Active ingredients: Methotrexate
Reumaflex 50 mg / ml solution for injection, pre-filled syringe
Why is Reumaflex used? What is it for?
Reumaflex contains methotrexate as the active ingredient. Methotrexate is a substance with the following properties:
- it interferes with the growth of some cells in the body that reproduce rapidly
- reduces the activity of the immune system (the body's defense mechanism)
- it has anti-inflammatory effects
Reumaflex is indicated for the treatment of:
- active rheumatoid arthritis in adult patients;
- polyarthritic forms of severe juvenile idiopathic arthritis in the active phase, with inadequate response to non-steroidal anti-inflammatory drugs (NSAIDs);
- severe, relapsing and disabling psoriasis that does not respond adequately 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, in cases where adequate treatment with other drugs is not possible.
Rheumatoid arthritis (RA) is a chronic connective tissue disease characterized by inflammation of the synovial membranes (membranes of the joints). These membranes produce a liquid that acts as a lubricant for many joints. Inflammation causes thickening of these membranes and swelling of the joints.
Juvenile idiopathic arthritis affects children and adolescents under the age of 16. Polyarthritic forms are those that affect 5 or more joints within the first six months of the onset of the disease.
Psoriatic arthritis is a type of arthritis with psoriatic lesions of the skin and nails, especially in the joints of the fingers and toes
Psoriasis is a common chronic skin disease characterized by red patches lined with dry, thick, silver-colored scales that are difficult to peel off.
Reumaflex has been shown to be able to modify and slow the progression of these diseases.
Crohn's disease is a type of inflammatory bowel disease that can affect any part of the gastrointestinal tract causing symptoms such as abdominal pain, diarrhea, vomiting or weight loss.
Contraindications When Reumaflex should not be used
Do not take Reumaflex
- if you are allergic to methotrexate or any of the other ingredients of this medicine
- if you have severe liver or kidney disease or blood disorders.
- if you regularly drink large quantities of alcoholic beverages.
- if you have a severe infection, eg tuberculosis, HIV or other immunodeficiency syndromes.
- if you suffer from mouth ulcers or stomach or intestinal ulcer.
- if you are pregnant or breastfeeding.
- if you are being vaccinated at the same time with live vaccines.
Precautions for use What you need to know before taking Reumaflex
Talk to your doctor or pharmacist before taking Reumaflex if:
- are elderly or generally feel sick and weak.
- have liver function problems.
- suffer from dehydration (loss of water).
Subsequent examinations and recommended safety measures
Even if Reumaflex is given in a low dose, serious side effects can occur. To identify them promptly, the doctor must carry out checks and laboratory tests.
Before therapy
Before starting treatment, a blood sample should be taken to check that there are sufficient blood cells and tests to check the function of the liver and kidney, and the amount of serum albumin (a blood protein ). Your doctor will also make sure you are not suffering from tuberculosis (an infectious disease associated with small lumps in the affected tissue) by taking a chest X-ray.
During therapy
At least once a month for the first six months and at least every three months thereafter, the following tests must be performed:
- Examination of the mouth and throat to verify that there are no changes in the mucosa
- Blood tests
- Control of liver function
- Control of renal function
- Check of the respiratory system and, if necessary, pulmonary function tests
Methotrexate can affect the immune system and vaccination results. It can also affect the result of immunoassays. Inactive chronic infections such as herpes zoster [Saint Anthony's fire], tuberculosis, hepatitis B or C may flare up. You should not be vaccinated with live vaccines while taking Reumaflex.
Radiation dermatitis and sunburn may reappear during methotrexate therapy (recall reaction). Psoriatic lesions can worsen following the concomitant use of ultraviolet radiation and methotrexate.
Enlarged lymph nodes (lymphoma) may appear and therapy must therefore be discontinued.
Diarrhea can be a toxic effect of Reumaflex and requires discontinuation of therapy. If you suffer from diarrhea, please speak to your doctor.
Encephalopathy (brain disease) and leukoencephalopathy (particular white matter disease of the brain) have occurred in patients with tumors receiving methotrexate, and it cannot be excluded that they may occur during methotrexate therapy in other diseases.
Interactions Which drugs or foods can modify the effect of Reumaflex
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
The treatment effect may be modified if Reumaflex is administered concomitantly with other drugs such as:
- Medicines that are harmful to the liver or blood cells, eg. leflunomide
- Antibiotics (medicines to prevent / fight certain infections) such as: tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibiotics, penicillins, glycopeptides, sulphonamides (sulfur-containing medicines that prevent / fight some infections), ciprofloxacin and cephalothin
- Non-steroidal or salicylated anti-inflammatory drugs (analgesics and / or anti-inflammatories)
- Probenecid (gout medicine)
- Weak organic acids such as loop diuretics or some medicines used for the treatment of pain and inflammatory diseases (eg acetylsalicylic acid, dicoflenac and ibuprofen) and pyrazolone derivatives (eg metamizole for pain treatment)
- Medicines that can have undesirable effects on the bone marrow, eg. trimethoprimsulfamethoxazole (an antibiotic) and pyrimethamine
- Sulfasalazine (an antirheumatic)
- Azathioprine (an immunosuppressant sometimes used in severe forms of rheumatoid arthritis)
- Mercaptopurine (a cytostatics)
- Retinoids (medicine against psoriasis and other dermatological diseases)
- Theophylline (medicine for bronchial asthma and other lung diseases)
- Proton pump inhibitors (medicines for stomach disorders)
- Hypoglycaemics (medicines used to lower blood sugar)
Vitamin complexes that contain folic acid can impair the effect of the treatment and should only be taken under medical supervision.
Vaccinations with live vaccines should be avoided.
Using Reumaflex with food, drink and alcohol
During treatment with Reumaflex the following should be avoided: alcoholic beverages, copious amounts of coffee, caffeinated soft drinks and black tea.
Warnings It is important to know that:
Pregnancy, breastfeeding 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 using this medicine.
Reumaflex should not be used during pregnancy, as there is a risk of harm to the fetus and miscarriage. Men and women should use an effective method of birth control during treatment and for six months after stopping treatment with Reumaflex.
In women of childbearing potential, an ongoing pregnancy should be safely ruled out by carrying out a pregnancy test before starting therapy.
Since methotrexate can be genotoxic, all women wishing to become pregnant are advised to consult a genetic counseling center possibly prior to therapy, and men are advised to inquire about sperm storage possibilities before starting therapy.
Breastfeeding should be discontinued before and during treatment with Reumaflex.
Driving and using machines
Treatment with Reumaflex can cause adverse reactions affecting the central nervous system, such as tiredness and dizziness. Therefore the ability to drive a vehicle and / or to use machines could, in some cases, be impaired. If you feel tired or sleepy, you should not drive or operate machinery.
