ORENCIA 125 mg solution for injection in pre-filled pen

Update to the "Important Instructions for Use" Step 2 to enhance the instructions for use of ORENCIA 125 mg solution for injection in pre-filled pen during preparation of the injection.

Change to PIL : Removal or legal representatives and update to revision date

Date of revision to the text updated to 24 September

Date of revision to the text updated to 24 September

To change the name/address of BMS-Anagni to CATALENT Pharma Solutions, Inc - batch release site of ORENCIA Drug Product

Date of revision of the text updated to align with the Patient Leaflet Date of revision of the text - 30 March 2020

ORENCIA contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say i.e. essentially 'sodium-free'.

3.       How to use ORENCIA

Talk to your doctor if you have any questions about giving yourself an injection. You will find detailed instructions for the preparation and administration of ORENCIA at the end of this leaflet (see in the booklet "Important instructions for use") provided separately in the carton.

4.4     Special warnings and precautions for use

Patients on controlled sodium diet

 This medicinal product contains 0.014 mmol sodium (0.322 mg) per pre-filled pen, that is to say i.e. essentially ‘sodium- free’.

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.

Updated version to include the changes for the MAH details (section 7)

- In Section 4.2:

Special populations

Paediatric population

The safety and efficacy of ORENCIA solution for injection in pre-filled pen for subcutaneous administration in children below 18 years of age have not been established. No data are available.

ORENCIA powder for concentrate for solution for infusion is available for paediatric patients 6 years of age and older for the treatment of pJIA (see Summary of Product Characteristics for ORENCIA powder for concentrate for solution for infusion).

ORENCIA solution for injection pre-filled syringe for subcutaneous administration is available for paediatric patients 2 years of age and older for the treatment of pJIA (see Summary of Product Characteristics for ORENCIA Solution for Injection pre-filled syringe).

- In Section 4.5:

"ORENCIA" has been replaced with "abatacept"

- In section 4.6:

Pregnancy and women of childbearing potential

There are no adequate data from use of abatacept in pregnant women. In pre-clinical embryo-fetal development studies no undesirable effects were observed at doses up to 29-fold a human 10 mg/kg dose based on AUC. In a pre- and postnatal development study in rats, limited changes in immune function were observed at 11-fold higher than a human 10 mg/kg dose based on AUC (see section 5.3).

ORENCIA should not be used during pregnancy unless the clinical condition of the woman requires treatment with abatacept.

Women of childbearing potential have to use effective contraception during treatment and up to 14 weeks after the last dose of abatacept.

Breast-feeding

Abatacept has been shown to be present in rat milk.

It is unknown whether abatacept is excreted in human milk.

A risk to the newborns/infants cannot be excluded.

Breast-feeding should be discontinued during treatment with ORENCIA and for up to 14 weeks after the last dose of abatacept treatment.

- In Section 5.1:

Paediatric population

ORENCIA powder for concentrate for solution for infusion and ORENCIA solution for injection in pre-filled syringe are approved in the paediatric patients with pJIA. Please refer to the ORENCIA powder for concentrate for solution for infusion 250 mg and ORENCIA solution for injection in pre-filled syringe 125 mg, 87.5 mg and 50 mg SmPCs.

- In Section 10:

DATE OF REVISION OF THE TEXT 

08 April 2019

Section 7: Change to MAH Address

Section 4.1 has been updated with a new a indication

Section 4.2 has been updated with the method of administration

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Section 4.8   has been updated with a summary of the summary of the safety profile in psoriatic arthritis

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In addition the reporting details for the yellow card scheme has been updated following update to Appendix 5

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Section 5.1 has been updated with Clinical efficacy and safety in adult psoriatic arthritis

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section 5.2  has been updated with the data from adults with psoriatic arthritis

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Section 10 has been updated with the date of revision - 25th July 2017

Section 4.4 - The patient numbers  and percentages from some of the clinical studies  have been updated

Section 4.5 -Changes to the frequencies of adverse events

4.       Clinical particulars

4.1     Therapeutic indications

 Rheumatoid arthritis

ORENCIA, in combination with methotrexate, is indicated for:

§    the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who responded inadequately to previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) or a tumour necrosis factor (TNF)-alpha inhibitor.

