriasis because of its haematopoietic suppressive effects, manifesting as anaemia, aplastic anaemia, pancytopenia, leukopenia, 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.

Recommended examinations and safety measures before and during use.

Before commencing or reinstituting methotrexate therapy after a rest period.

Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum albumin, chest X-ray and renal function tests. If clinically indicated, exclude tuberculosis and hepatitis.

During therapy (every 1 to 2 months).

An increased monitoring frequency should be considered also when the dose is increased.
1. Examination of the mouth and throat for mucosal changes.
2. Complete blood count with differential blood count and platelets: haemopoietic suppression caused by methotrexate may occur abruptly and with apparently safe dosages. Any profound drop in white cell or platelet counts indicates immediate withdrawal of the medicinal product and appropriate supportive therapy. Patients should be advised to report all signs and symptoms suggestive of infection. Patients taking simultaneous administration of haematotoxic medicinal products (e.g. leflunomide) should be monitored closely with blood count and platelets.
3. Liver function tests: Treatment should not be initiated or should be discontinued if there are persistent or significant abnormalities in liver function tests, other non-invasive investigations of hepatic fibrosis, or liver biopsies.
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).
Temporary increases in transaminases to two or three times the upper limit of normal have been reported in patients at a frequency of 13-20%. Persistent elevation of liver enzymes and/or decrease in serum albumin may be indicative for severe hepatotoxicity. In the event of a persistent increase in liver enzymes, consideration should be given to reducing the dose or discontinuing therapy.
Histological changes, fibrosis and more rarely liver cirrhosis may not be preceded by abnormal liver function tests. There are instances in cirrhosis where transaminases are normal. Therefore, non-invasive diagnostic methods for monitoring of liver condition should be considered, in addition to liver function tests. Liver biopsy should be considered on an individual basis taking into account the patient's comorbidities, medical history and the risks related to biopsy. Risk factors for hepatotoxicity include excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver disorders, diabetes mellitus, obesity and previous contact with hepatotoxic drugs or chemicals and prolonged methotrexate treatment.
Additional hepatotoxic medicinal products should not be given during treatment with methotrexate unless clearly necessary. Alcohol consumption should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Closer monitoring of liver enzymes should be undertaken in patients concomitantly taking other hepatotoxic medicinal products.
Increased caution should be exercised in patients with insulin-dependent diabetes mellitus, as during methotrexate therapy, liver cirrhosis developed in isolated cases without any elevation of transaminases.
4. Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function is recommended.
As methotrexate is eliminated mainly by renal route, increased serum concentrations are to be expected in the case of renal insufficiency, which may result in severe undesirable effects. 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.
Where renal function may be compromised (e.g. in the elderly), monitoring should take place more frequently. This applies in particular, when medicinal products are administered concomitantly, which affect the elimination of methotrexate, cause kidney damage (e.g. nonsteroidal anti-inflammatory medicinal products) or which can potentially lead to impairment of blood formation. Dehydration may also intensify the toxicity of methotrexate.
5. Assessment of respiratory system: methotrexate has been associated with pulmonary toxicity, which is potentially fatal. Patients should be closely monitored for pulmonary symptoms and, if necessary, lung function test should be performed. Pulmonary affection requires a quick diagnosis and discontinuation of methotrexate. Pulmonary symptoms (especially a dry, nonproductive cough) or a nonspecific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. 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.
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.
6. Methotrexate may, due to its effect on the immune system, impair the response to vaccination and affect the result of immunological tests. Particular caution is also needed in the presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) for reasons of eventual activation. Vaccination using live vaccines must not be carried out under methotrexate therapy.
If vomiting, diarrhoea or stomatitis occur, resulting in dehydration, methotrexate should be discontinued until recovery occurs.
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.
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 and advanced age. 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.
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 leukopenia occurs during therapy. In this instance, the drug should be discontinued and appropriate antibiotic therapy instituted. If severe bone marrow depression occurs, blood or platelet transfusions may be required.
Pneumonia (in some cases leading to respiratory failure) may occur. Potentially fatal opportunistic infections, especially Pneumocystis jirovecii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis jirovecii pneumonia should be considered.
Immunisation 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. Recovery has been reported with discontinuation of therapy.
Even following low dose there have been occasional reports of significant CNS toxicity. Patients should be closely monitored for neurologic symptoms, and if these occur, treatment should be discontinued and appropriate therapy instituted.
Encephalopathy/leukoencephalopathy have been reported in oncologic patients receiving methotrexate therapy and cannot be excluded for methotrexate therapy in non-oncologic indications.

Progressive multifocal leukoencephalopathy (PML).

