Abatacept

Name: Abatacept

How should I use abatacept?

Before you start treatment with abatacept, your doctor may perform tests to make sure you do not have tuberculosis or other infections.

Abatacept is injected under the skin, or into a vein through an IV. You may be shown how to use injections at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of needles, IV tubing, and other items used.

Abatacept is injected under the skin when given to a child between 2 and 6 years old.

Abatacept must be given slowly when infected into a vein, and the IV infusion can take at least 30 minutes to complete.

This medicine is usually given every 1 to 4 weeks. Follow your doctor's instructions.

You may need to mix abatacept with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medication.

Do not shake the medication bottle or you may ruin the medicine. Prepare your dose only when you are ready to give an injection. Do not use if the medicine has changed colors or has particles in it. Call your pharmacist for new medicine.

Each single-use vial (bottle) or prefilled syringe of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

If you need surgery, tell the surgeon ahead of time that you are using abatacept.

If you have ever had hepatitis B, abatacept can cause this condition to come back or get worse. You will need frequent blood tests to check your liver function during treatment and for several months after you stop using this medicine.

This medicine can cause false results with certain blood glucose tests, showing high blood sugar readings. If you have diabetes, talk to your doctor about the best way to check your blood sugar while you are using abatacept.

Autoimmune disorders are often treated with a combination of different drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

Store abatacept in the refrigerator. Do not freeze. Keep the medicine in original carton to protect it from light. Do not use abatacept if the expiration date on the medicine label has passed.

If you need to transport the medicine, place the syringes in a cooler with ice packs.

Abatacept that has been mixed with a diluent may be stored in a refrigerator or at room temperature and used within 24 hours.

Advice to Patients

  • Importance of providing patient a copy of the manufacturer’s patient information.1

  • Importance of patient informing clinician about existing infections prior to initiating therapy.1 Importance of patients informing clinicians promptly if any signs or symptoms of infection occur during therapy.1

  • Advise patients that this preparation contains maltose and may cause falsely elevated glucose readings when blood glucose monitoring systems based on glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) are used; importance of using glucose-specific test methods not affected by maltose.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., TNF blocking agents, biologic antirheumatic drugs, immunizations) and OTC drugs, as well as any other illnesses (e.g., concomitant or recurrent infections, history of tuberculosis, history of HBV infection, diabetes mellitus).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Auto-injector, Subcutaneous [preservative free]:

Orencia ClickJect: 125 mg/mL (1 mL)

Solution Prefilled Syringe, Subcutaneous [preservative free]:

Orencia: 50 mg/0.4 mL (0.4 mL); 87.5 mg/0.7 mL (0.7 mL); 125 mg/mL (1 mL)

Solution Reconstituted, Intravenous [preservative free]:

Orencia: 250 mg (1 ea)

Brand Names U.S.

  • Orencia
  • Orencia ClickJect

Pharmacologic Category

  • Antirheumatic, Disease Modifying
  • Selective T-Cell Costimulation Blocker

Use Labeled Indications

Juvenile idiopathic arthritis: Treatment of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA); may be used as monotherapy or in combination with methotrexate

Psoriatic arthritis: Treatment of active psoriatic arthritis (PsA) in adults

Rheumatoid arthritis: Treatment of moderately to severely active adult rheumatoid arthritis (RA); may be used as monotherapy or in combination with other DMARDs

Note: Abatacept should not be used in combination with anakinra or TNF-blocking agents

Dosing Adjustment for Toxicity

Discontinue in patients who develop a serious infection.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, nausea, signs of common cold, rhinitis, pharyngitis, abdominal pain, or back pain. Have patient report immediately to prescriber signs of infection, severe dizziness, passing out, severe headache, shortness of breath, skin growth, weight loss, night sweats, severe loss of strength and energy, flu-like symptoms, swelling, warmth, or redness of skin, or severe injection site irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Which drugs or supplements interact with abatacept?

Combining abatacept with TNF antagonists (for example, Enbrel, Humira and Remicade) increases the occurrence of infections and provides no additional relief of symptoms. Abatacept may reduce the effect of live vaccines. Live vaccines should not be given at the same time as abatacept or within three months of discontinuation of abatacept. Pediatric patients should receive all recommended immunizations prior to starting abatacept.

Warnings

Included as part of the PRECAUTIONS section.

Clinical pharmacology

Mechanism Of Action

Abatacept, a selective costimulation modulator, inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T lymphocytes are implicated in the pathogenesis of RA and PsA and are found in the synovium of patients with RA and PsA.

In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNFα), interferon-γ, and interleukin-2. In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production, and reduces antigen specific production of interferon-γ. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its clinical effects is unknown.

Pharmacodynamics

In clinical trials with ORENCIA at doses approximating 10 mg/kg, decreases were observed in serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), rheumatoid factor (RF), C-reactive protein (CRP), matrix metalloproteinase-3 (MMP3), and TNFα. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its clinical effects is unknown.

Pharmacokinetics

Healthy Adults And Adult RA - Intravenous Administration

The pharmacokinetics of abatacept were studied in healthy adult subjects after a single 10 mg/kg intravenous infusion and in RA patients after multiple 10 mg/kg intravenous infusions (see Table 5).

