Injexate 50 mg/ml Injektionsvätska, lösning i förfylld spruta

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

07-12-2020

Produktens egenskaper Produktens egenskaper (SPC)

12-04-2019

Aktiva substanser:
metotrexat
Tillgänglig från:
Accord Healthcare B.V. ,
ATC-kod:
L04AX03
INN (International namn):
methotrexate
Dos:
50 mg/ml
Läkemedelsform:
Injektionsvätska, lösning i förfylld spruta
Sammansättning:
metotrexat 50 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Förfylld spruta, 12 x 0,35 ml (17,5 mg); Förfylld spruta, 1 x 0,15 ml (7,5 mg); Förfylld spruta, 1 x 0,45 ml (22,5 mg); Förfylld spruta, 12 x 0,45 ml (22,5 mg); Förfylld spruta, 6 x 0,45 ml (22,5 mg); Förfylld spruta, 5 x 0,45 ml (22,5 mg); Förfylld spruta, 4 x 0,45 ml (22,5 mg); Förfylld spruta, 8 x 0,15 ml (7,5 mg); Förfylld spruta, 8 x 0,20 ml (10 mg); Förfylld spruta, 8 x 0,25 ml (12,5 mg); Förfylld spruta, 8 x 0,30 ml (15 mg); Förfylld spruta, 8 x 0,35 ml (17,5 mg); Förfylld spruta, 8 x 0,40 ml (20 mg); Förfylld spruta, 1 x 0,45 ml (22,5 mg); Förfylld spruta, 8 x 0,45 ml (22,5 mg); Förfylld spruta, 8 x 0,50 ml (25 mg); Förfylld spruta, 8 x 0,55 ml (27,5 mg); Förfylld spruta, 8 x 0,60 ml (30 mg); Förfylld spruta, 1 x 0,15 ml (7,5 mg) med fast nålskydd; Förfylld spruta, 1 x 0,20 ml (10 mg) med fast nålskydd; Förfylld spruta, 1 x 0,25 ml (12,5 mg) med fast nålskydd; Förfylld spruta, 1 x 0,30 ml (15 mg) med fast nålskydd; Förfylld spruta, 1 x 0,35 ml (17,5 mg) med fast nålskydd; Förfylld spruta, 1 x 0,40 ml (20 mg) med fast nålskydd; Förfylld spruta, 1 x 0,45 ml (22,5 mg) med fast nålskydd; Förfylld spruta, 1 x 0,50 ml (25 mg) med fast nålskydd; Förfylld spruta, 1 x 0,55 ml (27,5 mg) med fast nålskydd; Förfylld spruta, 1 x 0,60 ml (30 mg) med fast nålskydd; Förfylld spruta, 10 x 0,15 ml (7,5 mg) med fast nålskydd; Förfylld spruta, 10 x 0,20 ml (10 mg) med fast nålskydd; Förfylld spruta, 10 x 0,30 ml (15 mg) med fast nålskydd; Förfylld spruta, 10 x 0,40 ml (20 mg) med fast nålskydd; Förfylld spruta, 10 x 0,50 ml (25 mg) med fast nålskydd; Förfylld spruta, 12 x 0,15 ml (7,5 mg) med fast nålskydd; Förfylld spruta, 12 x 0,20 ml (10 mg) med fast nålskydd; Förfylld spruta, 12 x 0,25 ml (12,5 mg) med fast nålskydd; Förfylld spruta, 12 x 0,30 ml (15 mg) med fast nålskydd; Förfylld spruta, 12 x 0,35 ml (17,5 mg) med fast nålskydd; Förfylld spruta, 12 x 0,40 ml (20 mg) med fast nålskydd; Förfylld spruta, 12 x 0,45 ml (22,5 mg) med fast nålskydd; Förfylld spruta, 12 x 0,50 ml (25 mg) med fast nålskydd; Förfylld spruta, 12 x 0,55 ml (27,5 mg) med fast nålskydd; Förfylld spruta, 12 x 0,60 ml (30 mg) med fast nålskydd; Förfylld spruta, 2 x 0,15 ml (7,5 mg) med fast nålskydd; Förfylld spruta, 2 x 0,20 ml (10 mg) med fast nålskydd; Förfylld spruta, 2 x 0,30 ml (15 mg) med fast nålskydd; Förfylld spruta, 2 x 0,40 ml (20 mg) med fast nålskydd; Förfylld spruta, 2 x 0,50 ml (25 mg) med fast nålskydd; Förfylld spruta, 24 x 0,15 ml (7,5 mg) med fast nålskydd; Förfylld spruta, 24 x 0,20 ml (10 mg) med fast nålskydd; Förfylld spruta, 24 x 0,30 ml (15 mg) med fast nålskydd; Förfylld spruta, 24 x 0,40 ml (20 mg) med fast nålskydd; Förfylld spruta, 4 x 0,15 ml (7,5 mg) med fast nålskydd; Förfylld spruta, 4 x 0,20 ml (10 mg) med fast nålskydd; Förfylld spruta, 4 x 0,25 ml (12,5 mg) med fast nålskydd; Förfylld spruta, 4 x 0,30 ml (15 mg) med fast nålskydd; Förfylld spruta, 4 x 0,35 ml (17,5 mg) med fast nålskydd; Förfylld spruta, 4 x 0,40 ml (20 mg) med fast nålskydd; Förfylld spruta, 4 x 0,45 ml (22,5 mg) med fast nålskydd; Förfylld spruta, 4 x 0,50 ml (25 mg) med fast nålskydd; Förfylld spruta, 4 x 0,55 ml (27,5 mg) med fast nålskydd; Förfylld spruta, 4 x 0,60 ml (30 mg) med fast nålskydd; Förfylld spruta, 5 x 0,15 ml (7,5 mg) med fast nålskydd; Förfylld spruta, 5 x 0,20 ml (10 mg) med fast nålskydd; Förfylld spruta, 5 x 0,25 ml (12,5 mg) med fast nålskydd; Förfylld spruta, 5 x 0,30 ml (15 mg) med fast nålskydd; Förfylld spruta, 5 x 0,35 ml (17,5 mg) med fast nålskydd; Förfylld spruta, 5 x 0,40 ml (20 mg) med fast nålskydd; Förfylld spruta, 5 x 0,45 ml (22,5 mg) med fast nålskydd; Förfylld spruta, 5 x 0,50 ml (25 mg) med fast nålskydd; Förfylld spruta, 5 x 0,55 ml (27,5 mg) med fast nålskydd; Förfylld spruta, 5 x 0,60 ml (30 mg) med fast nålskydd; Förfylld spruta, 6 x 0,15 ml (7,5 mg) med fast nålskydd; Förfylld spruta, 6 x 0,20 ml (10 mg) med fast nålskydd; Förfylld spruta, 6 x 0,25 ml (12,5 mg) med fast nålskydd; Förfylld spruta, 6 x 0,30 ml (15 mg) med fast nålskydd; Förfylld spruta, 6 x 0,35 ml (17,5 mg) med fast nålskydd; Förfylld spruta, 6 x 0,40 ml (20 mg) med fast nålskydd; Förfylld spruta, 6 x 0,45 ml (22,5 mg) med fast nålskydd; Förfylld spruta, 6 x 0,50 ml (25 mg) med fast nålskydd; Förfylld spruta, 6 x 0,55 ml (27,5 mg) med fast nålskydd; Förfylld spruta, 6 x 0,60 ml (30 mg) med fast nålskydd; Förfylld spruta, 8 x 0,15 ml (7,5 mg) med fast nålskydd; Förfylld spruta, 8 x 0,20 ml (10 mg) med fast nålskydd; Förfylld spruta, 8 x 0,25 ml (12,5 mg) med fast nålskydd; Förfylld spruta, 8 x 0,30 ml (15 mg) med fast nålskydd; Förfylld spruta, 8 x 0,35 ml (17,5 mg) med fast nålskydd; Förfylld spruta, 8 x 0,40 ml (20 mg) med fast nålskydd; Förfylld spruta, 8 x 0,45 ml (22,5 mg) med fast nålskydd; Förfylld spruta, 8 x 0,50 ml (25 mg) med fast nålskydd; Förfylld spruta, 8 x 0,55 ml (27,5 mg) med fast nålskydd; Förfylld spruta, 8 x 0,60 ml (30 mg) med fast nålskydd; Förfylld spruta, 1 x 0,20 ml (10 mg); Förfylld spruta, 1 x 0,25 ml (12,5 mg); Förfylld spruta, 1 x 0,30 ml (15 mg); Förfylld spruta, 1 x 0,35 ml (17,5 mg); Förfylld spruta, 1 x 0,40 ml (20 mg); Förfylld spruta, 1 x 0,45 ml (22,5 mg); Förfylld spruta, 1 x 0,50 ml (25 mg); Förfylld spruta, 1 x 0,55 ml (27,5 mg); Förfylld spruta, 1 x 0,60 ml (30 mg); Förfylld spruta, 2 x 0,15 ml (7,5 mg); Förfylld spruta, 4 x 0,15 ml (7,5 mg); Förfylld spruta, 5 x 0,15 ml (7,5 mg); Förfylld spruta, 6 x 0,15 ml (7,5 mg); Förfylld spruta, 10 x 0,15 ml (7,5 mg); Förfylld spruta, 12 x 0,15 ml (7,5 mg); Förfylld spruta, 24 x 0,15 ml (7,5 mg); Förfylld spruta, 2 x 0,20 ml (10 mg); Förfylld spruta, 4 x 0,20 ml (10 mg); Förfylld spruta, 5 x 0,20 ml (10 mg); Förfylld spruta, 6 x 0,20 ml (10 mg); Förfylld spruta, 10 x 0,20 ml (10 mg); Förfylld spruta, 12 x 0,20 ml (10 mg); Förfylld spruta, 24 x 0,20 ml (10 mg); Förfylld spruta, 4 x 0,25 ml (12,5 mg); Förfylld spruta, 5 x 0,25 ml (12,5 mg); Förfylld spruta, 6 x 0,25 ml (12,5 mg); Förfylld spruta, 12 x 0,25 ml (12,5 mg); Förfylld spruta, 2 x 0,30 ml (15 mg); Förfylld spruta, 4 x 0,30 ml (15 mg); Förfylld spruta, 5 x 0,30 ml (15 mg); Förfylld spruta, 6 x 0,30 ml (15 mg); Förfylld spruta, 10 x 0,30 ml (15 mg); Förfylld spruta, 12 x 0,30 ml (15 mg); Förfylld spruta, 24 x 0,30 ml (15 mg); Förfylld spruta, 4 x 0,35 ml (17,5 mg); Förfylld spruta, 5 x 0,35 ml (17,5 mg); Förfylld spruta, 6 x 0,35 ml (17,5 mg); Förfylld spruta, 2 x 0,40 ml (20 mg); Förfylld spruta, 4 x 0,40 ml (20 mg); Förfylld spruta, 5 x 0,40 ml (20 mg); Förfylld spruta, 6 x 0,40 ml (20 mg); Förfylld spruta, 10 x 0,40 ml (20 mg); Förfylld spruta, 12 x 0,40 ml (20 mg); Förfylld spruta, 24 x 0,40 ml (20 mg); Förfylld spruta, 4 x 0,45 ml (22,5 mg); Förfylld spruta, 5 x 0,45 ml (22,5 mg); Förfylld spruta, 6 x 0,45 ml (22,5 mg); Förfylld spruta, 12 x 0,45 ml (22,5 mg); Förfylld spruta, 2 x 0,50 ml (25 mg); Förfylld spruta, 4 x 0,50 ml (25 mg); Förfylld spruta, 5 x 0,50 ml (25 mg); Förfylld spruta, 6 x 0,50 ml (25 mg); Förfylld spruta, 10 x 0,50 ml (25 mg); Förfylld spruta, 12 x 0,50 ml (25 mg); Förfylld spruta, 4 x 0,55 ml (27,5 mg); Förfylld spruta, 5 x 0,55 ml (27,5 mg); Förfylld spruta, 6 x 0,55 ml (27,5 mg); Förfylld spruta, 12 x 0,55 ml (27,5 mg); Förfylld spruta, 4 x 0,60 ml (30 mg); Förfylld spruta, 5 x 0,60 ml (30 mg); Förfylld spruta, 6 x 0,60 ml (30 mg); Förfylld spruta, 12 x 0,60 ml (30 mg)
Bemyndigande status:
Godkänd
Godkännandenummer:
51172
Tillstånd datum:
2015-11-26

