ORENCIA 50 mg, 87.5 mg and 125 mg solution for injection (pre-filled syringe)

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

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

XPIL formatting update (no changes to PIL content)

Reformatting to X-PIL text only

Patients on controlled sodium diet

This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e.that is to say 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.

Immunogenicity in patients with pJIA treated with subcutaneous abatacept

Antibodies directed against the whole abatacept molecule or to the CTLA-4 portion of abatacept were assessed by an ECL assays in patients with pJIA following repeated treatment with subcutaneous abatacept. Overall, 6.9% (15/218) of subjects (cohorts combined) had a positive immunogenicity response relative to baseline during the cumulative period, including the 4-month short-term treatment period, 20-month extension treatment period and the 6-month post abatacept follow-up period. In the 6 to 17 year age cohort, the overall rate of seropositivity during the cumulative period including post abatacept follow-up was 4.7% (8/172): 2.3% (4/172) on treatment and 13.6% (6/44) after discontinuation of abatacept (≥ 28 days after the last dose). In the 2 to 5 year age cohort, the overall rate of seropositivity during the cumulative period including post abatacept follow-up was 15.2% (7/46): 10.9% (5/46) on treatment and 37.5% (3/8) after discontinuation of abatacept (≥ 28 days after the last dose).The rate of seropositivity while patients were receiving abatacept therapy was 1.8% (4/218) during the first 4-month treatment period and 3.7% (8/218) during the cumulative period. In patients assessed for anti-abatacept antibodies after discontinuation of abatacept (≥ 28 days after last dose), 8 of 50 (16%) were seropositive.

OverallAnti-abatacept antibodies against abatacept were generally transient and of low titer. The absence of concomitant methotrexate did not appear to be associated with a higher rate of seropositivity. The significance of the higher incidence in the 2 to 5 year age cohort is unknown, taking into account the difference in sample size. The presence of antibodies was not associated with adverse reactions, or with changes in efficacy or serum abatacept concentrations, in either cohort.

Long-term extension period

During the extension period of the pJIA studies (20 months in the pJIA ongoing SC study and 5 years in the pJIA IV study), the safety profile in the pJIA patients aged 6 to 17 years was comparable to that seen in adult patients. One patient was diagnosed with multiple sclerosis while in the extension period of the pJIA IV study. One serious adverse reaction of infection (limb abscess) was reported in the 2 to 5 year age cohort during the 20-month extension period of the pJIA SC study.

Long-term safety data in 2 to 5 year old age cohortpatients with pJIA was limited, but the existing evidence did not reveal any new safety concern in this younger paediatric population. During the 24-month cumulative period of the pJIA SC study (4-month shortterm period plus 20-month extension period), a higher frequency of infections was reported in the 2 to 5 year age cohort (87.0%) compared to that reported in the 6 to 17 year age cohort (68.2%). This was mostly due to non-serious upper respiratory tract infections in the 2 to 5 year age cohort.

Paediatric population in polyarticular juvenile idiopathic arthritis

Subcutaneous

The efficacy of subcutaneous abatacept in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of established efficacy from intravenous abatacept in pJIA patients and subcutaneous abatacept in adult patients with RA, and is supported by data from an ongoing clinical study. In this study children and adolescents with moderately to severely active pJIA, ages 2 to 17 years (46 patients in the 2 to -5 year age cohort and 173 patients in the 6 to -17 year age cohort) with an inadequate response or intolerance to at least one DMARD, which may have included biologic agents, were treated. The safety and efficacy of subcutaneous abatacept were assessed in a single-arm, open-label study designed with a primary endpoint of steady-state trough concentration (c_min) at 4 months (short-term period) in the age cohort 6 to 17 years age cohort. Patients continued abatacept treatment in an ongoing open-label extension, which assessed long-term safety and efficacy for an additional 20 months.

Of the 219 patients treated, 205 completed the short-term period and 200 entered the ongoing long-term extension period. In the 2 to -5 year age cohort, 39 (84.8%) 24 patients completed 2 years and 15 patients are ongoing in the 2-year period. In the 6 to -17 year age cohort 132 (76.3%) patients completed 2 years.

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 in the booklet "Important instructions for use" provided separately in the carton. You will find detailed instructions for the preparation and administration of ORENCIA at the end of this leaflet (see "Important instructions for useInstructions for preparing and giving a subcutaneous injection of ORENCIA").

Updated version to include also the MAH change (Section 7)

- In Section 1:

ORENCIA 50 mg solution for injection in pre-filled syringe

ORENCIA 87.5 mg solution for injection in pre-filled syringe

ORENCIA 125 mg solution for injection in pre-filled syringe

- In Section 2:

ORENCIA 50 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 50 mg of abatacept in 0.4 mL.