Important information about some of the ingredients of Reumaflex
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, ie it is essentially "sodium free".
Dose, Method and Time of Administration How to use Reumaflex: Posology
The doctor will decide the dosage, to be adapted to the individual patient. Generally the effects of the treatment are noticeable after 4 - 8 weeks.
Reumaflex is given by or under the supervision of a doctor or healthcare professional as an injection once a week only. Together with your doctor, decide which day of the week you want to have the weekly injection.
Reumaflex can be injected intramuscularly (into a muscle), intravenously (into a vein) or subcutaneously (under the skin).
Due to the limited availability of data on intravenous administration in children and adolescents, the product should only be injected subcutaneously or intramuscularly in these patients.
The doctor will decide the appropriate dosage for children and adolescents with polyarthritis of juvenile idiopathic arthritis.
Reumaflex is not recommended for children under 3 years of age due to little experience with this age group.
Method of administration and duration of treatment
Reumaflex is administered once a week!
The duration of treatment is decided by the attending physician. Rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris, and psoriatic arthritis treatments with Reumaflex are long-term treatments.
At the start of therapy, Reumaflex can be administered by medical personnel. In some cases, your doctor may decide to explain how to inject Reumaflex yourself subcutaneously. If so, you will receive appropriate instructions.
Under no circumstances should you try to give yourself an injection of Reumaflex without having previously received these instructions.
Please refer to the instructions for use at the end of the package leaflet.
Handling and disposal should be done as for other cytostatic preparations in accordance with local regulations. Pregnant healthcare professionals should refrain from handling and / or administering Reumaflex.
Methotrexate must not come into contact with the skin surface or mucous membranes. In case of contamination, the affected area should be immediately rinsed with plenty of water.
If you have the impression that the effect of Reumaflex is too strong or too weak, please tell your doctor or pharmacist.
Side Effects What are the side effects of Reumaflex
Like all medicines, Reumaflex can cause side effects, although not everybody gets them.
The frequency as well as the severity of the undesirable effects depend on the dosage and frequency of administration. As some serious side effects can occur even at a low dose, it is important for your doctor to monitor them regularly.
Your doctor will then have to order tests to detect any abnormalities in your blood (eg reduced number of white blood cells, reduced number of platelets, lymphoma) and changes in the functioning of the kidneys and liver.
Tell your doctor right away if you notice any of the following symptoms, which may indicate serious, potentially life-threatening side effects that require urgent specific treatment:
- persistent dry cough without phlegm, shortness of breath and fever: these may be signs of a "lung infection (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 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]
- allergic symptoms such as rashes including red itchy skin, swelling of the hands, feet, ankles, face, lips, mouth or throat (which can cause difficulty in swallowing or breathing) and feeling faint - these can be signs of severe allergic reactions or anaphylactic shock [rare - may affect up to 1 in 1,000 people]
- symptoms of kidney damage such as swelling of the hands, ankles, feet or changes in urination frequency or decreased or no urine: these may be signs of kidney failure [rare - may affect up to 1 in 1,000 people]
- symptoms of infection, eg. fever, chills, aches, sore throat: methotrexate can make you more susceptible to infections. Rarely, serious infections [may affect up to 1 in 1,000 people] such as a specific type of pneumonia (Pneumocystis carinii pneumonia) or blood poisoning (sepsis) may occur
- severe diarrhea, vomiting with blood and black or dark stools: these symptoms may be indicative of a severe and rare complication [may affect up to 1 in 1,000 people] of the gastrointestinal system caused by methotrexate, eg. gastrointestinal ulcers
- symptoms associated with blockage (occlusion) of a blood vessel by a detached blood clot (thromboembolic event) such as weakness of one side of the body (stroke) or unusual pain, swelling, redness and warmth in one leg (deep vein thrombosis) : methotrexate can cause thromboembolic events [rare - may affect up to 1 in 1,000 people]
- fever and severe deterioration of general condition, or sudden fever accompanied by sore throat or sore mouth, or urinary problems: methotrexate can very rarely [may affect up to 1 in 10,000 people] a sharp decrease in the number of white blood cells (agranulocytosis ) and severe bone marrow depression
- sudden bleeding, eg. bleeding from the gums, blood in the urine, vomiting with blood or bruising: these may be signs of a severe reduction in the number of platelets caused by severe bone marrow depression [very rare - may affect up to 1 in 10,000 people]
- severe rash or blisters (can also occur on the mouth, eyes and genitals): these may be signs of a very rare condition [may affect up to 1 10,000 people] called Stevens Johnson syndrome or burned skin syndrome (toxic epidermal necrolysis).
Other side effects may also occur, listed below:
Very common: may affect more than 1 in 10 people
- Inflammation of the mouth, indigestion, nausea (malaise), loss of appetite
- Increased liver enzymes
Common: may affect up to 1 in 10 people
- Mouth ulcers, diarrhea
- Rash, redness of the skin, itching
- Headache, fatigue, sleepiness
- Reduced blood cell formation with decreased white and / or red blood cells and / or platelets (leukopenia, anemia, thrombocytopenia)
Uncommon: may affect up to 1 in 100 people
- Inflammation of the throat, inflammation of the intestines, vomiting
- Increased sensitivity to light, hair loss, increased number of rheumatic nodules, St. Anthony's fire, inflammation of blood vessels, herpes-like rashes, hives
- Onset of diabetes mellitus
- Dizziness, confusion, depression
- Decrease in serum albumin
- Reduction in the number of blood cells and platelets
- Inflammation and ulcer of the urinary bladder or vagina, impaired kidney function, problems with urination (passing urine)
- Joint pain, muscle pain, osteoporosis (decreased bone mass)
Rare: may affect up to 1 in 1,000 people
- Increased skin pigmentation, acne, bruising due to bleeding from blood vessels
- Allergic inflammation of blood vessels, fever, red eyes, infection, difficulty in healing wounds, decreased number of antibodies in the blood
- Visual disturbances
- Inflammation of the membrane surrounding the heart, accumulation of fluid in the membrane surrounding the heart
- Low blood pressure
- Pulmonary fibrosis, shortness of breath and bronchial asthma, accumulation of fluid in the membrane that lines the lungs
- Electrolyte disturbances.
Very rare: may affect up to 1 in 10,000 people
- Heavy bleeding, toxic megacolon (acute toxic dilation of the intestine)
- Increased nail pigmentation, inflammation of the areas around the nails (cuticles), furunculosis (deep infection of the hair follicles), visible enlargement of the capillaries
- Local damage (sterile abscess formation, fatty tissue changes) at the injection site after intramuscular or subcutaneous administration.