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Injexate 50 mg/ml solution for injection in prefilled syringe

methotrexate

Read all of this leaflet carefully before you start using this medicine

because it contains

important information for you

.

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

If you have any further questions, ask your doctor or pharmacist or nurse.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm

them, even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

What Injexate is and what it is used for

What you need to know before you use Injexate

How to use Injexate

Possible side effects

How to store Injexate

Contents of the pack and other information

1.

WHAT INJEXATE IS AND WHAT IT IS USED FOR

Injexate contains methotrexate as active substance

Methotrexate is a substance with following properties:

it interferes with the growth of certain cells in the body that reproduce quickly

it reduces the activity of the immune system (the body’s own defence mechanism)

it has anti-inflammatory effects

Injexate is indicated for the treatment of

active rheumatoid arthritis in adult patients.

polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to

nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate,

severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of

therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult

patients.

mild to moderate Crohn’s Disease in adult patients when adequate treatment with other

medicines is not possible.

Rheumatoid arthritis (RA)

is a chronic collagen disease, characterised by inflammation of the

synovial membranes (joint membranes). These membranes produce a fluid which acts as a

lubricant for many joints. The inflammation causes thickening of the membrane and swelling of

the joint.

Juvenile arthritis concerns children and adolescents less than 16 years. Polyarthritic forms are

indicated if 5 or more joints are affected within the first 6 months of the disease.

Psoriatic arthritis is a kind of arthritis with psoriatric lesions of the skin and nails, especially at

the joints of fingers and toes.

Psoriasis is a common chronic skin disease, characterised by red patches covered by thick, dry,

silvery, adherent scales.

Injexate modifies and slows down the progression of the disease.

Crohn’s Disease is a type of inflammatory bowel disease that may affect any part of the

gastrointestinal tract causing symptoms such as abdominal pain, diarrhoea, vomiting or weight

loss.

2.

WHAT YOU NEED TO KNOW BEFORE YOU USE INJEXATE

Do not use Injexate if you:

are allergic to methotrexate or any of the other ingredients of this medicine (listed in

section 6),

suffer from severe liver or kidney diseases or blood diseases.

regularly drink large amounts of alcohol.

suffer from a severe infection, e.g. tuberculosis, HIV or other immunodeficiency syndromes.

suffer from ulcers in the mouth, stomach ulcer or intestinal ulcer.

receive vaccinations with live vaccines at the same time.

are pregnant or breast-feeding (see section “Pregnancy, breast-feeding and fertility”)

Warnings and precautions

Talk to your doctor or pharmacist or nurse before taking Injexate if:

you are elderly or if you feel generally unwell and weak.

you have problems with the way your liver works.

you suffer from dehydration (water loss).

Acute bleeding from the lungs in patients with underlying rheumatologic disease has been

reported with methotrexate. If you experience symptoms of spitting or coughing up blood you

should contact your doctor immediately.

