Generated Narrative: Composition compositionruen Language: en Profile: Composition (ePI) org/fhir/dummyValidationReference: image1 org/fhir/dummyValidationReference: image2 org/fhir/dummyValidationReference: image3 org/fhir/dummyValidationReference: image4 org/fhir/dummyValidationReference: image5 org/fhir/dummyValidationReference: image7 org/fhir/dummyValidationReference: image8 org/fhir/dummyValidationReference: image9 org/fhir/dummyValidationReference: image10 org/fhir/dummyValidationReference: image11 org/fhir/dummyValidationReference: image12 identifier: https://www.minzdrav.gov.ru//0d69fdcb-33cf-407f-8209-a6529856ab4f status: Final type: Package Leaflet date: 2023-08-16 00:00:00+0000 author: Organization Pfizer Innovations LLC title: Enbrel® (etanercept) 50 mg/ml solution for subcutaneous injection Generated Narrative: Binary #image1 contentType: image/png data: (base64 data - 38,556 base64 chars) Generated Narrative: Binary #image2 contentType: image/png data: (base64 data - 12,784 base64 chars) Generated Narrative: Binary #image3 contentType: image/png data: (base64 data - 44,444 base64 chars) Generated Narrative: Binary #image4 contentType: image/png data: (base64 data - 18,332 base64 chars) Generated Narrative: Binary #image5 contentType: image/png data: (base64 data - 16,784 base64 chars) Generated Narrative: Binary #image7 contentType: image/png data: (base64 data - 19,268 base64 chars) Generated Narrative: Binary #image8 contentType: image/png data: (base64 data - 126,780 base64 chars) Generated Narrative: Binary #image9 contentType: image/png data: (base64 data - 16,852 base64 chars) Generated Narrative: Binary #image10 contentType: image/png data: (base64 data - 17,732 base64 chars) Generated Narrative: Binary #image11 contentType: image/png data: (base64 data - 68,280 base64 chars) Generated Narrative: Binary #image12 contentType: image/png data: (base64 data - 41,548 base64 chars)
Enbrel® (etanercept) 50 mg/ml solution for subcutaneous injection
MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT
Registration number: LSR-006652/09 Invented name: Enbrel® International non-proprietary name: etanercept Pharmaceutical form: solution for subcutaneous injection Composition Composition per 1 mL of solution active substance:etanercept 50.0 mg; excipients: L-arginine hydrochloride 5.3 mg, sodium chloride 5.8 mg, sucrose 10.0 mg, sodium hydrogen phosphate dihydrate 1.2 mg, sodium dihydrogen phosphate dihydrate 2.9 mg, water for injection to 1.0 mL. Description Clear or opalescent from colorless to yellow or light brown liquid. Small transparent to white amorphous particles are permissible. Pharmacotherapeutic group: tumor necrosis factor-α (TNF-α) inhibitor ATC Code: L04AB01
Tumor necrosis factor (TNF-α) is the main cytokine maintaining the inflammatory process in rheumatoid arthritis. An increase in the concentration of TNF has also been found in synovial membranes and psoriatic plaques in psoriatic arthritis patients, as well as in blood plasma and synovial tissues in ankylosing spondylitis patients. Etanercept is a competitive inhibitor of the binding of TNF to its receptors on the cell surface and thereby inhibits the biological activity of TNF. TNF and lymphotoxin are pro-inflammatory cytokines that bind to two different tumor necrosis factor receptors (TNFRs) on the cell surface: 55 kilodalton (р55) and 75 kilodalton (р75). Both TNFRs are present in the body in membrane-bound and free forms. Soluble TNFRs regulate the biological activity of TNF. TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on the cross-linking of TNFRs that are situated on the cell surface. Dimeric soluble receptors, such as etanercept, possess higher TNF binding affinity than monomeric receptors and, therefore, are significantly more potent competitive inhibitors of TNF binding to its cellular receptors. Moreover, the use of an immunoglobulin Fc region as a fusion element in the structure of a dimeric receptor prolongs the blood serum half-life period. The significant portion of pathological processes in joints in rheumatoid arthritis and ankylosing spondylitis, and also skin pathologies presenting as plaque psoriasis, develop due to the effect of pro-inflammatory molecules involved in a network controlled by TNF. The mechanism of action of etanercept is thought to be its competitive inhibition of TNF binding to TNF receptors on the cell surface. Thus, etanercept prevents TNF-mediated cellular responses by rendering TNF biologically inactive. Etanercept can also modulate biological responses controlled by additional downstream molecules (e.g., cytokines, adhesion molecules or proteinases). And these responses may either induce or control TNF. In patients with active psoriatic arthritis, Enbrel ® inhibits the progression of structural damage, improves physical activity and lowers the likelihood of development of lesions in the peripheral joints. After discontinuing treatment with Enbrel ® , the flare-up of the disease is possible within a month. The efficacy of the repeated administration of the medicinal product within 24 months after discontinuing the therapy is comparable to that in patients who have not interrupted the treatment.
Etanercept is slowly absorbed from the site of subcutaneous injection, reaching its maximum concentration in approximately 48 hours after the administration of a single dose of Enbrel®. The absolute bioavailability is 76%. When Enbrel® is administered twice a week, steady-state concentrations twice as high as those observed after a single administration are achieved. After the single subcutaneous administration of Enbrel® 25 mg, the mean maximum plasma concentration of etanercept was 1.65 ± 0.66 µg/mL, and the area under the concentration-time curve (AUC) was 235 ± 96.6 µg⋅h/mL. There was no apparent saturation of clearance across the dosing range. The dependence of the concentration of etanercept on time is represented by a biexponential curve. The mean volume of distribution is 7.6 L, whereas the steady-state volume of distribution is 10.4 L. Etanercept is cleared slowly from the body. The half-life (Т1/2) is about 70 hours. For patients with rheumatoid arthritis, the clearance is approximately 0.066 L/h, which is somewhat lower than a value of 0.11 L/h for healthy volunteers. The pharmacokinetic properties of etanercept in patients with rheumatoid arthritis, ankylosing spondylarthritis and psoriasis are similar. A single 50 mg dose of Enbrel® is bioequivalent to a dose consisting of two practically simultaneous injections of 25 mg of the medicinal product. Although there is elimination of radioactivity through the kidneys after the administration of radiolabeled etanercept to patients and healthy volunteers, no increase in the blood plasma concentrations of etanercept was observed in patients with acute renal or hepatic failure. In patients with acute renal or hepatic failure, no increase in the concentration of etanercept was observed. There are no significant differences in the pharmacokinetics of etanercept among men and women. Elderly patients The clearance and apparent volumes of distribution of etanercept in the group of patients aged from 65 to 87 years are similar to those in patients under 65. Children Juvenile idiopathic polyarthritis The blood serum concentration profile is similar to that of adult patients with rheumatoid arthritis. Simulation suggests that while older children (aged 10 to 17 years) and adults have roughly the same blood serum concentrations of etanercept, younger children will have appreciably lower levels. Psoriasis The steady-state concentrations of etanercept in the blood plasma of children aged from 4 to 17 years with psoriasis and children with juvenile idiopathic polyarthritis who had received Enbrel® at doses of 0.8 mg/kg once a week (the maximum dose of 50 mg per week) and 0.4 mg/kg twice a week (the maximum dose of 50 mg per week) over the course of 48 and 12 weeks were similar (1.6 to 2.1 μg/mL). The value of this metric coincided with that of adult patients with psoriasis administered Enbrel® at a dose of 25 mg twice a week.