- Disturbed vision, pain, loss of strength or a feeling of numbness or tingling in the arms and legs, changes in taste (metallic taste), seizures, paralysis, severe headache accompanied by fever
- Retinopathy (eye disorders of non-inflammatory origin) Loss of libido, impotence, enlargement of the male mammary glands (gynecomastia), abnormal sperm formation, menstrual disorders, vaginal discharge
- Enlarged lymph nodes (lymphoma)
Frequency not known: cannot be estimated from the available data:
- Leukoencephalopathy (white matter disease of the brain)
When methotrexate is administered intramuscularly, local side effects (burning sensation) or damage (sterile abscess formation, destruction of fatty tissue) at the injection site are common manifestations. Subcutaneous administration of methotrexate is locally well tolerated. Only mild local skin reactions were observed and reduced during therapy.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.You can also report side effects directly or via the Italian Medicines Agency - website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Store at a temperature not exceeding 25 ° C.
Store the pre-filled syringes in the outer carton in order to protect them from light.
Do not use this medicine after the expiry date which is stated on the carton. The expiry date refers to the last day of that month.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Reumaflex contains
- The active ingredient is methotrexate. 1 ml of solution contains disodium methotrexate corresponding to 50 mg of methotrexate.
- The other ingredients are sodium chloride, sodium hydroxide, water for injections.
What Reumaflex looks like and contents of the pack
Reumaflex pre-filled syringes contain a clear yellow-brown solution.
The following packs are available:
- Pre-filled syringes with fixed subcutaneous needle, graduated marks and alcohol pad, containing 0.15 ml, 0.20 ml, 0.30 ml, 0.40 ml and 0.50 ml solution for injection in packs of 1, 4, 6, 12 and 24 pre-filled syringes.
- Pre-filled syringes with separate subcutaneous needle, graduated marks and alcohol pad, containing 0.15 ml, 0.20 ml, 0.30 ml, 0.40 ml and 0.50 ml solution for injection in packs of 1, 4, 6, 12 and 24 pre-filled syringes. For intramuscular and intravenous use, a needle suitable for these routes of administration should be used. The separate needle included in the package is suitable for subcutaneous use only.
Not all pack sizes may be marketed.
Instructions for Use
Read these instructions carefully before starting the injection and always use the injection technique recommended by your doctor, pharmacist or nurse. If you have any problems or questions, please contact your doctor, pharmacist or nurse
Preparation
Choose a flat, clean and well-lit work surface.
Before starting, gather everything you need:
- 1 pre-filled syringe of Reumaflex
- 1 alcohol swab (provided in the package)
Wash your hands carefully. Before use, check the Reumaflex syringe for any visual defects (or cracks).
Injection site
The best injection sites are:
- upper thigh,
- abdomen, excluding the area surrounding the navel.
- If you have the help of a person for the injection, the injection can also be given in the back of the arm, just below the shoulder.
- Change the injection site for each injection. Doing so can reduce the risk of developing irritation at the injection site.
- Never inject into areas of delicate, bruised, red, hard, scarred, or stretch mark skin. If you suffer from psoriasis, try not to inject directly into lesions or areas of raised, thick, red or raised skin. with peeling of the skin or lesions.
Injection of the solution
1. Take the methotrexate pre-filled syringe out of the package and read the package leaflet carefully. Remove the pre-filled syringe from the package at room temperature.
2. Disinfection
Select an injection site and disinfect it with a swab dipped in disinfectant.
Let the disinfectant dry for at least 60 seconds.
3. Remove the protective plastic cap
Carefully remove the gray protective plastic cap by pulling it straight out of the syringe. If the cap is very sturdy, twist it gently by pulling outwards
Important: Do not touch the needle of the pre-filled syringe!
4. Inserting the needle
Grab a fold of skin with two fingers and quickly insert the needle into the skin at a 90 degree angle.
5. Injection
Insert the needle all the way into the skin fold. Push the plunger slowly and inject the liquid under the skin. Keep a firm grip on the skin fold until the injection is complete.
Carefully pull the needle out vertically
Methotrexate must not come into contact with the skin surface or mucosa. In case of contamination, the affected area should be immediately rinsed with plenty of water.
If you or someone close to you is injured with the needle, consult your doctor immediately and do not use the pre-filled syringe.
Disposal and other manipulations
Handling and disposal of this medicinal product and the pre-filled syringe should be in accordance with local requirements. Pregnant healthcare professionals should refrain from handling and / or administering Reumaflex
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
REUMAFLEX 50 MG / ML SOLUTION FOR INJECTION, PRE-FILLED SYRINGE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of solution contains 50 mg of methotrexate (as disodium methotrexate).
1 pre-filled syringe of 0.15 ml contains 7.5 mg of methotrexate.
1 pre-filled syringe of 0.20 ml contains 10 mg of methotrexate.
1 pre-filled syringe of 0.30 ml contains 15 mg of methotrexate.
1 pre-filled syringe of 0.40 ml contains 20 mg of methotrexate.
1 pre-filled syringe of 0.50 ml contains 25 mg of methotrexate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Solution for injection, pre-filled syringe.
Clear yellow-brown solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Reumaflex is indicated for the treatment of:
- active rheumatoid arthritis in adult patients,
- polyarthritic forms of severe juvenile idiopathic arthritis in the active phase, with inadequate response to non-steroidal anti-inflammatory drugs (NSAIDs),
- severe, relapsing and disabling psoriasis that does not respond adequately to other forms of therapy such as phototherapy, PUVA and retinoids, and severe psoriatic arthritis in adult patients.
- mild to moderate Crohn's disease, alone or in combination with corticosteroids in adult patients refractory or intolerant to thiopurines.
04.2 Posology and method of administration
Reumaflex should only be prescribed by doctors who are fully familiar with the various characteristics of the medicine and its mechanism of action. It should be administered routinely by healthcare professionals. In certain cases, if the clinical situation allows it, the treating physician can delegate Subcutaneous administration to the patient himself.In these cases, the physician is required to provide detailed instructions for administration.Reumaflex is administered once a week.
The patient must be explicitly informed of the dosing frequency of once a week. It is advisable to set a fixed day of the week as the injection day.
Elimination of methotrexate is reduced in patients with a "third space" of distribution (ascites, pleural effusions). These patients require close monitoring for toxicity and require dose reduction or, in some cases, discontinuation of dosing. of methotrexate (see sections 5.2 and 4.4).
Dosage in adult patients with rheumatoid arthritis
The recommended starting dose is 7.5 mg methotrexate once weekly, administered subcutaneously, intramuscularly or intravenously. Depending on the severity of the disease and the patient's demonstrated tolerability to the drug, the starting dose may be gradually increased by 2.5 mg per week. In general, the weekly dose of 25 mg should not be exceeded even if, already doses higher than 20 mg / week are associated with a significant increase in toxicity; in particular, suppression of bone marrow activity occurs. Response to treatment may occur after 4 - 8 weeks. Once the desired therapeutic result is achieved, the dose should be gradually reduced to the minimum effective maintenance dose.