Special precautionary measures for treatment with Injexate

Methotrexate temporarily affects sperm and egg production, which is reversible in most cases.

Methotrexate can cause miscarriage and severe birth defects. You must avoid becoming pregnant

when using methotrexate and for at least six months after treatment has stopped. See also section

“Pregnancy, breast-feeding and fertility”.

Recommended follow-up examinations and safety measures:

Even when Injexate is administered in low doses, severe side effects can occur. In order to detect

them in time, check-ups and laboratory tests have to be carried out by your doctor.

Before therapy:

Before starting the treatment, blood samples will be taken in order to check that you have enough

blood cells, tests to check your liver function, serum albumin (a protein in the blood) and kidney

function. Your doctor will also check if you suffer from tuberculosis (infectious disease in

combination with little nodules in the affected tissue) and a chest X-ray will be taken.

During therapy:

You will have the following tests at least once a month during the first six months and at least

every three months thereafter:

Examination of the mouth and throat for alterations of the mucosa

Blood tests

Check of liver function

Check of kidney function

Check of respiratory system and if necessary lung function test

Methotrexate may affect your immune system and vaccination results. It may also affect the

result

immunological

tests.

Inactive,

chronic

infections

(e.g. herpes

zoster

[shingles],

tuberculosis, hepatitis B or C) may flare up. During therapy with Injexate you must not be

vaccinated with live vaccines.

Radiation induced dermatitis and sun-burn can reappear under methotrexate therapy (recall-

reaction).

Psoriatic

lesions

exacerbate

during

UV-irradiation

simultaneous

administration of methotrexate.

Enlarged lymph nodes (lymphoma) may occur and therapy must then be stopped.

Diarrhoea can be a toxic effect of Injexate and requires an interruption of therapy. If you suffer

from diarrhoea please speak to your doctor.

Encephalopathy (a brain disorder)/leukoencephalopathy (a special disorder of the white brain

substance) have been reported in cancer patients receiving methotrexate therapy and cannot be

excluded for methotrexate therapy in other disease.

Other medicines and Injexate

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

The effect of the treatment may be affected if Injexate is administered at the same time as certain

other drugs:

Medicines harming the liver or the blood count, e.g. leflunomide

Antibiotics

(medicines

prevent/fight

certain

infections)

such

tetracyclines,

chloramphenicol, and non-absorbable broad-spectrum antibiotics, penicillines, glycopeptides,

sulphonamides

(sulphur

containing

medicines

that

prevent/fight

certain

infections),

ciprofloxacin and cefalotin

Non-steroidal

anti-inflammatory

drugs

salicylates

(medicines

against

pain

and/or

inflammation)

Probenecid (medicine against gout)

Weak

organic

acids

like

loop

diuretics

(“water

tablets”)

some

medicines

used

treatment

pain

inflammatory

diseases

(e.g.

acetylsalicylic

acid,

diclofenac

ibuprofen) and pyrazole (e.g. metamizol for treating pain)

Medicinal products, which may have adverse effects on the bone marrow, e.g. trimethoprim-

sulphamethoxazole (an antibiotic) and pyrimethamine

Sulphasalazine (antirheumatic medicine)

Azathioprine (an immunosuppressive agent sometimes used in severe forms of rheumatoid

arthritis)

Mercaptopurine (a cytostatic agent)

Retinoids (medicine against psoriasis and other dermatological diseases)

Theophylline (medicine against bronchial asthma and other lung diseases)

Proton-pump

inhibitors

(medicines

against

stomach

trouble

such

omeprazole

pantoprazole

Hypoglycaemics (medicines that are used to lower the blood sugar)

Vitamins containing folic acid may impair the effect of your treatment and should only be taken

when advised by your doctor.

Vaccination with live vaccine must be avoided.

Injexate with food, drink and alcohol

Alcohol as well as large amounts of coffee, caffeine-containing soft drinks and black tea should

be avoided during treatment with Injexate.

Pregnancy, breast-feeding and fertility

Pregnancy

Do not use Injexate during pregnancy or if you are trying to become pregnant. Methotrexate can

cause

birth

defects,

harm

unborn

child

cause

miscarriage.

associated

with

malformations of the skull, face, heart and blood vessels, brain and limbs. Therefore, it is very

important that Methotrexate is not given to pregnant patients or patients planning to become

pregnant. In women of child-bearing age any possibility of pregnancy must be excluded with

appropriate measures, e.g. a pregnancy test before starting treatment. You must avoid becoming

pregnant whilst taking methotrexate and for at least 6 months after treatment is stopped by using

reliable contraception throughout this time (see also section “Warnings and precautions”).

If you do become pregnant during treatment or suspect you might be pregnant, speak to your

doctor as soon as possible. You should be offered advice regarding the risk of harmful effects on

the child through treatment.

If you wish to become pregnant you should consult your doctor, who may refer you for specialist

advice before the planned start of treatment.

Male fertility

The available evidence does not indicate an increased risk of malformations or miscarriage if the

father takes methotrexate less than 30 mg/week. However, a risk cannot be completely excluded.

Methotrexate may be genotoxic. This means that the medicine may cause genetic mutation.

Methotrexate can affect sperm production with the potential to cause birth defects. Therefore,

you should avoid fathering a child or to donate semen whilst taking methotrexate and for at least

6 months after treatment is stopped.

Breast-feeding has to be stopped prior to and during treatment with Injexate.

Driving and using machines

Treatment with Injexate may cause adverse reactions affecting the central nervous system, e.g.

tiredness and dizziness. Thus the ability to drive a vehicle and/or to operate machines may, in

certain cases, be compromised. If you feel tired or drowsy you should not drive or use machines.

Injexate contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially

“sodium-free”.

3.

HOW TO USE INJEXATE

Your doctor decides on the dosage, which is adjusted individually. Usually it takes 4 – 8 weeks

before there is any effect of the treatment.

Injexate is administered subcutaneously (under the skin) by or under the supervision of a

physician or healthcare staff as an injection

once a week only

. Together with your doctor you

decide on a suitable weekday each week on which you receive your injection.

Important warning about the dose of Injexate

(methotrexate):

Use Injexate

only once a week

for the treatment of Rheumatoid arthritis, Juvenile arthritis,

Psoriatic arthritis, Psoriasis, Crohn’s disease . Using too much of Injexate (methotrexate) may

be fatal. Please read section 3 of this leaflet very carefully. If you have any questions, please talk

to your doctor or pharmacist before you take this medicine.

Use in children and adolescents

The doctor decides on the appropriate dose in children and adolescents with polyarthritic forms

of juvenile idiopathic arthritis.

Injexate is not recommended in children less than 3 years of age due to insufficient experience in

this age group.

Method and duration of administration

Injexate is injected

once weekly!

The duration of the treatment is determined by the treating physician. Treatment of rheumatoid

arthritis, juvenile idiopathic arthritis, psoriasis vulgaris, psoriatic arthritis and Crohn’s disease

with Injexate is a long-term treatment.

At the start of your treatment, Injexate may be injected by medical staff. However, your doctor

may decide that you can learn how to inject Injexate yourself. You will receive appropriate

training for you to do this. Under no circumstances should you attempt to inject yourself, unless

you have been trained to do so.

Please refer to the instructions for use at the end of the leaflet.

Please note that all of the contents have to be used.

The manner of handling and disposal must be consistent with that of other cytostatic preparations

in accordance with local requirements. Pregnant health care personnel should not handle and/or

administer Injexate.

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 use more Injexate than you should

If you use more Injexate than you should, talk to your doctor immediately.

If you forget to use Injexate

Do not take a double dose to make up for a forgotten dose.

If you stop using Injexate

If you stop using Injexate, talk to your doctor immediately.

