Orencia Sc 125 Mg Solution

Adult rheumatoid arthritis (RA) ORENCIA is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with active rheumatoid arthritis. ORENCIA may be used as monotherapy or concomitantly with DMARDs (disease modifying anti-rheumatic drugs) other than tumour necrosis factor (TNF) blocking agents.

Paediatrics and Adolescents The safety and efficacy of ORENCIA subcutaneous administration in children below 18 years of age have not been established. No data are available.

Posology Recommended dosage ORENCIA 125 mg solution for subcutaneous injection should be administered weekly at a dose of 125 mg by subcutaneous injection regardless of weight and used with or without an IV loading dose (see section 5.2). For patients initiating therapy with an IV loading dose, ORENCIA should be initiated with a single intravenous infusion followed by the first 125 mg subcutaneous injection administered within a day of the IV infusion, and then by subcutaneous injection once a week thereafter (please refer to section 4.2 for use for IV loading dose in the Professional Information of ORENCIA 250 mg lyophilisate solution for infusion). Patients switching from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Special populations Renal impairment, hepatic impairment As ORENCIA has not been studied in these patients, no dose recommendations can be made. Paediatric and adolescent The safety and efficacy of ORENCIA subcutaneous administration in children below 18 years of age have not been established. No data are available. Geriatric No dose adjustment is required.

Concomitant therapy MTX, other non-biologic DMARDs, corticosteroids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be used during treatment with ORENCIA.

Preparation and administration instructions for subcutaneous administration ORENCIA 125 mg solution for subcutaneous injection is not intended for IV infusion. ORENCIA solution for subcutaneous injection is intended for use under the guidance of a medical practitioner or healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject with ORENCIA solution for subcutaneous injection if a doctor determines that it is appropriate. Patients should be instructed to follow the detailed u201cInstructions for preparing and giving a subcutaneous injection of ORENCIAu201d provided at the end of the Patient Information Leaflet. ORENCIA should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Do not use ORENCIA prefilled syringes exhibiting particulate matter or discolouration. ORENCIA solution for subcutaneous injection should be clear to slightly opalescent and colourless to pale yellow. Any leftover product remaining in the prefilled syringe should not be used. Patients using ORENCIA solution for subcutaneous injection should be instructed to inject the full amount in the syringe (1,0 ml), which provides 125 mg of ORENCIA, according to the directions provided in the Patient Information Leaflet. Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red or hard.

• ORENCIA should not be administered to patients with known hypersensitivity to ORENCIA or any of its components.
• Active or dormant untreated tuberculosis.
• ORENCIA should NOT be used during pregnancy, or if a woman plans to become pregnant, or by mothers who are breastfeeding their infants (see section 4.6).

ORENCIA 125 mg Solution for subcutaneous injection is not indicated for juvenile idiopathic arthritis. Combination with TNF blocking agents ORENCIA should not be administered concomitantly with TNF blocking agents. There is limited experience with the use of ORENCIA in combination with TNF blocking agents. In placebo-controlled clinical trials in patients with adult RA, patients receiving concomitant intravenous ORENCIA and TNF blocking agent therapy experienced more infections (24 %) and serious infections (2,2 %) compared to patients treated with only TNF blocking agents (19 % and 0,8 %, respectively). Concurrent therapy with ORENCIA and a TNF blocking agent is not recommended. While transitioning from TNF blocking agent therapy to ORENCIA therapy, patients should be monitored for signs of infection.

Combination with other biologic agents ORENCIA is not recommended for use concomitantly with other biologic rheumatoid arthritis therapy, such as anakinra.

Hypersensitivity Hypersensitivity reactions including anaphylactic reactions have been reported with intravenous ORENCIA administration in clinical trials, where patients were not required to be pretreated to prevent hypersensitivity reactions. Other events potentially associated with hypersensitivity, such as hypotension, urticaria, and dyspnoea that occurred within 24 hours of ORENCIA infusion, may occur. Anaphylaxis or anaphylactoid reactions can occur after the first infusion and can be life-threatening. In postmarketing experience, a case of fatal anaphylaxis following the first infusion of ORENCIA has been reported. If an anaphylactic or other serious allergic reaction occurs, administration of ORENCIA should be stopped immediately with appropriate therapy instituted, and the use of ORENCIA should be permanently discontinued (see section 4.8).

Effects on the immune system The possibility exists for ORENCIA to affect vaccination responses and host defenses against infections and malignancies. Infections Serious infections, including sepsis and pneumonia, have been reported in patients receiving ORENCIA. Some of these infections have been fatal. Medical practitioners should exercise caution when considering the use of ORENCIA in patients with a history of recurrent infections, underlying conditions which may predispose them to infections, or chronic, latent, or localised infections. Patients who develop a new infection while undergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIA should be discontinued if a patient develops a serious infection. A higher rate of serious infections has been observed in adult RA patients treated with concurrent TNF blocking agents and ORENCIA. When treating patients with therapies that modulate the immune system, it is appropriate to screen and monitor for tuberculosis infections. ORENCIA has not been studied in patients with a positive tuberculosis screen, and the safety of ORENCIA in individuals with latent tuberculosis is unknown (see section 4.3).