Rheumatoid arthritis In combination with methotrexate, Enbrel® is prescribed to adults for the treatment of moderate and severe active rheumatoid arthritis when response to disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate, has been inadequate. Enbrel® may be prescribed as monotherapy in case of inefficacy or intolerance of methotrexate. Enbrel® is indicated for the treatment of severe active and progressive rheumatoid arthritis in adults who have not been previously treated with methotrexate. Juvenile idiopathic polyarthritis Treatment of active juvenile idiopathic polyarthritis (seropositive and seronegative) in children and adolescents aged 12 years and older with a body weight of more than 62.5 kg (for Enbrel® in the pharmaceutical form of a solution for subcutaneous injection), who have had an ineffective response or intolerance to methotrexate. Treatment of extended oligoarthritis in children and adolescents aged 12 years and older with a body weight of more than 62.5 kg (for Enbrel® in the pharmaceutical form of a “solution for subcutaneous injection”), who have had an ineffective response or intolerance to methotrexate. Treatment of psoriatic arthritis in adolescents aged 12 years and older with a body weight of more than 62.5 kg (for Enbrel® in the pharmaceutical form of a “solution for subcutaneous injection”), who have had an ineffective response or intolerance to methotrexate. Treatment of arthritis associated with enthesitis in adolescents aged 12 years and older with a body weight of more than 62.5 kg (for Enbrel® in the pharmaceutical form of a “solution for subcutaneous injection”), who have had an ineffective response or intolerance to standard therapy. Psoriatic arthritis Treatment of active and progressive psoriatic arthritis in adults who have had an inadequate response to DMARDs. Axial spondylarthritis Ankylosing spondylitis Treatment of severe active ankylosing spondylitis in adults for whom conventional therapy has not resulted in substantial improvement. Non-radiographic of axial spondylarthritis Etanercept is indicated for treatment of adult patients with severe course of axial spondylarthritis in the non-radiographic stage, in whom an inadequate response or resistance to standard treatment has been observed and who also have objective signs of active disease confirmed by an increased concentration of C-reactive protein (CRP) and/or MRI scan data. Psoriasis Treatment of adults with moderate and severe psoriasis, who have contraindications or intolerance to other systemic treatments, including cyclosporine, methotrexate or PUVA therapy. Treatment of children aged 12 years and older with a body weight of more than 62.5 kg (for Enbrel® in the pharmaceutical form of a “solution for subcutaneous injection”) with severe chronic psoriasis, who have had an intolerance or inadequate response to other systemic therapy or phototherapy.
Hypersensitivity to etanercept or any other component of the medication. Sepsis or risk of sepsis. Active infection, including chronic or localized infections. Patients aged under 12 years with a body weight of less than 62.5 kg (for Enbrel® in the pharmaceutical form of a “solution for subcutaneous injection”).
Demyelinating diseases, chronic heart failure (CHF), immunodeficiency conditions, diseases that cause predisposition to the development or activation of infections (diabetes, hepatitis), moderate and severe alcoholic hepatitis, hepatitis C, blood dyscrasia, diseases of the nervous system (multiple sclerosis, optic neuritis, transverse myelitis).
Use during pregnancy and breast-feeding period
Women of childbearing potential should consider the use of appropriate contraception to avoid becoming pregnant during therapy with Enbrel® and for three weeks after the discontinuation of the therapy.
The effects of etanercept on pregnancy outcomes have been investigated in two observational cohort studies. A higher rate of major birth defects was observed in one observational study comparing pregnancies exposed to etanercept during the first trimester, with pregnancies not exposed to etanercept or other TNF-antagonists. The types of major birth defects were consistent with those most commonly reported in the general population and no particular pattern of abnormalities was identified. No change in the rate of spontaneous abortion, stillbirth, or minor malformations was observed. In another observational multi-country registry study comparing the risk of adverse pregnancy outcomes in women exposed to etanercept during the first 90 days of pregnancy to those exposed to non-biologic medications, there was no observed increased risk of major birth defects. That study also showed no increased risks of minor birth defects, preterm birth, stillbirth, or infections in the first year of life for infants born to women exposed to etanercept during pregnancy. Enbrel® should only be used during pregnancy if clearly needed. Etanercept penetrates the placenta and is detected in the serum of infants born to female patients treated with Enbrel® during pregnancy. The clinical impact of this is unknown, however, infants may be at increased risk of infection. The administration of live vaccines to infants for 16 weeks after the mother’s last dose of etanercept is generally not recommended.
Limited information from the published literature indicates that etanercept has been detected at low levels in human milk. Etanercept could be considered for use during breast-feeding taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Although systemic exposure in a breastfed infant is expected to be low because etanercept is largely degraded in the gastrointestinal tract, limited data regarding systemic exposure in the breastfed infant are available. Therefore, the administration of live vaccines (eg, BCG) to a breastfed infant when the mother is receiving etanercept may be considered 16 weeks after stopping breast-feeding (or at an earlier timepoint if the infant’s etanercept serum levels are undetectable).
Preclinical data on the peri- and postnatal toxicity of etanercept and of effects of etanercept on fertility and overall reproductive performance are not available.
Subcutaneously. Treatment with Enbrel® must be prescribed and monitored by a physician experienced in the diagnosis and treatment of rheumatoid arthritis, juvenile idiopathic polyarthritis, psoriatic arthritis, ankylosing spondylitis or psoriasis. Enbrel® in the form of a 25 mg ready-for-use solution (a single-use syringe containing 0.5 mL of the medicinal product) and 50 mg (a single-use syringe containing 1.0 mL of the medicinal product) or 50 mg (injection pen containing 1 mL of the medicinal product) is used for patients with a body weight of more than 62.5 kg. For patients with a body weight of less than 62.5 kg, lyophilizate for the preparation of a solution should be used. before-injecting-the-medicinal-product-it-is-necessary-to-read-the-instructions-for-use-at-the-end-of-this-section-carefully. Before injecting the medicinal product, it is necessary to read the instructions for use at the end of this section carefully.