If you have the impression that the effect of Injexate is too strong or too weak, you should talk to

your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The frequency as well as the degree of severity of the side effects depends on the dosage level

and the frequency of administration. As severe side effects may occur even at low dosage, it is

important that you are monitored regularly by your doctor. Your doctor will do

tests to check

for abnormalities

developing in the blood (such as low white blood cells, low platelets,

lymphoma) and changes in the kidneys and the liver.

Tell your doctor immediately

if you experience any of the following symptoms, as these may

indicate

serious,

potentially

life-threatening

side

effect,

which

require

urgent

specific

treatment:

persistent dry, non-productive cough, shortness of breath and fever

; these may be

signs of an inflammation of the lungs [common - may affect up to 1 in 10 people]

spitting or coughing blood

symptoms of liver damage such as yellowing of the skin and whites of the eyes;

methotrexate can cause chronic liver damage (liver cirrhosis), formation of scar tissue in

the liver (liver fibrosis), fatty degeneration of the liver [all uncommon - may affect up to

1 in 100 people], inflammation of the liver (acute hepatitis) [rare - may affect up to 1 in

1,000 people] and liver failure [very rare - may affect up to 1 in 10,000 people]

allergy symptoms such as skin rash including red itchy skin, swelling of the hands,

feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or

breathing) and feeling you are going to faint;

these may be signs of severe allergic

reactions or an anaphylactic shock [rare - may affect up to 1 in 1,000 people]

symptoms of kidney damage such as swelling of the hands, ankles or feet or changes

in frequency of urination or decrease (oliguria) or absence of urine (anuria);

these

may be signs of kidney failure [rare - may affect up to 1 in 1,000 people]

symptoms of infections, e.g. fever, chills, achiness, sore throat;

methotrexate can make

you more susceptible to infections. Rarely [may affect up to 1 in 1,000 people] severe

infections like a certain type of pneumonia (

Pneumocystis carinii pneumonia

) or blood

poisoning (sepsis) may occur

symptoms such as weakness of one side of the body (stroke) or pain, swelling,

redness and unusual warmth in one of your legs (deep vein thrombosis);

This may

happen

when

a

dislodged

blood

clot

causes

a

blockage

of

a

blood

vessel

(thromboembolic event) [rare - may affect up to 1 in 1,000 people]

fever

and

serious

deterioration

of

your

general

condition,

or

sudden

fever

accompanied by a sore throat or mouth, or urinary problems

; methotrexate can very

rarely [may affect up to 1 in 10,000 people] cause a sharp fall in certain white blood cells

(agranulocytosis) and severe bone marrow suppression

unexpected bleeding, e.g. bleeding gums, blood in the urine, vomiting blood or

bruising,

these can be signs of a severely reduced number of blood platelets caused by

severe courses of bone marrow depression [very rare - may affect up to 1 in 10,000

people]

symptoms such as severe headache often in combination with fever, neck stiffness,

feeling sick, vomiting, disorientation and sensitivity to light

may indicate an

inflammation of the membranes of the brain (acute aseptic meningitis) [very rare - may

affect up to 1 in 10,000 people]

certain brain disorders (encephalopathy/ leukoencephalopathy) have been reported in

cancer patients receiving methotrexate. Such side effects cannot be excluded when

methotrexate therapy is used to treat other diseases. Signs of this kind of brain disorders

may be

altered mental state,

movement disorders (ataxia), visual disturbances or

disturbances of memory

[not known-

frequency cannot be estimated from the available

data ]

severe skin rash or blistering of the skin (this can also affect your mouth, eyes and

genitals)

; these may be signs of the very rare [may affect up to 1 in 10,000 people]

conditions called Stevens Johnson syndrome or burned skin syndrome (toxic epidermal

necrolysis/Lyell’s syndrome)

In the following, please find the other side effects that may occur:

Very common:

may affect more than 1 in 10 people

Inflammation of the mouth lining, indigestion, feeling sick, loss of appetite, abdominal

pain.

Abnormal liver function test (ASAT, ALAT, bilirubin, alkaline phosphatase).

Common:

may affect up to 1 in 10 people

Mouth ulcers, diarrhoea

Rash, reddening of the skin, itching

Headache, tiredness, drowsiness

Reduced blood cell formation with decrease in white and/or red blood cells and/or platelets

Uncommon:

may affect up to 1 in 100 people

Throat inflammation.

Inflammation of the bowels, vomiting,

inflammation

pancreas,

black

tarry

stools,

gastrointestinal ulcers and bleeding.

Increased sensitivity to light, loss of hair, increased number of rheumatic nodules, skin

ulcer, shingles, inflammation of blood vessels, herpes-like skin rash, hives.

Onset of diabetes mellitus.

Dizziness, confusion, depression.

Decrease in serum albumin.

Decrease in the number of all blood cells and platelets.

Inflammation

ulcer

urinary

bladder

vagina,

reduced

kidney

function,

disturbed urination.

Joint pain, muscle pain, reduction of bone mass

Rare:

may affect up to 1 in 1,000 people

Inflammation of gum tissue

Increased skin pigmentation, acne, blue spots

on the skin

due to vessel bleeding

(ecchymosis,

petechiae),

Allergic inflammation of blood vessels

Decreased number of anti-bodies in the blood

Infection (incl. reactivation of inactive chronic infection), red eyes (conjunctivitis).

Mood swings (mood alterations).

Visual disturbances

Inflammation of the sac around the heart, accumulation of fluid in the sac around the heart,

obstruction of cardiac filling due to fluid in the sac around the heart.

Low blood pressure

Formation of scar tissue in the lung (pulmonary fibrosis, shortness of breath and bronchial

asthma, accumulation of fluid in the sac around the lung.

Stress fracture.

Electrolyte disturbances

Fever, wound-healing impairment.

Very rare:

may affect up to 1 in 10,000 people

Acute toxic dilatation of the gut (toxic megacolon)

Increased pigmentation of the nails, inflammation of the cuticles (acute paronychia), deep

infection of hair follicles (furunculosis), visible enlargement of small blood vessels

Pain, loss of strength or sensation of numbness or tingling / having less sensitivity to

stimulation

than

normal

changes

taste

(metallic

taste),

convulsions,

paralysis,

meningism.

Impaired vision, non-inflammatory eye disorder (retinopathy).

Loss of sexual drive, impotence, male breast enlargement, defective sperm formation

(oligospermia), menstrual disorder, vaginal discharge

Enlargement of lymphatic nodes (lymphoma)

Lymphoproliferative disorders (excessive growth of white blood cells)

Not known:

frequency cannot be estimated from the available data:

Increased number of certain white blood cells.

Nosebleed.

Proteins in urine.

Feeling of weakness.

Bleeding from the lungs

Bone damage in the jaw (secondary to excessive growth of white blood cells)

Tissue destruction at injection site

Redness and shedding of skin

swelling

Subcutaneous application of methotrexate is locally well tolerated. Only mild local skin reactions

(such as burning sensations, erythema, swelling, discolouration, severe itching, pain) were

observed, decreasing during therapy.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet.

You can also report side effects directly via (see details below) . By reporting side effects you

can help provide more information on the safety of this medicine.

To be completed nationally

5.

HOW TO STORE INJEXATE

Keep this medicine out of the sight and reach of children.

Store below 30 °C.

Keep the pre-filled syringes in the outer carton in order to protect from light.

Do not use this medicine after the expiry date which is stated on the label/carton after EXP. The

expiry date refers to the last day of that month.

Do not use Injexate if you notice sign of colour change or contain visible particles.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how

to throw away medicines you no longer use. These measures will help protect the environment.

6.

CONTENTS OF THE PACK AND OTHER INFORMATION

What Injexate contains

The active substance is methotrexate. 1 ml of solution contains methotrexate disodium

corresponding to 50 mg methotrexate.

