Active ingredients: Etanercept
Enbrel 25 mg powder and solvent for solution for injection
Enbrel package inserts are available for pack sizes:- Enbrel 25 mg powder and solvent for solution for injection
- Enbrel 25 mg solution for injection in pre-filled syringes
- Enbrel 50 mg solution for injection in pre-filled syringes
- Enbrel 50 mg solution for injection in pre-filled pen
- Enbrel 10 mg powder and solvent for solution for injection for pediatric use
Why is Enbrel used? What is it for?
Enbrel is a biological medicine made from two human proteins. It blocks the activity of another protein that causes inflammation in the human body. Enbrel works by reducing the inflammation associated with some diseases.
In adults (18 years of age and older), Enbrel can be used for the treatment of moderate to severe rheumatoid arthritis, psoriatic arthritis, severe axial spondyloarthritis, including ankylosing spondylitis, and moderate to severe psoriasis. severe - usually when other widely used treatments have not worked well enough or are not suitable for you.
For rheumatoid arthritis, Enbrel is usually used in combination with methotrexate, although it can also be used alone if methotrexate treatment is not suitable for you. Whether used alone or in combination with methotrexate, Enbrel can slow the damage to the joints caused by rheumatoid arthritis and improves the ability to perform normal daily activities.
For patients with psoriatic arthritis involving multiple joints, Enbrel can improve the ability to perform daily activities. For patients with painful or swollen multiple symmetrical joints (for example, hands, wrists, and feet), Enbrel can slow down the structural damage to these joints caused by the disease.
Enbrel is also prescribed to treat the following conditions in children and adolescents:
- For the following types of juvenile idiopathic arthritis, when methotrexate treatment has not given a sufficiently good response or is inappropriate: Polyarthritis (rheumatoid factor positive or negative) and extensive oligoarthritis in patients from the age of 2 years; Psoriatic arthritis in patients from the age of 12.
- For enthesitis-related arthritis in patients from the age of 12, when other widely used treatments have not given a sufficiently good response or are not appropriate.
- Severe psoriasis in patients from 6 years of age who have had an inadequate response to (or cannot take) phototherapies or other systemic therapies.
Contraindications When Enbrel should not be used
Do not use Enbrel:
- if you or the child are allergic to etanercept or any of the other ingredients of Enbrel (listed in section 6). If you or the child experience allergic reactions such as chest tightness, shortness of breath, dizziness or a rash, do not inject more Enbrel and contact your doctor immediately.
- if you or the child have or are at risk of developing a "serious blood infection called sepsis. If you are unsure, contact your doctor.
- if you or the child have an infection of any kind. If you are unsure, talk to your doctor.
Precautions for use What you need to know before taking Enbrel
- Allergic reactions: If you or the child experience allergic reactions such as chest tightness, shortness of breath, dizziness or rash, do not inject more Enbrel and contact your doctor immediately.
- Infections / Surgery: If you or the child develop a new infection or are about to have any major surgery, your doctor may want to check your treatment with Enbrel.
- Infections / diabetes: Tell your doctor if you or the child have a history of recurring infections or have diabetes or other conditions that increase the risk of infection.
- Infections / monitoring: Tell your doctor about any recent travel outside Europe. If you or your child develop symptoms of an infection such as fever, chills or cough, tell your doctor immediately. Your doctor may decide to continue monitoring you or your child for infections after you or your child have stopped taking Enbrel.
- Tuberculosis: As cases of tuberculosis have been reported in patients treated with Enbrel, your doctor will check you for signs and symptoms of tuberculosis before starting treatment with Enbrel. This could include a thorough collection of your medical history, chest X-rays, and a tuberculin test. The results of these tests should be noted on the Patient Alert Card. It is very important that you tell your doctor if you or the child have ever contracted tuberculosis or if you have been in close contact with someone with tuberculosis. tuberculosis (such as persistent cough, weight loss, weakness, mild fever) or any other infection appearing during or after therapy, tell your doctor immediately.
- Hepatitis B: Tell your doctor if you or your child have or have ever had hepatitis B. Your doctor must test for hepatitis B before you or your child start treatment with Enbrel. Treatment with Enbrel may cause reactivation of hepatitis B in patients with previous hepatitis B virus infection. In this case, you should stop using Enbrel.
- Hepatitis C: Tell your doctor if you or the child have hepatitis C. Your doctor may want to monitor your treatment with Enbrel if the infection gets worse.
- Blood disorders: Seek immediate medical attention if you or the child have any signs or symptoms such as persistent fever, sore throat, bruising, bleeding or paleness. These symptoms may indicate the presence of potentially life-threatening blood disorders that may require you to stop taking Enbrel.
- Nervous system and eye disorders: Tell your doctor if you or the child have multiple sclerosis, optic neuritis (inflammation of the optic nerves) or transverse myelitis (inflammation of the spinal cord). Your doctor will consider whether Enbrel is an appropriate treatment.
- Congestive heart failure: Tell your doctor if you or the child have a history of congestive heart failure, as Enbrel should be used with caution in these circumstances.
- Cancer: Tell your doctor if you have or have ever had lymphoma (a type of blood cancer) or any other cancer before taking Enbrel. Patients with long-standing severe rheumatoid arthritis may be at a higher than average risk of developing lymphoma. Children and adults who take Enbrel may have an increased risk of developing lymphoma or another cancer. Some children and adolescent patients who have been treated with Enbrel or with other medicines that work like Enbrel have developed cancers, including unusual types, sometimes with a fatal outcome. Some patients receiving Enbrel have developed skin cancers. Tell your doctor if you or the child develop any changes in the appearance of the skin or growths on the skin.
- Chickenpox: Tell your doctor if you or the child are exposed to chickenpox when using Enbrel. Your doctor will consider whether preventive treatment for chickenpox is appropriate.
- Latex: The needle cap is made of latex (dried natural rubber). Contact your doctor before using Enbrel if the needle cap is being handled or if Enbrel is being administered to a person with known or possible hypersensitivity ( allergy) to latex.
- Alcohol abuse: Enbrel should not be used to treat alcohol-related hepatitis. Tell your doctor if you or the child have a history of alcohol abuse.
- Wegener's granulomatosis: Enbrel is not recommended for the treatment of Wegener's granulomatosis, a rare inflammatory disease. If you or the child have Wegener's granulomatosis, talk to your doctor.
- Anti-diabetes medicines: Tell your doctor if you or the child have diabetes or if you are taking medicines to treat diabetes. Your doctor can decide whether you or your child need less diabetes medicine while you are taking Enbrel.
Children and adolescents
- Vaccinations: If possible, children should be up to date with all vaccinations before using Enbrel. Some vaccines, such as oral polio vaccine, should not be taken while you are taking Enbrel. Consult your doctor before you or your child receive any vaccines.
- Inflammatory bowel disease (IBD): There have been cases of inflammatory bowel disease in juvenile idiopathic arthritis (JIA) patients treated with Enbrel. Tell your doctor if your child experiences abdominal cramps and pains, diarrhea, weight loss, or blood in the stool.
Enbrel should not normally be used in children with polyarthritis or extensive oligoarthritis less than 2 years of age, or in children with enthesitis-related arthritis or psoriatic arthritis less than 12 years of age, or in children with psoriasis less than 6 years of age. .
Interactions Which drugs or foods may change the effect of Enbrel
Tell your doctor or pharmacist if you or the child are taking, have recently taken or might take any other medicines (including anakinra, abatacept or sulfasalazine), even those obtained without a prescription. You or the child must not use Enbrel together with the active substance anakinra or abatacept.
Warnings It is important to know that:
Pregnancy and breastfeeding
The effects of Enbrel on pregnant women are not known, therefore the use of Enbrel in pregnancy is not recommended. Women using Enbrel should avoid becoming pregnant.
If you or the girl / girl become pregnant, you should contact your doctor. If you or the girl / girl received Enbrel during pregnancy, the baby may be at increased risk of infection. It is important to advise newborn pediatricians and other health care professionals of the use of Enbrel during pregnancy before the newborn receives any vaccine (for more information see section 2, "Vaccinations").
Women using Enbrel should not breastfeed, as Enbrel is excreted in breast milk.
Effects on ability to drive and use machines
The use of Enbrel is not expected to affect your ability to drive or use machines.
Dose, Method and Time of Administration How to use Enbrel: Posology
Always use Enbrel exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
If you have the impression that the effect of Enbrel is too strong or too weak, talk to your doctor or pharmacist.
Doses for adults (aged 18 years or over)
Rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis, including ankylosing spondylitis
The usual dose is 25 mg given twice weekly or 50 mg once weekly by subcutaneous injection. In each case, your doctor can determine a different frequency at which to inject Enbrel.
Plaque psoriasis
The usual dose is 25 mg given twice a week or 50 mg given once a week.
Alternatively, a 50 mg dose given twice weekly for up to 12 weeks may be given, followed by a 25 mg dose given twice a week or a 50 mg dose given once a week.
Your doctor will decide how long you need to take Enbrel and whether, based on your response, a new treatment is needed. If, after 12 weeks, Enbrel has no effect on your disease, your doctor may tell you to stop the treatment.
Use in children and adolescents
The appropriate dose and dosing frequency for your child or adolescent will depend on body weight and disease. Your doctor will provide you with detailed information on how to prepare and measure the appropriate dosage.
For polyarthritis or extensive oligoarthritis in patients from 2 years of age, or enthesitis-related arthritis or psoriatic arthritis in patients from 12 years of age, the usual dose is 0.4 mg of Enbrel per kg of body weight (up to a maximum of 25 mg), given twice a week, or 0.8 mg of Enbrel per kg of body weight (up to a maximum of 50 mg) given once a week.