Rheumatoid arthritis The recommended dose is 25 mg of Enbrel® twice a week with an interval of three to four days. An alternative dose is 50 mg once a week, which can be administered as a single subcutaneous injection of 50 mg or two practically simultaneous injections of 25 mg. Psoriatic arthritis The recommended dose is 25 mg of Enbrel® twice a week with an interval of three to four days. An alternative dose is 50 mg once a week, which can be administered as a single subcutaneous injection of 50 mg or two practically simultaneous injections of 25 mg. Ankylosing spondylitis The recommended dose is 25 mg of Enbrel® twice a week with an interval of three to four days. An alternative dose is 50 mg once a week, which can be administered as a single subcutaneous injection of 50 mg or two practically simultaneous injections of 25 mg. Pre-radiographic axial spondylarthritis The recommended dose is 25 mg of Enbrel® twice a week with an interval of three to four days. An alternative dose is 50 mg once a week, which can be administered as a single subcutaneous injection of 50 mg or two practically simultaneous injections of 25 mg. Psoriasis The recommended dose is 25 mg of Enbrel® twice a week with an interval of three to four days. It is possible to administer 50 mg of the medicinal product once a week as a single subcutaneous injection or two practically simultaneous injections of 25 mg. As an alternative, 50 mg of Enbrel® can be used twice a week for a period of not more than 12 weeks. If treatment needs to be continued, Enbrel® should be administered at a dose of 25 mg twice a week or 50 mg once a week. Treatment should be continued until remission is reached and, as a rule, for not more than 24 weeks. The administration of the medicinal product should be discontinued if, after 12 weeks of treatment, no improvement in symptoms is observed. In some cases, the length of treatment may be more than 24 weeks. In adult patients, depending on the physician’s evaluation and individual peculiarities of the patient, therapy can be either continuous or intermittent. If repeated administration of Enbrel® is needed, the duration of treatment stated above should be observed. It is recommended to prescribe a dose of 25 mg twice a week or 50 mg once a week. The duration of treatment for some patients may exceed 24 weeks. Elderly patients (65 years and older) There is no need to adjust the dose or method of administration.
Children (aged 12 years and older with a body weight of 62.5 kg and more)
In children aged under 12 years with a body weight of less than 62.5 kg (see “Contraindications” section), Enbrel® in the pharmaceutical form of a lyophilizate for solution for subcutaneous injection should be used, making it possible to administer a dose of less than 25 mg. Children aged 12 years and older with a body weight of more than 62.5 kg can be administered Enbrel® in the pharmaceutical form of a solution for subcutaneous injection in single-use syringes or injection pens. Juvenile idiopathic polyarthritis (children aged 12 years and older with a body weight of more than 62.5 kg [for Enbrel ® in the pharmaceutical form of a “solution for subcutaneous injection”]) Enbrel® in the pharmaceutical form of a “solution for subcutaneous injection” is administered in this patient group in the same way as in adult patients: a single 25 mg dose. The medicinal product is injected twice a week with an interval of three to four days. Treatment should be discontinued if, after four months of therapy, no improvement in symptoms is observed. The administration of a 50 mg dose once per week is possible. Extended oligoarthritis (children aged 12 years and older with a body weight of more than 62.5 kg [for Enbrel ® in the pharmaceutical form of a “solution for subcutaneous injection”]) Enbrel® in the pharmaceutical form of a “solution for subcutaneous injection” is administered in this patient group in the same way as in adult patients: a single 25 mg dose. The medicinal product is injected twice a week with an interval of three to four days. Treatment should be discontinued if, after four months of therapy, no improvement in symptoms is observed. The administration of a 50 mg dose once per week is possible. Psoriatic arthritis (adolescents aged 12 years and older, and with a body weight greater than 62.5 kg [for Enbrel ® in the pharmaceutical form of a “solution for subcutaneous injection”]) Enbrel® in the pharmaceutical form of a “solution for subcutaneous injection” is administered in this patient group in the same way as in adult patients: a single 25 mg dose. The medicinal product is injected twice a week with an interval of three to four days. Treatment should be discontinued if, after four months of therapy, no improvement in symptoms is observed. The administration of a 50 mg dose once per week is possible. Arthritis associated with enthesitis (adolescents aged 12 years and older with a body weight of more than 62.5 kg [for Enbrel ® in the pharmaceutical form of a “solution for subcutaneous injection”]) Enbrel® in the pharmaceutical form of a “solution for subcutaneous injection” is administered in this patient group in the same way as in adult patients: a single 25 mg dose. The medicinal product is injected twice a week with an interval of three to four days. Treatment should be discontinued if, after four months of therapy, no improvement in symptoms is observed. The administration of a 50 mg dose once per week is possible. Psoriasis (children aged 12 years and older with a body weight of more than 62.5 kg [for Enbrel ® in the pharmaceutical form of a “solution for subcutaneous injection”]) The single dose of the medicinal product is 50 mg. The medicinal product is injected once a week, and the duration of therapy is not more than 24 weeks. The injections of the medicinal product should be discontinued if, after 12 weeks of treatment, no response to the therapy is observed. If repeated administration of Enbrel® is needed, the duration of treatment stated above should be observed. The single dose of the medicinal product is 50 mg once a week. If a dose is missed at the appointed time, the drug must be injected as soon as remembered, but only on condition that the next injection will not be earlier than a day later. Otherwise, the forgotten dose should be skipped. Patients should continue to inject the medicine on the usual day (days). If a patient does not remember the day that the next injection is due, instruct the patient not to take a double dose. Impaired hepatic and renal function: there is no need to adjust the dose.
below-are-the-instructions-for-preparing-and-injecting-a-solution-for-subcutaneous-injection-of-enbrel-in-syringes-and-injection-pens. Below are the instructions for preparing and injecting a solution for subcutaneous injection of Enbrel® in syringes and injection pens. selecting-a-site-for-injection Three sites are recommended for the injection of Enbrel ®: (1) the front surface of the middle third of the thigh; (2) the abdomen, except for an area 5 cm in diameter around the navel; (3) the outer surface of the shoulder (see Fig. 1). If you are administering an injection to yourself, you should not use the outer surface of the shoulder. Fig. 1 Each injection should be administered in a different site. The site of each new injection should be at least 3 cm away from the site of the previous injection. DO NOT INJECT the medicinal product into areas where there is pain, skin redness, bruising or induration. Do not inject in areas with scars or stretch marks. (It may be useful to write down the sites of previous injections). If a child has psoriasis, try not to inject the medicinal product directly into raised, thickened or red areas or lesions with flaking (psoriatic plaques). 