Document: Injexate solution for injection, pre-filled syringe ENG PL change

• Injexate solution for injection, pre-filled syringe PL
• Injexate solution for injection, pre-filled syringe ENG PL

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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 medicinebecause 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:

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

Injexateis 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.

• are pregnant or breast‑feeding.

• receive vaccinations with live vaccines at the same time.

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).

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 of 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 can exacerbate during UV-irradiation and 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 to prevent/fight certain infections) such as: 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 or salicylates (medicines against pain and/or inflammation)

• Probenecid (medicine against gout)

• Weak organic acids like loop diuretics (“water tablets”) or some medicines used for treatment of pain and inflammatory diseases (e.g. acetylsalicylic acid, diclofenac and 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)

• 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 should 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

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

You must not take Injexate during pregnancy. There is a risk of harm to the foetus and miscarriage. Men and women should use an effective method of birth control during treatment and during a further six months after treatment with Injexate has been discontinued.

In women of child-bearing age, any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. pregnancy test, prior to therapy.

As methotrexate can be genotoxic, all women who wish to become pregnant are advised to consult a genetic counselling centre, if possible, already prior to therapy, and men should seek advice about the possibility of sperm preservation before starting therapy.

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.

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 therapy, Injexate may be injected by medical staff. In certain cases your doctor may decide to instruct you how to inject Injexate under the skin yourself. You will then receive appropriate training.

Under no circumstances should you try to inject Injexate yourself before you have received such training.

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 abnormalitiesdeveloping in the blood (such as low white blood cells, low platelets, lymphoma) and changes in the kidneys and the liver.

Tell your doctor immediatelyif you experience any of the following symptoms, as these may indicate a 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 (pneumonia) [common - may affect up to 1 in 10 people]

• 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 of 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 or absence of urine; 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

• severe diarrhoea, vomiting blood and black or tarry stools; these symptoms may indicate a rare [may affect up to 1 in 1,000 people] severe complication of the gastrointestinal system caused by methotrexate e.g. gastrointestinal ulcers

• symptoms associated with the blockage (occlusion) of a blood vessel by a dislodged blood clot (thromboembolic event) 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); methotrexate can cause thromboembolic events [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 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]

• 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)

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

Very common: may affect more than 1 in 10 people

• Mouth inflammation, indigestion, nausea (feeling sick), loss of appetite

• Increase in liver enzymes

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 (leukopenia, anaemia, thrombocytopenia)

Uncommon: may affect up to 1 in 100 people

• Throat inflammation, inflammation of the bowels, vomiting

• Increased sensitivity to light, loss of hair, increased number of rheumatic nodules, 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 blood cells and platelets

• Inflammation and ulcer of the urinary bladder or vagina, reduced kidney function, disturbed urination

• Joint pain, muscle pain, osteoporosis (reduction of bone mass)

Rare: may affect up to 1 in 1,000 people

• Increased skin pigmentation, acne, blue spots due to vessel bleeding

• Allergic inflammation of blood vessels, fever, red eyes, infection, wound-healing impairment, decreased number of anti-bodies in the blood

• Visual disturbances

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

• Low blood pressure

• Lung fibrosis, shortness of breath and bronchial asthma, accumulation of fluid in the sac around the lung

• Electrolyte disturbances

Very rare: may affect up to 1 in 10,000 people

• Profuse bleeding, toxic megacolon (acute toxic dilatation of the gut)

• Increased pigmentation of the nails, inflammation of the cuticles, furunculosis (deep infection of hair follicles), visible enlargement of small blood vessels

• Impaired vision, pain, loss of strength or sensation of numbness or tingling in arms and legs, changes in taste (metallic taste), convulsions, paralysis, severe headache with fever

• Retinopathy (noninflammatory eye disorder)

• Loss of sexual drive, impotence, male breast enlargement (gynaecomastia), defective sperm formation, menstrual disorder, vaginal discharge

• Enlargement of lymphatic nodes (lymphoma)

Not Known:frequency cannot be estimated from the available data:

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

Injexatepre‑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:

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

<to be completed nationally>

This leaflet was last revised in 2016-10-17

<to be completed nationally>

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:

Wash your hands carefully. Before use, check the Injexatesyringe 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