Table 5: Pharmacokinetic Parameters (Mean, Range) in Healthy Subjects and RA Patients After 10 mg/kg Intravenous Infusion(s)

PK Parameter Healthy Subjects (After 10 mg/kg Single Dose)
n=13
RA Patients (After 10 mg/kg Multiple Dosesa)
n=14
Peak Concentration (Cmax) [mcg/mL] 292 (175-427) 295 (171-398)
Terminal half-life (t1/2) [days] 16.7 (12-23) 13.1 (8-25)
Systemic clearance (CL) [mL/h/kg] 0.23 (0.16-0.30) 0.22 (0.13-0.47)
Volume of distribution (Vss) [L/kg] 0.09 (0.06-0.13) 0.07 (0.02-0.13)
a Multiple intravenous infusions were administered at days 1, 15, 30, and monthly thereafter.

The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be comparable. In RA patients, after multiple intravenous infusions, the pharmacokinetics of abatacept showed proportional increases of Cmax and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady state by day 60 with a mean (range) trough concentration of 24 mcg/mL (1 to 66 mcg/mL). No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in RA patients.

Population pharmacokinetic analyses in RA 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 clearance. Concomitant methotrexate, NSAIDs, corticosteroids, and TNF blocking agents did not influence abatacept clearance.

No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of abatacept.

Adult RA - Subcutaneous Administration

Abatacept exhibited linear pharmacokinetics following subcutaneous administration. The mean (range) for Cmin and Cmax at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 L/kg), and terminal half-life (14.3 days) were comparable between subcutaneous and intravenous administration.

Study SC-2 was conducted to determine the effect of monotherapy use of ORENCIA on immunogenicity following subcutaneous administration without an intravenous load. When the intravenous loading dose was not administered, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing.

Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous abatacept in RA 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.

Juvenile Idiopathic Arthritis - Intravenous Administration

In Study JIA-1 among patients 6 to 17 years of age, the mean (range) steady state serum peak and trough concentrations of abatacept were 217 mcg/mL (57 to 700 mcg/mL) and 11.9 mcg/mL (0.15 to 44.6 mcg/mL). Population pharmacokinetic analyses of the serum concentration data showed that clearance of abatacept increased with baseline body weight. The estimated mean (range) clearance of abatacept in the juvenile idiopathic arthritis patients was 0.4 mL/h/kg (0.20 to 1.12 mL/h/kg). After accounting for the effect of body weight, the clearance of abatacept was not related to age and gender. Concomitant methotrexate, corticosteroids, and NSAIDs were also shown not to influence abatacept clearance.

Juvenile Idiopathic Arthritis - Subcutaneous Administration

In Study JIA-2 among 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 44.4 mcg/mL (13.4 to 88.1 mcg/mL), 46.6 mcg/mL (22.4 to 97.0 mcg/mL), and 38.5 mcg/mL (9.3 to 73.2 mcg/mL) in pediatric JIA patients weighing 10 to < 25 kg, 25 to < 50 kg, and ≥ 50 kg, respectively.

Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous abatacept in JIA 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.

Adult Psoriatic Arthritis - Intravenous And Subcutaneous Administration

In Study PsA-I, a dose ranging study, IV abatacept was administered at 3 mg/kg, 10 mg/kg (weight range-based dosing: 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg), or two doses of 30 mg/kg followed by weight range-based dose of 10 mg/kg. Following monthly IV administration, abatacept showed linear PK over the dose range of 3 mg/kg to 10 mg/kg. At 10 mg/kg, the steady state of abatacept was reached by Day 57 and the geometric mean (CV%) trough concentration (Cmin) was 24.3 mcg/mL (40.8%) at Day 169. In Study PsA-II following weekly SC administration of abatacept at 125 mg, the steady state of abatacept was reached at Day 57 and the geometric mean (CV%) Cmin was 25.6 mcg/mL (47.7%) at Day 169.

Consistent with the RA results, population pharmacokinetic analyses for abatacept in psoriatic arthritis patients revealed that there was a trend toward higher clearance (L/h) of abatacept with increasing body weight. In addition, relative to the RA patients with the same body weight, abatacept clearance in psoriatic arthritis patients was approximately 8% lower, resulting in higher abatacept exposures in patients with PsA. This slight difference in exposures, however, is not considered to be clinically meaningful.

Animal Toxicology And/Or Pharmacology

A juvenile animal study was conducted in rats dosed with abatacept from 4 to 94 days of age in which an increase in the incidence of infections leading to death occurred at all doses compared with controls. Altered T-cell subsets including increased T-helper cells and reduced T-regulatory cells were observed. In addition, inhibition of T-cell-dependent antibody responses (TDAR) was observed. Upon following these animals into adulthood, lymphocytic inflammation of the thyroid and pancreatic islets was observed.

In studies of adult mice and monkeys, inhibition of TDAR was apparent. However, infection and mortality, altered T-helper cells, and inflammation of thyroid and pancreas were not observed.

Clinical Studies

Adult Rheumatoid Arthritis

The efficacy and safety of ORENCIA for intravenous administration were assessed in six randomized, double-blind, controlled studies (five placebo-controlled and one active-controlled) in patients ≥ 18 years of age with active RA diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, IV, and VI required patients to have at least 12 tender and 10 swollen joints at randomization. Study V did not require any specific number of tender or swollen joints. ORENCIA or placebo treatment was given intravenously at weeks 0, 2, and 4 and then every 4 weeks thereafter in intravenous Studies I, II, III, IV, and VI. The safety and efficacy of ORENCIA for subcutaneous administration were assessed in Study SC-1, which was a randomized, double-blind, double-dummy, non-inferiority study that compared abatacept administered subcutaneously and intravenously in 1457 subjects with rheumatoid arthritis (RA), receiving background methotrexate (MTX), and experiencing an inadequate response to methotrexate (MTX-IR).

