Enbrel 25 mg, 50 mg Powder and solvent for solution for injection

Rheumatoid arthritis

ENBREL can be used alone or in combination with methotrexate to reduce the signs and symptoms and inhibit the progression of structural damage as measured by X-ray of active rheumatoid arthritis (RA) in adults when the response to one or more disease modifying antirheumatic medicines has proven inadequate. ENBREL is also indicated for the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.

Juvenile idiopathic arthritis

Treatment of polyarticular-course juvenile idiopathic arthritis (JIA) in children and adolescents from the age of 2 years when the response to one or more disease-modifying antirheumatic drugs (DMARDs) has proved inadequate. ENBREL is indicated for treatment of active polyarticular-course juvenile idiopathic arthritis and extended oligoarthritis in children and adolescents from the age of 2 years who have had inadequate response to, or who have proved intolerant of, methotrexate. Treatment of psoriatic arthritis in adolescents from the age of 12 years who have had an inadequate response to, or who have proved intolerant of, methotrexate. Treatment of enthesitis-related arthritis in adolescents from the age of 12 years who have had an inadequate response to, or who have proved intolerant of, conventional therapy.

Psoriatic arthritis

ENBREL is indicated for reducing signs and symptoms and inhibiting the progression of structural damage of active arthritis in patients with psoriatic arthritis. ENBREL can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Axial spondylarthritis

Ankylosing spondylitis (AS) ENBREL is indicated to reduce signs and symptoms in patients with ankylosing spondylitis.

Non-radiographic axial spondyloarthritis

ENBREL is indicated for the treatment of adults with severe non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated CRP and/or MRI evidence, who have had an inadequate response to, or are intolerant to, conventional therapy.

Plaque psoriasis

ENBREL is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Paediatric plaque psoriasis

ENBREL is indicated for the treatment of chronic severe plaque psoriasis in children and adolescents from the age of 6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.

Posology

Use in adults

Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondylarthritis

The recommended dose of ENBREL for adult patients 18 years and older with rheumatoid arthritis is 25 mg reconstituted in 1,0 mL of water for injection administered twice weekly (72 to 96 hours apart) as a subcutaneous injection. 50 mg per week provides the optimal therapeutic response in rheumatoid arthritis. ENBREL can be administered as follows:

• once weekly (two 25 mg subcutaneous injections reconstituted in 1,0 mL of water for injection or two ENBREL 25 mg PS pre-filled syringes) administered subcutaneously at approximately the same time or
• one single 25 mg subcutaneous injection reconstituted in 1,0 mL of water for injection or one ENBREL 25 mg PS pre-filled syringe administered twice weekly, 3 u2013 4 days apart (i.e. two 25 mg single dose vials or two 25 mg PS pre-filled syringes per week) or
• ENBREL 50 mg PS pre-filled syringe or pre-filled pen administered once weekly as a subcutaneous injection.

In psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondylarthritis, the recommended dose is 50 mg per week (given as one single 25 mg injection reconstituted in 1,0 mL of water for injection or as one ENBREL 25 mg PS pre-filled syringe given twice weekly, 3 u2013 4 days apart). Doses other than 25 mg administered twice weekly have not been studied. Methotrexate, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be continued during treatment with ENBREL in adults.

Plaque psoriasis

In plaque psoriasis, the dose of ENBREL is 50 mg per week given as one single 25 mg injection reconstituted in 1,0 mL water for injection or as one ENBREL 25 mg PS pre-filled syringe administered twice weekly, 3 u2013 4 days apart or ENBREL 50 mg PS pre-filled syringe or pre-filled pen administered once weekly. Higher responses may be achieved from initial treatment up to 12 weeks with a dose of 50 mg given twice weekly. Adult patients may be treated intermittently or continuously, based on physician judgement and individual patient needs. Treatment should be discontinued in patients who show no response after 12 weeks. With intermittent use, treatment cycles subsequent to the initial cycle should use a dose of 50 mg once weekly or 25 mg twice weekly.

Special populations

Use in elderly patients

No dosage adjustment is required.

Use in patients with renal impairment

No dosage adjustment is required.

Use in patients with hepatic impairment

No dosage adjustment is required.

Paediatric population

The dosage of ENBREL is based on body weight for paediatric patients. Patients weighing less than 62,5 kg should be accurately dosed on a mg/kg basis using ENBREL 25 mg/mL powder and solvent for solution for injection (see below for dosing for specific indications). Patients weighing 62,5 kg or more may be dosed using a fixed-dose pre-filled syringe or pre-filled pen.