Dosage in children and adolescents under 16 years of age with polyarthritic forms of juvenile idiopathic arthritis
The recommended dose is 10 - 15 mg / m2 of body surface area / once weekly. In cases of refractory to therapy, the weekly dose can be increased up to 20 mg / m2 of body surface area / once a week. In case of dose increase, it is recommended to increase the monitoring frequency.
Due to the limited availability of data on intravenous administration in children and adolescents, parenteral administration should be limited to subcutaneous and intramuscular injections.
Juvenile idiopathic arthritis patients should always be referred to specialized rheumatologists for the treatment of children / adolescents.
Use in children below 3 years of age is not recommended due to the limited availability of safety and efficacy data for this patient 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 parenterally be administered one week prior to therapy to detect any idiosyncratic adverse reactions. The recommended starting dose of methotrexate is 7.5 mg once weekly, administered subcutaneously, intramuscularly or intravenously. The dose may be increased gradually but, in general, it should never exceed a weekly dose of 25 mg of methotrexate. Doses above 20 mg per week may already be associated with a significant increase in toxicity, in particular with suppression of bone marrow activity. Response to treatment may occur after 2 - 6 weeks. Once the desired therapeutic result is achieved, the dose should be gradually reduced to the lowest effective maintenance dose.
The dose should be increased as needed but, in general, should not exceed the maximum recommended weekly dose of 25 mg. Only in exceptional cases, a higher dose could be clinically justified, but should not exceed the maximum weekly dose of 30 mg of methotrexate, as toxicity is significantly increased.
Dosage in patients with Crohn's disease:
• Induction therapy:
25 mg / week administered subcutaneously, intravenously or intramuscularly.
Response to treatment can be expected after approximately 8 to 12 weeks.
• Maintenance therapy:
15 mg / week administered subcutaneously, intravenously or intramuscularly.
There is insufficient experience in the pediatric population to recommend Reumaflex 50 mg / ml in the treatment of Crohn's disease in this population.
Patients with renal impairment
Reumaflex should be used with caution in patients with impaired renal function. The dose should be adjusted as follows:
Patients with hepatic impairment
Methotrexate should be administered with great caution, particularly in patients suffering from severe liver disease, either current or previous, especially if due to alcohol. Methotrexate is contraindicated in cases where bilirubin is higher than 5 mg / dl ( 85.5 mcmol / l).
For a full list of contraindications, see section 4.3.
Use in elderly patients
In elderly patients the dose may be decreased due to reduced liver and kidney function and reduced folate reserves associated with age.
Use in patients with a "third space" of distribution (pleural effusions, ascites)
In patients with a "third space" of distribution, the half-life of methotrexate may increase up to 4-fold, therefore a dose reduction or, in some cases, interruption of methotrexate administration may be required (see sections 5.2 and 4.4).
Duration and method of administration
The medicine is for single use only.
Reumaflex solution for injection can be administered intramuscularly, intravenously or subcutaneously (in children and adolescents, subcutaneously or intramuscularly only).
The overall duration of treatment is decided by the doctor.
Note:
Switching from oral treatment to parenteral administration may require a dose reduction due to the variability of the bioavailability of methotrexate after oral administration.
Folic acid supplementation can be considered in accordance with current guidelines.
04.3 Contraindications
Reumaflex is contraindicated in case of
- hypersensitivity to methotrexate or to any of the excipients, listed in section 6.1,
- Severe hepatic impairment (see section 4.2),
- alcohol abuse,
- severe renal impairment (creatinine clearance less than 20 ml / min, see sections 4.2 and 4.4),
- pre-existing blood dyscrasias such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia,
- severe, acute or chronic infections such as tuberculosis, HIV or other immunodeficiency syndromes,
- mouth ulcers and history of active gastrointestinal ulcer,
- pregnancy, lactation (see section 4.6),
- concomitant vaccination with live vaccines.
04.4 Special warnings and appropriate precautions for use
Patients should be clearly informed that therapy should be done once a week and not every day.
Patients undergoing therapy should be subjected to appropriate controls in order to promptly identify and assess the appearance of possible toxic effects or adverse reactions. Methotrexate should therefore only be administered by or under the supervision of physicians who have knowledge and experience in the use of antimetabolite therapy. Due to possible serious, even fatal toxic reactions, the patient must be adequately informed by the physician of the possible risks and on the safety measures to be taken.
Use in children below 3 years of age is not recommended due to the limited availability of safety and efficacy data for this patient population (see section 4.2).
Recommended examinations and safety measures
Before initiating or reinstituting methotrexate therapy after discontinuation:
Complete and differential blood counts, platelet counts, liver enzymes, bilirubin, serum albumin, chest x-ray and kidney function tests. If clinically indicated, exclude tuberculosis and hepatitis.
During therapy (at least once a month for the first six months and every three months thereafter):
Increase the frequency of monitoring if the dose is increased.
1. Examination of the mouth and throat for any mucosal changes.
2. Complete and differential blood counts and platelet counts. The suppression of hematopoiesis caused by methotrexate can occur suddenly and with apparently safe dosages. A drastic reduction in white blood cell or platelet counts leads to immediate discontinuation of the drug and the initiation of adequate supportive therapy. Patients should be urged. to report all signs and symptoms that suggest an infection. Blood and platelet counts should be closely monitored in patients concomitantly taking other myelotoxic medicinal products (e.g. leflunomide).
3. Liver function tests: particular attention should be paid to the occurrence of liver toxicity. Treatment should not be given or should be discontinued if abnormal liver function tests or liver biopsy are found or develop during therapy. These abnormalities should return to normal within two weeks, after which treatment can be resumed at the physician's discretion. There is no evidence to support the use of liver biopsy for monitoring liver toxicity in rheumatological indications.
For patients with psoriasis, the need for liver biopsy before and during therapy is controversial. Further research is needed to establish whether serial liver or type III collagen propeptide chemical tests are capable of promptly and effectively reporting hepatotoxicity. Assessment should be made on a case-by-case basis and should differentiate between patients without risk factors. and patients with risk factors such as previous alcohol abuse, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver disease, diabetes mellitus, obesity, history of significant exposure to hepatotoxic drugs or chemicals, prolonged treatment with methotrexate or cumulative doses of 1.5 g or more.
Control of liver enzymes in serum: Temporary increases in transaminases of up to two or three times the upper limit of normal have been reported by patients with a frequency of 13 - 20%. In the event of a steady rise in liver enzymes, consideration should be given to reducing the dose or discontinuing therapy.
Due to the potentially toxic effect on the liver, no other hepatotoxic medicinal products should be taken during treatment with methotrexate.unless they are clearly needed and alcohol consumption should be avoided or significantly reduced (see section 4.5). Careful monitoring of liver enzymes should be performed in patients concomitantly taking other hepatotoxic medicinal products (e.g. leflunomide). The same applies to concomitant administration of haematotoxic medicinal products (e.g. leflunomide).