Study I evaluated ORENCIA as monotherapy in 122 patients with active RA who had failed at least one non-biologic DMARD or etanercept. In Study II and Study III, the efficacy and safety of ORENCIA were assessed in patients with an inadequate response to methotrexate and who were continued on their stable dose of methotrexate. In Study IV, the efficacy and safety of ORENCIA were assessed in patients with an inadequate response to a TNF blocking agent, with the TNF blocking agent discontinued prior to randomization; other DMARDs were permitted. Study V primarily assessed safety in patients with active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued. Patients in Study V were not excluded for comorbid medical conditions. In Study VI, the efficacy and safety of ORENCIA were assessed in methotrexate-naive patients with RA of less than 2 years disease duration. In Study VI, patients previously naive to methotrexate were randomized to receive ORENCIA plus methotrexate or methotrexate plus placebo. In Study SC-1, the goal was to demonstrate the efficacy and safety of ORENCIA subcutaneous relative to ORENCIA intravenous administration in subjects with moderate to severely active RA and experiencing inadequate response to methotrexate, using a non-inferiority study design.

Study I patients were randomized to receive one of three doses of ORENCIA (0.5, 2, or 10 mg/kg) or placebo ending at week 8. Study II patients were randomized to receive ORENCIA 2 or 10 mg/kg or placebo for 12 months. Study III, IV, V, and VI patients were randomized to receive a dose of ORENCIA based on weight range or placebo for 12 months (Studies III, V, and VI) or 6 months (Study IV). The dose of ORENCIA was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg. In Study SC-1, patients were randomized with stratification by body weight ( < 60 kg, 60 to 100 kg, > 100 kg) to receive ORENCIA 125 mg subcutaneous injections weekly, after a single intravenous loading dose of ORENCIA based on body weight or ORENCIA intravenously on Days 1, 15, 29, and every four weeks thereafter. Subjects continued taking their current dose of methotrexate from the day of randomization.

Clinical Response

The percent of ORENCIA-treated patients achieving ACR 20, 50, and 70 responses and major clinical response in Studies I, III, IV, and VI are shown in Table 6. ORENCIA-treated patients had higher ACR 20, 50, and 70 response rates at 6 months compared to placebo-treated patients. Month 6 ACR response rates in Study II for the 10 mg/kg group were similar to the ORENCIA group in Study III.

In Studies III and IV, improvement in the ACR 20 response rate versus placebo was observed within 15 days in some patients and within 29 days versus methotrexate in Study VI. In Studies II, III, and VI, ACR response rates were maintained to 12 months in ORENCIA-treated patients. ACR responses were maintained up to three years in the open-label extension of Study II. In Study III, ORENCIA-treated patients experienced greater improvement than placebo-treated patients in morning stiffness.

In Study VI, a greater proportion of patients treated with ORENCIA plus methotrexate achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 at 12 months compared to those treated with methotrexate plus placebo (Table 6). Of patients treated with ORENCIA plus methotrexate who achieved DAS28-CRP less than 2.6, 54% had no active joints, 17% had one active joint, 7% had two active joints, and 22% had three or more active joints, where an active joint was a joint that was rated as tender or swollen or both.

In Study SC-1, the main outcome measure was ACR 20 at 6 months. The pre-specified noninferiority margin was a treatment difference of -7.5%. As shown in Table 6, the study demonstrated non-inferiority of ORENCIA administered subcutaneously to intravenous infusions of ORENCIA with respect to ACR 20 responses up to 6 months of treatment. ACR 50 and 70 responses are also shown in Table 6. No major differences in ACR responses were observed between intravenous and subcutaneous treatment groups in subgroups based on weight categories (less than 60 kg, 60 to 100 kg, and more than 100 kg; data not shown).

Table 6: Clinical Responses in Controlled Trials

Response Rate Percent of Patients
Intravenous Administration Subcutaneous Administration
Inadequate Response to DMARDs Inadequate Response to Methotrexate (MTX) Inadequate Response to TNF Blocking Agent MTX-Naive Inadequate Response to MTX
Study I Study III Study IV Study VI Study SC-1
ORNa
n=32
PBO
n=32
ORNb +MTX
n=424
PBO +MTX
n=214
ORNb + DMARDs
n=256
PBO + DMARDs
n=133
ORNb +MTX
n=256
PBO +MTX
n=253
ORNe SC +MTX
n=693
ORNe IV +MTX
n=678
ACR 20
Month 3 53% 31% 62%‡ 37% 46%‡ 18% 64%* 53% 68% 69%
Month 6 NA NA 68%‡ 40% 50%‡ 20% 75%† 62% 76%§ 76%
Month 12 NA NA 73%‡ 40% NA NA 76%‡ 62% NA NA
ACR 50
Month 3 16% 6% 32%‡ 8% 18%† 6% 40%‡ 23% 33% 39%
Month 6 NA NA 40%‡ 17% 20%‡ 4% 53%‡ 38% 52% 50%
Month 12 NA NA 48%‡ 18% NA NA % 7 5 42% NA NA
ACR 70
Month 3 6% 0 13%‡ 3% 6%* 1% 19%† 10% 13% 16%
Month 6 NA NA 20%‡ 7% 10%† 2% 32%† 20% 26% 25%
Month 12 NA NA 29%‡ 6% NA NA 43%‡ 27% NA NA
Major Clinical Responsec NA NA 14%‡ 2% NA NA 27%‡ 12% NA NA
DAS28-CRP < 2.6d
Month 12 NA NA NA NA NA NA 41%‡ 23% NA NA
* p < 0.05, ORENCIA (ORN) vs placebo (PBO) or MTX.
† p < 0.01, ORENCIA vs placebo or MTX.
‡ p < 0.001, ORENCIA vs placebo or MTX.
§ 95% CI: -4.2, 4.8 (based on prespecified margin for non-inferiority of -7.5%).
a 10 mg/kg.
b Dosing based on weight range [see DOSAGE AND ADMINISTRATION].
c Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period.
d Refer to text for additional description of remaining joint activity.
e Per protocol data is presented in table. For ITT; n=736, 721 for SC and IV ORENCIA, respectively.