ORENCIA 87.5 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 87.5 mg of abatacept in 0.7 mL.

ORENCIA 125 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 125 mg of abatacept in one mL.

Abatacept is a fusion protein produced by recombinant DNA technology in Chinese hamster ovary cells.

For the full list of excipients, see section 6.1.

- In Section 4.1:

Polyarticular juvenile idiopathic arthritis

ORENCIA in combination with methotrexate is indicated for the treatment of moderate to severe active polyarticular juvenile idiopathic arthritis (pJIA) in paediatric patients 2 years of age and older who have had an inadequate response to previous DMARD therapy.

ORENCIA can be given as monotherapy in case of intolerance to methotrexate or when treatment with methotrexate is inappropriate.

- In Section 4.2:

Paediatric population

Polyarticular juvenile idiopathic arthritis

The recommended weekly dose of ORENCIA solution for injection in pre-filled syringe for patients 2 to 17 years of age with polyarticular juvenile idiopathic arthritis should be initiated without an intravenous loading dose and administered utilizing the weight range-based dosing as specified in the table below:

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

ORENCIA powder for concentrate for solution for infusion for intravenous administration 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).

[...]

Special populations

Paediatric population

The safety and efficacy of ORENCIA in children below 2 years of age have not been established. No data are available.

There is no relevant use of ORENCIA in children under two years old.

- In Section 4.6:

Pregnancy and women of childbearing potential

[..]

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 4.8

Paediatric population

Abatacept has been studied in patients with pJIA in 2 clinical trials (ongoing pJIA SC study and pJIA IV study). The pJIA SC study included 46 patients in the 2 to 5 year age cohort and 173 patients in the 6 to 17 year age cohort. The pJIA IV study included 190 patients in the 6 to 17 year age cohort. During the first 4-month open-label period, the overall safety profile in these 409 pJIA patients was similar to that observed in the RA population with the following exceptions in the pJIA patients:

• Common adverse reactions: pyrexia
• Uncommon adverse reactions: haematuria, otitis (media and externa).

Description of selected adverse reactions

Infections

Infections were the most commonly reported adverse events in patients with pJIA. The types of infections were consistent with those commonly seen in outpatient paediatric populations. During the first 4-month treatment period of intravenous and subcutaneous abatacept in 409 patients with pJIA, the most common adverse reactions were nasopharyngitis (3.7% patients) and upper respiratory tract infection (2.9% patients). Two serious infections (varicella and sepsis) were reported during the initial 4 months of treatment with abatacept.

Injection reactions

Of the 219 patients with pJIA treated with subcutaneous abatacept during the first 4-month abatacept treatment, the frequency of local injection reactions was 4.6% (10/219); injection site pain and injection site erythema were the most frequently reported local injection reactions. No systemic hypersensitivity reactions were reported.

Immunogenicity in patients with pJIA treated with subcutaneous abatacept

Antibodies directed against the whole abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ECL assays in patients with pJIA following repeated treatment with subcutaneous abatacept. The rate of seropositivity while patients were receiving abatacept therapy was 1.8% (4/218) during the first 4-month treatment period and 3.7% (8/218) during the cumulative period. In patients assessed for anti-abatacept antibodies after discontinuation of abatacept (≥ 28 days after last dose), 8 of 50 (16%) were seropositive. Anti-abatacept antibodies were generally transient and of low titer. The absence of concomitant methotrexate did not appear to be associated with a higher rate of seropositivity. The presence of antibodies was not associated with adverse reactions, or with changes in efficacy or serum abatacept concentrations.

Long-term extension period

During the extension period of the pJIA studies (20 months in the pJIA ongoing SC study and 5 years in the pJIA IV study), the safety profile in the pJIA patients aged 6 to 17 years was comparable to that seen in adult patients. One patient was diagnosed with multiple sclerosis while in the extension period of the pJIA IV study. Long-term safety data in 2 to 5 year old patients with pJIA was limited, but the existing evidence did not reveal any new safety concern in this younger paediatric population.