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving methotrexate, mostly in combination with other immunosuppressive medication. PML can be fatal and should be considered in the differential diagnosis in immunosuppressed patients with new onset or worsening neurological symptoms.

Fertility and reproduction.

Fertility.

Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy, and to cause impaired fertility, affecting spermatogenesis and oogenesis during the period of its administration - effects that appear to be reversible on discontinuing therapy (see Section 4.6 Fertility, Pregnancy and Lactation).

Teratogenicity - reproductive risk.

Methotrexate causes embryotoxicity, abortion and fetal defects in humans. Therefore, the possible risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing potential (see Section 4.6 Fertility, Pregnancy and Lactation). The absence of pregnancy must be confirmed before Trexject is used. If women of a sexually mature age are treated, effective contraception must be used during treatment and for at least six months after. For contraception advice for men, see Section 4.6 Fertility, Pregnancy and Lactation.

Use in hepatic impairment.

Methotrexate should not be used in patients with alcoholism or hepatic disorders, including alcoholic liver disease or other chronic liver disease. See Boxed Warnings; see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Recommended examinations and safety measures before and during use.

Use in renal impairment.

Methotrexate should not be used in patients with severe renal impairment. See Boxed Warnings; see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Recommended examinations and safety measures before and during use.

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.

Trexject is not recommended for use in paediatric patients.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Alcohol, hepatotoxic medicinal products, haematotoxic medicinal products.

The probability of methotrexate exhibiting a hepatotoxic effect is increased by regular alcohol consumption and when other hepatotoxic medicinal products are taken at the same time. Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide) should be monitored with special care. The same should be taken into account with the simultaneous administration of haematotoxic medicinal products (e.g. leflunomide, azathioprine, retinoids, sulfasalazine).
Combined treatment with methotrexate and retinoids like acitretin increases the risk of hepatotoxicity (see Section 4.3 Contraindications).

Leflunomide.

The incidence of pancytopenia and hepatotoxicity can be increased when leflunomide is combined with methotrexate.

Medicinal products with high plasma protein binding.

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.

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 intestinal and 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, glycopeptides, ciprofloxacin, cefalotin and sulfonamides. There is a considerable risk of methotrexate toxicity. Use of methotrexate with penicillins and these antibiotics 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.

Products containing folic acid or folinic acid.

Concomitant treatment with folinic acid or folic acid may decrease the incidence or severity of adverse effects from methotrexate therapy but also the efficacy of methotrexate. Medicinal products containing folic acid or folinic acid (including certain vitamin preparations) should not be given to patients on the same day as methotrexate treatment.

Probenecid, weak organic acids, pyrazoles and nonsteroidal anti-inflammatory agents.

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 for 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 these studies and in the treatment of rheumatoid arthritis (generally 7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that 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 and pyrazoles (phenylbutazone) may increase the methotrexate plasma half-life and thereby increase blood levels.

Proton pump inhibitors.

A potential interaction may exist between methotrexate and proton pump inhibitors (e.g. omeprazole, pantoprazole). Concomitant administration of methotrexate and omeprazole has led to delayed renal elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case.

Allopurinol.

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

Medicinal products which cause folate deficiency.

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.

Nitrous oxide anaesthesia.

The use of nitrous oxide anaesthesia potentiates the effect of methotrexate on folate metabolism, yielding severe, unpredictable myelosuppression and stomatitis. Whilst this effect can be reduced by administering folinic acid, avoid concomitant use of nitrous oxide in patients receiving methotrexate.

Medicinal products with adverse reactions on the bone marrow.

In the case of medication with medicinal products, which may have adverse reactions on the bone marrow (e.g. sulphonamides, trimethoprim/ sulphamethoxazole, chloramphenicol, pyrimethamine); attention should be paid to the possibility of pronounced impairment of blood formation.

Other antirheumatic medicinal products.

An increase in the toxic effects of methotrexate is, in general, not to be expected when Trexject is administered simultaneously with other antirheumatic medicinal products (e.g. gold compounds, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporin).

Sulfasalazine.

Although the combination of methotrexate and sulfasalazine can cause an increase in efficacy of methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis through sulfasalazine, such undesirable effects have only been observed in rare individual cases in the course of several studies.

Amiodarone.

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

Theophylline.

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

Mercaptopurine.

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

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).

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.

Caffeine or theophylline containing beverages.