The other ingredients are sodium chloride, sodium hydroxide (for pH adjustment) and

water for injections.

What Injexate looks like and contents of the pack

Injexate pre-filled syringes contain a clear, yellow to brown solution. Pre-filled syringes are

prefixed with needle safety guard.

Package containing pre-filled syringe (s), are with or without

blister and alcohol swab. The blister packs are for individual syringes with prefixed needle safety

guard.

The following pack sizes are available:

For 0.15 mL, 0.20 mL, 0.30 mL and 0.40 mL: packs containing 1, 2, 4, 5, 6, 8, 10, 12 and

24 prefilled syringe (s), with fixed needle covered with rigid needle shield. Further pre-

filled syringes prefixed with needle safety guard.

For 0.25 mL, 0.35 mL, 0.45 mL, 0.55 mL and 0.60 mL: packs containing 1, 4, 5, 6, 8 and

12 prefilled syringe (s), with fixed needle covered with rigid needle shield. Further pre-

filled syringes prefixed with needle safety guard.

For 0.50 mL: packs containing 1, 2, 4, 5, 6, 8, 10 and 12 prefilled syringe (s), with fixed

needle covered with rigid needle shield. Further pre-filled syringes prefixed with needle

safety guard.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

<To be completed nationally>

This leaflet was last revised in

2021-03-01

Instructions for use

Carefully read the instructions below before starting your injection, and always use the injection

technique advised by your doctor, pharmacist or nurse.

For any problem or question, contact your doctor, pharmacist or nurse.

Preparation

Select a clean, well-lit and flat working surface.

Collect necessary items before you begin:

1 Injexate pre-filled syringe with needle safety guard

Wash your hands carefully. Before use, check the Injexate syringe for visual defects (or cracks).

Injection site

The best sites for injection are:

- upper thighs,

- abdomen except around the navel.

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 try not to inject directly into any

raised, thick, red or scaly skin patches or lesions

Injecting the solution

Unpack the methotrexate pre-filled syringe with prefixed needle safety guard and read the

package leaflet carefully. Remove the pre-filled syringe with prefixed needle safety guard

from the packaging at room temperature.

Disinfection

Choose an injection site and

disinfect it with alcohol swab.

Allow at least 60 seconds for the

disinfectant to dry.

Ensure the system is intact/ not damaged

Do not use the product:

- If you see any damage (syringe

or needle safety guard breakage) or

lose components;

- If the needle safety guard is on

safety position before use as shown

on picture 7 because this indicate

system already operated.

In general the product should not

be used if it does not conform to the

figure on the left side.

If so discard the product in a

biohazard (sharps) container

Remove the protective cap

- Hold the body of the needle safety

guard in one hand with the needle

end pointing away from you and

without touching the plunge rod;

- Pull the needle cap straight off

with your other hand;

- After removal, throw away the

needles cap in a biohazard (sharps)

container.

Insert the Needle

- Lightly pinch the skin at the

injection site with one hand;

- With the other hand insert the

needle into the injection site without

touching the plunger rod head (with90

degree angle).

Injection

- Place the thumb on the plunger

rod head;

- Depress the plunger rod and

push

firmly

at the end of the injection to

ensure that syringe emptying is

completed. Hold the skin securely

until the injection is completed.

Needle stick protection

The safety system will activate once

the plunger rod is fully depressed:

- Keep the syringe still and slowly lift

your thumb off of the plunger rod

head;

- The plunger rod will move up with

your thumb and the spring retracts the

needle from the site, into the Needle

safety guard.

Discard the needle safety guard

Once the syringe has been used,

immediately discard the needle safety

guard into biohazard (sharp)

containers.

Do not throw away the used needle

safety guard syringe in a household

trash.

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

The manner of handling and throwing away of the medicine and pre-filled syringe must be in

consistent with that of other cytostatic preparations in accordance with local requirements.

Pregnant healthcare personnel should not handle and/or administer Injexate.

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Injexate 50 mg/ml solution for injection in pre-filled syringe

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution contains 50 mg methotrexate (as methotrexate disodium).

1 pre-filled syringe of 0.15 ml contains 7.5 mg methotrexate.

1 pre-filled syringe of 0.20 ml contains 10 mg methotrexate.

1 pre-filled syringe of 0.25 ml contains 12.5 mg methotrexate.

1 pre-filled syringe of 0.30 ml contains 15 mg methotrexate.

1 pre-filled syringe of 0.35 ml contains 17.5 mg methotrexate.

1 pre-filled syringe of 0.40 ml contains 20 mg methotrexate.

1 pre-filled syringe of 0.45 ml contains 22.5 mg methotrexate.

1 pre-filled syringe of 0.50 ml contains 25 mg methotrexate.

1 pre-filled syringe of 0.55 ml contains 27.5 mg methotrexate.

1 pre-filled syringe of 0.60 ml contains 30 mg methotrexate

Excipient with known effect:

Each pre-filled syringe contains <1 mmol sodium.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection in pre-filled syringe.

Clear, yellow to brown solution.

pH: Between 7.0 to 9.0

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Methotrexate is indicated for the treatment of

active rheumatoid arthritis in adult patients,

polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal

anti-inflammatory drugs (NSAIDs) has been inadequate,

severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy

such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients.

mild to moderate Crohn’s disease either alone or in combination with corticosteroids in adult patients

refractory or intolerant to thiopurines.

4.2

Posology and method of administration

Methotrexate should only be prescribed by physicians with expertise in the use of methotrexate and a full

understanding of the risks of methotrexate therapy.

The administration should routinely be done by health professionals. If the clinical situation permits the

treating

physician

can,

selected

cases,

delegate

subcutaneous

administration

patient

her/himself

Patients

must

educated

trained

proper

injection

technique

when

self-

administering methotrexate. The first injection of Injexate should be performed under direct medical

supervision.

Methotrexate is injected

once weekly

The patient must be explicitly informed about the fact of administration

once weekly

. It is advisable to

determine a fixed, appropriate weekday as 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 and 4.4).

Important warning about the dosage of Injexate (methotrexate)

Injexate (methotrexate)

must only be used once a week

for the treatment of Rheumatoid arthritis,

Juvenile arthritis, Psoriatic arthritis, Psoriasis, Crohn’s disease.

Dosage errors in the use of Injexate

(methotrexate) can result in serious adverse reactions, including death. Please read this section of the

summary of product characteristics very carefully.

Posology

Dosage in adult patients with rheumatoid arthritis

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 in general not be exceeded.

However, doses exceeding 20 mg/week are associated with 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 in children and adolescents below 16 years with polyarthritic forms of juvenile idiopathic arthritis

Children with body surface area below 0.75 m

could not be treated with this product. If lower doses than

7.5 mg are required, another medical product should be used.

The recommended dose is 10-15 mg/m² body surface area (BSA)/

once weekly

. In therapy-refractory

cases the weekly dosage may be increased up to 20mg/m

body surface area/

once weekly

. However, an

increased monitoring frequency is indicated if the dose is increased.

limited

data

availability

about

intravenous

children

adolescents,

parenteral

administration is limited to subcutaneous injection.

Patients

with

should

always

referred

rheumatology

specialist

treatment

children/adolescents.

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety is

available for this population. (see section 4.4)

Dosage in patients with psoriasis vulgaris and psoriatic arthritis

It is recommended that a test dose of 5 – 10 mg should be administered parenterally, one week prior to

therapy to detect idiosyncratic adverse reactions. The recommended initial dose is 7.5 mg of methotrexate

once weekly

, administered subcutaneously. The dose is to be increased gradually but should not, in

general, exceed a weekly dose of 25 mg of methotrexate. Doses exceeding 20 mg per week can be

associated

with

significant

increase

toxicity,

especially

bone

marrow

suppression.