Juvenile idiopathic arthritis (age 2 years and above)

Children (u2265 2 to < 18 years) 0,4 mg/kg (up to a maximum of 25 mg per dose) after reconstitution of 25 mg ENBREL in 1,0 mL of water for injection or ENBREL 25 mg PS pre-filled syringe, given twice weekly as a subcutaneous injection with an interval of 3 u2013 4 days between doses or 0,8 mg/kg (up to a maximum of 50 mg per dose) given once weekly. Glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be continued during treatment with ENBREL in children. ENBREL has not been studied in children < 2 years of age.

Paediatric plaque psoriasis (age 6 years and above)

Children (u2265 6 to < 18 years) 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. If re-treatment with ENBREL is indicated, the above guidance on treatment duration should be followed. The dose should be 0,8 mg/kg (up to a maximum of 50 mg per dose) once weekly.

Method of administration

For subcutaneous injection.

Preparation of ENBREL

ENBREL is intended for use under the guidance and supervision of a physician. Patients may self-inject only if their physician determines that it is appropriate and with medical follow-up, as necessary, after proper training in injection technique.

Administration

Administer ENBREL as subcutaneous injections in the thigh, abdomen, or upper arm. Alternate injection sites. New injections 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.

• ENBREL should not be administered to patients with known hypersensitivity to etanercept or to any of the excipients of ENBREL listed in section 6.1.
• ENBREL should not be administered to patients with sepsis or risk of sepsis.
• Treatment with ENBREL should not be initiated in patients with serious active infections, including chronic or localised infections.

Infections

SERIOUS INFECTIONS INCLUDING SEPSIS AND TUBERCULOSIS (TB) HAVE BEEN REPORTED WITH THE USE OF ENBREL (SEE SECTION 4.8). SOME OF THESE INFECTIONS HAVE BEEN FATAL. THESE INFECTIONS WERE DUE TO BACTERIA, MYCOBACTERIA, FUNGI, VIRUSES, AND PARASITES (INCLUDING PROTOZOA). OPPORTUNISTIC INFECTIONS HAVE ALSO BEEN REPORTED (INCLUDING LISTERIOSIS AND LEGIONELLOSIS). PATIENTS WHO DEVELOP A NEW INFECTION WHILE UNDERGOING TREATMENT WITH ENBREL SHOULD BE MONITORED CLOSELY. ADMINISTRATION OF ENBREL SHOULD BE DISCONTINUED IF A PATIENT DEVELOPS A SERIOUS INFECTION. CAUTION SHOULD BE EXERCISED WHEN CONSIDERING THE USE OF ENBREL IN PATIENTS WITH A HISTORY OF RECURRING OR CHRONIC INFECTIONS OR WITH UNDERLYING CONDITIONS WHICH MAY PREDISPOSE PATIENTS TO INFECTIONS (SEE SECTIONS 4.3 AND 4.8).

Patients should be evaluated for infections, including active or latent tuberculosis, hepatitis B and C before, during and after treatment with ENBREL (see below). ENBREL treatment should be discontinued if a patient develops life-threatening infection. Caution should be exercised in patients at high risk of developing serious infection, including patients undergoing major surgeries.

Opportunistic infections, including invasive fungal infections, have been reported in patients receiving ENBREL. In some cases, fungal and other opportunistic infections are not recognised, and this has resulted in delays in appropriate treatment, sometimes resulting in death. In many of the reports, patients have also received concomitant medicines including immunosuppressants. In evaluating patients for infections, health care providers should consider the patientu2019s risk for relevant opportunistic infections (e.g. exposure to endemic mycoses).

TREATMENT WITH ENBREL SHOULD NOT BE INITIATED IN PATIENTS WITH ACTIVE INFECTIONS INCLUDING CHRONIC OR LOCALISED INFECTIONS. HEALTH CARE PROVIDERS SHOULD EXERCISE CAUTION WHEN CONSIDERING THE USE OF ENBREL IN PATIENTS WITH A HISTORY OF RECURRING INFECTIONS OR WITH UNDERLYING CONDITIONS WHICH MAY PREDISPOSE PATIENTS TO INFECTIONS, SUCH AS ADVANCED OR POORLY CONTROLLED DIABETES.