The results of the components of the ACR response criteria for Studies III, IV, and SC-1 are shown in Table 7 (results at Baseline [BL] and 6 months [6 M]). In ORENCIA-treated patients, greater improvement was seen in all ACR response criteria components through 6 and 12 months than in placebo-treated patients.

Table 7: Components of ACR Responses at 6 Months

Component (median) Intravenous Administration Subcutaneous Administration
Inadequate Response to Methotrexate (MTX) Inadequate Response to TNF Blocking Agent Inadequate Response to MTX
Study III Study IV Study SC-1c
ORN +MTX
n=424
PBO +MTX
n=214
ORN +DMARDs
n=256
PBO +DMARDs
n=133
ORN SC +MTX
n=693
ORN IV +MTX
n=678
BL 6 M BL 6 M BL 6 M BL 6 M BL 6 M BL 6 M
Number of tender joints (0-68) 28 7‡ 31 14 30 13‡ 31 24 27 5 27 6
Number of swollen joints (0-66) 19 5‡ 20 11 21 10‡ 20 14 18 4 18 3
Paina 67 27‡ 70 50 73 43† 74 64 71 25 70 28
Patient global assessmenta 66 29‡ 64 48 71 44‡ 73 63 70 26 68 27
Disability indexb 1.75 1.13‡ 1.75 1.38 1.88 1.38‡ 2.00 1.75 1.88 1.00 1.75 1.00
Physician global assessmenta 69 21‡ 68 40 71 32‡ 69 54 65 16 65 15
CRP (mg/dL) 2.2 0.9‡ 2.1 1.8 3.4 1.3‡ 2.8 2.3 1.6 0.7 1.8 0.7
† p < 0.01, ORENCIA (ORN) vs placebo (PBO), based on mean percent change from baseline.
‡ p < 0.001, ORENCIA vs placebo, based on mean percent change from baseline.
a Visual analog scale: 0 = best, 100 = worst.
b Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
c SC-1 is a non-inferiority study. Per protocol data is presented in table.

The percent of patients achieving the ACR 50 response for Study III by visit is shown in Figure 1. The time course for the ORENCIA group in Study VI was similar to that in Study III.

Figure 1: Percent of Patients Achieving ACR 50 Response by Visit* (Study III)

The percent of patients achieving the ACR 50 response for Study SC-1 in the ORENCIA subcutaneous (SC) and intravenous (IV) treatment arms at each treatment visit was as follows: Day 15-SC 3%, IV 5%; Day 29-SC 11%, IV 14%; Day 57-SC 24%, IV 30%; Day 85- SC 33%, IV 38%; Day 113-SC 39%, IV 41%; Day 141-SC 46%, IV 47%; Day 169-SC 51%, IV 50%.

Radiographic Response

In Study III and Study VI, structural joint damage was assessed radiographically and expressed as change from baseline in the Genant-modified Total Sharp Score (TSS) and its components, the Erosion Score (ES) and Joint Space Narrowing (JSN) score. ORENCIA/methotrexate slowed the progression of structural damage compared to placebo/methotrexate after 12 months of treatment as shown in Table 8.

Table 8: Mean Radiographic Changes in Study IIIa and Study VIb

Parameter ORENCIA/ MTX Placebo/ MTX Differences P-valued
Study III
First Year
  TSS 1.07 2.43 1.36 < 0.01
  ES 0.61 1.47 0.86 < 0.01
  JSN score 0.46 0.97 0.51 < 0.01
Second Year
  TSS 0.48 0.74c - -
  ES 0.23 0.22c - -
  JSN score 0.25 0.51c - -
Study VI
First Year
  TSS 0.6 1.1 0.5 0.04
a Patients with an inadequate response to MTX.
b MTX-naive patients.
c Patients received 1 year of placebo/MTX followed by 1 year of ORENCIA/MTX.
d Based on a nonparametric ANCOVA model.

In the open-label extension of Study III, 75% of patients initially randomized to ORENCIA/methotrexate and 65% of patients initially randomized to placebo/methotrexate were evaluated radiographically at Year 2. As shown in Table 8, progression of structural damage in ORENCIA/methotrexate-treated patients was further reduced in the second year of treatment.

Following 2 years of treatment with ORENCIA/methotrexate, 51% of patients had no progression of structural damage as defined by a change in the TSS of zero or less compared with baseline. Fifty-six percent (56%) of ORENCIA/methotrexate-treated patients had no progression during the first year compared to 45% of placebo/methotrexate-treated patients. In their second year of treatment with ORENCIA/methotrexate, more patients had no progression than in the first year (65% vs 56%).

