Benepali 50 mg solution for injection in pre-filled syringe

update the frequency of ‘Glomerulonephritis’ adverse reaction from ‘Not Known’ to ‘Rare’

update the frequency of ‘Glomerulonephritis’ adverse reaction from ‘Not Known’ to ‘Rare’

Addition of "damage to the tiny filters inside your kidneys leading to poor kidney function (glomerulonephritis)" to Section 4 - Possible side effects

Addition of "Glomerulonephritis" as undesirable effect to Section 4.8. 

Section 4: Other medicines and Benepali

Tell your doctor or pharmacist if you or the child are taking, have recently taken or might take any other medicines (including anakinra, abatacept or sulfasalazine). 

Section 4: Pregnancy and breast-feeding

If you received Benepali during pregnancy, your baby may have a higher risk of getting an infection. In addition, one study found more birth defects when the mother had received etanercept in pregnancy, compared with mothers who had not received etanercept or other similar medicines (TNF-antagonists), but there was no particular kind of birth defect reported. Another study found no increased risk of birth defects when the mother had received etanercept in pregnancy. Your doctor will help you to decide whether the benefits of treatment outweigh the potential risk to your baby. It is important that you tell the baby’s doctors and other healthcare professionals about the use of Benepali during pregnancy before the baby receives any vaccine (for more information see section 2, “Vaccinations”)

Women using Benepali should not breast feed, since Benepali passes into human breast milk. Talk to your doctor if you want to breastfeed while on Benepali treatment. It is important that you tell your baby’s doctors and other healthcare professionals about the use of Benepali during pregnancy and breastfeeding before your baby receives any vaccine.

Section 4.6: Breast-feeding

Etanercept has been reported to be excreted in human milk following subcutaneous administration. In lactating rats following subcutaneous administration, etanercept was excreted in the milk and detected in the serum of pups. Because immunoglobulins, in common with many medicinal products, can be excreted in human milk, a decision must be made whether to discontinue breast-feeding or to discontinue Benepali therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Limited information from the published literature indicates 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.

While 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 (e.g., BCG) to a breastfed infant when the mother is receiving etanercept could be considered 16 weeks after stopping breast-feeding (or at an earlier timepoint if the infant etanercept serum levels are undetectable).

Section 5.1 – Pharmacodynamic properties – Clinical efficacy and safety: Adult patients with plaque psoriasis

Etanercept is recommended for use in patients as defined in section 4.1. Patients who “failed to respond to” in the target population is defined by insufficient response (PASI < 50 or PGA less than good), or worsening of the disease while on treatment, and who were adequately dosed for a sufficiently long duration to assess response with at least each one of the three major systemic therapies as available. 

Section 5.1 – Pharmacodynamic properties – Clinical efficacy and safety: Paediatric population (pJIA)

Of the 127 patients in the parent study, 109 participated in the open-label extension study and were followed for an additional 8 years for a total of up to 10 years.

…..

Studies have not been done in patients with juvenile idiopathic arthritis to assess the effects of continued etanercept therapy in patients who do not respond within 3 months of initiating etanercept therapy. Additionally, studies have not been conducted to assess the effects of reducing the recommended dose of etanercept following its long-term use in patients with JIA.

Editorial updates

Editorial revisions

Correction of the storage temperature: Benepali may be stored outside of the refrigerator at temperatures up to a maximum of 30°C for a single period of up to 31 days; after which, it should not be refrigerated again.

Change to section 5 – how to store or dispose. The storage conditions when not storing the product refrigerated have been revised, it may be stored outside of the refrigerator at temperatures up to a maximum of 30°C for a single period of up to 31 days.

Change to section 6.4 - Special precautions for storage. The storage conditions when storing the product outside of the refrigerator have been revised, it may be stored at temperatures up to a maximum of 30°C for a single period of up to 31 days.

Addition of text referring to package leaflet section 3 for detailed instructions on unintentional dosing or scheduling variations, including missed doses.