Tuberculosis (TB)

Tuberculosis (including disseminated or extrapulmonary presentation) has been observed in patients receiving TNF-blocking medicines, including ENBREL. Tuberculosis may be due to reactivation of latent TB infection or to new infection. BEFORE INITIATION OF THERAPY WITH ENBREL, ANY PATIENT AT INCREASED RISK FOR TB SHOULD BE EVALUATED FOR ACTIVE OR LATENT INFECTION. PROPHYLAXIS OF LATENT TB INFECTION SHOULD BE INITIATED PRIOR TO THERAPY WITH ENBREL. SOME PATIENTS WHO TESTED NEGATIVE FOR LATENT TUBERCULOSIS PRIOR TO RECEIVING ENBREL HAVE DEVELOPED ACTIVE TUBERCULOSIS. HEALTH CARE PROVIDERS SHOULD MONITOR PATIENTS RECEIVING ENBREL FOR SIGNS AND SYMPTOMS OF ACTIVE TUBERCULOSIS, INCLUDING PATIENTS WHO TESTED NEGATIVE FOR LATENT TUBERCULOSIS INFECTION. APPLICABLE LOCAL GUIDELINES SHOULD BE CONSULTED. PATIENTS WITH RA APPEAR TO HAVE AN INCREASED RATE OF TB INFECTION.

Hepatitis B (HBV) reactivation

REACTIVATION OF HEPATITIS B IN PATIENTS WHO WERE PREVIOUSLY INFECTED WITH THE HEPATITIS B VIRUS (HBV) AND HAD RECEIVED CONCOMITANT ANTI-TNF MEDICINES INCLUDING ENBREL HAS BEEN REPORTED. THE MAJORITY OF THESE REPORTS HAVE OCCURRED IN PATIENTS CONCOMITANTLY RECEIVING OTHER MEDICINES THAT SUPPRESS THE IMMUNE SYSTEM, WHICH MAY ALSO CONTRIBUTE TO HEPATITIS B REACTIVATION. PATIENTS AT RISK FOR HBV INFECTION SHOULD BE EVALUATED FOR PRIOR EVIDENCE OF HBV INFECTION BEFORE INITIATING ANTI-TNF THERAPY. CAUTION SHOULD BE EXERCISED WHEN ADMINISTERING ENBREL FOR PATIENTS PREVIOUSLY INFECTED WITH HBV. THESE PATIENTS SHOULD BE MONITORED FOR SIGNS AND SYMPTOMS OF ACTIVE HBV INFECTION.

Worsening of hepatitis C

THERE HAVE BEEN REPORTS OF WORSENING OF HEPATITIS C IN PATIENTS RECEIVING ENBREL.

Concurrent treatment with anakinra

CONCURRENT ADMINISTRATION OF ENBREL AND ANAKINRA HAS BEEN ASSOCIATED WITH AN INCREASED RISK OF SERIOUS INFECTIONS AND NEUTROPENIA. THE COMBINATION HAS NOT DEMONSTRATED INCREASED CLINICAL BENEFIT; SUCH USE IS NOT RECOMMENDED (SEE SECTION 4.5).

Concurrent treatment with abatacept

IN CLINICAL STUDIES, CONCURRENT ADMINISTRATION OF ABATACEPT AND ENBREL THERAPY RESULTED IN INCREASED INCIDENCES OF SERIOUS ADVERSE EVENTS. THIS COMBINATION HAS NOT DEMONSTRATED INCREASED CLINICAL BENEFIT; SUCH USE IS NOT RECOMMENDED (SEE SECTION 4.5).

Wegeneru2019s granulomatosis

IN A PLACEBO-CONTROLLED STUDY OF 180 PATIENTS WITH WEGENERu2019S GRANULOMATOSIS, THE ADDITION OF ENBREL TO STANDARD TREATMENT (INCLUDING CYCLOPHOSPHAMIDE AND HIGH-DOSE STEROIDS) WAS NO MORE EFFICACIOUS THAN STANDARD TREATMENT ALONE. THE GROUP OF PATIENTS WHO RECEIVED ENBREL EXPERIENCED MORE NON-CUTANEOUS MALIGNANCIES OF VARIOUS TYPES THAN THE PATIENT GROUP RECEIVING STANDARD TREATMENT ALONE. THE USE OF ENBREL FOR TREATMENT OF WEGENERu2019S GRANULOMATOSIS IS NOT RECOMMENDED.