Response

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 dose should be increased as necessary but should in general not exceed the maximum recommended

weekly dose of 25 mg. In a few exceptional cases a higher dose might be clinically justified, but should

not exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will markedly increase.

Dosage in patients with Crohn’s Disease

Induction treatment:

25 mg/week administered subcutaneously.

Response to treatment can be expected after approximately 8 to 12 weeks.

Maintenance treatment:

15 mg/week administered subcutaneously.

There is not sufficient experience in the paediatric population to recommend methotrexate for the

treatment of Crohn’s Disease in this population.

Patients with renal impairment:

Methotrexate should be used with caution in patients with impaired renal function. The dose should be

adjusted as follows:

Creatinine clearance (ml/min)

Dose

> 60

100 %

30 – 59

50 %

< 30

Methotrexate must not be used

See section 4.3

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 (85.5 µmol/l), methotrexate is

contraindicated.

For a full list of contraindications, see section 4.3.

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 patient 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 (see section 5.2 and 4.4).

Duration and method of administration

The pre-filled syringe is for single use only.

Please note that all of the contents should be used.

Methotrexate solution for injection is given by the subcutaneous route.

The overall duration of the treatment is decided by the physician.

Instructions for subcutaneous use (see section 6.6)

Note:

If changing from oral to parenteral 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 current treatment guidelines.

4.3

Contraindications

Methotrexate is contraindicated in the case of

hypersensitivity to methotrexate or to any of the excipients listed in section 6.1,

severe liver impairment (see section 4.2),

alcohol abuse,

severe renal impairment (creatinine clearance less than 20 ml/min., see section 4.2 and section 4.4),

pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or

significant anaemia,

serious, acute or chronic infections such as tuberculosis, HIV or other immunodeficiency syndromes,

ulcers of the oral cavity and known active gastrointestinal ulcer disease,

pregnancy, breast-feeding (see section 4.6),

concurrent vaccination with live vaccines.

4.4

Special warnings and precautions for use

Patients must be clearly informed that the therapy has to be administered

once a week

, not every day.

Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic

effects or adverse reactions may be detected and evaluated with minimal delay. Therefore methotrexate

should be only administered by, or under the supervision of physicians whose knowledge and experience

includes the use of antimetabolite therapy. Because of the possibility of severe or even fatal toxic

reactions,

patient

should

fully

informed

physician

risks

involved

recommended safety measures.

Recommended examinations and safety measures

Before beginning 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 (at least once a month during the first six months and every three months thereafter):

An increased monitoring frequency should be considered also when the dose is increased.

Examination of the mouth and throat for mucosal changes

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.

Liver function tests: Particular attention should be given to the appearance of liver toxicity.

Treatment should not be instituted or should be discontinued if any abnormality of liver function

tests, or liver biopsy, is present or develops during therapy. Such abnormalities should return to

normal within two weeks after which treatment may be recommenced at the discretion of the

physician. There is no evidence to support use of a liver biopsy to monitor hepatic toxicity in

rheumatological indications.

For psoriasis patients the need for a liver biopsy prior to and during therapy is controversial. Further

research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen

can detect hepatotoxicity sufficiently. The evaluation should be performed case by case and

differentiate between patients with no risk factors and patients with risk factors such as excessive

prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family

history of inheritable liver disease, diabetes mellitus, obesity, and history of significant exposure to

hepatotoxic drugs or chemicals and prolonged Methotrexate treatment or cumulative doses of 1.5 g

or more.

Check of liver-related enzymes in serum: Temporary increases in transaminases to twice or three

times of the upper limit of normal have been reported by patients at a frequency of 13 – 20 %. In the

case of a constant increase in liver-related enzymes, a reduction of the dose or discontinuation of

therapy should be taken into consideration.

Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should not

be taken during treatment with methotrexate

unless clearly necessary

and the consumption of

alcohol should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver enzymes

should be exercised in patients taking other hepatotoxic medicinal products concomitantly (e.g.

leflunomide). The same should be taken into account with the simultaneous administration of

haematotoxic medicinal products (e.g. leflunomide).

Renal function should be monitored by renal function tests and urinanalysis (see sections 4.2

and 4.3).

As methotrexate is eliminated mainly by renal route, increased serum concentrations are to be

expected in the case of renal impairment, which may result in severe undesirable effects.

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

elimination

methotrexate,

cause

kidney

damage

(e.g.

non-steroidal

anti-

inflammatory medicinal products) or which can potentially lead to impairment of blood formation.

Dehydration may also intensify the toxicity of methotrexate.

Assessment of respiratory system: Alertness for symptoms of lung function impairment and, if

necessary lung function test. Pulmonary affection requires a quick diagnosis and discontinuation of

methotrexate. Pulmonary symptoms (especially a dry, non-productive cough) or a non-specific

pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous

lesion and require interruption of treatment and careful investigation. 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, dyspnoea, hypoxemia, and an infiltrate on chest X-ray, infection needs to be

excluded. This lesion can occur at all doses.

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.

Methotrexate may, due to its effect on the immune system, impair the response to vaccination results

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.

Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must

be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation

of cytotoxic therapy.

Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been

reported to cause an acute megaloblastic pancytopenia in rare instances.

Radiation induced dermatitis and sun-burn can reappear under methotrexate therapy (recall-reaction).

Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of methotrexate.

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. Pleural effusions and ascites should be drained

prior to initiation of methotrexate treatment (see section 5.2).

Diarrhoea and ulcerative stomatitis can be toxic effects and require interruption of therapy, otherwise

haemorrhagic enteritis and death from intestinal perforation may occur.

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease

the effectiveness of methotrexate.

For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis

which is not adequately responsive to other forms of therapy, but only when the diagnosis has been

established by biopsy and/or after dermatological consultation.

Encephalopathy / Leukoencephalopathy have been reported in oncologic patients receiving methotrexate

therapy and cannot be excluded for methotrexate therapy in non-oncologic indications.

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.

Teratogenicity – Reproductive risk

Methotrexate causes embryotoxicity, abortion and foetal 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). The absence of pregnancy must be confirmed before

Injexate is used. If women of a sexually mature age are treated, effective contraception must be

performed during treatment and for at least six months after.

For contraception advice for men see section 4.6.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially "sodium free".

Paediatric population

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are

available for this population (see section 4.2).

4.5

Interaction with other medicinal products and other forms of interaction

Alcohol, hepatotoxic medicinal products, haematotoxic medicinal products

probability

methotrexate

exhibiting

hepatotoxic

effect

increased

regular

alcohol

consumption and when other hepatotoxic medicinal products are taken at the same time (see section 4.4).

Patients

taking

other

hepatotoxic

medicinal

products

concomitantly

(e.g.

leflunomide)

should

monitored with special care. The same should be taken into account with the simultaneous administration

haematotoxic

medicinal

products

(e.g.

leflunomide,

azathioprine,

retinoids,

sulfasalazine).

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

methotrexate.

The use of nitrous oxide potentiates the effect of methotrexate on folate, yielding increased toxicity such

severe

unpredictable

myelosuppression

stomatitis.

Whilst

this

effect

reduced

administering calcium folinate, the concomitant use of nitrous oxide and methotrexate should be avoided.

Combined treatment with methotrexate and retinoids like acitretin or etretinate increases the risk of

hepatotoxicity.

Oral antibiotics

Oral antibiotics like tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics can

interfere with the enterohepatic circulation, by inhibition of the intestinal flora or suppression of the

bacterial metabolism.

Antibiotics

Antibiotics, like penicillines, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual

cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate

with simultaneous haematological and gastro-intestinal toxicity may occur.