1) INSTRUCTIONS FOR PREPARATION AND INJECTION OF A SOLUTION FOR SUBCUTANEOUS INJECTION OF ENBREL® IN A SYRINGE Patients or their parents/guardians who are going to perform injections should be informed of how to do it correctly. In cases where the patient or his/her parent/guardian performs the future injections by him-/herself, the first injection must be performed under the supervision of qualified medical personnel. Preparation for Injection This medicinal product must not be mixed with any other medicinal products in a single syringe or vial! Remove the carton with pre-filled syringes of Enbrel® from the refrigerator and place it on a clean, well-lit, flat work surface. Take one pre-filled syringe. Do not shake the syringe. Put the carton with the remaining pre-filled syringes back in the refrigerator. Leave the syringe with a solution of Enbrel® for 15 to 30 minutes to allow it to reach room temperature. DO NOT REMOVE the cap from the syringe needle until it reaches room temperature. Do not warm up Enbrel® by any other means (for example, in a microwave oven or in hot water). Wash your hands with soap and warm water. Make sure that the solution in the syringe is clear or opalescent, colorless to yellow or to light brown, it may contain a small amount of semi-transparent or white amorphous particles. If this is not the case, do not inject the solution. Use a different pre-filled syringe of Enbrel®. You will also need: an alcohol wipe, which is included in the kit, and a cotton ball or gauze pad. Preparation of the skin site and injection of the solution of Enbrel® Wipe the skin site where you will inject Enbrel® in circular motions with a clean alcohol wipe. DO NOT TOUCH this area until you have completed the injection. Remove the cap from the needle by pulling it forcefully from the syringe (see Fig. 2). Be careful not to bend or over-twist the cap while removing, so as not to damage the needle. When removing the cap, a drop of fluid may appear on the tip of the needle; this is permissible. Do not touch the needle and do not let it touch any other surface. Do not touch or press on the plunger. This can lead to fluid leaking from the syringe. Fig. 2 When a cleaned skin area is completely dry, pinch the skin into a fold with one hand and hold it. With the other hand, hold the syringe like a pencil. With a quick, short motion, direct the needle into the skin at an angle between 45° and 90° (see Fig. 3). In time you will find the angle that is most comfortable for the injection. Try not to push the needle into the skin too slowly or with excessive force. Fig. 3 After the needle has fully entered the skin, release the fold of skin you have been holding. With your free hand, hold the base of the syringe to stabilize its position. Then press the plunger to inject all of the solution at a slow, constant speed (see Fig. 4). Fig. 4 When the syringe is empty, remove the needle from the skin, being careful to keep it at the same angle as when it was inserted. Press on the injection site with a cotton ball or gauze pad for 10 seconds. A small amount of bleeding may occur. DO NOT WIPE the injection site. A bandage may be applied. Waste disposal The pre-filled syringe is intended for single use only. NEVER reuse the syringe and needle. NEVER recap the needle. Dispose of the needle and syringe as instructed by your physician or nurse. If you have questions, please contact a physician or nurse who works with Enbrel®. 2) INSTRUCTIONS FOR PREPARATION AND INJECTION OF A SOLUTION FOR SUBCUTANEOUS INJECTION OF ENBREL®IN AN INJECTION PEN Do not attempt to perform an injection by yourself if you have not understood how to use the injection pen properly. If you have questions regarding injections, please ask your physician or nurse. Fig. 5 Pre-filled injection pen Step 1. Preparation for the injection of Enbrel® Select a clean, well-lit, flat working surface. Gather the following items needed for the injection and place them on the working surface: One pre-filled injection pen and one alcohol wipe (take them out of the carton of injection pens that you store in the refrigerator). Do not shake the injection pen. One cotton ball or gauze pad. Check the expiry date on the injection pen. Do not use the injection pen if the date is past. Consult with your treating physician. Assess the condition of the solution in the injection pen through the transparent inspection window. It is only permissible to inject a clear or opalescent, colorless to yellow or light brown solution, which may contain a small quantity of semi-transparent or white amorphous particles. If this is not the case, you should use a different injection pen and then ask a pharmacist for assistance. Without removing the white needle cap, wait approximately 15 to 30 minutes for the Enbrel® solution in the injection pen to warm up to room temperature. This will make the injection more comfortable. Do not warm the injection pen by any other method. Always keep the injection pen out of reach of children. While the solution in the injection pen is warming up to room temperature, read the information on Step 2 activities (below) and select an injection site. Step 2. Injection of Enbrel® After warming the solution up to room temperature for approximately 15 to 30 minutes, wash your hands with soap and water. With circular motions, wipe the area of skin where you are going to inject Enbrel® with a clean alcohol wipe and allow to dry. DO NOT TOUCH this area until you have completed the injection. Take the injection pen and remove the white cap by pulling it straight toward yourself (see Fig. 7). To avoid damaging the needle, which is covered by the cap, do not tilt the cap when removing it, and do not attempt to put it back on after removing. After removing the needle cap, you will see a purple protective screen, which protrudes slightly from the edge of the injection pen. The needle itself will remain inside the injection pen until the moment it is activated. Do not use the injection pen if it dropped on the floor after you had removed the protective cap from the needle. Fig. 7 Carefully pinch the skin into a fold between the thumb and index finger of your free hand; this will make it easier to administer the medicinal product and make it more comfortable. Try not to touch the prepared surface of the skin. Place the injection pen at a right angle (90º) to the injection site and press the open end firmly against the skin, so that the protective screen goes fully inside the injection pen. You will see a slight indentation of the skin (Fig. 8). The injection pen will be activated only when the protective screen of the needle has fully gone into the injection pen. Fig. 8 Press the injection pen firmly against the skin and make sure that the purple protective screen has gone completely inside it. To inject, press at the center of the green button located on the upper part of the injection pen (Fig. 9). After pressing the button, you will hear a click. Continue to hold the injection pen pressed firmly to the skin either until the second click or for 10 seconds after the first click (whichever occurs first). Note: if you cannot start the injection as described above, press the injection pen more tightly against the skin and press the green button again. Fig. 9 After the second click (or in 10 seconds), the injection is complete (Fig. 10), and you can release the pressure on the skin (Fig. 11); the purple protective screen will automatically come out and cover the needle. Fig. 10 Fig. 11 When this is done, the color of the inspection window of the injection pen will change to purple (see Fig. 12), which confirms that the dose has been injected correctly. If this does not occur, you should ask a physician, nurse or pharmacist for assistance, as there is no guarantee in this situation that the full dose of Enbrel® has been injected. Do not attempt to reuse this injection pen, and do not use a new injection pen without consulting with a nurse or pharmacist. Fig. 12 If drops of blood appear at the injection site, press a cotton ball or gauze pad against the site and hold it for 10 seconds. Do not rub the injection site. Step 3. Disposal of the used injection pen The injection pen is intended for single use only; therefore, its reuse is not permissible. Used injection pens should be disposed of as instructed by a physician, nurse or pharmacist. Do not try to re-attach the needle protective cap. If you have questions, please ask a physician, nurse or pharmacist experienced in working with Enbrel®.
Summary of the safety profile The most commonly reported adverse reactions are injection site reactions (such as pain, swelling, itching, reddening and bleeding at the puncture site), infections (such as upper respiratory infections, bronchitis, bladder infections and skin infections), allergic reactions, development of autoantibodies, itching, and fever. Serious adverse reactions have also been reported during the use of Enbrel®. TNF-antagonists, such as etanercept, negatively affect the immune system and their use may have a negative effect on the body’s defenses against infections and malignancies. Serious infections affect fewer than one in 100 patients treated with Enbrel®. Reports have included fatal and life-threatening infections and sepsis. Various malignancies have also been reported with the use of Enbrel®, including cancers of the breast, lung, skin and lymph glands (lymphoma). Serious hematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia and very rare reports of aplastic anemia. Central and peripheral demyelinating events have been seen rarely and very rarely, respectively, with the use of Enbrel®. There have been rare reports of lupus, lupus-related conditions, and vasculitis.