- In section 5.1:

Paediatric population in polyarticular juvenile idiopathic arthritis

Subcutaneous

The efficacy of subcutaneous abatacept in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of established efficacy from intravenous abatacept in pJIA patients and subcutaneous abatacept in adult patients with RA, and is supported by data from an ongoing clinical study. In this study children and adolescents with moderately to severely active pJIA, ages 2 to 17 years (46 patients in the 2-5 year cohort and 173 patients in the 6-17 year cohort) with an inadequate response or intolerance to at least one DMARD, which may have included biologic agents, were treated. The safety and efficacy of subcutaneous abatacept were assessed in a single-arm, open-label study designed with a primary endpoint of steady-state trough concentration (c_min) at 4 months (short-term period) in the age cohort 6 to 17 years. Patients continued abatacept treatment in an ongoing open-label extension, which assessed long-term safety and efficacy for an additional 20 months.

At baseline 79% of 219 patients enrolled and treated in the study were taking methotrexate (mean dose at study entry, 12.3 mg/m²/week) and 21% of patients received abatacept monotherapy. Of the 219 patients entering the study, 56 (25.6%) had previously been treated with biologic DMARD therapy (including TNF inhibitors and tocilizumab).

Patients entered in the trial were a mean 10.6 years of age with mean disease duration of 2.4 years. They had active disease, with a mean active joint count of 11.8, mean number of joints with loss of motion of 10.3, and a mean elevated C-reactive protein (CRP) level of 1.24 mg/dL at baseline.

Of the 219 patients treated, 205 completed the short-term period and 200 entered the ongoing long-term extension period. In the 2-5 year cohort, 24 patients completed 2 years and 15 patients are ongoing in the 2-year period. In the 6-17 year cohort 132 patients completed 2 years.

Response rates at the end of the short-term exposure are summarised in Table 9:

* No active joints, physician’s global assessment of disease severity ≤10 mm and CRP ≤0.6 mg/dL.

The ACRP responses and inactive disease results were maintained through 2 years.

Intravenous

Children and adolescents with moderate to severe active pJIA, ages 6 to 17 years with an inadequate response or intolerance to at least one DMARD, which may have included biologic agents, were enrolled. The safety and efficacy of intravenous abatacept were assessed in a three-part study. Period A was a 4-month open-label lead-in designed to induce an ACR Pedi 30 response. Patients achieving at least a ACR Pedi 30 response at the end of Period A were randomised into a double-blind, withdrawal phase (Period B), and received either abatacept or placebo for 6 months or until pJIA disease flare as defined in the study. Unless they had discontinued due to safety reasons, all patients who completed, or had a flare during Period B or were non-responders in Period A were offered entry into Period C, the open-label extension, which assessed long-term safety and efficacy.

In Period A all patients received 10 mg/kg of abatacept on days 1, 15, 29, 57 and 85 and were assessed on day 113. During period A, 74% were taking methotrexate (mean dose at study entry, 13.2 mg/m²/week) thus, 26% of patients received abatacept monotherapy in Period A. Of the 190 patients entering the study, 57 (30%) had previously been treated with TNF-inhibitor therapy.

ACR Pedi 30 responders at the end of Period A were randomised into Period B, the double-blind, withdrawal phase, to receive either abatacept or placebo for 6 months or until JIA flare.

Flare was defined as:

• ≥ 30% worsening in at least 3 of the 6 pJIA core set variables
• ≥ 30% improvement in not more than 1 of the 6 pJIA core set variables
• ≥ 2 cm (possible up to 10 cm) of worsening must have been present if the Physician or Parent Global Assessment was used to define flare
• worsening in ≥ 2 joints must have been present if the number of active joints or joints with limited range of motion was used to define flare

The patients entered in the trial were a mean of 12.4 years of age with mean disease duration of 4.4 years. They had active disease, with baseline mean active joint count of 16 and a mean number of joints with loss of motion of 16; and elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dl) and ESRs (mean, 32 mm/h). Their pJIA subtypes at disease onset were: oligoarticular (16%), polyarticular (64%; 20% of the total were rheumatoid factor positive), and systemic (20%).

Of the 190 patients enrolled, 170 completed Period A, 65% (123/190) achieved an ACR Pedi 30 response, and 122 were randomised to Period B. Responses were similar in all subtypes of pJIA studied and for patients with or without methotrexate use. Of the 133 (70%) patients with no prior TNF-inhibitor therapy, 101 (76%) achieved at least an ACR Pedi 30 response; of the 57 patients who had received prior TNF-inhibitor therapy, 22 (39%) achieved at least an ACR Pedi 30 response.

During Period B, the time to disease flare for the patients randomised to placebo was significantly shorter than for those randomised to abatacept (primary endpoint, p=0.0002; log-rank test). Significantly more placebo recipients flared during Period B (33/62; 53%) than those maintained on abatacept (12/60; 20%; chi-square p<0.001). The risk of disease flare for patients continuing on abatacept was less than one third that for placebo-treated patients (hazard ratio estimate=0.31; 95% CI 0.16, 0.59).