Medicinal products with high plasma protein binding

Methotrexate is plasma protein bound and may be displaced by other protein bound medicinal products

such

salicylates,

hypoglycaemics,

diuretics,

sulphonamides,

diphenylhydantoins,

tetracyclines,

chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, which can lead to

increased toxicity when used concurrently.

Probenecid, weak organic acids, pyrazoles and non-steroidal anti-inflammatory agents

Probenecid, weak organic acids such as loop diuretics, and pyrazoles (phenylbutazone) can reduce the

elimination

methotrexate

higher

serum

concentrations

assumed

inducing

higher

haematological toxicity. There is also a possibility of increased toxicity when low dose methotrexate and

non steroidal anti-inflammatory medicinal products or salicylates are combined.

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.

Medicinal products which cause folate deficiency

concomitant

administration

products

which

cause

folate

deficiency

(e.g.

sulphonamides,

trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular care is therefore

advisable in the presence of existing folic acid deficiency.

Products containing folic acid or folinic acid

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease

the effectiveness of methotrexate.

Other antirheumatic medicinal products

An increase in the toxic effects of methotrexate is, in general, not to be expected when Methotrexate is

administered

simultaneously

with

other

antirheumatic

medicinal

products

(e.g.

gold

compounds,

penicillamine, hydroxychloroquine, sulphasalazine, azathioprin, cyclosporin).

Sulphasalazine

Although the combination of methotrexate and sulphasalazine can cause an increase in efficacy of

methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis through

sulphasalazine, such undesirable effects have only been observed in rare individual cases in the course of

several studies.

Mercaptopurine

Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and

mercaptopurine may therefore require dose adjustment.

Proton-pump inhibitors

A concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to

interactions: Concomitant administration of methotrexate and omeprazole has led to delayed renal

elimination

methotrexate.

combination

with

pantoprazole

inhibited

renal

elimination

metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case.

Theophylline

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when

used concurrently with methotrexate.

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

Women of childbearing potential/ Contraception in females

Women must not get pregnant during methotrexate therapy, and effective contraception must be used

during treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior to initiating

therapy, women of childbearing potential must be informed of the risk of malformations associated with

methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures,

e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after

any gap of contraception). Female patients of reproductive potential must be counselled regarding

pregnancy prevention and planning.

Contraception in males

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.

Pregnancy

Methotrexate is contraindicated during pregnancy in non-oncological indications (see section 4.3). If

pregnancy occurs during treatment with methotrexate and up to six 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 foetal development.

In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester (see

section 5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported to cause

foetal death, miscarriages and/or congenital abnormalities (e.g. 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

42.5%

pregnant

women

exposed

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 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.

Breast-feeding

Methotrexate is excreted in breast milk in such concentrations that there is a risk for the infant, and

accordingly, breast-feeding has to be discontinued prior to and throughout administration (see section

4.3).

Fertility

Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans, methotrexate

has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea. These effects appear to

be reversible after discontinuation of therapy in most cases.

4.7

Effects on ability to drive and use machines

Central nervous symptoms such as tiredness and dizziness can occur during treatment, Methotrexate has

minor or moderate influence on the ability to drive and use machines.

4.8

Undesirable effects

Summary of the safety profile

Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity,

hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and Stevens-

Johnson syndrome.

Most frequently (very common) observed adverse reactions of methotrexate include gastrointestinal

disorders e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite and abnormal liver function

tests e.g. increased ALAT, ASAT, bilirubin, alkaline phosphatase. Other frequently (common) occurring

adverse reactions are leukopenia, anaemia, thrombopenia, headache, tiredness, drowsiness, pneumonia,

interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema,

erythema and pruritus.

Tabulated list of adverse reactions

The most relevant undesirable effects are suppression of the haematopoietic system and gastrointestinal

disorders.

The following headings are used to organise the undesirable effects in order of frequency:

Very common (

1/10), common (

1/100 to < 1/10), uncommon (

1/1,000 to < 1/100), rare (

1/10,000

to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data)

Infections and infestations

Uncommon: Pharyngitis.

Rare: Infection (incl. reactivation of inactive chronic infection), sepsis, conjunctivitis.

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

Very rare: There have been reports of individual cases of lymphoma which subsided in a number of cases

once treatment with methotrexate had been discontinued. In a recent study, it could not be established that

methotrexate therapy increases the incidence of lymphomas.

Blood and lymphatic system disorders

Common: Leukopenia, anaemia, thrombopenia.

Uncommon: Pancytopenia.

Very rare: Agranulocytosis, severe courses of bone marrow depression, Lymphoproliferative disorders

(see “description” below).

Not known: Eosinophilia

Immune system disorders

Rare: Allergic reactions, anaphylactic shock, hypogammaglobulinaemia.

Metabolism and nutrition disorders

Uncommon: Precipitation of diabetes mellitus.

Psychiatric disorders

Uncommon: Depression, confusion.

Rare: Mood alterations.

Nervous system disorders

Common: Headache, tiredness, drowsiness.

Uncommon: Dizziness.

Very rare: Pain, muscular asthenia or Paraesthesia/hypoaesthesia, changes in sense of taste (metallic

taste), convulsions, meningism, acute aseptic meningitis, paralysis.

Not known: Encephalopathy / leukoencephalopathy.

Eye disorders

Rare: Visual disturbances.

Very rare: Impaired vision ,Retinopathy.

Cardiac disorders

Rare: Pericarditis, pericardial effusion, pericardial tamponade.

Vascular disorders

Rare: Hypotension, thromboembolic events.

Respiratory, thoracic and mediastinal disorders

Common: Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia. Symptoms

indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough, short of

breath and fever.

Rare: Pulmonary fibrosis,

Pneumocystis carinii

pneumonia, shortness of breath and bronchial asthma,

pleural effusion.

Not known: Epistaxis, Pulmonary alveolar haemorrhage

Gastrointestinal disorders

Very common: Stomatitis, dyspepsia, nausea, loss of appetite, abdominal pain.

Common: Oral ulcers, diarrhoea.

Uncommon: Gastrointestinal ulcers and bleeding, enteritis, vomiting, pancreatitis.

Rare: Gingivitis.

Very rare: Haematemesis, haematorrhea, toxic megacolon.

Hepatobiliary disorders (see section 4.4)

Very

common:

Abnormal

liver

function

tests

(increased

ALAT,

ASAT,

alkaline

phosphatase

bilirubin).

Uncommon: Cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum albumin.

Rare: Acute hepatitis.

Very rare: Hepatic failure.

Skin and subcutaneous tissue disorders

Common: Exanthema, erythema, pruritus.

Uncommon: Photosensitisation, loss of hair, increase in rheumatic nodules, herpes zoster, vasculitis,

herpetiform eruptions of the skin, urticaria.

Rare: Increased pigmentation, acne, petechiae ,ecchymosis , allergic vasculitis.

Very

rare:

Stevens-Johnson

syndrome,

toxic

epidermal

necrolysis

(Lyell’s

syndrome),

increased

pigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia.

Not known: Skin exfoliation / dermatitis exfoliative

Musculoskeletal and connective tissue disorders

Uncommon: Arthralgia, myalgia, osteoporosis.

Rare: Stress fracture.

Unknown: Osteonecrosis of jaw (secondary to lymphoproliferative disorders)

Renal and urinary disorders

Uncommon: Inflammation and ulceration of the urinary bladder, renal impairment, disturbed micturition.

Rare: Renal failure, oliguria, anuria, electrolyte disturbances.

Not known: Proteinuria.

Reproductive system and breast disorders

Uncommon: Inflammation and ulceration of the vagina.

Very rare: Loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation, vaginal

discharge.

General disorders and administration site conditions

Rare: Fever, wound-healing impairment.