For psoriasis in patients aged 6 years and above, the usual dose is 0.8 mg of Enbrel per kilogram of body weight (up to a maximum of 50 mg) and should be administered once weekly. If Enbrel has no effect on your baby's condition after 12 weeks, your doctor may tell you to stop taking this medicine.
Method and route of administration
Enbrel is given by injection under the skin (subcutaneous injection).
Enbrel can be taken with or without food and drink.
The powder must be dissolved before use. Detailed instructions on how to prepare and inject Enbrel are provided in section 7, Instructions for preparing and giving an injection of Enbrel. Do not mix Enbrel solution with other medicines.
To help you remember, it may be helpful to write in a diary which day (s) of the week Enbrel should be used.
Instructions for preparing and giving an injection of Enbrel
Introduction
The following instructions explain how to prepare and inject Enbrel. Read the instructions carefully and follow them step by step. You will be instructed by your doctor or nurse on self-injection technique or on administering an injection to a child. A "dose preparation guide" (specially made on the underside of the tray) is provided to assist you in "aligning the vial and solvent syringe. Do not attempt to administer an injection until you are sure you understand how to prepare and how to do the injection. This injection must not be mixed with any other medicine.
Preparation of the injection
- Wash your hands thoroughly.
- The dose tray should contain the materials listed below (if not, do not use the tray and consult your pharmacist). Use only the materials listed. DO NOT use any other syringes. Enbrel vial Pre-filled syringe containing clear, colorless solvent (water for injections) Syringe plunger 2 alcohol swabs Dose preparation guide (bottom of tray).
- Check the expiration dates on both the vial and syringe labels. They should not be used after the month and year indicated. c.
Prepare the Enbrel dose for injection using the "Dose Preparation Guide" (on the back of the tray)
- Remove the contents of the tray and turn the tray upside down. The underside of the tray is a "dose preparation guide." It is specially designed to hold the vial and syringe in place while the Enbrel solution is being prepared.
- Remove the plastic cap from the Enbrel vial. DO NOT remove the gray cap or aluminum ring around the neck of the vial.
- Use a new alcohol swab to clean the gray stopper on the Enbrel vial. After cleaning, do not touch the gray cap with your hands.
- Push the Enbrel vial into the space to the right of the mark in the dose preparation guide; the gray cap will point towards the center of the tray (see Figure 1).
- Remove the syringe needle cap by pulling it firmly taking care not to touch the needle or allow the needle to touch any surface (see Figure 2). Be careful not to bend or twist the cap to avoid damaging the needle .
- Turn the vial so that the slit in the stopper is facing up and visible. With the needle pointing towards the vial, align the "0.5 ml" mark on the syringe with the edge of the dose preparation guide . Keep both needle and syringe horizontal so that the needle does not touch the tray. Slide the syringe into the dose preparation guide until the needle has passed through the center of the gray vial stopper ring (see Figure 3). If the needle is properly aligned, you will feel a slight resistance and then a "pop" indicating that the needle has passed through the center of the cap. Look at the tip of the needle through the slit in the stopper (see Figure 4). If the needle is not aligned correctly, you will feel constant resistance as it passes through the stopper, without any "pop". Insert the needle without tilting it; this could cause the needle to bend and / or hinder the correct introduction of the solvent into the vial (see Figure 5).
- Slide the plunger into the syringe.
- Turn plunger clockwise until slight resistance is felt (see Figure 6).
Adding the solvent
- Push the plunger in VERY SLOWLY until all the solvent has passed into the vial. This will help reduce foaming (numerous bubbles) (see Figure 7).
- Leave the syringe in place. To dissolve the powder, gently move the dose preparation guide a few times in circular motions (see Figure 8). DO NOT shake the dose preparation guide. Wait until all the powder has dissolved (usually less than 10 minutes). The solution should appear clear and colorless, without any fragments, flakes or particles. Some amount of white foam may remain in the vial - this is normal.DO NOT use Enbrel if all the powder in the vial does not dissolve within 10 minutes. Start over with another dose tray.
Withdrawing the Enbrel solution from the vial
- With the needle still in the vial, hold the dose preparation guide with the vial upside down at eye level. Slowly pull back the plunger to draw liquid into the syringe (see Figure 9). As soon as the liquid level in the vial goes down, the needle may need to be partially withdrawn to keep the tip in the liquid. For adult patients, withdraw the entire volume. For children, withdraw only the portion of liquid as prescribed by the child's doctor.
- With the needle still in the vial, check the syringe for air bubbles. Gently tap the syringe so that all air bubbles rise to the top of the syringe, near the needle (see Figure 10). Push the plunger slowly to push the air bubbles from the syringe into the vial. If liquid is accidentally returned to the vial during this step, slowly pull the plunger back to draw the liquid back into the syringe.
- Pull the syringe completely out of the dose preparation guide. Again, do not touch the needle and do not let it touch any surface (see Figure 11). (Note: After completing these steps, a small amount of liquid may remain in the vial. This is normal).
Choose an injection site
- The three recommended injection sites for Enbrel include: the front center of the thighs; the abdomen, except for the area 5 cm away around the navel; and the outer area of the upper arms (see Figure 12). If you are self-injecting yourself, you should not use the outer area of the upper arms.
- A different site should be used for each new injection. Each new injection should be given at least 3 cm from a previous site. Do not inject into areas where the skin is tender, bruised, red or hard. Avoid areas with scars or stretch marks. (It may be helpful to note the location of previous injection sites).
- If you or your child have psoriasis, try not to inject directly into swollen, thickened, red, or scaly areas of the skin ("psoriasis skin lesions"). g. Prepare the injection site and inject the Enbrel solution.
- Wipe the injection site where Enbrel is to be injected with the alcohol swab using a circular motion. DO NOT touch this area again before injecting.
- When the cleaned area of skin has dried, squeeze and hold it firmly with one hand. With the other hand, hold the syringe like a pencil.
- With a quick, short motion, fully penetrate the needle into the skin at an angle of 45 ° to 90 ° (see Figure 13). With experience, you will find the angle that is most comfortable for you or the baby. Be careful not to push the needle into the skin too slowly, or with great force.
- When the needle has fully entered the skin, let go of the skin you are holding. With your free hand, hold the syringe close to its base to stabilize it. Then push the plunger to inject all of the solution at a slow and steady rate (see Figure 14).
- When the syringe is empty, remove the needle from your skin being careful to keep it at the same angle it was when it was inserted.
- Press a cotton swab over the injection site for 10 seconds. Slight bleeding may occur. DO NOT rub the injection site. A bandage is optional.
Disposal of the material
- The syringe and needle must NEVER be reused. Never close the needle. Dispose of the needle and syringe as advised by your doctor, nurse or pharmacist.
If you have any questions, talk to a doctor, nurse or pharmacist familiar with Enbrel.
Overdose What to do if you have taken too much Enbrel
If you use more Enbrel than you should:
If you have used more Enbrel than you should (either by injecting too much on one occasion or using it too frequently), talk to your doctor or pharmacist immediately. Always take the medicine pack with you, even if it is empty.
If you forget to take Enbrel:
If you miss a dose, administer it as soon as you notice the forgotten dose, unless the next dose is scheduled for the next day, in which case you must skip the missed dose. Then continue to administer the medicine on the designated day (s). If you have forgotten your dose until the day your next dose is due, do not take a double dose (two doses on the same day) to make up for a forgotten dose.
If you stop taking Enbrel:
Symptoms of the disease may return after stopping treatment. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Enbrel
Like all medicines, Enbrel can cause side effects, although not everybody gets them.
Allergic reactions
If any of the following side effects occur, do not inject Enbrel anymore. Tell your doctor immediately, or go to the nearest hospital emergency room.
- Difficulty swallowing or breathing
- Swelling of the face, throat, hands or feet
- Feeling nervous or anxious, palpitations, sudden redness of the skin and / or a feeling of warmth
- Severe rash, itching, hives (raised patches of red or light skin that often itch)
Severe allergic reactions are rare. However, any of the above symptoms may indicate an allergic reaction to Enbrel; therefore, you must seek medical attention immediately.
Serious side effects
If you notice any of the following, you or your child may need urgent medical attention.
- Symptoms of serious infections, such as high fever which may be accompanied by cough, shortness of breath, chills, weakness, or a hot, red, tender, sore area in the skin or joints.
- Symptoms of blood disorders, such as bleeding, bruising or paleness.
- Symptoms of nerve changes, such as numbness or tingling, changes in vision, pain in the eyes or onset of weakness in an arm or leg.
- Symptoms of worsening heart failure, such as fatigue or shortness of breath during activity, swollen ankles, a swollen feeling in the neck or abdomen, shortness of breath at night or cough, bluish color of the nails or lips.
- Symptoms of tumors: Tumors can affect any part of the body, including skin and blood, and the possible symptoms depend on the type and location of the tumor. These symptoms may include weight loss, fever, swelling (with or without pain), persistent cough, presence of cysts or growths on the skin.
- Symptoms of autoimmune reactions (where antibodies are created that can damage normal body tissues), such as pain, itching, weakness, abnormalities in breathing, thinking, feeling or vision.
- Symptoms of lupus or lupus-like syndrome, such as changes in body weight, persistent rash, fever, joint or muscle pain, or fatigue.
- Symptoms of inflammation of the blood vessels, such as pain, fever, redness or warmth of the skin or itching.
These side effects are rare or uncommon, but they are serious conditions (some of which can rarely cause death). If these symptoms occur, tell your doctor immediately, or go to the nearest hospital emergency room.
Known side effects of Enbrel include the following, grouped by decreasing frequency:
- Very common (may affect more than 1 in 10 patients): Infections (including colds, sinusitis, bronchitis, urinary tract infections and skin infections); injection site reactions (including bleeding, bruising, redness, itching, pain and swelling). Injection site reactions (these do not occur as often after the first month of treatment). Some patients have developed a reaction at one site previously used injection.