An excessive consumption of caffeine or theophylline containing beverages (coffee, caffeine containing soft drinks, black tea) should be avoided during methotrexate therapy.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans, methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhea. These effects appear to be reversible after discontinuation of therapy in most cases. Animal studies show that methotrexate impairs fertility (see Section 5.3 Preclinical Safety Data, Genotoxicity).
(Category D)
Methotrexate is contraindicated during pregnancy in non-oncological indications (see Section 4.3 Contraindications). Methotrexate has been shown to be teratogenic to humans. It has been reported to cause fetal death, miscarriages and/or congenital abnormalities (craniofacial, cardiovascular, central nervous system and extremity related). Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine growth restriction and congenital malformations in case of exposure during pregnancy.
Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dose methotrexate treatment (less than 30 mg/week), compared to a reported rate of 22.5% in disease-matched patients treated with drugs other than methotrexate.
Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births in disease-matched patients treated with drugs other than methotrexate.
Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg/week, but higher rates of spontaneous abortions and congenital malformations are expected.
When methotrexate was discontinued prior to conception, normal pregnancies have been reported.
Women of childbearing potential should not be started on methotrexate until pregnancy is excluded with certainty by taking appropriate measures e.g. pregnancy test. During treatment, pregnancy tests should be repeated as clinically required (e.g. after any gap in contraception). Effective contraception must be used during treatment with methotrexate and at least 6 months thereafter. Female patients of reproductive potential must be counselled regarding pregnancy prevention and planning. Prior to initiating therapy, women of childbearing potential must be fully counselled on the risk of malformations associated with methotrexate to the fetus should they become pregnant while undergoing treatment. If pregnancy occurs during treatment with methotrexate and for up to 6 months thereafter, medical advice should be given regarding the risk of harmful effects on the child associated with treatment and ultrasonography examinations should be performed to confirm normal fetal development.

Contraception in males.

Pregnancy should be avoided if either partner is receiving methotrexate. It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic in animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be excluded. Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to low-dose methotrexate (less than 30 mg/week). For higher doses, there is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure. As precautionary measures, sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 6 months after cessation of methotrexate. Men should not donate semen during therapy or for 6 months following discontinuation of methotrexate.
 Methotrexate is excreted in human breast milk. Due to the potential for serious adverse reactions in breast-fed infants, Trexject is contraindicated during breastfeeding (see Section 4.3 Contraindications). Breast-feeding must be discontinued prior to and throughout Trexject therapy.

4.7 Effects on Ability to Drive and Use Machines

Central nervous symptoms such as tiredness and dizziness can occur during treatment, Trexject has minor or moderate influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

The major toxic effects of methotrexate occur on normal, rapidly proliferating tissues, particularly the bone marrow and gastrointestinal tract. Ulcerations of the oral mucosa are usually the earliest signs of toxicity.
In clinical study MC-MTX.6/RH, the overall incidence of adverse events (AEs) over the total period of study within the safety analysis set was similar for both treatment groups, with AEs reported in 66.3% of patients in the SC group and 61.7% in the oral group.
As expected, the most commonly reported AEs in both treatment groups belonged to the category gastrointestinal disorders with a total of 42% of study patients. No statistically significant differences were observed between rates of gastrointestinal AEs in both treatment groups (SC group 45.6% vs oral group 38.3%). The overall incidence of serious adverse events was also similar for both treatment groups (5.7% vs 4.3%).
More patients reported nausea and anorexia in the SC group, but stomatitis occurred more often in the oral group. Comparing the frequency distribution of at least moderate adverse events, no significant differences were found regarding nausea, stomatitis and anorexia.
The incidence of diarrhoea was significantly increased in the oral group. All other adverse events were not significantly increased in one or another treatment group.
Other sources report ulcerative stomatitis, leukopenia, nausea and abdominal distress as the most common adverse reactions. Others reported include malaise, undue fatigue, chills and fever, dizziness, drowsiness, tinnitus, and decreased resistance to infection. The incidence and severity of side effects generally appear to be dose and frequency related. Adverse reactions have been reported for the various systems.

Skin and subcutaneous tissue disorders.

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. Skin exfoliation/dermatitis exfoliative reactions have been reported.

Musculoskeletal and connective tissue disorders.

Arthralgia, myalgia, osteoporosis, stress fracture, osteonecrosis of jaw (secondary to lymphoproliferative disorders).

Blood and lymphatic system.

Bone marrow depression, leukopenia, neutropenia, eosinophilia, pancytopenia, agranulocytosis, thrombocytopenia, anaemia (including aplastic anaemia), hypogammaglobulinaemia, decrease in serum albumin. Clinical sequelae such as fever, infections, haemorrhage from various sites, septicaemia, lymphadenopathy and lymphoproliferative disorders 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, 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, 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, foetal defects, foetal death, severe nephropathy, vaginitis, vaginal discharge.

Respiratory, thoracic and mediastinal disorders.