4. Renal function should be monitored by renal function tests and urine analysis (see sections 4.2 and 4.3).
Since methotrexate is eliminated primarily via the kidney, increases in serum concentrations may occur in the case of renal impairment, which can lead to serious undesirable effects.
Where renal function may be impaired (e.g. in the elderly), monitoring should be more frequent. Frequent monitoring should be applied particularly in cases where medicinal products capable of affecting the elimination of methotrexate and causing kidney damage (eg non-steroidal anti-inflammatory drugs), or potentially leading to impaired hematopoiesis, are administered concomitantly. Dehydration can also increase the toxicity of methotrexate.
5. Evaluation of the respiratory system: vigilance for symptoms of impaired lung function and, if necessary, pulmonary function tests. Lung involvement requires quick diagnosis and discontinuation of methotrexate. Pulmonary symptoms (particularly a dry cough and nonproductive) or nonspecific pneumonia occurring during methotrexate therapy, may be indicative of a potentially dangerous injury and require "discontinuation of treatment and" careful investigation. Acute or chronic interstitial pneumonia may arise, often associated with blood eosinophilia, and some deaths have been recorded.Once pulmonary infections have been ruled out, the typical methotrexate-induced pulmonary disease in the patient, although clinically variable, presents with fever, cough, dyspnoea, hypoxemia, and infiltrates on chest radiographs. Pulmonary impairment requires early diagnosis and discontinuation and methotrexate therapy. This impairment can arise regardless of the dosages used.
6. Due to its effect on the immune system, methotrexate can impair the response to vaccination results and affect the result of immunological tests. Particular care should also be taken in the presence of chronic inactive infections (eg herpes zoster, tuberculosis, hepatitis B or C) due to eventual activation. Vaccination with live vaccines should not be performed during methotrexate therapy.
Malignant lymphomas may occur in patients receiving low dose methotrexate, and in this case therapy should be discontinued. If the lymphoma shows no signs of spontaneous regression, cytotoxic therapy should be initiated.
In rare cases, concomitant administration of folate antagonists such as trimethoprim-sulfamethoxazole has induced acute megaloblastic pancytopenia.
Radiation dermatitis and sunburn may reappear during methotrexate therapy (recall reaction). Psoriatic lesions can exacerbate following the concomitant use of ultraviolet radiation and methotrexate.
Elimination of methotrexate is reduced in patients with a "third space" of distribution (ascites, pleural effusions). These patients require close monitoring for toxicity and require dose reduction or, in some cases, discontinuation of dosing. of methotrexate. Pleural effusions and ascites must be drained before starting treatment with methotrexate (see section 5.2).
Diarrhea and ulcerative stomatitis can be toxic effects and require discontinuation of therapy, otherwise hemorrhagic enteritis and death from intestinal perforation can occur.
Vitamin preparations or other medicines that contain folic acid, folinic acid or derivatives may reduce the effectiveness of methotrexate.
For the treatment of psoriasis, methotrexate should be limited to severe, relapsing and disabling psoriasis that does not respond adequately to other forms of therapy, but only when the diagnosis is confirmed by a biopsy and / or dermatological consultation.
Encephalopathy / leukoencephalopathy have been reported in cancer patients receiving methotrexate and cannot be excluded for methotrexate therapy in non-cancer indications.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, and is essentially considered to be "sodium-free".
The absence of pregnancy must be ascertained before administering Reumaflex. Methotrexate can cause embryotoxicity, abortion and fetal defects in women. Methotrexate affects spermatogenesis and oogenesis during the administration period and may cause decreased fertility. These effects appear to be reversible upon discontinuation of therapy. Effective male and female contraception should be practiced during treatment and, at least, for the six months following the end of treatment. Patients of childbearing potential and their partners should be appropriately informed about the possible risks and reproductive effects (see section 4.6).
04.5 Interactions with other medicinal products and other forms of interaction
Alcohol, hepatotoxic drugs, haematotoxic drugs
The likelihood of methotrexate to induce hepatotoxic effects is increased by regular alcohol consumption and the concomitant intake of other hepatotoxic medicinal products (see section 4.4). Patients concomitantly taking other hepatotoxic medicinal products (eg leflunomide) should be closely monitored. Caution. The same applies to concomitant administration of haematotoxic medicinal products (eg leflunomide, azathioprine, retinoids, sulfasalazine). Concomitant administration of methotrexate and leflunomide may increase the incidence of pancytopenia and hepatotoxicity.
Combined treatment with methotrexate and retinoids such as acitretin or etretinate increases the risk of hepatotoxicity.
Oral antibiotics
Oral antibiotics such as tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibiotics, by inhibiting intestinal flora or suppressing bacterial metabolism, can interfere with the enterohepatic circulation of methotrexate.
Antibiotics
Antibiotics such as penicillins, glycopeptides, sulfonamides, ciprofloxacin and cephalothin can, in individual cases, reduce the renal clearance of methotrexate, causing increases in serum methotrexate concentrations with consequent haematological and gastrointestinal toxicity.
Medicinal products with high plasma protein binding
Circulating methotrexate binds to plasma proteins and can be replaced by other protein binding drugs such as salicylates, hypoglycemic agents, diuretics, sulfonamides, diphenylhydantoin, tetracyclines, chloramphenicol, p-aminobenzoic acid and anti-inflammatory acids, resulting in potentially 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 pyrazolone derivatives (phenylbutazone), may reduce the elimination of methotrexate with possible higher serum concentrations and potential for increased haematological toxicity. Toxicity may also increase when low dose methotrexate and non-steroidal anti-inflammatory drugs or salicylates are combined together.
Medicines with adverse reactions on the bone marrow
In case of treatment with medicinal products that may be responsible for adverse reactions on the bone marrow (eg sulfonamides, trimethoprim-sulfamethoxazole, chloramphenicol, pyrimethamine), attention should be paid to the possibility of severe impairment of hematopoiesis.
Medicines that cause folate deficiency
Concomitant administration of medicinal products that cause folate deficiency (e.g. sulfonamides, trimethoprim-sulfamethoxazole) may result in increased methotrexate toxicity. Particular attention is therefore recommended to pre-existing folic acid deficiencies.
Products that contain folic or folinic acid
Vitamin preparations or other products that contain folic acid, folinic acid or their derivatives may reduce the effectiveness of methotrexate.
Other antirheumatic medicines
In general, an increase in the toxic effects of methotrexate is not expected when Reumaflex is administered concomitantly with other antirheumatic medicinal products (eg gold salts, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine).
Sulfasalazine
Only in rare individual cases observed in clinical trials, the inhibition of folic acid synthesis induced by sulfasalazine concomitantly administered with methotrexate resulted in an increase in the efficacy of methotrexate and consequently a greater number of undesirable effects.