- Common (may affect up to 1 in 10 patients): Allergic reactions; fever; itch; antibodies directed against normal tissue (formation of autoantibodies)
- Uncommon (may affect up to 1 in 100 people): Serious infections (including pneumonia, deep skin infections, joint infections, blood infections and infections at various sites); reduced number of platelets in the blood; skin cancer (excluding melanoma); localized swelling of the skin (angioedema); hives (raised patches of red or light skin that often itch); eye inflammation; psoriasis (first appearance or aggravation), rash; inflammation or scarring of the lungs; inflammation of the blood vessels affecting more than one organ.
- Rare (may affect up to 1 in 1000 people): Severe allergic reactions (including severe localized swelling of the skin and breathing difficulties); lymphoma (a type of blood cancer); melanoma (a type of skin cancer); joint reduction in the number of platelets, red blood cells and white blood cells; changes in the nervous system (with severe muscle weakness and signs and symptoms similar to those of multiple sclerosis or inflammation of the nerves in the eye or spinal cord); tuberculosis; worsening of heart failure; convulsions; lupus or lupus-like syndrome (symptoms may include "persistent rash, fever, joint pain and tiredness); low red blood cell count, low white blood cell count, low neutrophil count (a type of white blood cell); elevated blood liver; rash which can lead to severe blistering and peeling of the skin; inflammation of the liver caused by your immune system (autoimmune hepatitis); immune disorder which can affect the lungs, skin and lymph nodes (sarcoidosis).
- Very rare (may affect up to 1 in 10,000 people): inability of the bone marrow to produce essential blood cells.
- Not known (frequency cannot be estimated from the available data): leukemia (a cancer affecting the blood and bone marrow); Merkel cell carcinoma (a type of skin cancer); excessive activation of white blood cells associated with inflammation (macrophage activation syndrome); return of hepatitis B (a liver infection); worsening of a condition called dermatomyositis (inflammation and muscle weakness accompanied by a rash).
Side effects in children and adolescents
The side effects and their frequency observed in children and adolescents are similar to those described above.
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 via the national reporting system listed in Appendix V. 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.
Do not use Enbrel after the expiry date which is stated on the carton and label after "EXP". The expiry date refers to the last day of that month.
Store in the refrigerator (between 2 ° C and 8 ° C). Do not freeze.
Before preparing the Enbrel solution, the medicine can be stored out of the fridge at a maximum temperature of 25 ° C for up to 4 weeks, for one time only; after this period it cannot be put back in the fridge. If not used within 4 weeks out of the fridge, Enbrel should be discarded. It is recommended to note the date Enbrel is placed out of the fridge and the date by which Enbrel must be disposed of (no more than 4 weeks out of the fridge).
Immediate use is recommended after preparing the Enbrel solution. However, the solution can be used within 6 hours if stored at a maximum temperature of 25 ° C.
Do not use Enbrel if you notice that the solution is not clear or if it contains particles. The solution should appear clear and colorless or pale yellow in color, without any lumps, flocs or particles.
Thoroughly discard any Enbrel solution that has not been injected within 6 hours.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Enbrel contains
The active substance of Enbrel is etanercept. Each vial of Enbrel 25 mg contains 25 mg of etanercept.
The other excipients are:
Powder: Mannitol (E421), sucrose and trometamol
Solvent: Water for injections
What Enbrel looks like and contents of the pack
Enbrel 25 mg is supplied as a white powder and solvent for solution for injection. Each pack contains 4 single-dose vials, 4 pre-filled syringes of water for injections and 8 alcohol swabs.
Not all pack sizes may be marketed.
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
ENBREL 25 MG / ML
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 25 mg of etanercept. After reconstitution, the solution contains 25 mg / ml of etanercept.
Etanercept is a fusion protein of the human tumor necrosis factor receptor p75 with Fc, obtained by recombinant DNA techniques through a mammalian expression system in Chinese Hamster Ovary (CHO) cells. Etanercept is a dimer of a chimeric protein. genetically prepared by fusion of the extracellular domain of the human tumor necrosis factor receptor-2 (TNFR2 / p75) responsible for binding to the ligand, with the Fc fraction of human IgG1 immunoglobulin. This Fc fraction contains the hinge region, the CH2 and CH3 regions but not the CH1 region of IgG1. Etanercept contains 934 amino acids and has an apparent molecular weight of approximately 150 kilodalton.
The specific activity of etanercept is 1.7 x 106 units / mg.
The solution contains 9 mg / ml benzyl alcohol as a preservative (see section 4.4). For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder and solvent for solution for injection (powder for injection).
The powder is white. The solvent is a clear, colorless liquid.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Juvenile idiopathic arthritis
Treatment of polyarthritis (rheumatoid factor positive or negative) "and" extensive oligoarthritis in children and adolescents from 2 years of age who have shown an inadequate response, or who have been found to be intolerant, to methotrexate.
Treatment of psoriatic arthritis in adolescents from 12 years of age who have shown an inadequate response, or who have been found to be intolerant, to methotrexate.
Treatment of enthesitis-related arthritis in adolescents from 12 years of age who have shown an inadequate response, or who have been found to be intolerant, to conventional therapy.
Enbrel has not been studied in children less than 2 years of age.
Pediatric plaque psoriasis
Treatment of severe chronic plaque psoriasis in children and adolescents from 6 years of age who are not adequately controlled by other systemic therapies or phototherapies or who are intolerant to them.
04.2 Posology and method of administration
Treatment with Enbrel should be initiated and supervised by a specialist doctor who has experience in the diagnosis and treatment of juvenile idiopathic arthritis or pediatric plaque psoriasis.
Patients treated with Enbrel must be provided with the Patient Alert Card.
Each vial of Enbrel 25 mg / ml should be used for a maximum of 2 doses administered to the same patient.
Dosage
Special populations
Renal and hepatic insufficiency
No dosage adjustment is necessary.
Pediatric population
Juvenile idiopathic arthritis
The recommended dose is 0.4 mg / kg (up to a maximum of 25 mg per dose), administered twice weekly by subcutaneous injection with an interval of 3-4 days between doses or 0.8 mg / kg ( up to a maximum of 50 mg per dose) administered once a week. In patients who show no response after 4 months of treatment, treatment discontinuation should be considered.
Children with juvenile idiopathic arthritis weighing less than 25 kg may be more appropriate to administer the 10 mg strength vial.
No clinical studies have been performed in children aged 2 to 3 years. However, the limited safety data from a patient registry indicates that the safety profile in children aged 2-3 years is similar to that observed in adults and children aged 4 years and older when the product is administered weekly. with a dosage of 0.8 mg / kg subcutaneously (see section 5.1).
Enbrel is generally not suitable for children under 2 years of age for the Juvenile Idiopathic Arthritis indication.
Pediatric plaque psoriasis (from 6 years of age)
The recommended dose is 0.8 mg / kg (up to a maximum of 50 mg per dose) once weekly for up to 24 weeks. Treatment should be discontinued in patients who show no response after 12 weeks.
In the event that treatment with Enbrel is again indicated, the instructions on duration of treatment above should be followed. The dose should be 0.8 mg / kg (up to a maximum of 50 mg per dose) once weekly.
Enbrel is generally not suitable for children under 6 years of age for the plaque psoriasis indication.
Method of administration
Enbrel is administered by subcutaneous injection (see section 6.6).
Detailed instructions for the preparation, administration and re-use of the reconstituted Enbrel vial are provided in the package leaflet, section 7, "Instructions for preparing and administering an" injection of Enbrel "
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Sepsis or risk of sepsis.
Enbrel treatment should not be initiated in patients with active infection, including chronic or localized infections.
Enbrel must not be given to premature babies or newborns as the solvent contains benzyl alcohol.
04.4 Special warnings and appropriate precautions for use
Infections
Patients should be tested for infections before, during and after treatment with Enbrel, considering that the mean half-life of etanercept is approximately 70 hours (range 7 to 300 hours).
Serious infections, sepsis, tuberculosis and other opportunistic infections, including invasive fungal infections, listeriosis and legionellosis, have been reported with the use of Enbrel (see section 4.8).
These infections were due to bacteria, mycobacteria, fungi, viruses and parasites (including protozoa). In some cases, particular fungi or other opportunistic infections were not recognized, causing delay in appropriate treatment and in some cases death. When examining patients for infections, the patient's risk of relevant opportunistic infections (eg exposure to endemic mycosis) must be considered.
Patients who develop a new infection while on treatment with Enbrel should be closely monitored. If the patient develops a severe infection, administration of Enbrel should be discontinued. The safety and efficacy of Enbrel in patients with chronic infections have not been evaluated. Physicians should be cautious when evaluating the use of Enbrel in patients with a history of recurrent or chronic infections, or with underlying conditions that may predispose patients to infection, as well as with advanced or poorly controlled diabetes.
Tuberculosis
Cases of active tuberculosis including miliary tuberculosis and tuberculosis with extra-pulmonary localization have been reported in patients treated with Enbrel.
Before starting treatment with Enbrel, all patients must be tested for active and inactive ("latent") tuberculosis. This evaluation should include a detailed medical history including personal history of tuberculosis or possible previous contacts with tuberculosis and previous and / or current immunosuppressive therapy. Appropriate screening tests, for example tuberculin skin test and chest X-rays, should be performed on all patients (local recommendations may apply). It is recommended to record these tests on the patient alert card. Doctors are reminded of the risk of a false negative tuberculin skin test, especially in seriously ill or immunocompromised patients.