Not known: Asthenia, Injection site necrosis, Oedema

The appearance and degree of severity of undesirable effects depends on the dosage level and the

frequency of administration. However, as severe undesirable effects can occur even at lower doses, it is

indispensable that patients are monitored regularly by the doctor at short intervals.

Subcutaneous application of methotrexate is locally well tolerated. Only mild local skin reactions (such as

burning sensations, erythema, swelling, discolouration, pruritus, severe itching, pain) were observed,

decreasing during therapy.

Description of selected adverse reactions

Lymphoma/Lymphoproliferative disorders: there have been reports of individual cases of lymphoma and

other

lymphoproliferative

disorders

which

subsided

number

cases

once

treatment

with

methotrexate had been discontinued.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system

[to be completed

nationally]

4.9

Overdose

Symptoms of overdosage

Toxicity of methotrexate mainly affects the haematopoietic system.

Treatment measures in the case of overdosage

Calcium folinate is the specific antidote for neutralising the toxic undesirable effects of methotrexate.

In cases of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose of

methotrexate should be administered intravenously or intramuscularly within one hour and dosing

continued until the serum levels of methotrexate are below 10

mol/l.

In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation

of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis

has been shown to improve methotrexate elimination. Effective clearance of methotrexate has been

reported with acute, intermittent haemodialysis using a high flux dialyser.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Folic acid analogues

ATC code: L04AX03

Antirheumatic medicinal product for the treatment of chronic, inflammatory rheumatic diseases and

polyarthritic forms of juvenile idiopathic arthritis. Immunomodulating and anti-inflammatory agent for

the treatment of Crohn’s disease.

Mechanism of action

Methotrexate is a folic acid antagonist which belongs to the class of cytotoxic agents known as

antimetabolites. It acts by the competitive inhibition of the enzyme dihydrofolate reductase and thus

inhibits DNA synthesis. It has not yet been clarified, as to whether the efficacy of methotrexate, in the

management of psoriasis, psoriasis arthritis, chronic polyarthritis and Crohn’s disease, is due to an anti-

inflammatory or immunosuppressive effect and to which extent a methotrexate-induced increase in

extracellular adenosine concentration at inflamed sites contributes to these effects.

International clinical guidelines reflect the use of methotrexate as a second choice for Crohn’s disease

patients

that

intolerant

have

failed

respond

first-line

immunomodulating

agents

azathioprine (AZA) or 6-mercaptopurine (6-MP).

adverse

events

observed

studies

performed

with

methotrexate

Crohn’s

disease

cumulative doses have not shown a different safety profile of methotrexate than the profile it is already

known. Therefore, similar cautions must be taken with the use of methotrexate for the treatment of

Crohn’s disease as in other rheumatic and non-rheumatic indications of methotrexate (see sections 4.4 and

4.6).

5.2

Pharmacokinetic properties

Absorption

Following oral administration, methotrexate is absorbed from the gastrointestinal tract. In case of low-

dosed administration (dosages between 7.5 mg/m² and 80 mg/m² body surface area), the mean

bioavailability is approx. 70 %, but considerable interindividual and intraindividual deviations are

possible (25 – 100 %). Maximum serum concentrations are achieved after 1 – 2 hours. Bioavailability of

subcutaneous, intravenous and intramuscular injection is comparable and nearly 100 %.

Distribution

Approximately 50 % of methotrexate is bound to serum proteins. Upon being distributed into body

tissues, high concentrations in the form of polyglutamates are found in the liver, kidneys and spleen in

particular, which can be retained for weeks or months. When administered in small doses, methotrexate

passes into the cerebrospinal fluid in minimal amounts.

Biotransformation

Approx. 10 % of the administered methotrexate dose is metabolised intrahepatically. The principle

metabolite is 7-hydroxymethotrexate.

Elimination

Excretion takes place, mainly in unchanged form, primarily renal via glomerular filtration and active

secretion in the proximal tubulus.

Approx. 5 – 20 % methotrexate and 1 – 5 % 7-hydroxymethotrexate are eliminated biliary. Pronounced

enterohepatic blood flow exists.

The terminal half-life is on average 6 – 7 hours and demonstrates considerable variation (3 – 17 hours).

The half-life can be prolonged to 4 times the normal length in patients who possess a third distribution

space (pleural effusion, ascites).

Special populations

In the case of renal impairment, elimination is delayed significantly. Impaired elimination with regard to

hepatic impairment is not known.

5.3

Preclinical safety data

Animal studies show that methotrexate impairs fertility, is embryo- and foetotoxic and teratogenic.

Methotrexate is mutagenic

in vivo

in vitro

. 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 (for pH adjustment)

Water for injections

6.2

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal

products.

6.3

Shelf-life

2 years

6.4

Special precautions for storage

Store below 30 °C. Keep the pre-filled syringes in the outer carton in order to protect from light.

6.5

Nature and contents of container

Nature of container:

Pre-filled syringes of colourless glass (type I) of 1 ml capacity with fixed needle covered with rigid

needle shield. Further pre-filled syringes prefixed with needle safety guard. Syringe Plungers are made of

Plunger rod with chlorbutyl rubber stopper.

Pack sizes:

For 0.15 mL, 0.20 mL, 0.30 mL and 0.40 mL: packs containing 1, 2, 4, 5, 6, 8, 10, 12 and 24

prefilled syringe (s), with fixed needle covered with rigid needle shield. Further pre-filled

syringes prefixed with needle safety guard.

For 0.25 mL, 0.35 mL, 0.45 mL, 0.55 mL and 0.60 mL: packs containing 1, 4, 5, 6, 8 and 12

prefilled syringe (s), with fixed needle covered with rigid needle shield. Further pre-filled

syringes prefixed with needle safety guard.

For 0.50 mL: packs containing 1, 2, 4, 5, 6, 8, 10 and 12 prefilled syringe (s), with fixed needle

covered with rigid needle shield. Further pre-filled syringes prefixed with needle safety guard.

All pack sizes are available without graduation marks. Package containing pre-filled syringe (s), with or

without blister pack and alcohol swabs. The blister packs are for individual syringes with prefixed needle

safety guard.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

The manner of handling and disposal must be consistent with that of other cytotoxic preparations in

accordance with local requirements. Pregnant health care personnel should not handle and/or administer

Methotrexate.

Methotrexate should not come into contact with the skin or mucosa. In the event of contamination, the

affected area must be rinsed immediately with ample amount of water.

For single use only and please note that all of the contents should be used.

Any unused medicinal product or waste should be disposed of in accordance with local requirements.

Instructions of subcutaneous use

The best places for the injection are:

- upper thighs,

- abdomen except around the navel.

Clean the area around the chosen injection site (e.g. by using alcohol swab).

Pull the protective cap straight off.

Build a skin fold by gently squeezing the area at the injection site.

The fold must be held pinched until the syringe is removed from the skin after the injection.

Push the needle fully into the skin at a 90-degree angle.

Depress the plunger slowly and evenly until the entire dose has been given and the plunger cannot be

depressed any further. While maintaining pressure on the plunger, remove the syringe from the skin

at the same 90 degree angle. The needle safety guard will cover the needle when releasing the

plunger. The needle safety guard covers the needle after injection to prevent needle stick injury. This

does not affect normal operation of the syringe.

Please note that all of the syringe contents should have to be used; this product is not intended to deliver

partial dose.

7.

MARKETING AUTHORISATION HOLDER

<To be completed nationally>

8.

MARKETING AUTHORISATION NUMBER

<To be completed nationally>

9.

DATE OF FIRST MARKETING AUTHORISATION/RENEWAL OF THE

AUTHORISATION

2015-10-01

<To be completed nationally>

10.

DATE OF REVISION OF THE TEXT

2021-03-01

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