Section 6 has been updated as follows:

Manufacturer

FUJIFILM Diosynth Biotechnologies Denmark ApS

Biotek Allé 1

Hillerød, 3400

Denmark

Section 5.1 has been updated as follows:

In another open-label single-arm study (n=127), 60 patients with extended oligoarthrits (EO) (15 patients aged 2 to 4, 23 patients aged 5 to 11 and 22 patients aged 12 to 17 years old), 38 patients with enthesitis-related arthritis (12 to 17 years old), and 29 patients with psoriatic arthritis (12 to 17 years old) were treated with etanercept at a dose of 0.8 mg/kg (up to a maximum of 50 mg per dose) administered weekly for 12 weeks. In each of the JIA subtypes, the majority of patients met ACR Pedi 30 criteria and demonstrated clinical improvement in secondary endpoints such as number of tender joints and physician global assessment. The safety profile was consistent with that observed in other JIA studies.

Of the 127 patients in the parent study, 109 participated in the open-label extension study and were followed for 8 years. At the end of the extension study, 84/109 (77%) patients had completed the study; 27 (25%) while actively taking etanercept, 7 (6%) had withdrawn from treatment due to low/inactive disease; 5 (5%) had re-started etanercept following an earlier withdrawal from treatment; and 45 (41%) had stopped etanercept (but remained under observation); 25/109 (23%) patients permanently discontinued from the study. Improvements in clinical status achieved in the parent study were generally maintained for all efficacy endpoints during the entire follow-up period. Patients actively taking etanercept could enter an optional withdrawal-retreatment period once during the extension study based on investigator’s judgement of clinical response. 30 patients entered the withdrawal period. 17 patients were reported to have a flare (defined as ≥ 30% worsening in at least 3 of the 6 ACR Pedi components with ≥ 30% improvement in not more than 1 of the remaining 6 components and a minimum of 2 active joints); median time to flare after etanercept withdrawal was 190 days. 13 patients were re-treated and the median time to re-treatment from withdrawal was estimated as 274 days. Due to the small number of data points, these results should be interpreted with caution.

The safety profile was consistent with that observed in the parent study.

Patient Alert Card has been renamed to Patient Card according to EMA’s request and in order to align with the Patient Card of the reference product Enbrel. A sentence stating that Benapali is not indicated for use in children and adolescents weighing less than 62.5kg has been removed as this information is sufficiently communicated in the SmPC and the package leaflet.

Section 2 has been updated as follows:

Section 4 has been updated as follows:

Other side effects

The known side effects of Benepali include the following in groups of decreasing frequency:

• Very common (may affect more than 1 in 10 people)

Infections (including colds, sinusitis, bronchitis, urinary tract infections and skin infections); injection site reactions (including bleeding, bruising, redness, itching, pain, and swelling).

Reactions at the injection site (these do not occur as often after the first month of treatment); some patients have developed a reaction at an injection site that was used before; and headache.

Section 2

Etanercept is a human tumour necrosis factor receptor p75 Fc fusion protein produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian expression system. Etanercept is a dimer of a chimeric protein genetically engineered by fusing the extracellular ligand binding domain of human tumour necrosis factor receptor-2 (TNFR2/p75) to the Fc domain of human IgG1. This Fc component contains the hinge, CH2 and CH3 regions, but not the CH1 region of IgG1. Etanercept contains 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. The specific activity of etanercept is 1.7 × 106 units/mg.

Section 4.1 and 4.2:

Text regarding studies in children aged less than 2 years moved between sections:

4.2: Paediatric population

…

The dosage of etanercept 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 the powder and solvent for solution for injection presentations or the powder for solution for injection presentations (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.

The safety and efficacy of etanercept in children aged less than 2 years has not been established.

No data are available

Section 4:4

Section 4.7:

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

Etanercept has no or neglegible influence on the ability to drive and use machines.

Section 4.8:

Section 5.1

Additional study in “Adult patients with non-radiographic axial spondyloarthritis” (Study 1 and study 2).

Section 4,8

Reporting of suspected adverse reactions sub section has been updated to include the following:

United Kingdom (Northern Ireland)
Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

In section 6, local representative contact details for United Kingdom (Northern Ireland) have been added;  Biogen Netherlands BV has been added as a manufaturer, and name and address of Biogen Hillerod  has been changed to FUJIFILM .

- Patient Alert Card' has been renamed to 'Patient Card'.

- Black triangle and explanation have been removed.

- In section 1, 'psoriasis' has been updated to 'plaque psoriasis'.