If active tuberculosis is diagnosed, Enbrel therapy must not be initiated. If inactive ("latent") tuberculosis is diagnosed, treatment for latent tuberculosis should be started with anti-tuberculosis therapy before starting Enbrel therapy and according to local regulations.
In this situation, the risk / benefit balance with Enbrel treatment must be carefully considered.
All patients should be advised to seek medical attention if signs / symptoms suggestive of tuberculosis (e.g. persistent cough, wasting / weight loss, low-grade fever) appear during or after treatment with Enbrel.
Reactivation of the hepatitis B virus
Reactivation of hepatitis B virus (HBV) has been reported in chronic carriers of this virus who receive anti-TNFs such as Enbrel. Patients at risk of HBV infection should undergo preliminary testing for HBV infection before begin therapy with Enbrel.
Particular caution should be exercised when administering Enbrel to patients with HBV. If Enbrel is used in HBV carriers, patients should be monitored for signs and symptoms of active HBV infection and appropriate treatment initiated if necessary.
Worsening of hepatitis C
Worsening of hepatitis C has been reported in patients treated with Enbrel. Enbrel should be used with caution in patients with a history of hepatitis C.
Simultaneous treatment with anakinra
Co-administration of Enbrel and anakinra was associated with an increased risk of serious infections and neutropenia compared with the use of Enbrel alone. This combination did not demonstrate an increase in clinical benefit. Therefore, the combined use of Enbrel and anakinra did not. is recommended (see sections 4.5 and 4.8).
Simultaneous treatment with abatacept
In clinical studies, concomitant treatment with abatacept and Enbrel resulted in an increased incidence of serious adverse events. This combination did not demonstrate an increase in clinical benefit; therefore use is not recommended (see section 4.5).
Allergic reactions
Allergic reactions associated with Enbrel administration have been commonly reported.
Allergic reactions included angioedema and urticaria; there have been severe reactions. If any severe allergic or anaphylactic reaction occurs, therapy with Enbrel should be stopped immediately and appropriate therapy initiated.
Immunosuppression
The possibility exists that TNF antagonists, including Enbrel, affect the host's defenses against infections and malignancies, as TNF mediates inflammation and modulates cellular immune responses. In a study of 49 adult rheumatoid arthritis patients treated with Enbrel, there was no evidence of depression of delayed-type hypersensitivity, decreased immunoglobulin levels, or changes in the number of effector cell populations.
Two juvenile idiopathic arthritis patients developed chickenpox infection and signs and symptoms of aseptic meningitis, which resolved without sequelae. Patients with significant exposure to varicella virus should temporarily discontinue Enbrel therapy and prophylactic treatment with varicella zoster immunoglobulin should be considered.
The safety and efficacy of Enbrel in patients with immunosuppression have not been evaluated.
Lymphoproliferative disorders and malignant tumors
Solid and hematopoietic malignancies (excluding skin cancers)
The development of malignancies (including breast and lung cancer and lymphoma) has been reported in the post-marketing period (see section 4.8).
In clinical trials with anti-TNF drugs with control group, more cases of lymphoma were observed in patients receiving an anti-TNF drug than in the control group. However, cases were rare and the observation period for placebo-treated patients was shorter than for TNF-treated patients. Since marketing, cases of leukemia have been reported in patients treated with anti-TNF drugs. There is an increased underlying risk of lymphoma and leukemia in rheumatoid arthritis patients with long-lasting and severely active inflammatory disease, which complicates risk estimation.
Based on current knowledge, the development of lymphomas, leukemias or other solid or hematopoietic malignancies in patients treated with anti-TNF drugs cannot be excluded. Caution should be used when considering anti-TNF drug therapy in patients with a history of malignancy or continuation of therapy in patients who develop malignancy.
Malignant tumors, sometimes fatal, have been reported in children, adolescents and young adults (up to 22 years of age) treated with anti-TNF drugs (initiation of therapy
Skin tumors
Melanomas and non-melanoma skin cancers (NMSCs) have been reported in patients treated with TNF antagonists, including Enbrel. Cases of Merkel cell carcinoma in patients treated with Enbrel have been reported very rarely in post-marketing experience. Periodic skin examinations are recommended for all patients, particularly those with risk factors for developing skin cancers.
Combining results from controlled clinical trials, more cases of NMSC were observed in patients treated with Enbrel than in control patients, particularly in patients with psoriasis.
Vaccinations
Live vaccines should not be given concurrently with Enbrel. There are no data on secondary transmission of infection from live vaccines in patients receiving Enbrel. In a randomized, double-blind, placebo-controlled clinical trial in adult psoriatic arthritis patients, 184 patients also received a pneumococcal multivalent polysaccharide vaccine at week 4. In this study, the majority of psoriatic arthritis patients receiving Enbrel were capable of producing an effective B-cell immune response to the pneumococcal polysaccharide vaccine, but the titer in the pool was moderately lower and few patients showed a double increase in titer compared to patients not receiving Enbrel. The clinical significance of this is unknown. .
Formation of autoantibodies
Treatment with Enbrel may cause the formation of autoimmune antibodies (see section 4.8).
Hematological reactions
Rare cases of pancytopenia and very rare cases of aplastic anemia, some with fatal outcome, have been reported in patients treated with Enbrel. Caution should be exercised in patients treated with Enbrel who have a "history of blood dyscrasias. All patients and parents / healthcare professionals should be advised that if the patient develops signs and symptoms indicative of blood dyscrasias or infections (eg persistent fever, sore throat, bruising, bleeding, paleness) while taking Enbrel, should seek immediate medical attention.Such patients should be seen immediately, including a complete blood count; if blood dyscrasias are confirmed, treatment with Enbrel should be stopped.
Neurological pathologies
There are rare reports of CNS demyelinating diseases in patients treated with Enbrel (see section 4.8). In addition, there have been very rare reports of peripheral demyelinating polyneuropathies (including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy).
Although no clinical studies have been performed to evaluate Enbrel therapy in multiple sclerosis patients, clinical studies in multiple sclerosis patients treated with other TNF antagonists have shown increased disease activity.
Careful benefit / risk assessment, including a neurological assessment, is recommended when prescribing Enbrel to patients with pre-existing or recent onset demyelinating disease, or for those patients who are considered to be at high risk of developing demyelinating disease.
Combined therapy
In a two-year controlled clinical study in adult patients with rheumatoid arthritis, the combination of Enbrel and methotrexate did not yield unexpected safety results and the safety profile of Enbrel when given in combination with methotrexate was similar to that of profile in studies of Enbrel and methotrexate given alone. Long-term studies aimed at combination therapy are ongoing.
The long-term safety of Enbrel in combination with other disease-modifying antirheumatic drugs (DMARDs) has not been evaluated.
In the treatment of psoriasis, the use of Enbrel in combination with other systemic therapies or phototherapy has not been studied.
Renal and hepatic insufficiency
Based on pharmacokinetic data (see section 5.2) no dose modification is required in patients with renal or hepatic impairment; clinical data on such patients are limited.
Congestive heart failure
Physicians should be cautious when using Enbrel in patients with congestive heart failure (Congestive Heart Failure, CHF). There are post-marketing reports of worsening of CHF, with and without identifiable precipitating factors, in patients treated with Enbrel. Two large clinical trials evaluating the use of Enbrel in the treatment of CHF were stopped early due to lack of efficacy. Although inconclusive, some data from one of these studies suggest a possible trend towards worsening of CHF in those patients assigned to treatment. with Enbrel.
Alcoholic Hepatitis
In a randomized, placebo-controlled phase II study involving 48 hospitalized patients treated with Enbrel or placebo for moderate to severe alcoholic hepatitis, Enbrel was not effective and, after 6 months, the death rate of patients treated with Enbrel was significantly higher.
Consequently, Enbrel should not be used in patients for the treatment of alcoholic hepatitis. Physicians should be cautious when using Enbrel in patients with moderate to severe alcoholic hepatitis.
Wegener's granulomatosis
In a placebo-controlled study, in which 89 adult patients were treated with Enbrel in addition to standard therapy (which included cyclophosphamide or methotrexate and glucocorticoids) for a mean duration of 25 months, Enbrel was not found to be an effective treatment for granulomatosis. by Wegener. The incidence of non-cutaneous malignancies of various types was significantly higher in patients treated with Enbrel than in the control group. Enbrel is not recommended for the treatment of Wegener's granulomatosis.
Hypoglycemia in patients being treated for diabetes
Following initiation of Enbrel therapy in patients receiving diabetes medicines, there have been reports of hypoglycaemia requiring reduction of the anti-diabetes medicine in some of these patients.
Special populations
Elderly patients (≥ 65 years old)
In the phase 3 studies in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, overall there were no differences in the occurrence of adverse events, serious adverse events and serious infections between patients aged 65 years and older and younger patients. However, elderly patients should be treated with caution and particular attention should be paid to the occurrence of infections.
Pediatric population
Vaccinations
It is recommended that pediatric patients, prior to initiating therapy with Enbrel, have, if possible, completed all immunizations in accordance with current immunization guidelines (see Vaccinations above).
Inflammatory bowel disease (Inflammatory bowel disease, IBD) and uveitis in patients with juvenile idiopathic arthritis (Juvenile Idiopathic Arthritis, JIA)
Cases of IBD and uveitis have been reported in JIA patients treated with Enbrel (see section 4.8).
Benzyl alcohol
Enbrel contains the excipient benzyl alcohol, which may cause toxic and anaphylactoid reactions in infants and children up to 3 years of age and should not be given to premature babies or newborns.