Physical Function Response And Health-Related Outcomes

Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). In the HAQ-DI, ORENCIA demonstrated greater improvement from baseline versus placebo in Studies II-V and versus methotrexate in Study VI. In Study SC-1, improvement from baseline as measured by HAQ-DI at 6 months and over time was similar between subcutaneous and intravenous administration. The results from Studies II and III are shown in Table 9. Similar results were observed in Study V compared to placebo and in Study VI compared to methotrexate. During the open-label period of Study II, the improvement in physical function has been maintained for up to 3 years.

Table 9: Mean Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)

HAQ Disability Index Inadequate Response to Methotrexate
Study II Study III
ORENCIAa +MTX
(n=115)
Placebo +MTX
(n=119)
ORENCIAb +MTX
(n=422)
Placebo+ MTX
(n=212)
Baseline (Mean) 0.98c 0.97c 1.69d 1.69d
Mean Improvement Year 1 0 40c*** 0.15c 0.66d*** 0.3 7d
*** p < 0.001, ORENCIA vs placebo.
a 10 mg/kg.
b Dosing based on weight range [see DOSAGE AND ADMINISTRATION].
c Modified Health Assessment Questionnaire: 0 = best, 3 = worst; 8 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
d Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in Studies II, III, and IV and at 12 months in Studies II and III. In these studies, improvement was observed in the ORENCIA group as compared with the placebo group in all 8 domains of the SF-36 as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS).

Juvenile Idiopathic Arthritis

Juvenile Idiopathic Arthritis - Intravenous Administration

The safety and efficacy of ORENCIA with intravenous administration were assessed in Study JIA-1, a three-part study including an open-label extension in children with polyarticular juvenile idiopathic arthritis (JIA). Patients 6 to 17 years of age (n=190) with moderately to severely active polyarticular JIA who had an inadequate response to one or more DMARDs, such as methotrexate or TNF antagonists, were treated. Patients had a disease duration of approximately 4 years with moderately to severely active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and ESR (mean, 32 mm/h). The patients enrolled had subtypes of JIA that at disease onset included Oligoarticular (16%), Polyarticular (64%; 20% were rheumatoid factor positive), and Systemic (20%). At study entry, 74% of patients were receiving methotrexate (mean dose, 13.2 mg/m² per week) and remained on a stable dose of methotrexate (those not receiving methotrexate did not initiate methotrexate treatment during the study).

In Period A (open-label, lead-in), patients received 10 mg/kg (maximum 1000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed utilizing the ACR Pediatric 30 definition of improvement, defined as ≥ 30% improvement in at least 3 of the 6 JIA core set variables and ≥ 30% worsening in not more than 1 of the 6 JIA core set variables. Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase (Period B) and received either ORENCIA or placebo for 6 months or until disease flare. Disease flare was defined as a ≥ 30% worsening in at least 3 of the 6 JIA core set variables with ≥ 30% improvement in not more than 1 of the 6 JIA core set variables; ≥ 2 cm of worsening of the Physician or Parent Global Assessment was necessary if used as 1 of the 3 JIA core set variables used to define flare, and worsening in ≥ 2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare.

At the conclusion of Period A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively. Pediatric ACR 30 responses were similar in all subtypes of JIA studied.

During the double-blind randomized withdrawal phase (Period B), ORENCIA-treated patients experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among patients continuing on ORENCIA was less than one-third than that for patients withdrawn from ORENCIA treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]). Among patients who received ORENCIA throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR 30/50/70 responders has remained consistent for 1 year.

Juvenile Idiopathic Arthritis - Subcutaneous Administration

ORENCIA for subcutaneous administration without an intravenous loading dose was assessed in Study JIA-2, a 2-period, open-label study that included children 2 to 17 years of age (n=205). Patients had active polyarticular disease at the time of the study and had inadequate response to at least one nonbiologic or biologic DMARD. The patient subtypes at study entry included Polyarticular (79%; 22% were rheumatoid factor positive), Extended and Persistent Oligoarticular (14%), Enthesitis-Related Arthritis (1%), and Systemic (2%). Patients had a mean disease duration of 2.5 years with active joints (mean, 11.9), joints with loss of motion (mean, 10.4), and elevated C-reactive protein (CRP) levels (mean, 1.2 mg/dL). At study entry, 80% of patients were receiving methotrexate and remained on a stable dose of methotrexate. Patients received weekly open-label ORENCIA subcutaneously by a weight-tiered dosing regimen. The primary objective of the study was evaluation of PK in order to support the extrapolation of efficacy based on exposure to ORENCIA supported by descriptive efficacy [see CLINICAL PHARMACOLOGY].

JIA ACR 30/50/70 responses assessed at 4 months in the 2- to 17-year-old patients were consistent with the results from the intravenous study, JIA-1.

Adult Psoriatic Arthritis

The efficacy of ORENCIA was assessed in 594 patients with psoriatic arthritis, in two randomized, double-blind, placebo-controlled studies (Studies PsA-I and PsA-II) in adult patients, age 18 years and older. Patients had active psoriatic arthritis ( ≥ 3 swollen joints and ≥ 3 tender joints) despite prior treatment with DMARD therapy and had one qualifying psoriatic skin lesion of at least 2 cm in diameter. In PsA-I and PsA-II, 37% and 61% of patients, respectively, were treated with TNFi previously.

