Medicinal Products

ENBREL 25 mg

Generic drug of the therapeutic class: Immunology
active ingredients: Etanercept
laboratory: Pfizer Limited

Injectable solution
Set of 4 pre-filled 0.5 mL syringes
All forms

Indication

Rheumatoid arthritis

Enbrel in combination with methotrexate is indicated for the treatment of moderate to severely active rheumatoid arthritis in adults with inadequate response to DMARDs, including methotrexate (unless contraindicated).


Enbrel may be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is unsuitable.


Enbrel is also indicated for the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.


Enbrel, alone or in combination with methotrexate, has been shown to slow the progression of structural joint damage as measured by X-ray and improve functional abilities.


Juvenile idiopathic arthritis

Treatment of rheumatoid arthritis (positive or negative rheumatoid factor) and extensive oligoarthritis in children from 2 years of age and adolescents in case of inadequate response or proven intolerance to methotrexate.


Treatment of psoriatic arthritis of the adolescent from the age of 12 years in case of inadequate response or proven intolerance to methotrexate.


Treatment of enthesitis-related arthritis in adolescents from the age of 12 years in the event of an inadequate response or proven intolerance to the reference treatment.

Enbrel has not been studied in children under 2 years old.


Psoriatic arthritis

Treatment of active and progressive psoriatic arthritis of the adult in case of inadequate response to previous background therapy. Enbrel has been shown to improve functional abilities in patients with psoriatic arthritis, and to slow the progression of peripheral joint structural damage as measured by radiography in patients with symmetrical polyarticular forms of the disease.


Axial spondyloarthritis


Ankylosing spondylitis (AS)

Treatment of severe and active ankylosing spondylitis in adults with inadequate response to conventional therapy.


Non-radiographic axial spondyloarthritis

Treatment of severe non-radiographic axial spondyloarthritis of the adult with objective signs of inflammation, resulting in a high level of C-reactive protein (CRP) and / or visible signs on magnetic resonance imaging (MRI), in case of inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs).


Plaque psoriasis

Treatment of moderate-to-severe plaque psoriasis in adults in the event of failure, contra-indication, or intolerance to other systemic therapies, including ciclosporin, methotrexate, or PUVA (see section 5.1 ).


Psoriasis in plaques of the child

Treatment of severe chronic plaque psoriasis in children from 6 years of age and adolescents in case of inadequate control, or intolerance to other systemic treatments or phototherapy.

Dosage ENBREL 25 mg Injection solution Pack of 4 0.5 mL pre-filled syringes

Treatment with Enbrel must be initiated and supervised by a medical specialist experienced in the diagnosis and treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, plaque psoriasis or plaque psoriasis in the child. The Patient Monitor Card should be given to patients treated with Enbrel.


Enbrel is available in dosages of 10, 25 and 50 mg.


Dosage

Rheumatoid arthritis

The recommended dose of Enbrel is 25 mg twice weekly. However, the efficacy and safety of administration of 50 mg once a week has been demonstrated (see section 5.1 ).

Psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis The recommended dose is 25 mg Enbrel twice weekly or 50 mg once weekly.


For all the above indications, the available data suggest that a clinical response is usually achieved within 12 weeks of treatment. Further treatment should be carefully reconsidered in a patient who has not responded within this time frame.

Plaque psoriasis

The recommended dose of Enbrel is 25 mg twice daily or 50 mg once weekly. However, a dose of 50 mg twice a week may be used up to 12 weeks followed, if necessary, by a dose of 25 mg twice weekly or 50 mg once a week. Treatment with Enbrel should be continued until remission is achieved, up to a maximum of 24 weeks. Continuous treatment beyond 24 weeks may be appropriate for some adult patients (see section 5.1 Pharmacodynamic properties ). Treatment with Enbrel should be discontinued in patients with no response after 12 weeks of treatment.


If re-treatment with Enbrel is indicated, the same treatment duration schedule should be followed. The dose should be 25 mg given twice a week or 50 mg once a week.


Special populations

Patients with renal and hepatic impairment

No dosage adjustment is necessary.

Elderly (≥65 years old)

No dosage adjustment is necessary. The dosage and administration are identical to those of adults aged 18 to 64 years.

Pediatric population

The dose of Enbrel depends on the weight of pediatric patients. Patients weighing less than 62.5 kg should be given an exact dose calculated in mg / kg using the powder and solvent for solution for injection or the powder for solution for injection (see below for doses as indicated). Patients weighing 62.5 kg or more can receive a fixed dose using the pre-filled syringe or pre-filled pen (50 mg / week).