04.5 Interactions with other medicinal products and other forms of interaction
Simultaneous treatment with anakinra
A higher incidence of serious infections was observed in adult patients treated with Enbrel and anakinra than in patients treated separately with either Enbrel or anakinra (historical data).In addition, in a double-blind placebo-controlled clinical study in adult patients already receiving methotrexate, patients treated with Enbrel and anakinra had a higher incidence of serious infections (7%) and neutropenia than patients treated with Enbrel ( see sections 4.4 and 4.8). The combination of Enbrel and anakinra has not shown increased clinical benefit and is therefore not recommended.
Simultaneous treatment with abatacept
In clinical studies, concomitant treatment with abatacept and Enbrel resulted in an increased incidence of serious adverse events. This combination did not demonstrate an increase in clinical benefit; therefore use is not recommended (see section 4.4).
Simultaneous treatment with sulfasalazine
In a clinical study in adult patients receiving established doses of sulfasalazine, to which Enbrel was added, patients in the combination group showed a statistically significant decrease in mean white blood cell count compared to the groups treated with Enbrel alone or with sulfasalazine only The clinical significance of this interaction is unknown Physicians should be cautious when considering combination therapy with sulfasalazine.
Not interactions
During clinical trials, no interactions were observed when Enbrel was administered with glucocorticoids, salicylates (except sulfasalazine), non-steroidal anti-inflammatory drugs (NSAIDs), analgesics or methotrexate. See section 4.4 for vaccination warnings.
No significant pharmacokinetic drug-drug interactions were observed in studies with methotrexate, digoxin or warfarin.
04.6 Pregnancy and lactation
Women of childbearing age
Women of childbearing potential should be advised of the need to use appropriate contraceptive measures to avoid becoming pregnant during and up to three weeks after stopping treatment with Enbrel.
Pregnancy
Developmental toxicity studies in rats and rabbits revealed no evidence of harm due to etanercept to the fetus or newborn rat. There are no studies with Enbrel in pregnant women.
Therefore Enbrel is not recommended during pregnancy.
Feeding time
Following subcutaneous administration, excretion of etanercept in human milk has been reported. In lactating rats, following subcutaneous administration, etanercept was excreted in milk and recovered in the serum of pups.
Since immunoglobulins, like many other medicinal products, may be secreted into breast milk, a decision must be made whether to discontinue breast-feeding or to discontinue Enbrel therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. .
Fertility
There are no preclinical data on the peri- and postnatal toxicity of etanercept and on the effects of etanercept on fertility and overall reproductive performance.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
04.8 Undesirable effects
Summary of the safety profile
Pediatric population
Undesirable effects in pediatric patients with juvenile idiopathic arthritis
Generally, adverse events in pediatric patients with juvenile idiopathic arthritis were similar in frequency and type to those seen in adult patients (see below Undesirable effects in adults). Differences from adults and other special considerations are discussed in the following paragraphs.
The types of infections observed during clinical trials in juvenile idiopathic arthritis patients aged 2 to 18 years were generally mild to moderate and similar to those commonly seen in an outpatient pediatric population. Serious adverse events reported included chicken pox with signs and symptoms of aseptic meningitis which resolved without sequelae (see also section 4.4), appendicitis, gastroenteritis, depression / personality changes, skin ulcer, esophagitis / gastritis, group A streptococcal septic shock, diabetes type I mellitus, soft tissue infection and surgical wound infection.
In a study of children with juvenile idiopathic arthritis aged 4 to 17 years, 43 of 69 children (62%) developed an infection while receiving Enbrel during the 3 months of the study (part 1 open label) and the frequency and the severity of infections was similar in 58 patients who completed therapy in the 12-month open label extension. The type and proportion of adverse events in juvenile idiopathic arthritis patients were similar to those seen in the Enbrel studies on adult patients with rheumatoid arthritis and were mostly mild. Many adverse events were reported more commonly in the 69 juvenile idiopathic arthritis patients taking Enbrel for 3 months compared to 349 adults with rheumatoid arthritis. These included headache (19% of patients, 1.7 events per patient / year), nausea (9%, 1.0 event per patient / year), abdominal pain (19%, 0.74 events per patient / year) no) and vomiting (13%, 0.74 events per patient / year).
Four cases of macrophage activation syndrome were reported in juvenile idiopathic arthritis clinical trials.
In post-marketing experience there have been cases of inflammatory bowel disease and uveitis in JIA patients treated with Enbrel, including a very limited number of cases with positive rechallenge (see section 4.4).
Undesirable effects in pediatric patients with plaque psoriasis
In a 48-week study involving 211 children aged 4-17 years with pediatric plaque psoriasis, the adverse events reported were similar to those seen in previous studies in adults with plaque psoriasis.
Adult population
Side effects in adults
The most commonly reported adverse reactions are injection site reactions (such as pain, swelling, itching, redness and bleeding at the injection site), infections (such as upper respiratory tract infections, bronchitis, bladder infections and skin infections ), allergic reactions, development of antibodies, itching and fever.
Serious adverse reactions have also been reported with Enbrel. TNF antagonists, such as Enbrel, affect the immune system and their use can affect the body's defenses against infections and cancer. Serious infections have been found in less than 1 in 100 patients treated with Enbrel. Reports also included cases of sepsis and infections with a fatal or life-threatening outcome. Various malignancies associated with the use of Enbrel have been reported, including breast, lung, skin and lymph gland cancers ( lymphoma).
Severe haematological, neurological and autoimmune reactions have also been reported. These reactions include the rare case reports of pancytopenia and the very rare case reports of aplastic anemia. Central and peripheral demyelination events have been reported rarely and very rarely with the use of Enbrel, respectively. There have been reports of lupus, lupus-related conditions and vasculitis.
List of adverse reactions
The following list of adverse reactions is based on experience from clinical trials in adults and post-marketing experience.
Within the system organ class, adverse reactions are listed according to frequency classes (presumed number of patients with that reaction), using the following categories: very common (≥1 / 10); common (≥1 / 100,
Infections and infestations:
Very common: Infections (including upper respiratory tract infections, bronchitis, cystitis, skin infections) *
Uncommon: Severe infections (including pneumonia, cellulitis, septic arthritis, sepsis and parasitic infections) *
Rare: Tuberculosis, opportunistic infections (including invasive fungal, protozoal, atypical bacterial and mycobacterial infections and Legionella).
Not known: Listeria, hepatitis B reactivation
Neoplasms benign, malignant and unspecified (including cysts and polyps):
Uncommon: Non-melanoma skin cancer * (see section 4.4)
Rare: Lymphoma, melanoma (see section 4.4)
Not known: Leukemia, Merkel cell carcinoma (see section 4.4)
Disorders of the blood and lymphatic system:
Uncommon: Thrombocytopenia
Rare: Anemia, leukopenia, neutropenia, pancytopenia *
Very rare: Aplastic anemia *
Disorders of the immune system:
Common: Allergic reactions (see Skin and subcutaneous tissue disorders), formation of autoantibodies *
Uncommon: Systemic vasculitis (including vasculitis associated with antineutrophil cytoplasmic antibodies)
Rare: Severe allergic and anaphylactic reactions (including angioedema and bronchospasm), sarcoidosis
Not known: Macrophage activation syndrome †
Nervous system disorders:
Rare: Convulsions,
Episodes of CNS demyelination indicative of multiple sclerosis or localized situations of demyelination such as optic neuritis and transverse myelitis (see section 4.4)
Very rare: Peripheral demyelination events, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy and multifocal motor neuropathy (see section 4.4)
Eye disorders:
Uncommon: Uveitis, scleritis
Cardiac pathologies
Rare: Worsening of congestive heart failure (see section 4.4)
Respiratory, thoracic and mediastinal disorders:
Uncommon: Interstitial lung disorders (including pneumonia and pulmonary fibrosis) *
Hepato-biliary disorders:
Rare: Elevated liver enzymes, autoimmune hepatitis
Skin and subcutaneous tissue disorders:
Common: Itching
Uncommon: Angioedema, urticaria, rash, psoriasiform rash, psoriasis (including new onset or worsening, and pustular, primarily palms and soles)
Rare: Cutaneous vasculitis (including leukocytoclastic vasculitis), Steven-Johnson syndrome, erythema multiforme
Very rare: Toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders:
Rare: Subacute cutaneous lupus erythematosus, discoid lupus erythematosus, lupus-like syndrome
General disorders and administration site conditions:
Very common: Injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling) *
Common: Fever
* see "Description of selected adverse reactions" below.
† See subsection "Undesirable effects in pediatric patients with juvenile idiopathic arthritis" above.
Description of selected adverse reactions
Malignant tumors and lymphoproliferative disorders
One hundred twenty-nine new malignancies of various types. The frequency and incidence observed in these clinical trials were similar to those expected for the population studied. A total of 2 malignancies were reported in clinical trials lasting approximately 2 years involving 240 psoriatic arthritis patients treated with Enbrel.
In clinical studies conducted for more than two years in 351 patients with ankylosing spondylitis, 6 malignancies have been reported in patients treated with Enbrel.
In a group of 2,711 plaque psoriasis patients treated with Enbrel in double-blind and open-label studies of up to 2.5 years duration, 30 malignancies and 43 non-melanoma skin cancers were reported.
18 lymphomas were reported in a group of 7,416 patients treated with Enbrel in clinical trials in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and psoriasis.
Reports of various malignancies (including breast and lung carcinoma, and lymphoma) have also been received in the post-marketing period (see section 4.4).
Reactions at the injection site
Compared to placebo, patients with rheumatic diseases treated with Enbrel had a significantly higher incidence of injection site reactions (36% versus 9%). Injection site reactions usually occurred during the first month. The mean duration ranged from approximately 3 to 5 days. Most of the injection site reactions occurring in the groups receiving Enbrel were untreated while the majority of patients receiving therapy received topical preparations such as corticosteroids. In addition, some patients have developed injection site booster reactions characterized by a skin reaction at the most recent injection site, along with a simultaneous appearance of injection site reactions from previous injection sites. Usually, these reactions were transient and did not recur during treatment.