Most randomised Period B patients entered Period C (58/60 Period B abatacept recipients; 59/62 Period B placebo recipients), as did 36 of the 47 Period A non-responders (n=153 total patients).

Response rates at the end of Period A, at the end of Period B and after 5 years exposure in Period C are summarized in Table 10:

^a day 169 Last Observation Carried Forward (LOCF) for patients treated in Period C

^b As observed

Participants in Period C at day 1765 included 33 of the 58 Period B abatacept recipients, 30 of the 59 Period B placebo recipients, and 13 of the 36 Period A non-responders. The median duration of abatacept treatment in Period C was 1815 days (range 57–2,415 days; nearly 61 months). One hundred and two (67%) of the subjects had received at least 1,080 days (~ 36 months) of abatacept therapy in Period C. All patients had at least 4 months of prior, open-label abatacept treatment in Period A.

- In Section 5.2

Paediatric pJIA population

Pharmacokinetics of abatacept for subcutaneous injection have been studied in patients 2 to 17 years of age.

Steady state of abatacept was achieved by day 85 following the weekly body-weight–tiered subcutaneous abatacept dosing. Comparable trough concentrations across weight tiers and age groups were achieved by the body-weight–tiered subcutaneous dosing regimen. The mean (range) trough concentration of abatacept at day 113 was 46.2 mcg/mL (13.4 to 96.2 mcg/mL), 48.0 mcg/mL (22.4 to 122.1 mcg/mL), and 38.5 mcg/mL (9.3 to 73.2 mcg/mL) in paediatric pJIA patients weighing 10 to <25 kg, 25 to <50 kg, and ≥50 kg, respectively.

The pharmacokinetics of abatacept is similar in adult RA and paediatric pJIA patients except for the higher SC absorption in pJIA patients. SC bioavailability (F) increased by 28% and the absorption rate constant (KA) was higher in pJIA patients than RA patients.

Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous abatacept in pJIA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance.

- In section 6.5:

ORENCIA 50 mg solution for injection in pre-filled syringe

0.4 mL pre-filled syringe (type 1 glass) with an automatic needle safety guard and flange extenders (white plunger).

Packs of 4 pre-filled syringes with needle guard.

ORENCIA 87.5 mg solution for injection in pre-filled syringe

0.7 mL pre-filled syringe (type 1 glass) with an automatic needle safety guard and flange extenders (light blue plunger).

Packs of 4 pre-filled syringes with needle guard.

ORENCIA 125 mg solution for injection in pre-filled syringe

One mL pre-filled syringe (type 1 glass) with flange extenders or one mL pre-filled syringe with an automatic needle safety guard and flange extenders (orange plunger).

Packs of 1 or 4 pre-filled syringes and multipack containing 12 pre-filled syringes (3 packs of 4).

Packs of 1, 3 or 4 pre-filled syringes with needle guard and multipack containing 12 pre-filled syringes with needle guard (3 packs of 4).

The type 1 glass syringe has a coated bromobutyl stopper and fixed stainless steel needle covered with a rigid needle shield.

- In section 8:

EU/1/07/389/004-010

EU/1/07/389/013-014

- In Section 10: DATE OF REVISION OF THE TEXT 08 April 2019

- In Section 4.1:

Polyarticular juvenile idiopathic arthritis

ORENCIA in combination with methotrexate is indicated for the treatment of moderate to severe active polyarticular juvenile idiopathic arthritis (pJIA) in paediatric patients 6 years of age and older who have had an inadequate response to previous DMARD therapy.

ORENCIA can be given as monotherapy in case of intolerance to methotrexate or when treatment with methotrexate is inappropriate.

- In Section 4.2:

Paediatric population

Polyarticular juvenile idiopathic arthritis

[...] ORENCIA solution for injection in 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 in pre-filled syringe).

Method of administration

For intravenous use.

The entire, fully diluted ORENCIA solution should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 to 1.2 μm). For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

- In section 4.4:

Patients on controlled sodium diet

This medicinal product contains 34.5 mg sodium per maximum dose of 4 vials (8.625 mg sodium per vial), equivalent to 1.7% of the WHO recommended maximum daily dietary intake of 2 g sodium for an adult.