Alcoholic hepatitis

In a study of 48 hospitalised patients treated with ENBREL or placebo for moderate to severe alcoholic hepatitis [mean Model of End-stage Liver Disease (MELD) score = 25], ENBREL was not efficacious and the mortality rate in patients treated with ENBREL was significantly higher after 6 months. Infections were also higher in the group treated with ENBREL The use of ENBREL in patients for the treatment of alcoholic hepatitis is not recommended. Health care providers should use caution when using ENBREL in patients who also have moderate to severe alcoholic hepatitis.

Allergic reactions

Parenteral administration of any biologic medicine should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Allergic reactions associated with ENBREL administration have been reported. If any serious allergic or anaphylactic reaction occurs, ENBREL therapy should be discontinued immediately and appropriate therapy initiated.

ENBREL 25 mg powder and solvent for solution for injection

The rubber closure of the solvent syringe contains latex (dry natural rubber). Patients or caregivers should contact their health care provider before using ENBREL if the rubber closure of the solvent syringe will be handled by or if ENBREL will be given to someone with a known or possible hypersensitivity (allergy) to latex.

ENBREL 25 mg and 50 mg PS solution for injection in pre-filled syringe or pre-filled pen

The needle cover of the pre-filled syringe and the needle cap of the pre-filled pen contain latex (dry natural rubber). Patients or caregivers should contact their health care provider before using ENBREL PS if the needle cover will be handled by or if ENBREL PS will be given to someone with a known or possible hypersensitivity (allergy) to latex.

Concurrent treatment with anakinra

Patients treated with ENBREL and anakinra were observed to have a higher rate of serious infection when compared with patients who were treated with ENBREL alone (historical data). In addition, in a double-blind placebo-controlled trial in patients receiving background methotrexate, patients treated with ENBREL and anakinra were observed to have a higher rate of serious infections and neutropenia than patients treated with ENBREL alone (see section 4.4).

Concurrent treatment with abatacept

In clinical studies, concurrent administration of abatacept and ENBREL therapy resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended (see section 4.4).

Concurrent treatment with sulfasalazine

In a clinical study of patients who were receiving established doses of sulfasalazine, to which ENBREL was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell count in comparison to groups treated with ENBREL or sulfasalazine alone. The clinical significance of this interaction is unknown.

Non-interactions

Methotrexate has no effect on the pharmacokinetics of ENBREL and may therefore be administered in combination with methotrexate. Interactions between ENBREL and other medicines have not been evaluated in formal studies. No confirmed medicine interactions have been reported with the use of ENBREL. No interactions have been observed when ENBREL was administered with glucocorticoids, salicylates (except sulfasalazine), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics or methotrexate in clinical trials with adult rheumatoid arthritis patients. No clinically significant pharmacokinetic drug-drug interactions were observed in studies with digoxin and warfarin.

Pregnancy

The safe use of ENBREL during pregnancy and lactation has not been established. Use ENBREL during pregnancy only if clearly needed. ENBREL crosses the placenta and has been 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. Administration of live vaccines to infants for 16 weeks after the motheru2019s last dose of ENBREL is generally not recommended.

Breastfeeding

The safe use of ENBREL during lactation has not been established. In lactating rats following subcutaneous administration, ENBREL was excreted in the milk and detected in the serum of pups. Limited information from the published literature indicates ENBREL has been detected at low levels in human milk. ENBREL could be considered for use during breastfeeding if clearly needed, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. While systemic exposure in a breastfed infant is expected to be low because ENBREL is largely degraded in the gastrointestinal tract, limited data regarding systemic exposure in the breastfed infant are available. Therefore, the administration of live vaccines (e.g., BCG) to a breastfed infant when the mother is receiving ENBREL could be considered 16 weeks after stopping breastfeeding (or at an earlier timepoint if the infant etanercept serum levels are undetectable).

Fertility

No fertility or long-term perinatal/postnatal studies are available.

No studies on the effects on the ability to drive and use machines have been performed.

Summary of the safety profile

Adult patients

The proportion of patients who discontinued treatment due to adverse reactions in controlled clinical studies in patients with rheumatoid arthritis was the same in both the ENBREL and placebo treatment groups. Based on the results of clinical studies in rheumatoid arthritis, normally no special laboratory evaluations are necessary in addition to careful medical management and supervision of patients.

Tabulated summary of adverse reactions

The following list of adverse reactions is based on experience from clinical trials in adults. Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data).