Juvenile idiopathic arthritis

The recommended dose is 0.4 mg / kg (maximum 25 mg per injection), administered twice a week as a subcutaneous injection, with an interval of 3-4 days between two injections or 0.8 mg / kg (at most 50 mg per injection) administered once a week. Discontinuation of treatment should be considered in non-responder patients after 4 months.


The 10 mg dosage is more suitable for administration to children with JIA less than 25 kg.


No clinical trials have been conducted in children aged 2 to 3 years. Limited safety data from a patient registry, however, suggests that the safety profile in children aged 2 to 3 years is similar to that of adults and children over 4 years of age, at a dose of 0, 8 mg / kg subcutaneously weekly (see section 5.1 Pharmacodynamic properties ).

Enbrel is generally not recommended for use in children under 2 years of age for juvenile idiopathic arthritis.

Plaque psoriasis of the child (6 years old and over)


The recommended dose is 0.8 mg / kg (maximum 50 mg per injection) once a week up to 24 weeks. Treatment should be discontinued in patients who do not respond after 12 weeks of treatment.


If resumption of treatment with Enbrel is indicated, the treatment duration schedule described above should be followed. The dose should be 0.8 mg / kg (maximum 50 mg per injection) once a week.


Enbrel is generally not recommended for use in children under 6 years of age for plaque psoriasis.


Administration mode

Enbrel is administered by subcutaneous injection (see section Instructions for use, handling and disposal ).


Full instructions for administration of Enbrel are given in the package leaflet, section 7 "Instructions for the preparation and administration of an injection of Enbrel".

Against indications

Hypersensitivity to the active substance or to any of the excipients.

Septicemia or risk of sepsis.

Treatment with Enbrel should not be initiated in patients with active infection including chronic or localized infections.

Enbrel side effects

Summary of the safety profile 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 infections, bronchitis, cystitis and skin infections), allergic reactions, development of auto-antibodies, itching and fever.


Serious side effects 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 infection and cancer. Serious infections affect less than 1 in 100 patients treated with Enbrel. Reported cases included fatal infections, 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 nodes (lymphoma).


Serious hematological, neurological and autoimmune adverse reactions have also been reported. These included rare cases of pancytopenia and very rare cases of bone marrow failure. Demyelinating episodes, central and peripheral, have been observed, respectively rarely and very rarely, during the use of Enbrel. Rare cases of lupus, lupus syndrome and vasculitis have been observed.


Tabulated list of adverse effects

The following list of adverse reactions is based on clinical trial experience in adults and data reported since marketing.


According to the organ classification system, adverse reactions are listed below in order of frequency (number of patients likely to have a given effect), using the following categories: very common (≥1 / 10); frequent (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10000 to <1/1000); very rare (<1/10000); indeterminate frequency (can not be estimated based on available data).

Infections and infestations:


Very common: Infections (including upper respiratory tract infections, bronchitis, cystitis, skin infections) *
Uncommon: Serious infections (including pneumonia, cellulitis, septic arthritis, septicemia and parasitic infection) *
Rare: Tuberculosis, opportunistic infections (including invasive fungal infections, protozoa, atypical bacterial and mycobacterial infections and Legionella) *

Not known: Listeriosis, reactivation of hepatitis B

Benign, malignant and unspecified tumors (including cysts and polyps):


Uncommon: Non-melanoma skin cancer * (see Warnings and Precautions section )

Rare: Lymphoma, melanoma (see section Warnings and precautions for use )

Frequency not known: Leukemia, Merkel cell carcinoma (see Warnings and precautions for use )

Hematological and lymphatic system disorders:


Uncommon: Thrombocytopenia

Rare: Anemia, leukopenia, neutropenia, pancytopenia *

Very rare: Medullary Aplasia *

Immune system disorders:


Common: Allergic reactions (see Skin and subcutaneous tissue disorders), autoantibody formation *

Uncommon: Systemic vasculitis (including neutrophil-positive anti-cytoplasmic vasculitis)

Rare: Serious allergic / anaphylactic reactions (including angioedema, bronchospasm), sarcoidosis

Not known: Macrophage activation syndrome *, worsening of dermatomyositis symptoms

Nervous system disorders:


Rare: Convulsions

CNS demyelinating episodes may suggest multiple sclerosis or localized demyelinization such as optic neuritis or transverse myelitis (see Warnings and Precautions section )

Very rare: Peripheral demyelinating episodes, including Guillain's syndrome

Barré, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy and multifocal motor neuropathy (see Warnings and precautions for use section )

Eye disorders:


Uncommon: Uveitis, scleritis

Heart conditions:


Rare: Aggravation of congestive heart failure (see section Warnings and precautions for use )

Respiratory, thoracic and mediastinal disorders:


Uncommon: Interstitial lung disease (including pneumonitis and pulmonary fibrosis) *