Mercaptopurine
Methotrexate increases plasma mercaptopurine levels. The combination of methotrexate and mercaptopurine may therefore require dosage adjustment.
Proton pump inhibitors
Concomitant administration of proton pump inhibitors such as omeprazole or pantoprazole may lead to interactions. Concomitant administration of methotrexate and omeprazole resulted in delayed renal elimination of methotrexate. The combination with pantoprazole resulted in a case of inhibition of renal elimination of the metabolite 7-hydroxymethotrexate with myalgia and tremor.
Theophylline
Methotrexate can reduce the theophylline clearance; theophylline levels should be monitored when used concomitantly with methotrexate.
Beverages containing caffeine or theophylline
Excessive consumption of caffeinated or theophylline-containing beverages (coffee, caffeinated soft drinks, black tea) should be avoided during methotrexate therapy.
04.6 Pregnancy and lactation
Pregnancy
Reumaflex is contraindicated in pregnancy (see section 4.3). In animal studies, methotrexate has shown toxic effects on reproduction (see section 5.3). Methotrexate has been shown to be teratogenic in humans; Cases of fetal death and / or congenital anomalies have been reported. Exposure of a limited number of pregnant women has shown an increased incidence (1:14) of malformations (cranial, cardiovascular and limb). With methotrexate discontinued prior to conception, normal pregnancies were recorded. Women must not become pregnant while on methotrexate therapy. If pregnancy occurs during therapy, the physician should be consulted about the risk of adverse reactions to the baby associated with methotrexate therapy. Consequently, patients of sexually mature age (men and women) must practice "effective contraception during treatment with Reumaflex extended to at least six months after the end of therapy (see section 4.4).
Before initiating therapy in women of childbearing potential, an existing pregnancy should be safely ruled out by a pregnancy test.
Feeding time
methotrexate is excreted into breast milk in concentrations that pose a risk to the newborn and, consequently, breastfeeding must be discontinued before and during administration
Fertility
Since methotrexate can be genotoxic, all women wishing to become pregnant are advised to consult a genetic counseling center if possible before starting therapy, and for men to inquire about the possibilities of storing sperm before starting therapy.
04.7 Effects on ability to drive and use machines
Central nervous system symptoms such as tiredness and dizziness may occur during treatment; Reumaflex has "mild or moderate influence on the ability to drive and use machines."
04.8 Undesirable effects
The most relevant undesirable effects are the suppression of hematopoiesis and gastrointestinal disturbances.
The following titles are used to classify undesirable effects by frequency:
Very common (≥ 1/10), common (≥ 1/100,
Neoplasms benign, malignant and unspecified (including cysts and polyps).
Very rare: Single cases of regression of lymphomas have been reported after discontinuation of methotrexate treatment. In a recent study, it was not possible to establish whether methotrexate therapy increases the incidence of lymphomas.
Disorders of the blood and lymphatic system
Common: leukopenia, anemia, thrombocytopenia.
Uncommon: pancytopenia.
Very rare: agranulocytosis, severe bone marrow depression.
Metabolism and nutrition disorders
Uncommon: decompensated diabetes mellitus.
Nervous system disorders
Common: headache, fatigue, somnolence.
Uncommon: dizziness, confusion, depression.
Very rare: visual impairment, pain, muscle weakness or paraesthesia in the limbs, taste changes (metallic taste), convulsions, meningism, paralysis.
Not known: leukoencephalopathy
Eye disorders
Rare: visual disturbances.
Very rare: retinopathy.
Cardiac pathologies
Rare: pericarditis, pericardial effusion, pericardial tamponade.
Vascular pathologies
Rare: hypotension, thromboembolic events.
Respiratory, thoracic and mediastinal disorders
Common: pneumonia, alveolitis / interstitial pneumonia often associated with eosinophilia. Symptoms that indicate a potentially serious lung injury (interstitial pneumonia) are: dry, non-productive cough, shortness of breath and fever.
Rare: pulmonary fibrosis, pneumonia from Pneumocystis carinii, shortness of breath and bronchial asthma, pleural effusion.
Gastrointestinal disorders
Very common: stomatitis, dyspepsia, nausea, loss of appetite.
Common: oral ulcers, diarrhea.
Uncommon: pharyngitis, enteritis, vomiting.
Rare: gastrointestinal ulcers.
Very rare: haematemesis, haemorrhage, toxic megacolon.
Hepatobiliary disorders (see section 4.4)
Very common: elevated transaminases.
Uncommon: cirrhosis, fibrosis and fatty liver disease, decreased serum albumin.
Rare: acute hepatitis.
Very rare: hepatic failure.
Skin and subcutaneous tissue disorders
Common: rash, erythema, pruritus.
Uncommon: photosensitization, hair loss, increased rheumatic nodules, herpes zoster, vasculitis, herpetiform skin eruptions, urticaria.
Rarei: increased pigmentation, acne, bruising.
Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), nail pigmentation changes, acute paronychia, furunculosis, telangiectasia.
Musculoskeletal and connective tissue disorders
Uncommon: arthralgia, myalgia, osteoporosis.
Renal and urinary disorders
Uncommon: inflammation and ulcer of the urinary bladder, renal impairment, urination disturbances.
Rare: renal failure, oliguria, anuria, electrolyte disturbances.
Diseases of the reproductive system and breast
Uncommon: inflammation and ulcer of the vagina.
Very rare: loss of libido, impotence, gynecomastia, oligospermia, menstrual disturbances, vaginal discharge.
General disorders and administration site conditions
Rare: allergic reactions, anaphylactic shock, allergic vasculitis, fever, conjunctivitis, infection, sepsis, delayed wound healing, hypogammaglobulinemia.
Very rare: Local damage (sterile abscess formation, lipodystrophy) at the injection site following intramuscular or subcutaneous administration.
The occurrence and severity of undesirable effects depend on the dosage and frequency of administration. However, as serious side effects can occur even at low doses, it is imperative that patients are monitored by their doctor at short and regular intervals.
When methotrexate is administered intramuscularly, local side effects (burning sensation) or lesions (sterile abscess formation, destruction of fatty tissue) at the injection site are common manifestations. Subcutaneous administration of methotrexate is locally well tolerated. Only mild local skin reactions regressed during the course of therapy were observed.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. - website: www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
a) Symptoms of overdose
The toxicity of methotrexate primarily affects the haematopoietic system.
b) Intervention measures in case of overdose
Calcium folinate is the specific antidote to neutralize the unwanted toxic effects of methotrexate.
In cases of accidental overdose, a dose of calcium folinate equal to or greater than the toxic dose of methotrexate should be administered intravenously or intramuscularly within one "hour, followed by further doses until serum methotrexate levels below 10-7mol are obtained. /L.