In PsA-I, a dose-ranging study, 170 patients received study drug IV at Day 1, 15, 29, and then every 28 days thereafter in a double blind manner for 24 weeks, followed by open-label ORENCIA every 28 days. Patients were randomized to receive placebo or ORENCIA 3 mg/kg, 10 mg/kg (weight range-based dosing: 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg), or two doses of 30 mg/kg followed by weight range-based dosing of 10 mg/kg without escape for 24 weeks. Patients were allowed to receive stable doses of concomitant methotrexate, low dose corticosteroids (equivalent to ≤ 10 mg of prednisone) and/or NSAIDs during the trial. At enrollment, approximately 60% of patients were receiving methotrexate. At baseline, the mean (SD) CRP for ORENCIA IV was 17 mg/L (33.0) and mean number (SD) of tender joints and swollen joints was 22.2 (14.3) and 10.9 (7.6), respectively.

In PsA-II, 424 patients were randomized 1:1 to receive weekly doses of SC placebo or ORENCIA 125 mg without a loading dose for 24 weeks-in a double-blind manner, followed by open-label ORENCIA 125 mg SC weekly. Patients were allowed to receive stable doses of concomitant methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, low dose corticosteroids (equivalent to ≤ 10 mg of prednisone) and/or NSAIDs during the trial. At randomization, 60.4% of patients were receiving methotrexate. The baseline disease characteristics included presence of joint erosion on X-rays in 84% (341/424) with a mean (SD) PsA-modified Sharp van der Heijde erosion score (SHS) of 10.8 (24.2), elevated serum C reactive protein (CRP) in 66% [277/424]) with a mean (SD) of 14.1 mg/L (25.9), and polyarticular disease in 98% (416/424) of patients with a mean number (SD) of tender joints and swollen joints of 20.2 (13.3) and 11.6 (7.5), respectively. Patients who had not achieved at least a 20% improvement from baseline in their swollen and tender joint counts by Week 16 escaped to open-label ORENCIA 125 mg SC weekly.

The primary endpoint for both PsA-I and PsA-II was the proportion of patients achieving ACR 20 response at Week 24 (Day 169).

Clinical Response

A higher proportion of patients achieved an ACR20 response after treatment with ORENCIA 10 mg/kg IV (weight range-based dosing as described above) or 125 mg SC compared to placebo at Week 24. Responses were seen regardless of prior TNFi treatment and regardless of concomitant non-biologic DMARD treatment. The percent of patients achieving ACR 20, 50, or 70 responses in Studies PsA-I and PsA-II are presented in Table 10 below.

Table 10: Proportion of Patients With ACR Responses at Week 24 in Studies PsA-I and PsA-IIa

  PsA-I PsA-II
ORENCIA 10mg/kg IVb
N=40
Placebo
N=42
ORENCIA 125 mg SC
N=213
Placebo
N=211
ACR 20 47.5%* 19.0% * 39.4% 22.3%
ACR 50 25.0% 2.4% 19.2% 12.3%
ACR 70 12.5% 0% 10.3% 6.6%
* p < 0.05 versus placebo
a Patients who had less than 20% improvement in tender or swollen joint counts at Week 16 met escape criteria and were considered non-responders.
b Weight range-based dosing (as described above).

The percentage of patients in PsA-II achieving ACR20 response through Week 24 is shown below in Figure 2.

Figure 2: Percent of Patients Achieving ACR20 Responsea in PsA-II Study Through Week 24 (Day 169)

Results were generally consistent across the ACR components in Study PsA-I and PsA-II.

Improvements in enthesitis and dactylitis were seen with ORENCIA treatment at Week 24 in both PsA-I and PsA-II.

Physical Function Response

In study PsA-I, there was a higher proportion of patients with at least a 0.30 decrease from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 24, with an estimated difference for ORENCIA 10 mg/kg (weight range-based dosing as described above) (45.0%) vs. placebo (19.0%) of 26.1 (95% confidence interval: 6.8, 45.5). In study PsA-II, the proportion of patients with at least a 0.35 decrease from baseline in HAQ-DI on ORENCIA was 31%, as compared to 24% on placebo (estimated difference: 7%; 95% confidence interval: -1%, 16%). There was a higher adjusted mean change from baseline in HAQ-DI on ORENCIA (-0.33) vs. placebo (-0.20) at Week 24, with an estimated difference of -0.13 (95% confidence interval: -0.25, -0.01).

Abatacept Overview

Abatacept is a prescription medication used to treat rheumatoid arthritis, juvenile idiopathic arthritis, and active psoriatic arthritis. 

Abatacept belongs to a group of drugs called immunomodulators which work by blocking the activity of T-cells. A T-cell is a cell of the immune system that can cause swelling and joint damage in rheumatoid arthritis.

This medication comes in an injectable form that is usually given directly into a vein (IV) by a healthcare provider. Abatacept may also be given as an injection just under the skin.

Common side effects of abatacept include headache, upper respiratory tract infection, sore throat, and nausea.

Abatacept Brand Names

Abatacept may be found in some form under the following brand names:

  • Orencia

Side effects

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to abatacept in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Clinical Studies Experience In Adult RA Patients Treated With Intravenous ORENCIA

The data described herein reflect exposure to ORENCIA administered intravenously in patients with active RA in placebo-controlled studies (1955 patients with ORENCIA, 989 with placebo). The studies had either a double-blind, placebo-controlled period of 6 months (258 patients with ORENCIA, 133 with placebo) or 1 year (1697 patients with ORENCIA, 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF blocking agent (204 patients with ORENCIA, 134 with placebo).

The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA: methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, TNF blocking agents, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra.

The most serious adverse reactions were serious infections and malignancies.