Hepatobiliary disorders:


Rare: Elevated liver enzymes, autoimmune hepatitis

Skin and subcutaneous tissue disorders: Common: Pruritus,

Uncommon: Angioedema, urticaria, rash, psoriasiform rash, psoriasis, and

including first involvement or aggravation and pustular involvement (mainly palm-plantar)

Rare: Cutaneous vasculitis (including leukocytoclastic vasculitis),

Stevens-Johnson, erythema multiforme

Very rare: Lyell Syndrome

Musculoskeletal and systemic disorders:


Rare: subacute cutaneous lupus erythematosus, discoid lupus erythematosus, lupus syndrome

General disorders and administration site defects:


Very common: Injection site reactions (including bleeding, contusion, erythema, itching, pain, swelling) *
Common: Fever

* See Description of some side effects, below.
Description of some adverse effects

Malignant neoplasms and lymphoproliferative disorders

The occurrence of 129 new malignant tumors of different types was observed in a total of 4, 114 patients with rheumatoid arthritis treated with Enbrel in clinical trials up to approximately 6 years of age, including 231 patients treated with Enbrel plus methotrexate in the controlled study versus active treatment lasting 2 years. The rates and incidences observed in these clinical trials were similar to those expected in the study population. A total of 2 malignancies have been reported in clinical trials involving 240 patients with psoriatic arthritis treated with Enbrel for approximately 2 years. In clinical studies conducted for more than 2 years in 351 patients with ankylosing spondylitis, 6 malignancies have been reported in patients treated with Enbrel. In a group of 2711 patients with plaque psoriasis treated with Enbrel for up to 2.5 years in double-blind and open studies, 30 malignant tumors and 43 non-melanoma skin cancers were reported.


In a group of 7416 patients treated with Enbrel in clinical trials in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and psoriasis, 18 lymphomas were reported.


Various cases of malignancies (including breast cancer, lung cancer, lymphoma) have also been reported after marketing (see Warnings and Precautions ).

Injection site reactions

The incidence of injection site reactions was significantly higher in patients with rheumatic diseases treated with Enbrel compared to placebo (36% vs. 9%). Injection site reactions usually occurred during the first month of treatment. Their average duration was approximately 3 to 5 days. The majority of injection site reactions in the Enbrel-treated groups required no treatment. The majority of patients who received treatment received topical preparations, such as corticosteroids, or oral antihistamines. Moreover, some patients have developed "booster" reactions characterized by the appearance of a cutaneous reaction at the most recent injection site, accompanied by cutaneous reactions at the sites of previous injections. These reactions were usually transient and did not reappear during further treatment.


In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients treated with Enbrel developed injection site reactions compared to 3.4% of placebo-treated patients in the first 12 weeks of treatment. treatment.

Serious infections

In placebo-controlled trials, there was no increase in the incidence of serious (life-threatening, life-threatening infections requiring hospitalization or intravenous antibiotics). Serious infections occurred in 6.3% of patients with Enbrel-treated rheumatoid arthritis up to 48 months of age. These infections included abscesses (various locations), bacteremia, bronchitis, bursitis, infectious cellulitis, cholecystitis, diarrhea, diverticulitis, endocarditis (suspected), gastroenteritis, hepatitis B, herpes, leg ulcer, oral infection, osteomyelitis, otitis, peritonitis, pneumonia, pyelonephritis, septicemia, septic arthritis, sinusitis, skin infection, skin ulcer, urinary tract infection, vasculitis and infected wound. In the 2-year controlled-versus-active study, in which patients were treated with either Enbrel alone, or with methotrexate alone, or with Enbrel plus methotrexate, the rates of serious infections were similar among treatment groups. However, it can not be excluded that the combination of Enbrel with methotrexate may be associated with an increased rate of infections.


There was no difference in infection rates among Enbrel and placebo-treated patients for plaque psoriasis in placebo-controlled trials lasting up to 24 weeks. Serious infections reported in patients treated with Enbrel included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis, gastritis, appendicitis, streptococcal fasciitis, myositis, septic shock, diverticulitis and abscess. In the double-blind and open-label trials in psoriatic arthritis, one case of severe infection (pneumonia) has been reported.


Serious or fatal infections have been reported while using Enbrel; the identified pathogens are bacteria, mycobacteria (including tuberculosis bacillus), viruses and fungi. Some appeared weeks after the start of treatment with Enbrel in patients with predisposing factors (eg diabetes, heart failure, history of infection or chronic infection) in addition to their rheumatoid arthritis (see Warnings and Precautions section). ). Treatment with Enbrel may increase mortality in patients with known sepsis.