In cases of massive overdose, hydration and urinary alkalinization may be required to prevent precipitation of methotrexate and / or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis have shown an improvement in the elimination of methotrexate. "Effective elimination of methotrexate with" acute intermittent hemodialysis using a high-flux dialyzer has been reported.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: folic acid analogues.
ATC code: L01BA01.
Antirheumatic medicine 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 belonging to the class of cytotoxic agents known as antimetabolites. It acts by competitive inhibition of the dihydrofolate reductase enzyme and thus inhibits DNA synthesis. However, it has not yet been clarified whether the efficacy of methotrexate in the treatment of psoriasis, psoriatic arthritis, chronic polyarthritis and Crohn's disease is due to an anti-inflammatory or immunosuppressive effect and to what extent an increase in the concentration of extracellular adenosine induced by methotrexate at the sites of inflammation contribute to obtaining these effects.
International clinical guidelines indicate the use of methotrexate as a second-line treatment for Crohn's disease patients who are intolerant or have not responded to first-line treatment with immunomodulating agents such as azathioprine (AZA) or 6-mercaptopurine (6- MP).
Adverse events observed in studies conducted with methotrexate for Crohn's disease at cumulative doses did not show a different safety profile of methotrexate from that already known. Therefore, similar cautions should be used with the use of methotrexate for the treatment of Crohn's disease as for the other indications of methotrexate in rheumatic and non-rheumatic diseases (see sections 4.4 and 4.6).
05.2 Pharmacokinetic properties
Distribution
Administered orally, methotrexate is absorbed from the gastrointestinal tract. In case of administration of low doses (dosages between 7.5 mg / m2 and 80 mg / m2 of body surface area), the mean bioavailability is about 70%, but numerous inter- and intra-individual variations are possible (25 - 100 %). Maximum serum concentrations are reached after 1 - 2 hours.
Biotransformation
The bioavailability of methotrexate administered subcutaneously, intravenously and intramuscularly is similar and close to 100%.
Elimination
About 50% of methotrexate is bound to whey proteins. After being distributed in various body tissues, high concentrations in the form of polyglutamates are found mainly in the liver, kidneys and spleen in particular, where they can remain for weeks or months. When given in low doses, only small amounts of methotrexate pass into the CSF. The half-life of the product is on average 6 - 7 hours, but with considerable variability (3 - 17 hours). The half-life can increase up to 4 times in patients with a "third space" of distribution (pleural effusion, ascites) .
Approximately 10% of the administered methotrexate dose is metabolised by the liver. The major metabolite is 7-hydroxymethotrexate.
Excretion occurs primarily via the kidney as unchanged methotrexate, via glomerular filtration and active secretion in the proximal tubule.
Approximately 5 - 20% of methotrexate and 1 - 5% of 7-hydroxymethotrexate are eliminated via the bile. The enteropathic circulation is intense.
Elimination is considerably delayed in the case of renal insufficiency, while it is not known in the case of hepatic insufficiency.
05.3 Preclinical safety data
Animal studies show that methotrexate impairs fertility, is embryotoxic, foetotoxic and teratogenic. Methotrexate is mutagenic in vivo And in vitro. Since formal carcinogenicity studies have not been conducted and chronic toxicity studies in rodents are not adequate, methotrexate is considered unclassifiable with respect to its carcinogenicity in humans.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sodium chloride
Sodium hydroxide for pH regulation
Water for injections
06.2 Incompatibility
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
Do not store above 25 ° C. Store the pre-filled syringes in the outer carton in order to protect them from light.
06.5 Nature of the immediate packaging and contents of the package
Nature of the container:
Pre-filled syringes of colorless glass (type I) of 1 ml capacity with fixed injection needle. Chlorobutyl rubber stoppers (type I) and polystyrene rods inserted into the stopper to form the syringe plunger
or
Pre-filled syringes of colorless glass (type I) of 1 ml capacity with separate injection needle. Chlorobutyl rubber stoppers (type I) and polystyrene rods inserted over the stopper to form the syringe plunger.
Packaging:
Pre-filled syringes containing 0.15 ml, 0.20 ml, 0.30 ml, 0.40 ml, 0.50 ml, of solution, available in packs of 1, 4, 6, 12 and 24 pre-filled syringes with fixed subcutaneous needle and alcohol swabs.
And
Pre-filled syringes containing 0.15 mL, 0.20 mL, 0.30 mL, 0.40 mL, 0.50 mL solution, available in packs of 1, 4, 6, 12 and 24 pre-filled syringes with separate subcutaneous needle and alcohol swabs.
For intramuscular and intravenous use, a needle suitable for these routes of administration must be used: the needle included in the package is only suitable for subcutaneous use.
All packs are available with graduation marks.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Handling and disposal should be done in the same way as for other cytotoxic preparations in accordance with local regulations. Pregnant healthcare professionals should refrain from handling and / or administering Reumaflex.
Methotrexate must not come into contact with the skin or mucous membranes. In case of contamination, the affected area should be immediately rinsed with plenty of water.
For single use only.
Unused medicine or waste derived from this medicine must be disposed of in accordance with local regulations.
Instructions for subcutaneous use
The most appropriate injection sites are:
• upper thigh,
• abdomen, excluding the periumbilical area.
1. Clean the area surrounding the chosen injection site (eg with the use of the alcohol swab).
2. Remove the protective plastic cap by keeping it straight.
3. Fold the skin by gently pinching the injection site area.
4. The fold must be maintained for the duration of the injection.
5. Fully insert the needle into the skin at a 90 degree angle.
6. Slowly push the plunger and inject the liquid under the skin. Pull the syringe out of the skin while maintaining a 90 degree "tilt" of the needle.
07.0 MARKETING AUTHORIZATION HOLDER
ALFA WASSERMANN S.p.A.