The most commonly reported adverse events (occurring in ≥ 10% of patients treated with ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis, and nausea.

The adverse events most frequently resulting in clinical intervention (interruption or discontinuation of ORENCIA) were due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1.0%), bronchitis (0.7%), and herpes zoster (0.7%). The most frequent infections resulting in discontinuation were pneumonia (0.2%), localized infection (0.2%), and bronchitis (0.1%).

Infections

In the placebo-controlled trials, infections were reported in 54% of ORENCIA-treated patients and 48% of placebo-treated patients. The most commonly reported infections (reported in 5%-13% of patients) were upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, influenza, and bronchitis. Other infections reported in fewer than 5% of patients at a higher frequency ( > 0.5%) with ORENCIA compared to placebo, were rhinitis, herpes simplex, and pneumonia [see WARNINGS AND PRECAUTIONS].

Serious infections were reported in 3.0% of patients treated with ORENCIA and 1.9% of patients treated with placebo. The most common (0.2%-0.5%) serious infections reported with ORENCIA were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis [see WARNINGS AND PRECAUTIONS].

Malignancies

In the placebo-controlled portions of the clinical trials (1955 patients treated with ORENCIA for a median of 12 months), the overall frequencies of malignancies were similar in the ORENCIA and placebo-treated patients (1.3% and 1.1%, respectively). However, more cases of lung cancer were observed in ORENCIA-treated patients (4, 0.2%) than placebo-treated patients (0). In the cumulative ORENCIA clinical trials (placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years). The rate observed for lymphoma is approximately 3.5-fold higher than expected in an age- and gender-matched general population based on the National Cancer Institute's Surveillance, Epidemiology, and End Results Database. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. Other malignancies included skin, breast, bile duct, bladder, cervical, endometrial, lymphoma, melanoma, myelodysplastic syndrome, ovarian, prostate, renal, thyroid, and uterine cancers [see WARNINGS AND PRECAUTIONS]. The potential role of ORENCIA in the development of malignancies in humans is unknown.

Infusion-Related Reactions And Hypersensitivity Reactions

Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V [see Clinical Studies] were more common in the ORENCIA-treated patients than the placebo patients (9% for ORENCIA, 6% for placebo). The most frequently reported events (1%-2%) were dizziness, headache, and hypertension.

Acute infusion-related events that were reported in > 0.1% and ≤ 1% of patients treated with ORENCIA included cardiopulmonary symptoms, such as hypotension, increased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild (68%) to moderate (28%). Fewer than 1% of ORENCIA-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 ORENCIA-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events.

In clinical trials of 2688 adult RA patients treated with intravenous ORENCIA, there were two cases ( < 0.1%) of anaphylaxis or anaphylactoid reactions. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients and generally occurred within 24 hours of ORENCIA infusion. Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see WARNINGS AND PRECAUTIONS].

Adverse Reactions In Patients With COPD

In Study V [see Clinical Studies], there were 37 patients with chronic obstructive pulmonary disease (COPD) who were treated with ORENCIA and 17 COPD patients who were treated with placebo. The COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in ORENCIA-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of ORENCIA-treated patients developed a serious adverse event compared to placebo-treated patients (27% vs 6%), including COPD exacerbation (3 of 37 patients [8%]) and pneumonia (1 of 37 patients [3%]) [see WARNINGS AND PRECAUTIONS].

Other Adverse Reactions

Adverse events occurring in 3% or more of patients and at least 1% more frequently in ORENCIA-treated patients during placebo-controlled RA studies are summarized in Table 3.

Table 3: Adverse Events Occurring in 3% or More of Patients and at Least 1% More Frequently in ORENCIA-Treated Patients During Placebo-Controlled RA Studies

Adverse Event (Preferred Term) ORENCIA
(n=1955)a Percentage
Placebo
(n=989)b Percentage
Headache 18 13
Nasopharyngitis 12 9
Dizziness 9 7
Cough 8 7
Back pain 7 6
Hypertension 7 4
Dyspepsia 6 4
Urinary tract infection 6 5
Rash 4 3
Pain in extremity 3 2
a Includes 204 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).
b Includes 134 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).

Immunogenicity

Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in RA patients for up to 2 years following repeated treatment with ORENCIA. Thirty-four of 1993 (1.7%) patients developed binding antibodies to the entire abatacept molecule or to the CTLA-4 portion of abatacept. Because trough levels of abatacept can interfere with assay results, a subset analysis was performed. In this analysis it was observed that 9 of 154 (5.8%) patients that had discontinued treatment with ORENCIA for over 56 days developed antibodies.

Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies in a cell-based luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.

No correlation of antibody development to clinical response or adverse events was observed.

The data reflect the percentage of patients whose test results were positive for antibodies to abatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to abatacept with the incidence of antibodies to other products may be misleading.

Clinical Experience In Methotrexate-Naive Patients

Study VI was an active-controlled clinical trial in methotrexate-naive patients [see Clinical Studies]. The safety experience in these patients was consistent with Studies I-V.

Clinical Studies Experience In Adult RA Patients Treated With Subcutaneous ORENCIA

Study SC-1 was a randomized, double-blind, double-dummy, non-inferiority study that compared the efficacy and safety of abatacept administered subcutaneously (SC) and intravenously (IV) in 1457 subjects with rheumatoid arthritis, receiving background methotrexate, and experiencing an inadequate response to methotrexate (MTX-IR) [see Clinical Studies]. The safety experience and immunogenicity for ORENCIA administered subcutaneously was consistent with intravenous Studies I-VI. Due to the route of administration, injection site reactions and immunogenicity were evaluated in Study SC-1 and two other smaller studies discussed in the sections below.