During the first 12 weeks of treatment in controlled clinical trials in patients with plaque psoriasis, approximately 13.6% of patients treated with Enbrel developed injection site reactions compared with 3.4% of patients treated with placebo.
Severe infections
In placebo-controlled studies, no increase in the incidence of serious infections (fatal, life-threatening or requiring hospitalization or intravenous antibiotics) was observed.
Serious infections occurred in 6.3% of rheumatoid arthritis patients treated with Enbrel for up to 48 months. These include abscess (at various sites), bacteremia, bronchitis, bursitis, cellulitis, cholecystitis, diarrhea, diverticulitis, endocarditis (suspected), gastroenteritis, hepatitis B herpes zoster, leg ulcer, mouth infection, osteomyelitis, otitis peritonitis, pneumonia, pyelonephritis, sepsis, septic arthritis, sinusitis, skin infections, skin ulcer, urinary tract infection, vasculitis and wound infection. In the two-year active-controlled clinical study where patients were treated with Enbrel alone or with methotrexate alone or with Enbrel in combination with methotrexate the rate of serious infections was similar between the treated groups. However, it cannot be excluded that the combination of Enbrel with methotrexate could be associated with an increased rate of infections.
There were no differences in the incidence of infections between patients treated with Enbrel and those treated with placebo for plaque psoriasis in placebo-controlled clinical trials of up to 24 weeks duration. Serious infections including cellulitis, gastroenteritis, pneumonia, were reported. cholecystitis, osteomyelitis, gastritis, appendicitis, streptococcal fasciitis, myositis, septic shock, diverticulitis and abscesses in patients treated with Enbrel. In the double-blind and open-label psoriatic arthritis studies, 1 patient reported a severe infection (pneumonia).
Serious and fatal infections have been reported during use of Enbrel; pathogens found include bacteria, mycobacteria (including tuberculosis), viruses and fungi. Some have occurred within a few weeks of initiating treatment with Enbrel in patients who had conditions underlying predisposers (e.g. diabetes, congestive heart failure, history of current or chronic infections) in addition to their rheumatoid arthritis (see section 4.4). Treatment with Enbrel may increase mortality in patients with diagnosed sepsis.
Opportunistic infections have been reported in association with Enbrel including invasive fungal, parasitic (including protozoal) and bacterial (including Listeria And Legionella) and atypical mycobacteria. In a dataset from clinical trials, the overall incidence of opportunistic infections was 0.09% for 15,402 subjects who received Enbrel. The exposure-adjusted rate was 0.06 events per 100 patients. -year. In postmarketing experience, approximately half of all cases of global opportunistic infections were invasive fungal infections. The most commonly reported invasive fungal infections were from
Pneumocystis And Aspergillus. Invasive fungal infections account for more than half of fatal events in patients who have developed opportunistic infections. Most of the cases with a fatal outcome were in patients with pneumonia Pneumocystis, nonspecific systemic fungal infections and aspergillosis (see section 4.4).
Autoantibodies
Serum samples from adult patients were tested for autoantibodies at various time points. Among rheumatoid arthritis patients tested for antinuclear antibodies (ANA), the proportion of patients who developed a new positivity to ANA (≥1: 40) was higher among patients treated with Enbrel (11%) compared to patients treated with placebo (5%). The percentage of patients who developed a new positive DNA-double helix antibody was even higher by radioimmunoassay (15% of patients treated with Enbrel versus 4% of patients treated with placebo) and by the test Crithidia luciliae (3% of Enbrel-treated patients compared to none of the placebo-treated patients). The percentage of Enbrel-treated patients who developed anticardiolipin antibodies increased similar to that seen in placebo-treated patients. The impact of long-term treatment with Enbrel on the development of autoimmune diseases is unknown.
Development of other autoantibodies in association with a lupus-like syndrome or clinically and biopsically compatible skin reactions with subacute cutaneous lupus or lupus has rarely been reported in some patients, including those with rheumatoid factor positive. discoid.
Pancytopenia and aplastic anemia
There have been post-marketing reports of pancytopenia and aplastic anemia, some of which were fatal (see section 4.4).
Interstitial lung diseases
There have been post-marketing reports of interstitial lung disease (including pneumonia and pulmonary fibrosis) some of which have been fatal.
Simultaneous treatment with anakinra
In studies where adult patients were treated concurrently with Enbrel plus anakinra, a "higher incidence of serious infections was observed than with Enbrel alone, and 2% of patients (3/139) developed neutropenia (absolute neutrophil count 3) One neutropenic patient developed cellulitis which resolved after hospitalization (see sections 4.4 and 4.5).
Pediatric population
See above, Summary of the safety profile.
04.9 Overdose
No borderline toxicity doses were observed in clinical trials in rheumatoid arthritis patients. The highest dose evaluated was an intravenous loading dose of 32 mg / m2 followed by a subcutaneous dose of 16 mg / m2 administered twice weekly. One rheumatoid arthritis patient mistakenly self-administered 62 mg of Enbrel subcutaneously twice a week for 3 weeks, without experiencing side effects. The antidote for Enbrel is unknown.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, Tumor Necrosis Factor α (TNF- α) inhibitors.
ATC code: L04AB01.
Tumor necrosis factor (TNF) is a predominant cytokine in the inflammatory process of rheumatoid arthritis. Elevated levels of TNF have also been found in the synovium and psoriatic plaques of patients with psoriatic arthritis and in the serum and synovial tissue of patients with spondylitis. Ankylosing In plaque psoriasis, infiltration of inflammatory cells, including T cells, leads to an increase in TNF levels in psoriatic lesions relative to levels in unaffected skin. Etanercept is a competitive inhibitor of the binding of TNF to its cell surface receptors and therefore inhibits the biological activity of TNF.
TNF and lymphotoxin are pro-inflammatory cytokines that bind to two distinct cell surface receptors: the 55 kilodalton (p55) and 75 kilodalton (p75) tumor necrosis factor (TNFR) receptors. Both TNFRs naturally exist in membrane-bound and soluble forms.
TNFRs in the soluble form are thought to regulate the biological activity of TNF.
TNF and lymphotoxin predominantly exist as homotrimers with their biological activity dependent on cross-linking to cell surface TNFRs. Soluble dimeric receptors, such as etanercept, have a higher binding affinity for TNF than monomeric receptors and are significantly more potent competitive inhibitors of TNF binding to its cellular receptors.
Furthermore, the use of an immunoglobulin Fc region as a fusion element in the construction of a dimeric receptor confers a longer plasma half-life.
Mechanism of action
Most of the joint disease in rheumatoid arthritis and ankylosing spondylitis and skin disease in plaque psoriasis is mediated by pro-inflammatory molecules that are linked in a TNF-controlled network. etanercept consists of a competitive inhibition of TNF binding to TNFR surface receptors, which prevents TNF-mediated cellular responses by rendering TNF biologically inactive. Etanercept can also modulate biological responses controlled by additional cascade molecules (eg cytokines, molecules adhesion or proteinase) which are induced or regulated by TNF.
Clinical efficacy and safety
This section presents data from three studies in juvenile idiopathic arthritis, one study in pediatric patients with plaque psoriasis, four studies in adults with rheumatoid arthritis and four studies in adults with plaque psoriasis.
Pediatric population
Juvenile idiopathic arthritis
The safety and efficacy of Enbrel were evaluated in a two-part study involving 69 children with polyarticular course juvenile idiopathic arthritis who had different types of juvenile idiopathic arthritis onset (polyarthritis, paucyarthritis, systemic onset). Patients aged between 4 and 17 years with moderate to severe polyarticular juvenile idiopathic arthritis in the active phase, refractory or intolerant to methotrexate, were enrolled; patients remained on a stable dose of a single non-steroidal anti-inflammatory drug and / or prednisone (active joints, limitation of movement, overall physician and patient / parent assessment, functional assessment and erythrocyte sedimentation rate (ESR). disease was defined as ≥ 30% worsening in three of six JRA core criteria, ≥ 30% improvement in no more than one of six JRA core criteria, and a minimum of two active joints.
In Part 1 of the study, 51 of 69 (74%) patients experienced a clinical response and entered Part 2. In Part 2, 6 of 25 (24%) patients continuing on Enbrel experienced disease flare, versus 20 patients of 26 (77%) receiving placebo (p = 0.007).
From the start of Part 2, the median time to exacerbation was ≥ 116 days for patients receiving Enbrel and 28 days for patients receiving placebo. 2 of the study, some of those who stayed on Enbrel continued to improve from month 3 to month 7, while those who received placebo did not improve.
In an open-label extension safety study, 58 pediatric patients from the previous study (from the age of 4 to the time of enrollment) continued to receive Enbrel for up to 10 years. The rates of serious adverse events and serious infections did not increase with long-term exposure.
The long-term safety of Enbrel monotherapy (n = 103), Enbrel with methotrexate (n = 294) or methotrexate monotherapy (n = 197) was evaluated for up to 3 years in a registry of 594 children aged between 2 and 18 years with juvenile idiopathic arthritis, 39 of whom were 2 to 3 years of age. Overall, infections were reported more commonly in patients treated with etanercept than in those treated with methotrexate alone (3.8 versus 2%), and infections associated with etanercept use were more severe.
In another single-arm, open-label study, 60 patients with extensive oligoarthritis (15 patients aged 2-4 years, 23 patients aged 5 to 11 years and 22 patients aged 12 to 17 years), 38 patients with related arthritis enthesitis (12-17 years of age) and 29 psoriatic arthritis patients (12-17 years of age) were treated with Enbrel at a dose of 0.8 mg / kg (up to a maximum of 50 mg per dose), administered weekly for 12 weeks. In each of the JIA subtypes, the majority of patients met ACR Pedi 30 criteria and demonstrated clinical improvement in secondary endpoints such as number of tender joints and overall physician assessment. The safety profile was consistent with that observed in other JIA studies.