System organ class Frequency Adverse reaction

Infections and infestations Very common Infection (including upper respiratory tract infections, bronchitis, cystitis, skin infections) Uncommon Serious infections (including pneumonia, cellulitis, bacterial arthritis, sepsis and parasitic infection)

Rare Tuberculosis, opportunistic infection (including invasive fungal, bacterial, atypical mycobacterial, viral infections, and Legionella) (see section 4.4) Neoplasms, benign, malignant and unspecified (including cysts and polyps) Uncommon Non-melanoma skin cancers (see section 4.4) Rare Malignant melanoma (see section 4.4) Blood and lymphatic system disorders Uncommon Thrombocytopenia, anaemia, leukopenia, neutropenia Rare Pancytopenia (see section 4.4) Immune system disorders Common Allergic reactions (see Skin and subcutaneous tissue disorders, below), auto-antibody formation Uncommon Vasculitis (including ANCA positive vasculitis) Rare Serious allergic/anaphylactic reactions (including angioedema, bronchospasm), sarcoidosis Nervous system disorders Rare CNS demyelinating events, including multiple sclerosis and localised demyelinating conditions such as optic neuritis and transverse myelitis (see section 4.4), seizure Eye disorders Uncommon Uveitis, scleritis Cardiac disorders Uncommon Worsening of congestive cardiac failure Rare New onset congestive cardiac failure Respiratory, thoracic and mediastinal disorders Rare Interstitial lung disease (including pulmonary fibrosis and pneumonitis) Hepato-biliary disorders Uncommon Elevated liver enzymes Rare Autoimmune hepatitis Skin and subcutaneous tissue disorders Common Pruritus, rash Uncommon Angioedema, psoriasis (new onset or exacerbation including all sub-types), urticaria Rare Cutaneous vasculitis (including hypersensitivity vasculitis Musculoskeletal, and connective tissue disorders Rare Lupus-like syndrome Renal and urinary disorders Not known Glomerulonephritis General disorders and administration site conditions Very common Injection site reactions (including bleeding, bruising, erythema, itching, pain and swelling) Common Pyrexia

Post-marketing side effects

System organ class Side effect Infections and infestations Hepatitis B reactivation, Listeria Neoplasms benign, malignant and unspecified (including cysts and polyps) Lymphoma, leukaemia, Merkel cell carcinoma (see section 4.4) Blood and lymphatic system disorders Aplastic anaemia (see section 4.4), histiocytosis haematophagic (macrophage activation syndrome) Nervous system disorders Headache, peripheral demyelinating events, including Guillain-Barru00e9 syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy and multifocal motor neuropathy (see section 4.4), Gastrointestinal disorders Inflammatory bowel disease Skin and subcutaneous tissue disorders Psoriasiform rash, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders Subacute cutaneous lupus erythematosus, cutaneous lupus erythematosus

Spontaneous reports Malignancies affecting various sites.

Description of selected adverse reactions

Injection site reactions Patients in controlled clinical studies treated with ENBREL had a significantly higher incidence of injection site reactions (erythema and/or itching, pain, or swelling) compared with placebo-treated patients. The frequency of injection site reactions was greatest in the first month and subsequently decreased in frequency. In clinical trials, these reactions were generally transient with a mean duration of 4 days. Some patients who experienced injection site reactions also experienced reactions at previous injection sites. Injection site bleeding and bruising have also been observed in conjunction with ENBREL therapy. In controlled trials in patients with plaque psoriasis, 14 % of patients treated with ENBREL developed injection site reactions during the first three months of treatment.

Infections Serious and fatal infections have been reported; reported pathogens include bacteria, mycobacteria (including tuberculosis), viruses, and fungi. Opportunistic infections have also been reported including invasive fungal, parasitic (including protozoal), viral (including herpes zoster) bacterial (including Listeria and Legionella), and atypical mycobacterial infections (see section 4.4). The most commonly reported invasive fungal infections included Candida, Pneumocystis, Aspergillus, and Histoplasma. In controlled trials in patients with rheumatoid arthritis, the rates of reported serious (fatal, life threatening, or required hospitalisation or intravenous antibiotics) and non-serious infections were similar for ENBREL and placebo when adjusted for duration of exposure. Upper respiratory infections were the most reported non-serious infections. Data from a clinical trial in patients with established sepsis suggest that ENBREL treatment may increase mortality in these patients. In placebo-controlled psoriatic arthritis and plaque psoriasis trials, there were no differences in rates of infection among patients treated with ENBREL and those treated with placebo. In psoriatic arthritis trials, no serious infections occurred in patients treated with ENBREL. In the double-blind and open-label plaque psoriasis trials of up to 15 months, serious infections experienced by ENBREL-treated patients included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis and abscess.