Injection Site Reactions In Adult RA Patients Treated With Subcutaneous ORENCIA

Study SC-1 compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the intravenous abatacept group (subcutaneous placebo), respectively. All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation.

Immunogenicity In Adult RA Patients Treated With Subcutaneous ORENCIA

Study SC-1 compared the immunogenicity to abatacept following subcutaneous or intravenous administration. 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 correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy.

Immunogenicity And Safety Of Subcutaneous ORENCIA Administration As Monotherapy Without An Intravenous Loading Dose

Study SC-2 was conducted to determine the effect of monotherapy use of ORENCIA on immunogenicity following subcutaneous administration without an intravenous load in 100 RA patients, who had not previously received abatacept or other CTLA4Ig, who received either subcutaneous ORENCIA plus methotrexate (n=51) or subcutaneous ORENCIA monotherapy (n=49). No patients in either group developed anti-product antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies.

Immunogenicity And Safety Of Subcutaneous ORENCIA Upon Withdrawal (Three Months) And Restart Of Treatment

Study SC-3 in the subcutaneous program was conducted to investigate the effect of withdrawal (three months) and restart of ORENCIA subcutaneous treatment on immunogenicity in RA patients treated concomitantly with methotrexate. One hundred sixty-seven patients were enrolled in the first 3-month treatment period and responders (n=120) were randomized to either subcutaneous ORENCIA or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label ORENCIA treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 patients who continued to receive subcutaneous ORENCIA developed anti-product antibodies compared to 7/73 (9.6%) of patients who had subcutaneous ORENCIA withdrawn during this period. Half of the patients receiving subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA at the start of period 3 and half received intravenous placebo. At the end of period 3, when all patients again received subcutaneous ORENCIA, the immunogenicity rates were 1/38 (2.6%) in the group receiving subcutaneous ORENCIA throughout, and 2/73 (2.7%) in the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in this study was consistent with that observed in the other studies.

Clinical Studies Experience In Juvenile Idiopathic Arthritis Patients Treated With Intravenous ORENCIA

In general, the adverse events in pediatric patients were similar in frequency and type to those seen in adult patients [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].

Study JIA-1 was a three-part study including an open-label extension that assessed the safety and efficacy of intravenous ORENCIA in 190 pediatric patients, 6 to 17 years of age, with polyarticular juvenile idiopathic arthritis. Overall frequency of adverse events in the 4-month, lead-in, open-label period of the study was 70%; infections occurred at a frequency of 36% [see Clinical Studies]. The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without sequelae, and the types of infections were consistent with those commonly seen in outpatient pediatric populations. Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain.

A total of 6 serious adverse events (acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare [2], and joint wear) were reported during the initial 4 months of treatment with ORENCIA.

Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults.

Upon continued treatment in the open-label extension period, the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single patient diagnosed with multiple sclerosis while on open-label treatment.

Immunogenicity

Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with juvenile idiopathic arthritis following repeated treatment with ORENCIA throughout the open-label period. For patients who were withdrawn from therapy for up to 6 months during the double-blind period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% (22/54), while for those who remained on therapy the rate was 13% (7/54). Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies.

The presence of antibodies was generally transient and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept. For patients who were withdrawn from ORENCIA during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of ORENCIA therapy.

Clinical Studies Experience In Juvenile Idiopathic Arthritis Patients Treated With Subcutaneous ORENCIA

Study JIA-2 was an open-label study with a 4-month short-term period and a long-term extension period that assessed the pharmacokinetics (PK), safety, and efficacy of subcutaneous ORENCIA in 205 pediatric patients, 2 to 17 years of age with juvenile idiopathic arthritis. The safety experience and immunogenicity for ORENCIA administered subcutaneously were consistent with the intravenous Study JIA-1.

There were no reported cases of hypersensitivity reactions. Local injection-site reactions occurred at a frequency of 4.4%.

Clinical Studies Experience In Adult PsA Patients

The safety of ORENCIA was evaluated in 594 patients with psoriatic arthritis (341 patients on ORENCIA and 253 patients on placebo), in two randomized, double-blind, placebo-controlled trials. Of the 341 patients who received ORENCIA, 128 patients received intravenous ORENCIA (PsA-I) and 213 patients received subcutaneous ORENCIA (PsA-II). The safety profile was comparable between studies PsA-I and PsA-II and consistent with the safety profile in rheumatoid arthritis [see WARNINGS AND PRECAUTIONS, Clinical Studies Experience in Adult RA Patients Treated with Intravenous ORENCIA and Clinical Studies Experience in Adult RA Patients Treated with Subcutaneous ORENCIA].

Postmarketing Experience

Adverse reactions have been reported during the postapproval use of ORENCIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ORENCIA. Based on the postmarketing experience in adult RA patients, the following adverse reaction has been identified during postapproval use with ORENCIA.

  • Vasculitis (including cutaneous vasculitis and leukocytoclastic vasculitis)

Read the entire FDA prescribing information for Orencia (Abatacept)

Read More »
  • Rheumatoid Arthritis (RA)
  • Rheumatoid Arthritis (RA) Medications

Abatacept Breastfeeding Warnings

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Yes Comment: -This drug is a large protein molecule. Only small amounts at most would be expected to enter breastmilk. No information is available on the use of this drug during breastfeeding, so an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

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