The following list of adverse reactions is based on experience from clinical trials and on post- marketing experience. Within the organ system classes, adverse reactions are listed under the following categories of frequency (number of patients expected to experience the reaction): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from available data). System Organ Class Very common ≥ 1/10 Common ≥ 1/100 to < 1/10 Uncommon ≥ 1/1,000 to < 1/100 Rare ≥ 1/10,000 to < 1/1,000 Very rare < 1/10,000 Frequency not known (cannot be estimated from available data) Infections and infestations Infections (including upper respiratory tract infections, bronchitis, cystitis, skin infections)* Serious infections (including pneumonia, cellulitis, arthritis bacterial, sepsis and parasitic infections)* Tuberculosis, opportunistic infection (including invasive fungal, protozoal, bacterial, atypical mycobacterial, viral infections, and Legionella)* Hepatitis B reactivation, listeria Neoplasms benign, malignant and unspecified (including cysts and polyps) Non-melanoma skin cancers* (see “Special warnings” section) Malignant melanoma (see “Special warnings” section), lymphoma, leukemia Merkel cell carcinoma (see “Special warnings” section) Kaposi’s sarcoma Blood and lymphatic system disorders Thrombocytopenia, anemia, leukopenia, neutropenia Pancytopenia* Aplastic anemia* Hematophagy histiocytosis (macrophage activation syndrome)* Immune system disorders Allergic reactions (see Skin and subcutaneous tissue disorders” section), autoantibody formation* Vasculitis (including anti- neutrophilic cytoplasmic antibody positive vasculitis) Serious allergic/anaphylactic reactions (including angioedema, bronchospasm), sarcoidosis Worsening of symptoms of dermatomyositis Nervous system disorders Headache* CNS demyelinating events suggestive of multiple sclerosis or localized demyelinating conditions, such as optic neuritis and transverse myelitis (see “Special warnings” section), peripheral demyelinating events, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy (see “Special warnings” section), seizure Eye disorders Uveitis, scleritis Cardiac disorders Worsening of congestive heart failure (see “Special warnings” section) New onset congestive heart failure (see “Special warnings” section) Respiratory, thoracic, and mediastinal disorders Interstitial lung disease (including pneumonitis and pulmonary fibrosis)* Gastrointestinal tract disorders Inflammatory bowel disease* Hepatobiliary disorders Elevated liver enzymes* Autoimmune hepatitis* Skin and subcutaneous tissue disorders Pruritus, rash Angioedema, psoriasis (including new onset or worsening and pustular, primarily palms and soles), urticaria, psoriasiform rash Stevens-Johnson syndrome, cutaneous vasculitis (including hypersensitivity vasculitis), erythema multiforme, lichenoid reactions Toxic epidermal necrolysis Musculoskeletal and connective tissue disorders Cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, lupus-like syndrome General disorders and administration site conditions Injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling)* Pyrexia *see “Description of selected adverse reactions” below.
Description of selected adverse reactions
Malignancies and lymphoproliferative disorders One hundred and twenty-nine (129) new malignancies of various types were observed in 4,114 rheumatoid arthritis patients treated in clinical trials with Enbrel® for up to approximately six years, including 231 patients treated with Enbrel® in combination with methotrexate in the two- year active-controlled study. The observed rates and incidences in these clinical trials were similar to those expected for the population studied. A total of two malignancies were reported in clinical studies of approximately two years duration involving 240 psoriatic arthritis patients who received Enbrel®. In clinical studies conducted for more than two years with 351 ankylosing spondylitis patients, six malignancies were 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, 30 malignancies and 43 non-melanoma skin cancers were reported. In a group of 7,416 patients treated with Enbrel® in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and psoriasis clinical trials, 18 lymphomas were reported. Reports of various malignancies (including breast and lung carcinoma and lymphoma) have also been received in the post-marketing period (see “Special warnings” section). Injection site reactions Compared to placebo, patients with rheumatic diseases treated with Enbrel® had a significantly higher incidence of injection site reactions (36% vs. 9%). Injection site reactions usually occurred in the first month. Mean duration was approximately three to five days. No treatment was given for the majority of injection site reactions in the groups receiving Enbrel®, and the majority of patients who were given treatment received topical preparations, such as corticosteroids, or oral antihistamines. Additionally, some patients developed recall injection site reactions characterized by a skin reaction at the most recent site of injection, along with the simultaneous appearance of injection site reactions at previous injection sites. These reactions were generally transient and did not recur with treatment. In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients treated with Enbrel® developed injection site reactions compared with 3.4% of placebo-treated patients during the first 12 weeks of treatment. Serious infections In placebo-controlled trials, no increase in the incidence of serious infections (fatal, life- threatening, or requiring hospitalization or intravenous antibiotics) was observed. Serious infections, including 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 infection, skin ulcer, urinary tract infection, vasculitis, and wound infection, occurred in 6.3% of rheumatoid arthritis patients treated with Enbrel® for up to 48 months. In the two-year active-controlled study where patients were treated with either Enbrel alone, methotrexate alone or Enbrel® in combination with methotrexate, the rates of serious infections were similar among the treatment groups. However, it cannot be excluded that the combination of Enbrel® with methotrexate could be associated with an increase in the rate of infections. There were no differences in rates of infection among patients treated with Enbrel® and those treated with placebo for plaque psoriasis in placebo-controlled trials lasting up to 24 weeks. Serious infections experienced by Enbrel®-treated patients included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis, gastritis, appendicitis, Streptococcal fasciitis, myositis, septic shock, diverticulitis and abscess. In the double-blind and open-label psoriatic arthritis trials, one patient reported a serious infection (pneumonia). Serious and fatal infections have been reported during the use of Enbrel®; they were caused by bacteria, mycobacteria (including tuberculosis), viruses and fungi. Some have occurred within a few weeks after initiating treatment with Enbrel® in patients who have underlying conditions (e.g., diabetes mellitus, congestive heart failure, history of active or chronic infections) in addition to their rheumatoid arthritis (see “Special warnings” section). Treatment with Enbrel® may increase mortality in patients with established sepsis. Opportunistic infections have been reported in association with treatment with Enbrel®, including invasive fungal, parasitic (including protozoal), viral (including herpes zoster), bacterial (including Listeria and Legionella), and atypical mycobacterial infections. In pooled data from clinical trials, the overall incidence of opportunistic infections was 0.09% for the 15,402 subjects who received Enbrel®. The exposure-adjusted incidence rate was 0.06 events per 100 patient- years. In post-marketing experience, approximately half of all case reports of opportunistic infections worldwide were invasive fungal infections. The most commonly reported invasive fungal infections included Candida, Pneumocystis Aspergillus, and Histoplasma. Invasive fungal infections accounted for more than half of the fatalities amongst patients who developed opportunistic infections. The majority of the reports with a fatal outcome were in patients with Pneumocystis pneumonia, unspecified systemic fungal infections, and aspergillosis (see “Special warnings” section). Formation of autoantibodies Adult patients had serum samples tested for autoantibodies at multiple timepoints. Of the rheumatoid arthritis patients evaluated for antinuclear antibodies (ANA), the percentage of patients who developed new positive ANA (≥ 1:40) was higher in patients treated with Enbrel® (11%) than in placebo-treated patients (5%). The percentage of patients who developed new positive anti- double-stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with Enbrel® compared to 4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treated with Enbrel® compared to none of the placebo-treated patients). The proportion of patients treated with Enbrel® who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients. The impact of long-term treatment with Enbrel® on the development of autoimmune diseases is unknown. There have been rare reports of patients, including rheumatoid factor positive patients, who have developed other autoantibodies in conjunction with a lupus-like syndrome or rashes that are compatible with subacute cutaneous lupus or discoid lupus by clinical presentation and biopsy. Pancytopenia and aplastic anemia There have been post-marketing reports of pancytopenia and aplastic anemia, some of which had fatal outcomes (see “Special warnings” section). Interstitial lung disease In controlled clinical trials of etanercept across all indications, the frequency (percentage of patients) of interstitial lung disease in patients receiving etanercept without concomitant methotrexate was 0.06% (frequency “rare”). In the controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (percentage of patients) of interstitial lung disease was 0.47% (frequency “uncommon”). There have been post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes. Concurrent treatment with anakinra In studies when adult patients received concurrent treatment with Enbrel® plus anakinra, a higher rate of serious infections compared to Enbrel® alone was observed and 2% of patients (3/139) developed neutropenia (absolute neutrophil count < 1000/mm3). While neutropenic, one patient developed cellulitis that resolved after hospitalization (see “Special warnings” and “Interaction with other medicinal products” sections). Elevated liver enzymes In the double-blind periods of controlled clinical trials of etanercept across all indications, the frequency (percentage of patients) of adverse events of elevated liver enzymes in patients receiving etanercept without concomitant methotrexate was 0.54% (frequency “uncommon”). In the double- blind periods of controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (percentage of patients) of adverse events of elevated liver enzymes was 4.18% (frequency “common”). Autoimmune hepatitis In controlled clinical trials of etanercept across all indications, the frequency (percentage of patients) of autoimmune hepatitis in patients receiving etanercept without concomitant methotrexate was 0.02% (frequency “rare”). In the controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of autoimmune hepatitis was 0.24% (frequency “uncommon”).