§    the treatment of highly active and progressive disease in adult patients with rheumatoid arthritis not previously treated with methotrexate.

4.8     Undesirable effects

In Study SC-III, similar immunogenicity rates were seen in patients on treatment for the abatacept+MTX, and abatacept monotherapy groups (2.9% (3/103) and 5.0% (5/101), respectively) during the double-blind 12 month period. As in Study SC-I, there was no effect of immunogenicity on safety or efficacy.

In SC-III, increased rates of immunogenicity were observed in subjects tested during 6 months of complete drug withdrawal in the abatacept+MTX and abatacept monotherapy groups (37.7% [29/77] and 44.1% [27/59], respectively) with generally low titer antibody responses. No clinical impact of these antibody responses was detected, and no safety concerns were observed upon reinitiation of abatacept therapy.

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

In Studies I, II, and V the efficacy and safety of abatacept compared to placebo were assessed in patients with an inadequate response to methotrexate and who continued on their stable dose of methotrexate. In addition, Study V investigated the safety and efficacy of abatacept or infliximab relative to placebo. In Study III the efficacy and safety of abatacept were assessed in patients with an inadequate response to a TNF-inhibitor, with the TNF-inhibitor discontinued prior to randomization; other DMARDs were permitted. Study IV primarily assessed safety in patients with active rheumatoid arthritis requiring additional intervention in spite of current therapy with non-biological and/or biological DMARDs; all DMARDs used at enrollment were continued. In Study VI, the efficacy and safety of abatacept were assessed in methotrexate-naive, Rheumatoid Factor (RF) and/or anti-Cyclic Citrullinated Peptide 2 (Anti-CCP2)-positive patients with early, erosive rheumatoid arthritis (≤ 2 years disease duration) who were randomized to receive abatacept plus methotrexate or methotrexate plus placebo. In Study SC-I, the goal was to demonstrate non-inferiority of the efficacy and comparability of the safety of abatacept subcutaneous relative to intravenous administration in subjects with moderate to severely active RA and experiencing inadequate response to MTX. Study SC-II investigated the relative efficacy and safety of abatacept and adalimumab, both given subcutaneously without an intravenous loading dose and with background MTX, in patients with moderate to severely active RA and an inadequate response to previous MTX therapy. In study SC-III, abatacept SC was evaluated in combination with methotrexate, or as abatacept monotherapy, and compared to MTX monotherapy in induction of remission following 12 months of treatment, and the possible maintenance of drug-free remission after complete drug withdrawal, in adult MTX-naive patients with highly active early rheumatoid arthritis (mean DAS28‑CRP of 5.4; mean symptom duration less than 6.7 months) with poor prognostic factors for rapidly progressive disease (e.g. anti-citrullinated protein antibodies [ACPA+], as measured by anti-CCP2 assay, and/or RF+, baseline joint erosions).

Studies I, II, III, IV, V, VI, SC-I, and SC-II, and SC-III evaluated 339, 638, 389, 1,441, 431, 509 1,371, and 646, and 351 adult patients, respectively.

Study SC-III: Induction of remission in methotrexate-naive RA patients

A randomized and double-blinded study evaluated abatacept SC in combination with methotrexate (abatacept + MTX), abatacept SC monotherapy, or methotrexate monotherapy (MTX group) in induction of remission following 12 months of treatment, and maintenance of drug-free remission after complete drug withdrawal in MTX-naive adult patients with highly active early rheumatoid arthritis with poor prognostic factors. Complete drug withdrawal led to loss of remission (return to disease activity) in all three treatment arms (abatacept with methotrexate, abatacept or methotrexate alone) in a majority of patients (Table 3).

^a DAS28-defined remission (DAS28-CRP <2.6)

^b SDAI criterion (SDAI ≤ 3.3)

In SC-III the safety profiles of the three treatment groups (abatacept + MTX, abatacept monotherapy, MTX group) were overall similar. During the 12-month treatment period, adverse reactions were reported in 44.5% (53/119), 41.4% (48/116), and 44.0% (51/116) and serious adverse reactions were reported in 2.5% (3/119), 2.6% (3/116) and 0.9% (1/116) of patients treated in the three treatment groups, respectively. Serious infections were reported in 0.8% (1/119), 3.4% (4/116) and 0% (0/116) patients.