No studies have been conducted in patients with juvenile idiopathic arthritis to evaluate the effects of continuous therapy with Enbrel in patients who did not respond within three months of starting therapy.
Similarly, no studies have been conducted to evaluate the effects of stopping or reducing the recommended dose of Enbrel after its long-term use in patients with JIA.
Pediatric patients with plaque psoriasis
The efficacy of Enbrel was evaluated in a randomized, double-blind, placebo-controlled study of 211 pediatric patients aged 4-17 years with moderate to severe plaque psoriasis (defined by an sPGA score ≥ 3, involving 10% or more of BSA, and PASI ≥ 12) Eligible patients had a history of treatment with phototherapy or systemic therapy or were inadequately controlled by topical therapy.
Patients received Enbrel 0.8 mg / kg (up to 50 mg) or placebo once weekly for 12 weeks. At week 12, more patients had positive efficacy responses (i.e. PASI 75) in the Enbrel randomized group compared to the placebo randomized group.
Abbreviations: sPGA-static Physician Global Assessment.
on p
After the 12-week double-blind treatment period, all patients received Enbrel 0.8 mg / kg (up to 50 mg) once weekly for an additional 24 weeks. The responses observed during the open label period were similar to those observed in the double-blind period.
During a randomized withdrawal period, the number of patients who had disease relapse (loss of response PASI 75) was significantly greater in the patient group re-randomized to placebo than in the group of patients re-randomized to Enbrel. . With continued therapy, responses were maintained for up to 48 weeks.
The long-term safety and efficacy of Enbrel 0.8 mg / kg (up to a maximum of 50 mg) once weekly was evaluated in an open-label extension study involving 181 pediatric patients with plaque psoriasis by administering the produced for up to 2 years beyond the 48 weeks noted above. Long-term experience with Enbrel was generally comparable to that seen in the original 48-week study and no new safety concerns emerged.
Adult patients with rheumatoid arthritis
The efficacy of Enbrel was evaluated in a randomized, double-blind, placebo-controlled study.
The study evaluated 234 adult patients with active rheumatoid arthritis who had failed to respond to therapy with at least one, but no more than four disease-modifying antirheumatic drugs (DMARDs). Doses of 10 mg or 25 mg of Enbrel or placebo were administered subcutaneously twice weekly for 6 consecutive months. The results of this controlled clinical trial were expressed as a percentage of improvement in rheumatoid arthritis using the American College of Rheumatology (ACR) response criterion.
ACR 20 and 50 responses were greater in patients treated with Enbrel at 3 and 6 months than in patients treated with placebo (ACR 20: Enbrel 62% and 59%, placebo 23% and 11% at three and 6 months, respectively : ACR 50: Enbrel 41% and 40%, placebo 8% and 5% at three and six months respectively; p
Approximately 15% of patients who received Enbrel achieved an ACR 70 response at month 3 and month 6, compared with less than 5% of subjects in the placebo arm. Among patients who received Enbrel, clinical responses were generally observed between 1 and 2 weeks after initiation of therapy and nearly all occurred within 3 months. A dose response was observed: results obtained with 10 mg are intermediate states between placebo and 25 mg. Enbrel was significantly better than placebo in all parameters of the ACR criteria, as well as in other assessments of rheumatoid arthritis disease activity not included in the ACR response criteria such as, for example, morning stiffness. A Health Assessment Questionnaire (HAQ) was administered every 3 months during the study, which included disability, vitality, mental health, general health conditions and sub-domains regarding arthritis-related health conditions All HAQ sub-domains improved in Enbrel-treated patients compared to controls at 3 and 6 months.
After stopping Enbrel, arthritis symptoms usually return within one month.
Resuming treatment with Enbrel after an interruption of up to 24 months results in the same magnitude of responses as patients who received Enbrel without interruption of therapy based on the results of the open-label studies. Durable responses persisted for up to 48 months were observed in the extension of therapy in open-label clinical trials when patients received Enbrel without interruption; longer-term experiences are not available.
The efficacy of Enbrel was compared with methotrexate in a third, randomized, active-controlled study with blinded radiographic evaluation as a primary objective in 632 adult patients with active rheumatoid arthritis (present since
In this study, structural joint damage was assessed by radiographic method and expressed as a change in the Total Sharp Score (TSS) which includes the rate of erosion and the rate of joint space reduction (JSN).
Radiographs of hands / wrists and feet were read at study initiation and at 6, 12 and 24 months. The 10 mg dose of Enbrel had a consistently less effect on structural damage than the 25 mg dose. 25 mg of Enbrel had a significantly greater effect on the erosion rate at both 12 and 24 months compared to methotrexate.The differences in TSS and JSN were not statistically significant between methotrexate and Enbrel 25 mg.
In a further randomized double-blind, active-controlled clinical trial, clinical efficacy, safety and radiographic progression in patients with rheumatoid arthritis treated with Enbrel alone (25 mg twice weekly), with methotrexate alone (from 7 , 5 to 20 mg per week, mean dose 20 mg) and with the combination of Enbrel and methotrexate, started at the same time, were compared in 682 adult patients with active rheumatoid arthritis from 6 months to 20 years (mean 5 years) who had shown an inadequate response to at least one disease-modifying antirheumatic drug (DMARD) other than methotrexate.
Patients in the Enbrel in combination with methotrexate therapy group had significantly higher ACR 20, ACR 50, ACR 70 response and improvement in DAS and HAQ scores at both 24 and 52 weeks compared to patients in both groups treated in monotherapy (the results are shown in the table below). Significant benefits were also observed after 24 months for Enbrel in combination with methotrexate compared to Enbrel alone and methotrexate alone.
Radiographic progression at 12 months was significantly lower in the Enbrel group than in the methotrexate group, while the combination of the two was significantly better than both monotherapies in slowing radiographic progression.
Significant benefits were also observed after 24 months for Enbrel in combination with methotrexate compared to Enbrel alone and methotrexate alone. Similarly, significant advantages for Enbrel alone over methotrexate alone were seen after 24 months.
In an analysis in which all patients who dropped out of the study for any reason were considered to have had radiological progression, the percentage of patients without progression (TSS change ≤ 0.5) at 24 months was higher in group treated with Enbrel in combination with methotrexate versus the group treated with Enbrel alone and with methotrexate alone (62%, 50%, and 36%, respectively; p
The safety and efficacy of Enbrel 50 mg (two 25 mg SC injections) administered once weekly were evaluated in a double-blind controlled study of 420 patients with active rheumatoid arthritis. In this study, 53 patients received placebo. , 214 patients received Enbrel 50 mg once weekly and 153 patients received Enbrel 25 mg twice weekly. The safety and efficacy profile of the two Enbrel treatment regimens were comparable at week 8, for their effects on the signs and symptoms of rheumatoid arthritis; data at week 16 did not show comparability (non-inferiority) between the two regimens.
Adult patients with plaque psoriasis
The use of Enbrel in patients is recommended as described in section 4.1.In the population studied, patients who "did not respond to" were defined by insufficient response (PASIPGA less than good), or disease worsening during treatment and who had been adequately treated for a period of time long enough to evaluate. the response to at least each of the three main systemic therapies according to availability.
The efficacy of Enbrel against other systemic therapies in patients with moderate to severe psoriasis (responsive to other systemic therapies) has not been evaluated in direct comparative studies between Enbrel and other systemic therapies. Instead, the safety and efficacy of Enbrel were evaluated in four randomized, double-blind, placebo-controlled trials.
The primary efficacy endpoint in all four studies was the proportion of patients in each treatment group who achieved PASI 75 at week 12 (i.e. an improvement of at least 75% from baseline in Psoriasis Area score and Severity Index [PASI]).
Study 1 was a Phase 2 study in patients ≥ 18 years of age with active but clinically stable plaque psoriasis affecting a "body surface area of ≥ 10%. One hundred twelve patients were randomized to receive a 25 mg dose. Enbrel (n = 57) or placebo (n = 55) twice weekly for 24 weeks.
Study 2 evaluated 652 patients with chronic plaque psoriasis using the same inclusion criteria as study 1 with the addition of a Psoriasis Area and Severity Index (PASI) of at least 10 at screening. Enbrel was administered at a dosage of 25 mg. once weekly, 25 mg twice weekly or 50 mg twice weekly for 6 consecutive months. During the first 12 weeks of the double-blind treatment period, patients received placebo or one of the three strengths of Enbrel mentioned above. After 12 weeks of treatment, patients in the placebo group started treatment with blinded Enbrel (25 mg twice weekly); patients in the active treatment groups continued through week 24 with the dosage they were at. were originally randomized.
Study 3 evaluated 583 patients and had the same inclusion criteria as study 2. Patients in this study received either 25 mg or 50 mg of Enbrel or placebo twice weekly for 12 weeks, after which all patients received 25 mg of open-label Enbrel twice a week for an additional 24 weeks.
Study 4 evaluated 142 patients and had similar inclusion criteria as study 2 and 3.
Patients in this study received either Enbrel 50 mg or placebo once weekly for 12 weeks, after which all patients received open-label Enbrel 50 mg once weekly for an additional 12 weeks.
In study 1, the Enbrel group had a significantly higher proportion of patients with a PASI 75 response at week 12 (30%) than the placebo group (2%) (p
Responses of Patients with Psoriasis in Studies 2, 3 and 4
* p ≤ 0.0001 compared to placebo
to. No statistical comparisons to placebo were made at week 24 in studies 2 and 4 as the original placebo group started receiving Enbrel 25 mg biweekly or 50 mg once weekly from week 13 to week 24.
b. Dermatologist Static Global Assessment. "Clear" or "Almost clear" defined as 0 or 1 on a scale of 0 to 5.