Adverse events in pediatric patients with juvenile idiopathic arthritis In general, the adverse events in pediatric patients with juvenile idiopathic arthritis were similar in frequency and type to those seen in adult patients. Differences from adults and other special considerations are discussed in the following paragraphs. The types of infections seen in clinical trials in juvenile idiopathic arthritis patients aged 2 to 18 years were generally mild to moderate and consistent with those commonly seen in outpatient pediatric populations. Severe adverse events reported included varicella with signs and symptoms of aseptic meningitis, which resolved without sequelae (see also “Special warnings” section), appendicitis, gastroenteritis, depression/personality disorder, cutaneous ulcer, esophagitis/gastritis, group A streptococcal septic shock, type I diabetes mellitus, and soft tissue and post-operative wound infection. In one study in children with juvenile idiopathic arthritis aged 4 to 17 years, 43 of 69 (62%) children experienced an infection while receiving Enbrel® after three months of the study (part 1, open-label), and the frequency and severity of infections were similar in 58 patients completing 12 months of open-label extension therapy. The types and frequency of adverse events in juvenile idiopathic arthritis patients were similar to those seen in trials of Enbrel® in adult patients with rheumatoid arthritis, and the majority were mild. Several adverse events were reported more commonly in 69 juvenile idiopathic arthritis patients receiving Enbrel® for three months compared to the 349 adult rheumatoid arthritis patients. 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), and vomiting (13%, 0.74 events per patient year). There were four reports of macrophage activation syndrome in juvenile idiopathic arthritis clinical trials. There have been reports of inflammatory bowel disease and uveitis in JIA patients treated with Enbrel® from post-marketing sources, including a very small number of cases indicating a positive rechallenge (see “Special warnings” section). Adverse events in pediatric patients with plaque psoriasis In a 48-week study in 211 children aged 4 to 17 years with pediatric plaque psoriasis, the adverse events reported were similar to those seen in previous studies in adults with plaque psoriasis.
In the case of an overdose of Enbrel ®, contact a physician or pharmacist immediately. Save the carton of Enbrel®, even if it is empty. The maximum dose of Enbrel® has not been established. In a clinical study, a single 60 mg/m2 dose was administered to healthy volunteers, which did not lead to the development of dose- limiting toxicity. In the treatment of patients with rheumatoid arthritis, no cases of the toxic dose limit being exceeded were documented. The highest dose injected intravenously was 32 mg/m2, with a subsequent subcutaneous injection of 16 mg/m2 twice a week. There is no known specific antidote for Enbrel®.
Interaction with other medicinal products
Anakinra During combined therapy with etanercept and anakinra, a significant increase in the frequency of serious infections and neutropenia was observed as compared with patients who were injected with only etanercept or only anakinra. Combined therapy with etanercept and anakinra did not show any clinical benefit and, therefore, is not recommended. Abatacept The simultaneous use of abatacept and etanercept was accompanied by an increase in the frequency of serious undesirable events. This drug combination did not show any clinical benefits and, therefore, is not recommended. Sulfasalazine In patients administered etanercept during treatment with sulfasalazine, a significant reduction in leukocyte count was documented compared to patients who received only etanercept or only sulfasalazine. Absence of interaction No adverse interactions were observed during the simultaneous use of etanercept with glucocorticosteroids, salicylates (with the exception of sulfasalazine), non-steroidal anti- inflammatory drugs (NSAIDs), analgesics or methotrexate. Methotrexate Methotrexate has no effect on the pharmacokinetics of etanercept. The effect of etanercept on the pharmacokinetics of methotrexate in humans has not been studied. Digoxin No clinically significant cross-effect on the pharmacokinetics of etanercept has been found. Warfarin No clinically significant cross-effect on the pharmacokinetics of etanercept has been found. Vaccination Live vaccines should not be administered during treatment with etanercept. There is no data on the secondary transmission of an infection through a live vaccine to patients receiving etanercept. Before beginning treatment with etanercept, it is recommended that children and adolescents receive all necessary vaccinations according to the current national vaccination calendar, if possible. An increase in B-cell immune response to the pneumococcal polysaccharide vaccine was observed in the majority of patients with psoriatic arthritis who had received etanercept, even if titers were slightly lower on the whole. A twofold increase in titers was observed in a lower number of patients in comparison with patients not receiving etanercept.