Opportunistic infections have been reported in association with Enbrel, including invasive fungal, parasitic (including protozoan), bacterial (including Listeria and Legionella), and atypical mycobacterial infections. Based on combined clinical trial data, the overall incidence of opportunistic infections was 0.09% among the 15, 402 subjects who received Enbrel. The event-related event rate was 0.06 events per 100 patient-years. About half of the post-marketing cases of opportunistic infections reported worldwide were invasive fungal infections. The most frequently reported invasive fungal infections were due to Pneumocystis and Aspergillus. More than half of the deaths related to opportunistic infections were due to invasive fungal infections. The majority of deaths occurred in patients with Pneumocystis pneumonia, unspecified systemic fungal infection, or aspergillosis (see Warnings and Precautions section ).

Autoantibodies

Blood tests for autoantibodies have been performed at different times in adult patients. Among patients with rheumatoid arthritis who were measured for antinuclear antibodies (ANA), the percentage of patients who developed new antinuclear antibodies (≥140) was higher in patients treated with Enbrel ( 11%) than in patients treated with placebo (5%). The percentage of patients who developed new anti-native DNA antibodies was also higher by radioimmunoassay (15% of patients treated with Enbrel versus 4% of patients treated with placebo) and by Crithidia lucilliae (3% of patients). treated with Enbrel versus 0% of placebo-treated patients). The proportion of patients treated with Enbrel who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients. The long-term impact of Enbrel treatment on the development of autoimmune diseases is unknown.


Have been reported rare cases of patients (including those with rheumatoid factor positive), who have developed other autoantibodies associated with lupus syndrome or clinically compatible rashes and after biopsy, with cutaneous lupus subacute or discoid lupus.

Pancytopenia and medullary aplasia

After marketing cases of pancytopenia and bone marrow suppression have been reported, some of which have had a fatal outcome (see Warnings and precautions for use ).

Interstitial lung disease

After commercialization, cases of interstitial lung disease (including pneumonitis and pulmonary fibrosis) have been reported, some of which have been fatal.

Concomitant treatment with anakinra

In studies in which adult patients received concomitant treatment with Enbrel and anakinra, a higher rate of serious infections was observed compared to Enbrel alone and 2% of patients (3/139) had neutropenia ( polymorphonuclear neutrophils <1000 / mm 3 ). While presenting with neutropenia, a patient developed cellulitis that healed after hospitalization

(see sections Warnings and precautions for use and Interactions with other medicinal products and other forms of interaction ).

Pediatric population

Adverse effects in children with juvenile idiopathic arthritis


In general, adverse events in children with juvenile idiopathic arthritis were similar in frequency and in nature to those seen in adults. Differences from adults and other special features are described in the following topics.


The types of infections reported in clinical trials in patients with juvenile idiopathic arthritis aged 2 to 18 years were generally mild to moderate and similar to the types of infections commonly seen in pediatric patients. The reported serious adverse events were chickenpox with signs and symptoms of aseptic meningitis followed by a cure without sequelae (see also section Warnings and precautions for use ), appendicitis, gastroenteritis, depression / personality disorder skin ulcer, esophagitis / gastritis, group A streptococcal septic shock, type I diabetes, and postoperative wound and soft tissue infection.


In a study of children with juvenile idiopathic arthritis aged 4 to 17 years, 43 of 69 children (62%) had an infection receiving Enbrel during the 3-month study period (part 1, open label) and the frequency and severity of infections were similar among the 58 patients who continued the open-label extension study for 12 months. The types and proportion of all adverse events in patients with juvenile idiopathic arthritis were similar to those observed in clinical trials of Enbrel in adults with rheumatoid arthritis and were predominantly mild. Several adverse events were reported more frequently in 69 patients with juvenile idiopathic arthritis who received Enbrel for 3 months compared to 349 adult patients with rheumatoid arthritis. These were headache (19% of patients, 1.7 events per patient-year), nausea (9%, 1.0 event per patient-year), abdominal pain (19%, 0.74 event per patient). year), and vomiting (13%, 0.74 event per patient-year).


Four cases of macrophage activation syndrome have been reported in clinical trials in juvenile idiopathic arthritis.


Since commercialization, cases of inflammatory bowel disease and uveitis have been reported in patients with JIA treated with Enbrel; a small number of these cases recurred when treatment with Enbrel was resumed (see Warnings and Precautions ).


Side effects in children with plaque psoriasis


In a 48-week study in 211 children aged 4 to 17 years with plaque psoriasis, the reported adverse events were similar to those seen in previous studies in adults with plaque psoriasis.


Reporting of suspected adverse reactions

The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Health professionals report any suspected adverse reactions via the national reporting system - see Annex V.

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