Malignancies and lymphoproliferative disorders Reports of malignancies affecting various sites have been received in the post-marketing period. Twenty-three malignancies were reported in plaque psoriasis patients treated with ENBREL in double-blind and open-label studies of up to 15 months involving 1 261 ENBREL-treated patients. There have been reports of malignancies in a clinical trial of patients being treated for Wegeneru2019s granulomatosis (see section 4.4).

Interstitial lung disease In controlled clinical trials of ENBREL across all indications, the frequency (incidence proportion) of interstitial lung disease in patients receiving ENBREL without concomitant methotrexate was 0,06 % (frequency rare). In the controlled clinical trials that allowed concomitant treatment with ENBREL and methotrexate, the frequency (incidence proportion) 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.

Elevated liver enzymes In the double-blind periods of controlled clinical trials of ENBREL across all indications, the frequency (incidence proportion) of adverse events of elevated liver enzymes in patients receiving ENBREL without concomitant methotrexate was 0,54 % (frequency uncommon). In the double-blind periods of controlled clinical trials that allowed concomitant treatment with ENBREL and methotrexate, the frequency (incidence proportion) of adverse events of elevated liver enzymes was 4,18 % (frequency common).

Autoimmune hepatitis In controlled clinical trials of ENBREL across all indications, the frequency (incidence proportion) of autoimmune hepatitis in patients receiving ENBREL without concomitant methotrexate was 0,02 % (frequency rare). In the controlled clinical trials that allowed concomitant treatment with ENBREL and methotrexate, the frequency (incidence proportion) of autoimmune hepatitis was 0,24 % (frequency uncommon).

Auto-antibodies In controlled trials, the percentage of patients who developed new positive antinuclear antibodies (ANA) (u2265 1:40), new positive anti-double-stranded DNA antibodies, and new anticardiolipin antibodies was increased compared to placebo-treated patients. The impact of long-term treatment with ENBREL on the development of autoimmune diseases is unknown. Reports have described patients, including those with rheumatoid factor positive RA, who have developed additional auto-antibodies in conjunction with a lupus-like syndrome or rashes compatible with subacute cutaneous lupus or discoid lupus by clinical presentation and biopsy (see Tabulated summary of adverse reactions above).

Paediatric population In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients. Side effects in paediatric patients with juvenile idiopathic arthritis Infection was the most common adverse event reported in paediatric patients taking ENBREL and occurred at an incidence similar to placebo. The types of infection reported in juvenile idiopathic arthritis patients were generally mild and consistent with those commonly seen in outpatient paediatric populations. In clinical trials, two cases of varicella infection with signs and symptoms suggestive of aseptic meningitis have been reported among juvenile idiopathic arthritis patients treated with ENBREL. There were four reports of macrophage activation syndrome in juvenile idiopathic arthritis clinical trials. Side effects in paediatric patients with plaque psoriasis In a 48-week study of 211 children aged 4 to 17 years with paediatric plaque psoriasis, the adverse events reported were similar to those seen in previous studies in adults with plaque psoriasis.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse medicine reactions to SA HPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Report any suspected adverse drug reactions associated with the use of the medicine directly to Pfizer via [email protected]

The maximum tolerated dose of ENBREL has not been established in humans. Single intravenous doses up to 60 mg/m2 have been administered to healthy volunteers in an endotoxaemia study without evidence of dose-limiting toxicities. The highest dose level evaluated in rheumatoid arthritis patients has been an intravenous loading dose of 32 mg/m2 followed by subcutaneous doses of 16 mg/m2 (~25 mg) administered twice weekly. ENBREL did not induce lethality or notable 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 elicit dose-limiting or target organ toxicity in cynomolgus monkeys following twice weekly subcutaneous administration for 4 or 26 consecutive weeks at a dose (15 mg/kg) that resulted in area under the curve (AUC) based serum medicine concentrations that were over 27-fold higher than that obtained in humans at the recommended human dose of 25 mg. No dose-limiting toxicities were observed during clinical trials of rheumatoid arthritis patients. In the case of accidental overdosage, treatment should be supportive and symptomatic. There is no known antidote to ENBREL.