After the discontinuation of Enbrel®, disease symptoms may recur. Infections Patients should be examined for infections before starting treatment with Enbrel®, during treatment and after completing the course of treatment, taking into account the mean half-life of etanercept, which is approximately 70 hours (seven to 300 hours). During treatment with Enbrel®, sepsis, tuberculosis, parasitic infections (including those caused by protozoa organisms) and severe infections, including opportunistic infections, such as invasive fungal infections, listeriosis and legionellosis (some with lethal outcomes), and viral infections (including caused by herpes zoster) were reported. The most commonly reported invasive fungal infections were caused by Candida Pneumocystis, Aspergillus and Histoplasma. Incorrect diagnosis of the above-mentioned infections, especially fungal and other opportunistic infections, led to the delayed prescription of necessary treatment and, in some cases, to lethal outcomes. In many cases, patients received treatment with other medicinal products, including immunosuppressants. When examining patients, it is important to consider the possible development of opportunistic infections, for example, endemic mycoses. Patients who develop new infections during treatment with Enbrel® should be kept under close observation. The administration of Enbrel® should be discontinued if a patient develops a severe infection. The administration of Enbrel® requires caution in patients with a history of frequent or chronic infections or underlying diseases, which may facilitate the development of infections (such as severe or poorly controlled diabetes mellitus). The safety and efficacy of Enbrel® in patients with chronic infections have not been evaluated. Tuberculosis During treatment with Enbrel®, cases of active tuberculosis have been reported, including miliary tuberculosis and extrapulmonary tuberculosis. Among rheumatoid arthritis patients, there is apparently a higher frequency of the development of tuberculosis infection. The development of tuberculosis infection may be connected with the reactivation of a latent infection or with the development of a new infection. Before starting treatment, all patients should be screened for the presence of active or latent tuberculosis. The screening should include a detailed examination of the patient’s medical history with regard to contraction of tuberculosis or contact with tuberculosis patients in the past and information on previous or current immunosuppressive therapy. All patients should undergo necessary screenings in accordance with local requirements. These must include: a tuberculin skin test and a chest x-ray. The possibility of a false negative tuberculin skin test should be considered, especially in patients in a serious condition or in immunocompromised patients. It is also necessary to consider the possibility of the development of tuberculosis in patients in whom signs of tuberculosis infection were not found before beginning treatment with Enbrel®. The attending physician should monitor the condition of the patient for any signs of tuberculosis, including patients who originally tested negative for tuberculosis infection. Enbrel® should not be used if a patient has active tuberculosis. If inactive tuberculosis is present before beginning the treatment with Enbrel®, a standard anti-tuberculosis therapy should be prescribed in accordance with local recommendations. In this case, the benefit-to-risk ratio of treatment with Enbrel® should be thoroughly analyzed. All patients should be advised to contact a physician if symptoms typical of tuberculosis (for example, persistent cough, weight loss, low-grade fever) appear during or after treatment with Enbrel®. Activation of hepatitis B virus Cases of the activation of hepatitis B virus in carrier patients who received TNF inhibitors, including Enbrel®, have been reported. The majority of these cases took place in patients who had simultaneously been receiving other medicinal products that suppress the immune system and could also promote the reactivation of hepatitis B virus. Before using Enbrel® in patients with a high risk of contracting hepatitis B, appropriate diagnostic screening should be conducted. Despite the fact that no connection with the use of Enbrel® has been proven, special care should be taken when using Enbrel® in patients who are carriers of hepatitis B virus. It is necessary to monitor the condition of patients for signs of hepatitis B. If symptoms of the disease appear, the possibility of specific therapy should be discussed. Exacerbation of hepatitis C Cases of the exacerbation of hepatitis C have been documented in patients receiving treatment with Enbrel®; however, no cause-and-effect relationship with the use of etanercept has been proven. Nevertheless, caution should be exercised when administering Enbrel® to patients with a history of hepatitis C. Allergic reactions The use of Enbrel® is frequently accompanied by allergic reactions. In case of any severe allergic or anaphylactic reactions, treatment with Enbrel® should be discontinued immediately, and appropriate treatment should be started. The protective cap of the injection pen contains latex (dry natural rubber). Patients or caregivers should consult their physician before taking Enbrel® when the needle protective cap is handled by or when Enbrel® is administered to a patient with known or possible latex sensitivity (allergy). Immunosuppression During treatment with TNF inhibitors, including Enbrel®, there is a possibility of suppressing the body’s defense mechanisms against infections and malignant neoplasms, since TNF is involved in inflammation processes and modulates cellular immune responses. However, in adult patients with rheumatoid arthritis, there was no evidence of depressed delayed-type hypersensitivity reactions, decreased immunoglobulin levels or changes in the effector cell population size during treatment with Enbrel®. In rare cases, children with juvenile idiopathic polyarthritis developed varicella infection and symptoms of aseptic meningitis, which resolved with no complications. Patients who have been in contact with varicella virus should temporarily discontinue Enbrel® and start prophylactic treatment with immune globulin to Varicella Zoster . The efficacy and safety of Enbrel® in patients with immunosuppression have not been studied. Malignant and lymphoproliferative diseases In the post-marketing period (see “Side effects” section), reports of various malignant neoplasms (including breast and lung carcinoma and lymphoma) were received. In a number of controlled clinical studies, lymphoma was diagnosed more frequently in patients taking TNF inhibitors compared to patients who did not receive them. However, these cases were rare, and the observation period for the patients in the placebo group was shorter than for the patients receiving treatment with TNF inhibitors. There are reports of the development of leukemia in patients undergoing treatment with TNF inhibitors. There is a high risk of lymphoma and leukemia developing in patients with rheumatoid arthritis – a long-term disease characterized by active inflammation, which in itself complicates risk evaluation. A subsequent analysis of the clinical studies of etanercept in patients with rheumatoid arthritis did not confirm or exclude an increase in the risk of developing cancers in patients who receive etanercept. However, based on current data, the possible risk of developing lymphomas, leukemia or other malignant neoplasms cannot be ruled out in patients receiving TNF inhibitors. Malignant neoplasms (in half of the cases, Hodgkin’s and non-Hodgkin’s lymphomas), some of which had lethal outcomes, were reported in children and adolescents who had received treatment with TNF inhibitors, including Enbrel®. The majority of patients received concomitant treatment with immunosuppressants. In other cases, there were various malignant neoplasms, including rare varieties, linked with immunosuppression. During the use of the medicinal product, it is necessary to consider the risk of developing malignant neoplasms. Skin cancer Melanoma and non-melanoma skin cancer (NMSC) were documented in patients who had received treatment with TNF inhibitors, including Enbrel®. NMSC is most frequently diagnosed in psoriasis patients. The development of Merkel cell carcinoma has been reported. For all patients at high risk, periodic skin examinations are recommended. Formation of autoimmune antibodies Treatment with Enbrel® may be accompanied by the formation of autoimmune antibodies (see “Side effects” section). These are not neutralizing antibodies and usually disappear shortly. No correlation has been observed between the formation of antibodies and the clinical efficacy of the medicinal product or the frequency of adverse reactions. Isolated cases of the formation of additional autoantibodies in conjunction with lupus-like syndrome or rash similar to a subacute form of lupus erythematosus or a discoid form of lupus erythematosus (data from clinical examination and biopsy) were observed in patients, including those with rheumatoid arthritis with a positive rheumatoid factor. Hematological reactions Rare cases of pancytopenia and very rare cases of aplastic anemia were reported, including lethal cases, in patients who had received Enbrel®. Caution should be exercised when using Enbrel® in patients with a history of blood disorders. All patients and their relatives/caregivers should be advised to seek medical attention immediately if a patient develops signs or symptoms typical of an infection or hematological disorders (for example, persistent fever, tonsillitis, bruises, bleeding, pallor) when taking Enbrel®. These patients should undergo examination immediately, including a complete blood count. If the diagnosis of a hematological disorder is confirmed, treatment with Enbrel® should be discontinued. CNS disorders There have been rare reports of demyelinating diseases of the CNS in patients receiving treatment with etanercept. There have also been very rare reports of peripheral demyelinating polyneuropathies (including Guillain-Barré syndrome). The studies of treatment with Enbrel® in patients with multiple sclerosis have not been conducted; however, studies of other TNF inhibitors in patients with this condition showed the possibility of its exacerbation. Before beginning the treatment with Enbrel®, a thorough evaluation of the risk-to-benefit ratio and a neurological assessment are recommended in patients with pre-existing or recent-onset demyelinating diseases as well as patients with a high risk of developing a demyelinating disease. CHF Caution should be exercised in prescribing Enbrel® for patients with CHF. Rare (< 0.1%) cases of CHF were reported, including those in patients without a confirmed underlying cardiovascular disease. Some patients were under 50 years old. The data from a number of studies suggest the possibility of exacerbation of CHF in patients receiving Enbrel®. Combination therapy The combination of Enbrel® and methotrexate yielded no unexpected results in safety testing. The long-term study of this combination continues. Data on the safety of Enbrel® prescribed in combination with methotrexate were similar to those from reports on the use of either Enbrel® or methotrexate alone. The long-term safety of taking Enbrel® in combination with other disease- modifying anti-rheumatic drugs has not been studied. No studies on Enbrel® in combination with other systemic therapy or phototherapy for psoriasis have been conducted. Wegener’s granulomatosis The frequency of developing various types of malignant extracutaneous tumors was significantly higher in patients with Wegener’s granulomatosis who had received Enbrel ® than in the control group. Therefore, Enbrel ® is not recommended for the treatment of Wegener’s granulomatosis patients. Alcoholic hepatitis The administration of etanercept for the treatment of alcoholic hepatitis is not recommended. Hypoglycemia in patients with diabetes mellitus There have been reports of hypoglycemia during treatment with Enbrel® in patients taking hypoglycemic medications, requiring their dose adjustment. Effect on the ability to drive and operate machinery No studies on the effect of Enbrel® on the ability to drive motor vehicles and operate complex machinery have been conducted. Therefore, caution should be exercised when driving or operating machinery.