In Study SC-III, structural joint damage was assessed by MRI. The abatacept + MTX group had less progression in structural damage compared with MTX group as reflected by mean treatment difference of the abatacept + MTX group versus MTX group (Table 5).

In Study SC-III, the proportion of subjects with a HAQ response as a measure of clinically meaningful improvement in physical function (reduction from baseline in HAQ-D1 score of > 0.3) was greater for the abatacept+ MTX group vs. the MTX group at Month 12 (65.5% vs 44.0%, respectively; treatment difference vs. MTX group of 21.6% [95% CI: 8.3, 34.9]).

10.     DATE OF REVISION OF THE TEXT

August 2016

4.8       Undesirable effects

Immunogenicity in adults treated with subcutaneous abatacept

Study SC-I compared the immunogenicity to abatacept following subcutaneous or intravenous administration as assessed by ELISA assay. During the initial double blind 6 months period (short-term period), the overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no effect of immunogenicity on pharmacokinetics, safety, or efficacy.

Immunogenicity to abatacept following long-term subcutaneous administration was assessed by a new ECL assay. Comparison of incidence rates across different assays is not appropriate, as the ECL assay was developed to be more sensitive and drug tolerant than the previous ELISA assay. The cumulative immunogenicity frequency to abatacept by the ECL assay with at least one positive sample in the short-term and long-term periods combined was 15.7% (215/1369) while on abatacept, with a mean duration of exposure of 48.8 months, and 17.3% (194/1121) after discontinuation (> 21 days up to 168 days after last dose). The exposure adjusted incidence rate (expressed per 100 person-years) remained stable over the treatment duration.

Consistent with previous experience, titers and persistence of antibody responses were generally low and did not increase upon continued dosing (6.8% subjects were seropositive on 2 consecutive visits), and there was no apparent correlation of antibody development to clinical response, adverse events, or PK.

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

In the open‑label extension of Studies I, II, III, VI, and SC-I durable and sustained ACR 20, 50, and 70 responses have been observed through 7 years, 5 years, 5 years, 2 years, and 5 years, respectively, of abatacept treatment. In study I, ACR responses were assessed at 7 years in 43 patients with 72% ACR 20 responses, 58% ACR 50 responses, and 44% ACR 70 responses. In study II, ACR responses were assessed at 5 years in 270 patients with 84% ACR 20 responses, 61% ACR 50 responses, and 40% ACR 70 responses. In study III, ACR responses were assessed at 5 years in 91 patients with 74% ACR 20 responses, 51% ACR 50 responses, and 23% ACR 70 responses. In study VI, ACR responses were assessed at 2 years in 232 patients with 85% ACR 20 responses, 74% ACR 50 responses, and 54% ACR 70 responses. In study SC-I, ACR responses were assessed at 5 years with 85% (356/421) ACR 20 responses, 66% (277/423) ACR 50 responses, and 45% (191/425) ACR 70 responses.

10.     DATE OF REVISION OF THE TEXT

April 2016

4.2     Posology and method of administration

Patients switching from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

4.6     Fertility, pregnancy and lactation

Pregnancy and Women of childbearing potential

There are no adequate data from use of abatacept in pregnant women. In pre-clinical embryo‑fetal development studies no undesirable effects were observed at doses up to 29‑fold a human 10 mg/kg dose based on AUC. In a pre‑ and postnatal development study in rats limited changes in immune function were observed at 11‑fold higher than a human 10 mg/kg dose based on AUC (see section 5.3). ORENCIA should not be used in pregnant women unless clearly necessary. Women of child‑bearing potential should use effective contraception during treatment with ORENCIA and up to 14 weeks after the last dose of abatacept treatment.

Abatacept may cross the placenta into the serum of infants born to women treated with abatacept during pregnancy. Consequently, these infants may be at increased risk of infection. The safety of administering live vaccines to infants exposed to abatacept in utero is unknown. Administration of live vaccines to infants exposed to abatacept in utero is not recommended for 14 weeks following the mother’s last exposure to abatacept during pregnancy.

10.     DATE OF REVISION OF THE TEXT

December 2015