Interstitial pneumonitis, interstitial fibrosis, reversible eosinophilic pulmonary infiltrates, respiratory fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, alveolitis, epistaxis, pulmonary alveolar haemorrhage, 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).

Nervous system disorders.

Headaches, tiredness, drowsiness, dizziness, pain, muscular asthenia or paraesthesia/hypoaesthesia, changes in sense of taste (metallic taste), meningism, acute aseptic meningitis, paralysis, encephalopathy/leukoencephalopathy, 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. 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 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 jirovecii pneumonia was the most common infection. Other reported infections include pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, herpes zoster, H. simplex hepatitis, disseminated H. simplex, fatal sepsis and cytomegalovirus, including cytomegaloviral pneumonia.

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.

General disorders and administration site conditions.

Fever, wound-healing impairment, local damage (formation of sterile abscess, lipodystrophy) of injection site following intramuscular or subcutaneous administration, asthenia, injection site necrosis, oedema.

Lymphoma/lymphoproliferative disorders.

There have been reports of individual cases of lymphoma and other lymphoproliferative disorders which subsided in a number of cases once treatment with methotrexate had been discontinued.
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, proteinuria, nodulosis, 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.

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-probl... Overdose

Discontinue methotrexate at the first sign of ulceration or bleeding, diarrhoea or marked depression of the haematopoietic system.
Symptoms following 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 nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinisation, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent haemodialysis with a high flux dialyzer may also be beneficial in these patients.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Methotrexate is an antimetabolite antineoplastic agent, which exerts its cytotoxic effect through competitive inhibition of dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolic acid results in interference with DNA synthesis and cellular reproduction.
Tissues with high rates of cellular proliferation, e.g. 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.

MC-MTX.6/RH.

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 prefilled syringe per week. Patients within arm B received one prefilled 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%).
Trexject 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.

5.2 Pharmacokinetic Properties

Absorption.

Methotrexate is incompletely absorbed after oral administration. 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.

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.

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.

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 2).
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 crossover. 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 3).
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 IM injection compared to SC 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 IM and SC 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.)

5.3 Preclinical Safety Data

Genotoxicity.

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.

Carcinogenicity.

As conventional carcinogenicity studies have not been performed and data from chronic toxicity studies in rodents are inconsistent, methotrexate is considered not classifiable as to its carcinogenicity to humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, sodium hydroxide, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

2 years.

6.4 Special Precautions for Storage

Store below 25°C. Keep the prefilled syringes in the outer carton in order to protect from light.

6.5 Nature and Contents of Container

Trexject is supplied in a pre-filled syringe of colourless glass (type I) of 1 mL capacity with an embedded needle, packed in blisters, for subcutaneous administration.
Plunger stoppers of chlorobutyl rubber (type I) and HDPE polystyrene or polypropylene rods form the syringe plunger. Each syringe is marked with graduation marks, the name and strength of the medicine, and the expiry date and batch number. The syringe barrel includes a colour coded plastic back stop for each strength as described below:

Pack sizes.

1. Syringe with 0.15 mL solution for injection, equivalent to 7.5 mg methotrexate. The syringe barrel is made of glass and has a red colour coded plastic backstop.
2. Syringe with 0.20 mL solution for injection, equivalent to 10 mg methotrexate. The syringe barrel is made of glass and has a green colour coded plastic backstop.
3. Syringe with 0.25 mL solution for injection, equivalent to 12.5 mg methotrexate. The syringe barrel is made of glass and has a light blue colour coded plastic backstop.
4. Syringe with 0.30 mL solution for injection, equivalent to 15 mg methotrexate. The syringe barrel is made of glass and has a purple colour coded plastic backstop.
5. Syringe with 0.35 mL solution for injection, equivalent to 17.5 mg methotrexate. The syringe barrel is made of glass and has a pink colour coded plastic backstop.
6. Syringe with 0.40 mL solution for injection, equivalent to 20 mg methotrexate. The syringe barrel is made of glass and has a dark red colour coded plastic backstop.
7. Syringe with 0.45 mL solution for injection, equivalent to 22.5 mg methotrexate. The syringe barrel is made of glass and has a dark green colour coded plastic backstop.
8. Syringe with 0.50 mL solution for injection, equivalent to 25 mg methotrexate. The syringe barrel is made of glass and has a blue colour coded plastic backstop.
Trexject is available in packs of 1, 4, 6, 12 and 24 syringes.
Not all presentations and pack sizes may be marketed.

6.6 Special Precautions for Disposal

Trexject is intended for single use in one patient on one occasion only. Discard any residue in accordance with Section 4.2 Dose and Method of Administration, Instructions for handling.

6.7 Physicochemical Properties

Chemical structure.

The structural formula is represented below.
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