50 mg/mL solution for subcutaneous injection. 0.5 mL (25 mg) or 1.0 mL (50 mg) of the medicinal product in colorless glass (type I) single- use syringes fitted with a stainless-steel needle covered with a two-layer cap, a plastic finger grip and a plunger rod with a rubber seal. Four syringes in a set with four individually wrapped alcohol wipes in a plastic package with a ventilation hole. One, two or six plastic packages (25 mg) or one, two or three plastic packages (50 mg) along with Instructions for Use in a carton with or without a tamper-evident seal. 1.0 mL (50 mg) of the drug in a single-use injection pen with a white plastic needle cap and a purple protective screen. The syringe inside the pen is of colorless glass (type I) and is fitted with a stainless-steel needle. Four injection pens in a set with four individually wrapped alcohol wipes in a plastic package with an air vent. One plastic package with Instructions for Use in a carton with or without a tamper-evident seal.
Store between 2 °C and 8 °C. Do not freeze. Keep out of reach of children!
Three years. Do not use after the expiry date indicated on the package!
Dispensed by prescription.
Pfizer Manufacturing Belgium NV, Belgium Address: 12 Rijksweg, 2870 Puurs-Sint-Amands, Belgium
Pfizer Inc, USA Organization receiving consumer claims Pfizer Innovations LLC 123112, Moscow, Presnenskaya nab., d. 10, BTs [Business Centre] “Bashnya na Naberezhnoy” (Blok C) Phone: + 7 (495) 287-5000 Fax: +7 (495) 287-5300/287-5067
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Generated Narrative: AdministrableProductDefinition ap50mg Profile: AdministrableProductDefinition (ePI) identifier: https://www.who-umc.org/phpid/identifier status: Active formOf: MedicinalProductDefinition: identifier = http://www.mhra.gov.uk/#471bb15-7f52-4fcd-b615-8674ce6eb91e; type = Medicinal Product; domain = Human use; status = active; legalStatusOfSupply = Medicinal product subject to medical prescription administrableDoseForm: Solution for injection unitOfPresentation: Syringe producedFrom: ManufacturedItemDefinition: identifier = https://www.minzdrav.gov.ru/#99b900c6-4776-4cde-8125-4f6de8e98b98 (use: official, ); status = active; manufacturedDoseForm = Solution for injection; unitOfPresentation = Syringe routeOfAdministration code: Subcutaneous use TargetSpecies - Code * Human
Generated Narrative: RegulatedAuthorization authorization50mg Profile: RegulatedAuthorization (ePI) identifier: https://spor.ema.europa.eu/pmswi/6ae5b5d9-7372-494c-874b-7dc67d386d2e (use: official, ) subject: MedicinalProductDefinition: identifier = http://www.mhra.gov.uk/#471bb15-7f52-4fcd-b615-8674ce6eb91e; type = Medicinal Product; domain = Human use; status = active; legalStatusOfSupply = Medicinal product subject to medical prescription type: Marketing Authorisation region: Russia status: Active statusDate: 2023-08-16 00:00:00+0000 holder: Organization Pfizer Innovations LLC
Generated Narrative: Organization orgpfizerusinc Profile: Organization (ePI) identifier: https://spor.ema.europa.eu/omswi/placeholder (use: official, ) active: true type: Marketing authorisation holder name: Pfizer Innovations LLC Contacts - Address * 123112, Moscow, Presnenskaya nab., d. 10, BTs [Business Centre] “Bashnya na Naberezhnoy” (Blok C)(work)
123112, Moscow, Presnenskaya nab., d. 10, BTs [Business Centre] “Bashnya na Naberezhnoy” (Blok C)
Generated Narrative: Organization orgpfizerbe Profile: Organization (ePI) identifier: https://spor.ema.europa.eu/omswi/placeholder (use: official, ) active: true type: Manufacturer name: Pfizer Manufacturing Belgium NV, Belgium Contacts - Address * 12 Rijksweg, 2870 Puurs-Sint-Amands, Belgium(work)
Pfizer Manufacturing Belgium NV, Belgium
12 Rijksweg, 2870 Puurs-Sint-Amands, Belgium
Generated Narrative: PackagedProductDefinition ppd50mgsyringe4 Profile: PackagedProductDefinition (ePI) identifier: https://spor.ema.europa.eu/pmswi/b42ab299-e84b-4be3-bdbb-a66cd4c8c6ab (use: official, ) name: Enbrel four syringe plastic package type: Biological Medicinal Product packageFor: MedicinalProductDefinition: identifier = http://www.mhra.gov.uk/#471bb15-7f52-4fcd-b615-8674ce6eb91e; type = Medicinal Product; domain = Human use; status = active; legalStatusOfSupply = Medicinal product subject to medical prescription status: Active statusDate: 2023-08-16 00:00:00+0000 containedItemQuantity: 50 mg (Details: UCUM codemg = 'mg') manufacturer: Organization Pfizer Manufacturing Belgium NV, Belgium Packagings - Identifier Type Quantity Material * https://spor.ema.europa.eu/pmswi/5913fadd-6172-4282-ad02-19ab9d063b66 Box 4 Plastic
Generated Narrative: MedicinalProductDefinition mp50mg Profile: MedicinalProductDefinition (ePI) identifier: http://www.mhra.gov.uk//471bb15-7f52-4fcd-b615-8674ce6eb91e type: Medicinal Product domain: Human use status: active legalStatusOfSupply: Medicinal product subject to medical prescription name productName: Enbrel (etanercept) 50 mg/ml solution for subcutaneous injection Usages - Country Jurisdiction Language * Russia Russia Russian
Medicinal product subject to medical prescription
Enbrel (etanercept) 50 mg/ml solution for subcutaneous injection