Via Enrico Fermi n.1
65020 - ALANNO (PE)
08.0 MARKETING AUTHORIZATION NUMBER
039153010 - "50 mg / ml solution for injection, pre-filled syringes" 1 pre-filled syringe of 0.15 ml with fixed subcutaneous needle;
039153022 - "50 mg / ml solution for injection, pre-filled syringes" 4 pre-filled syringes of 0.15 ml with fixed subcutaneous needle;
039153034 - "50 mg / ml solution for injection, pre-filled syringes" 6 pre-filled syringes of 0.15 ml with fixed subcutaneous needle;
039153046 - "50 mg / ml solution for injection, pre-filled syringes" 12 pre-filled syringes of 0.15 ml with fixed subcutaneous needle;
039153059 - "50 mg / ml solution for injection, pre-filled syringes" 24 pre-filled syringes of 0.15 ml with fixed subcutaneous needle;
039153061 - "50 mg / ml solution for injection, pre-filled syringes" 1 pre-filled syringe of 0.15 ml with separate subcutaneous needle;
039153073 - "50 mg / ml solution for injection, pre-filled syringes" 4 pre-filled syringes of 0.15 ml with separate subcutaneous needle;
039153085 - "50 mg / ml solution for injection, pre-filled syringes" 6 pre-filled syringes of 0.15 ml with separate subcutaneous needle;
039153097 - "50 mg / ml solution for injection, pre-filled syringes" 12 pre-filled syringes of 0.15 ml with separate subcutaneous needle;
039153109 - "50 mg / ml solution for injection, pre-filled syringes" 24 pre-filled syringes of 0.15 ml with separate subcutaneous needle;
039153111 - "50 mg / ml solution for injection, pre-filled syringes" 1 pre-filled syringe of 0.20 ml with fixed subcutaneous needle;
039153123 - "50 mg / ml solution for injection, pre-filled syringes" 4 pre-filled syringes of 0.20 ml with fixed subcutaneous needle;
039153135 - "50 mg / ml solution for injection, pre-filled syringes" 6 pre-filled syringes of 0.20 ml with fixed subcutaneous needle;
039153147 - "50 mg / ml solution for injection, pre-filled syringes" 12 pre-filled syringes of 0.20 ml with fixed subcutaneous needle;
039153150 - "50 mg / ml solution for injection, pre-filled syringes" 24 pre-filled syringes of 0.20 ml with fixed subcutaneous needle;
039153162 - "50 mg / ml solution for injection, pre-filled syringes" 1 pre-filled syringe of 0.20 ml with separate subcutaneous needle;
039153174 - "50 mg / ml solution for injection, pre-filled syringes" 4 pre-filled syringes of 0.20 ml with separate subcutaneous needle;
039153186 - "50 mg / ml solution for injection, pre-filled syringes" 6 pre-filled syringes of 0.20 ml with separate subcutaneous needle;
039153198 - "50 mg / ml solution for injection, pre-filled syringes" 12 pre-filled syringes of 0.20 ml with separate subcutaneous needle;
039153200 - "50 mg / ml solution for injection, pre-filled syringes" 24 pre-filled syringes of 0.20 ml with separate subcutaneous needle;
039153212 - "50 mg / ml solution for injection, pre-filled syringes" 1 pre-filled syringe of 0.30 ml with fixed subcutaneous needle;
039153224 - "50 mg / ml solution for injection, pre-filled syringes" 4 pre-filled syringes of 0.30 ml with fixed subcutaneous needle;
039153236 - "50 mg / ml solution for injection, pre-filled syringes" 6 pre-filled syringes of 0.30 ml with fixed subcutaneous needle;
039153248 - "50 mg / ml solution for injection, pre-filled syringes" 12 pre-filled syringes of 0.30 ml with fixed subcutaneous needle;
039153251 - "50 mg / ml solution for injection, pre-filled syringes" 24 pre-filled syringes of 0.30 ml with fixed subcutaneous needle;
039153263 - "50 mg / ml solution for injection, pre-filled syringes" 1 pre-filled syringe of 0.30 ml with separate subcutaneous needle;
039153275 - "50 mg / ml solution for injection, pre-filled syringes" 4 pre-filled syringes of 0.30 ml with separate subcutaneous needle;
039153287 - "50 mg / ml solution for injection, pre-filled syringes" 6 pre-filled syringes of 0.30 ml with separate subcutaneous needle;
039153299 - "50 mg / ml solution for injection, pre-filled syringes" 12 pre-filled syringes of 0.30 ml with separate subcutaneous needle;
039153301 - "50 mg / ml solution for injection, pre-filled syringes" 24 pre-filled syringes of 0.30 ml with separate subcutaneous needle;
039153313 - "50 mg / ml solution for injection, pre-filled syringes" 1 pre-filled syringe of 0.40 ml with fixed subcutaneous needle;
039153325 - "50 mg / ml solution for injection, pre-filled syringes" 4 pre-filled syringes of 0.40 ml with fixed subcutaneous needle;
039153337 - "50 mg / ml solution for injection, pre-filled syringes" 6 pre-filled syringes of 0.40 ml with fixed subcutaneous needle;
039153349 - "50 mg / ml solution for injection, pre-filled syringes" 12 pre-filled syringes of 0.40 ml with fixed subcutaneous needle;
039153352 - "50 mg / ml solution for injection, pre-filled syringes" 24 pre-filled syringes of 0.40 ml with fixed subcutaneous needle;
039153364 - "50 mg / ml solution for injection, pre-filled syringes" 1 pre-filled syringe of 0.40 ml with separate subcutaneous needle;
039153376 - "50 mg / ml solution for injection, pre-filled syringes" 4 pre-filled syringes of 0.40 ml with separate subcutaneous needle;
039153388 - "50 mg / ml solution for injection, pre-filled syringes" 6 pre-filled syringes of 0.40 ml with separate subcutaneous needle;
039153390 - "50 mg / ml solution for injection, pre-filled syringes" 12 pre-filled syringes of 0.40 ml with separate subcutaneous needle;
039153402 - "50 mg / ml solution for injection, pre-filled syringes" 24 pre-filled syringes of 0.40 ml with separate subcutaneous needle;
039153414 - "50 mg / ml solution for injection, pre-filled syringes" 1 pre-filled syringe of 0.50 ml with fixed subcutaneous needle;
039153426 - "50 mg / ml solution for injection, pre-filled syringes" 4 pre-filled syringes of 0.50 ml with fixed subcutaneous needle;
039153438 - "50 mg / ml solution for injection, pre-filled syringes" 6 pre-filled syringes of 0.50 ml with fixed subcutaneous needle;
039153440 - "50 mg / ml solution for injection, pre-filled syringes" 12 pre-filled syringes of 0.50 ml with fixed subcutaneous needle;
039153453 - "50 mg / ml solution for injection, pre-filled syringes" 24 pre-filled syringes of 0.50 ml with fixed subcutaneous needle;
039153465 - "50 mg / ml solution for injection, pre-filled syringes" 1 pre-filled syringe of 0.50 ml with separate subcutaneous needle;
039153477 - "50 mg / ml solution for injection, pre-filled syringes" 4 pre-filled syringes of 0.50 ml with separate subcutaneous needle;
039153489 - "50 mg / ml solution for injection, pre-filled syringes" 6 pre-filled syringes of 0.50 ml with separate subcutaneous needle;
039153491 - "50 mg / ml solution for injection, pre-filled syringes" 12 pre-filled syringes of 0.50 ml with separate subcutaneous needle;
039153503 - "50 mg / ml solution for injection, pre-filled syringes" 24 pre-filled syringes of 0.50 ml with separate subcutaneous needle.
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 29.12.2009
Date of last renewal: 29.12.2014
10.0 DATE OF REVISION OF THE TEXT
February 16, 2015