Among patients with plaque psoriasis who received Enbrel, significant responses compared to placebo were evident at the time of the first visit (2 weeks) and were maintained for 24 weeks of therapy.
Study 2 also included a treatment withdrawal period during which patients who achieved a PASI improvement of at least 50% at week 24 stopped treatment.
During the withdrawal period, patients were monitored for the occurrence of "rebound" events (PASI ≥150% of baseline) and for the time to relapse (defined as a loss of at least half of the improvement achieved between baseline and week 24). During the withdrawal period, psoriasis symptoms gradually recurred with a median time to relapse of 3 months. No rebound relapses and no psoriasis-related serious adverse events were observed. There was some evidence to support the benefit of new treatment with Enbrel in patients who were initially responsive to treatment.
In study 3, the majority of patients (77%) who were initially randomized to 50 mg twice weekly and who received a reduced dose of 25 mg Enbrel twice weekly at week 12 maintained a response. PASI 75 through week 36. For patients who received 25 mg twice weekly throughout the study, PASI 75 response continued to improve between weeks 12 and 36.
In study 4, the Enbrel group had a higher proportion of patients with PASI 75 at week 12 (38%) than the placebo group (2%) (p
In an open-label long-term (up to 34 months) study in which Enbrel was administered without interruption, the clinical response was maintained and the safety was comparable to that in the short-term studies.
An analysis of clinical trial data found no disease characteristics at baseline that can assist the clinician in selecting the most appropriate dosing option (intermittent or continuous). Consequently, the choice of continuous or intermittent therapy must be based on the judgment of the physician and the individual needs of the patient.
Antibodies to Enbrel
Antibodies to etanercept were detected in the serum of some subjects treated with etanercept. These antibodies have all been non-neutralizing and are generally transient. There appears to be no correlation between antibody development and clinical response or adverse events.
During clinical studies in subjects treated with approved doses of etanercept for up to 12 months, cumulative amounts of anti-etanercept antibodies were approximately 6% in subjects with rheumatoid arthritis, 7.5% in subjects with psoriatic arthritis, 2% in subjects with alkylosing spondylitis, 7% in subjects with psoriasis, 9.7 in subjects with pediatric psoriasis and 4.8% in subjects with juvenile idiopathic arthritis.
The proportion of subjects who developed antibodies to etanercept in longer-term studies (up to 3.5 years) increases with time, as expected. However, due to their transient nature, the incidence of antibodies detected at each assessment point was generally less than 7% in subjects with rheumatoid arthritis and in subjects with psoriasis.
In a long-term psoriasis study, in which patients received 50 mg twice weekly for 96 weeks, the incidence of antibodies observed at each assessment point was approximately 9%.
05.2 Pharmacokinetic properties
Serum values of etanercept were evaluated by the Enzyme-Linked Immunosorbent Assay (ELISA) method, which can detect both degradation products that react with the ELISA, and the parent compound.
Special populations
Kidney failure
Although there is elimination of radioactivity in the urine after administration of radiolabelled etanercept to patients and volunteers, no increase in etanercept concentrations has been observed in patients with acute renal failure. The presence of renal insufficiency should not require any dosage modification.
Hepatic insufficiency
No increased etanercept concentrations have been observed in patients with acute liver failure. The presence of hepatic insufficiency should not require modification of the dosage.
Pediatric population
Pediatric patients with juvenile idiopathic arthritis
In a polyarticular course juvenile idiopathic arthritis study with Enbrel, 69 patients (aged 4 to 17 years) received 0.4 mg / kg of Enbrel, twice weekly for three months.
The pattern of serum concentrations was similar to that observed in adult patients with rheumatoid arthritis. Younger children (4 years of age) had reduced clearance (increased clearance when normalized for weight) in comparison with older children ( 12 years of age) and adults A simulated dosing suggests that while older children (10-17 years of age) would have serum levels close to those seen in adults, younger children would have appreciably lower levels.
Pediatric patients with plaque psoriasis
Plaque psoriasis pediatric patients (aged 4-17 years) received 0.8 mg per kilo of etanercept (up to a maximum dose of 50 mg per week) once weekly for 48 weeks. Mean steady state serum concentrations ranged from 1.6 to 2.1 mcg / mL at weeks 12, 24 and 48.
These mean serum concentrations in patients with pediatric plaque psoriasis are similar to those seen in patients with juvenile idiopathic arthritis (treated with 0.4 mg per kilo of etanercept, twice weekly, up to a maximum dose of 50 mg per week). .
These mean concentrations are similar to those seen in adult plaque psoriasis patients treated with etanercept 25 mg once weekly.
Adults
Absorption
Etanercept is slowly absorbed from the subcutaneous injection site, reaching maximum concentration approximately 48 hours after a single dose. Absolute bioavailability is 76%. With two weekly doses, steady-state concentrations are expected to be approximately twice as high. compared to those observed after single doses. After a single subcutaneous dose of 25 mg of Enbrel, the mean maximum serum concentration observed in healthy volunteers was 1.65 ± 0.66 μg / ml and the area under the curve was 235 ± 96.6 mcg • hour / ml.
In treated RA patients, steady state mean serum concentration profiles were Cmax 2.4 mg / l vs 2.6 mg / l, Cmin 1.2 mg / l vs 1.4 mg / l, and partial AUC 297 mgh / l vs 316 mgh / l, respectively for 50 mg Enbrel once per week (n = 21) vs 25 mg Enbrel twice per week (n = 16). In an open-label, single-dose, two-treatment, cross-over study in healthy volunteers, etanercept administered as a single dose injection of 50 mg / mL was bioequivalent to two simultaneous injections of 25 mg / mL.
In a population pharmacokinetic analysis in patients with ankylosing spondylitis, the steady state AUCs of etanercept were 466 mcg • hr / ml and 474 mcg • hr / ml, for Enbrel 50 mg once weekly, respectively (N = 154) and 25 mg twice weekly (N = 148).
Distribution
A bi-exponential curve is required to describe the concentration-time curve of etanercept. The central volume of distribution of etanercept is 7.6 liters, while the volume of distribution at steady-state is 10.4 liters.
Elimination
Etanercept is slowly eliminated from the body. It has a long half-life of around 70 hours. Clearance is approximately 0.066 liters / hour in patients with rheumatoid arthritis, somewhat lower than the value of 0.11 liters / hour observed in healthy volunteers. Furthermore, the pharmacokinetics of Enbrel in patients with rheumatoid arthritis and ankylosing spondylitis and plaque psoriasis is similar.
There is no apparent difference in pharmacokinetics between males and females.
Linearity
Dose proportionality has not been formally assessed, but there is no apparent saturation of clearance over the dose range.
05.3 Preclinical safety data
No dose-limiting or target organ toxicity was observed in toxicology studies with Enbrel. Enbrel was found to be non-genotoxic in a number of studies in vitro and in vivo.
Due to the emergence of neutralizing antibodies in rodents, carcinogenicity studies and standard evaluation of fertility and postnatal toxicity have not been conducted with Enbrel. Enbrel did not cause detectable mortality or signs of toxicity in mice or rats following a single subcutaneous dose of 2,000 mg / kg or a single intravenous dose of 1,000 mg / kg. Enbrel did not cause dose-limiting or target organ toxicity in cynomolgus monkeys following subcutaneous administration twice weekly for 4 or 26 consecutive weeks at a dose (15 mg / kg) resulting in serum drug concentrations based on AUC. which were more than 27 times greater than those obtained in men at the recommended dose of 25 mg.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Dust:
Mannitol (E421)
Sucrose
Trometamol
Solvent:
Water for injections
Benzyl alcohol
06.2 Incompatibility
In the absence of compatibility studies, the medicinal product must not be mixed with other medicinal products.
06.3 Period of validity
3 years
After reconstitution, chemical and physical in-use stability has been demonstrated for 14 days at 2 ° C - 8 ° C.
From a microbiological point of view the reconstituted medicinal product can be stored for up to 14 days at 2 ° C - 8 ° C. Other storage times and conditions prior to use are the responsibility of the user.
06.4 Special precautions for storage
Store in the refrigerator (between 2 ° C and 8 ° C). Do not freeze.
Enbrel can be stored at a maximum temperature of 25 ° C for up to 4 weeks, for one time only; after this period it cannot be put back in the fridge. If not used within 4 weeks out of the fridge, Enbrel should be discarded.
For storage conditions of the reconstituted medicinal product see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Clear glass vials (4 ml, type I glass) with rubber stoppers, aluminum seals and removable plastic caps.
Enbrel comes with pre-filled syringes that contain bacteriostatic water for injections. The syringes are type I glass compound with stainless steel needles.
The packs contain 4 vials of Enbrel with 4 pre-filled solvent syringes, 8 empty plastic syringes, 20 stainless steel needles and 24 alcohol swabs.
06.6 Instructions for use and handling
Instructions for use and handling
Enbrel is reconstituted in 1 ml of bacteriostatic water for injections before use and administered subcutaneously. The solution should be clear and colorless or pale yellow with no lumps, flocculates or particles. Some white bubbles may remain in the vial. - this is normal. Enbrel should not be used if all the powder in the vial does not dissolve within 10 minutes of reconstitution. If so, repeat the process with another vial.
Detailed instructions for the preparation, administration and re-use of the reconstituted Enbrel vial are provided in the package leaflet, section 7, "Instructions for preparing and administering an" injection of Enbrel ".
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/99/126/012
034675165
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 3 February 2000
Date of last renewal: 3 February 2010