- In section 4.6:

Pregnancy and women of childbearing potential

[...] 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 4.8:

Summary of the safety profile in psoriatic arthritis

Abatacept has been studied in patients with active psoriatic arthritis in two placebo-controlled clinical trials (341 patients with abatacept, 253 patients with placebo) (see section 5.1). During the 24-week placebo-controlled period in the larger study PsA-II, the proportion of patients with adverse reactions was similar in the abatacept and placebo treatment groups (15.5% and 11.4%, respectively). There were no adverse reactions that occurred at ≥ 2% in either treatment group during the 24-week placebo-controlled period. The overall safety profile was comparable between studies PsA-I and PsA-II and consistent with the safety profile in rheumatoid arthritis (Table 2).

- In Section

Safety information related to the pharmacological class

Abatacept is the first selective co-stimulation modulator. Information on the relative safety in a clinical trial versus infliximab is summarised in section 5.1.

Paediatric population

Abatacept has been studied in patients with pJIA in two clinical trials (pJIA SC study and pJIA IV study). The pJIA SC study included 46 patients in the 2 to 5 year age cohort and 173 patients in the 6 to 17 year age cohort. The pJIA IV study included 190 patients in the 6 to 17 year age cohort. During the first 4-month open-label period, the overall safety profile in these 409 pJIA patients was similar to that observed in the RA population with the following exceptions in the pJIA patients:

• Common adverse reactions: pyrexia
• Uncommon adverse reactions: haematuria, otitis (media and externa).

Description of selected adverse reactions

Infections

Infections were the most commonly reported adverse events in patients with pJIA. The types of infections were consistent with those commonly seen in outpatient paediatric populations. During the first 4-month treatment period of intravenous and subcutaneous abatacept in 409 patients with pJIA, the most common adverse reactions were nasopharyngitis (3.7% patients) and upper respiratory tract infection (2.9% patients). Two serious infections (varicella and sepsis) were reported during the initial 4 months of treatment with abatacept.

[...]

Open-label extension period

During the extension period of the pJIA studies (20 months in the pJIA SC study and 5 years in the pJIA IV study), the safety profile in the pJIA patients aged 6 to 17 years was comparable to that seen in adult patients. One patient was diagnosed with multiple sclerosis while in the extension period of the pJIA IV study. Long-term safety data in 2 to 5 year old patients with pJIA was limited, but the existing evidence did not reveal any new safety concern in this younger paediatric population.

- In Section 5.1:

Paediatric population in polyarticular juvenile idiopathic arthritis

[...]

Abatacept in pJIA patients has also been studied with the subcutaneous formulation in children and adolescents with moderate to severe active pJIA, ages 2 to 17 years with an inadequate response or intolerance to at least one DMARD, which may have included biologic agents. The safety and efficacy of abatacept in the ongoing SC study were consistent with the results seen with abatacept in the IV study (see section 5.1 of the ORENCIA solution for injection in pre-filled syringe SmPC for complete study description and results).

- In Section 5.3:

Non-clinical studies relevant for use in the paediatric population

[...] The relevance of these results to humans is unknown.

- In section 6.3:

After reconstitution

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C. From a microbiological point of view, the reconstituted solution should be diluted immediately.

After dilution

When the reconstituted solution is diluted immediately, the chemical and physical in-use stability of the diluted infusion solution has been demonstrated for 24 hours at 2°C - 8°C. From a microbiological point of view, the product should be used immediately.

- In section 6.5:

Vial (15 mL Type 1 glass) with a stopper (halobutyl-rubber) and flip off seal (aluminium).

Pack of 1 vial and 1 silicone-free syringe (polyethylene), and multipacks containing 2, or 3 vials and 2, or 3 silicone-free syringes (2 or 3 packs of 1).

- In Section 6.6:

Dilution

[...]

4. When reconstitution and dilution are performed under aseptic conditions ORENCIA infusion solution can be used immediately or within 24 hours if stored refrigerated at 2°C to 8°C. Prior to administration, the ORENCIA solution should be inspected visually for particulate matter and discolouration. Discard the solution if any particulate matter or discolouration is observed.

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

​​

​​

​​

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

​​

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

​​

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

​​

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

​​

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 overall 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 9.315.7% (128215/1369) while on abatacept, with a mean duration of exposure of 29.948.8 months, and 12.717.3% (17194/1341121) 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 persist or increase upon continued dosing (1.66.8% 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, and VI, and SC-I durable and sustained ACR 20, 50, and 70 responses have been observed through 7 years, 5 years, 5 years, and 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

Minor typographical changes:-

-          ml to mL

-          SC to subcutaneous

-          IV to intravenous

Changes made as part of EMEA/H/C/000701/II/0087/G variation to add a new container / presentation (pre filled pen)

CHMP opinion received on 24 April 2015.