In section 4, the following changes have been made:

'Rare (may affect up to 1 in 1,000 people):
.....opportunistic infections (infections that occur because of a weakened immune system); lichenoid reactions (itchy reddish-purple skin rash and/or threadlike white-grey lines on mucous membranes), opportunistic infections (which include tuberculosis and other infections that occur when resistance to disease is lowered), erythema multiforme (inflammatory skin rash), cutaneous vasculitis (inflammation of blood vessels in the skin); damage to nerves, including Guillain-Barré syndrome (a serious condition which can affect breathing and damage body organs).'

Very rare (may affect up to 1 in 10,000 people):
Failure of the bone marrow to produce crucial blood cells; damage to nerves, including Guillain-Barré syndrome (a serious condition which can affect breathing and damage body organs); toxic epidermal necrolysis (a life-threatening skin condition). 

Not known (frequency cannot be estimated from available data)
Merkel cell carcinoma (a type of skin cancer); Kaposi’s sarcoma (a rare cancer related to infection with human herpes virus 8. Kaposi’s sarcoma most commonly appears as purple lesions on the skin); excessive activation of white blood cells associated with inflammation (macrophage activation syndrome); recurrence of hepatitis B (a liver infection); worsening of a condition called dermatomyositis (muscle inflammation and weakness with an accompanying skin rash); Llisteria (a bacterial infection).

 - Minor editorial changes have been made throughout the PL as requested and/or to align with reference product.

Section 4.2: 'Patient Alert Card' has been renamed to 'Patient Card'.

Section 4.4: 'Patient Alert Card' has been renamed to 'Patient Card'.

Formatting changes have also been made to this section, including the following:

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

Benepali contains sSodium contents

No clinically significant pharmacokinetic drug-drug interactions were observed in studies with methotrexate, digoxin or warfarin.

Section 4.8: Kaposi’s sarcoma was added to the tabulated list of adverse reactions, with unknown frequency to align with reference product.

Minor editorial changes have been made to other sections of the SPC as requested and/or to align with reference product.

Item number now reflects Irish pack

Samsung Bioepis NL B.V has been added as a manufacturer responsible for batch release.

 Uncommon side effects section has been updated to include 'abdominal cramps and pain, diarrhoea, weight loss or blood in the stool (signs of bowel problems).'

4.4     Special warnings and precautions for use section has been updated as follows:

​​Traceability

In order to improve the traceability of biological medicinal products, the trademark name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

​​4.8     Undesirable effects section has been updated to include Inflammatory bowel disease in the tabulated list of adverse reactions.

Section 4.6:

Update to align with the reference product to add additional information to this section - the following text has been added:

The effects of etanercept on pregnancy outcomes have been investigated in two observational cohort studies.....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 (n=425) to those exposed to non-biologic drugs (n=3497), there was no observed increased risk of major birth defects (crude odds ratio [OR]= 1.22, 95% CI: 0.79-1.90; adjusted OR = 0.96, 95% CI: 0.58-1.60 after adjusting for country, maternal disease, parity, maternal age and smoking in early pregnancy). This 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.

The following text has been updated to read: Benepali should only be used during pregnancy if clearly needed

Section 4.8 has been updated to include lichenoid skin reactions as a rare adverse event.

·         Summary of Product Characteristics (SmPC),

In section 4.2 and in Section 4.8, under the subtitle "special populations", "elderly (above 65 years)" was changed to state "elderly".

In Section 4.4 Special warnings and precautions for use, the text highlighted in red was added.

Congestive heart failure
Physicians should use caution when using Benepali in patients who have congestive heart failure (CHF). There have been postmarketing reports of worsening of CHF, with and without identifiable precipitating factors, in patients taking Etanercept. There have also been rare (< 0.1%) reports of new onset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. Two large clinical trials evaluating the use of Etanercept in the treatment of CHF were terminated early due to lack of efficacy. Although not conclusive, data from one of these trials suggest a possible tendency toward worsening CHF in those patients assigned to Etanercept treatment.

In section 4.8 Undesirable effects: "Worsening of congestive heart failure" was changed to "Congestive heart failure".

Section 5.1, under the subheader "Adult patients with non-radiographic axial spondyloarthritis" was updated due to new originator etanercept data as indicated below. The strike through text was deleted and purple text added.