Before starting treatment with ORENCIA, all patients must be evaluated for both active and inactive (u201clatentu201d) tuberculosis. This evaluation should include a detailed medical history with personal history of tuberculosis or possible previous contact with tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests, i.e., tuberculin skin test and chest x-ray should be performed in all patients (local recommendations may apply). Prescribers are reminded of the risk of false negative tuberculin skin test results especially in patients who are severely ill or immunocompromised. If active tuberculosis is diagnosed, ORENCIA treatment should not be initiated (see section 4.3).

If inactive (u201clatentu201d) tuberculosis is diagnosed, prophylactic anti-tuberculosis therapy must be started before the initiation of ORENCIA, and in accordance with local recommendations. In this situation, the benefit/risk balance of ORENCIA therapy should be carefully considered. Patients must be monitored closely for infections, including miliary tuberculosis, while on and after treatment with ORENCIA.

In clinical trials with ORENCIA, patients were not screened for HIV infection, however patients with known HIV infection were excluded from study. Anti-rheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with guidelines before starting therapy with ORENCIA. In clinical studies with ORENCIA, patients who screened positive for hepatitis were excluded from study.

Malignancies The potential role of long-term use (> 42 months) of ORENCIA in the development of malignancies in humans is unknown. The frequencies of malignancies in the placebo-controlled clinical trials were similar for ORENCIA-treated and placebo-treated patients (1,2 % and 0,9 % respectively) (see section 4.8). There have been reports of non-melanoma skin cancers in patients receiving abatacept. Periodic skin examinations are recommended for all patients, particularly those with risk factors for skin cancer.

Immunisations Live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. No data are available on the effects of vaccinations in patients receiving ORENCIA. Medicines that affect the immune system, including ORENCIA, may blunt the effectiveness of some immunisations. Patients treated with ORENCIA may receive concurrent non-live vaccines. Responses to pneumococcal and inactivated influenza vaccines have been studied in subjects receiving ORENCIA. Pneumococcal vaccination with the standard 23-valent vaccine was studied in healthy subjects to assess the effect of ORENCIA on the antibody response to pneumococcal vaccine. This study suggested that ORENCIA may blunt the effectiveness of the immune response but did not significantly inhibit the ability of healthy subjects to develop a clinically significant or positive immune response (at least a 2-fold increase above baseline) to 23-valent pneumococcal vaccines. ORENCIA was evaluated in an open-label study in RA patients administered the 23-valent pneumococcal vaccine. After pneumococcal vaccination, a majority of ORENCIA-treated patients (62/112) were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine. ORENCIA was also evaluated in an open-label study in rheumatoid arthritis patients administered the seasonal influenza trivalent virus vaccine. After influenza vaccination, 73 of 119 ORENCIA-treated patients without protective antibody levels at baseline were able to mount an adequate immune response of at least a 4-fold increase in antibody titers to trivalent influenza vaccine.

Paediatrics and adolescents The safety and efficacy of ORENCIA 125 mg solution for subcutaneous injection in children below 18 years of age have not been established. No data are available. Sucrose Contains sucrose, which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose mal-absorption or sucrose-isomaltase insufficiency should not receive ORENCIA.

Formal interaction studies have not been conducted with ORENCIA. Concurrent administration of a TNF blocking agent with ORENCIA has been associated with an increased risk of serious infections. Concurrent therapy with ORENCIA and TNF blocking agents is not recommended. There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with other biologic rheumatoid arthritis therapy, such as anakinra, and therefore such use is not recommended.

ORENCIA has not been studied in combination with agents which deplete lymphocyte count. Such combination therapy could potentiate the effects of ORENCIA on the immune system. Effect of other medicines on abatacept The majority of patients in the IV placebo-controlled clinical trials received concomitant DMARDs, NSAIDs, and/or corticosteroids. Most patients were taking MTX. Other less frequently used concomitant DMARDs included chloroquine/hydroxychloroquine, sulfasalazine and leflunomide. There is limited experience with abatacept in combination with other DMARDs such as azathioprine, gold and anakinra. Population pharmacokinetic analyses revealed that MTX, NSAIDs, corticosteroids, and TNF blocking agents did not influence abatacept clearance.

Pregnancy There are no studies in pregnant women. ORENCIA should NOT be used during pregnancy, or if a woman is planning to become pregnant. 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 for 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 10 weeks following the motheru2019s last exposure to abatacept during pregnancy.

Breastfeeding Abatacept has been shown to be present in rat milk. It is not known whether abatacept is excreted in human milk. Mothers should be instructed not to breastfeed if they are receiving ORENCIA.

Dizziness and reduced visual acuity have been reported as common and uncommon adverse reactions respectively, from patients treated with ORENCIA, therefore if a patient experiences such symptoms, driving and use of machines should be avoided.

The most frequently reported adverse drug reaction (ADRs) (u2265 5 %) among ORENCIA-treated patients in placebo-controlled clinical trials were headache and nausea. Listed below are ADRs that occurred with greater frequency (difference > 0,2 %) in ORENCIA-treated patients than in placebo-treated patients. Also listed are ADRs from clinical trials at least possibly causally-related to ORENCIA displayed by system organ class and frequency. The list is presented by system organ class and frequency, using the following categories: very common (u2265 10 %); common (u2265 1 %; < 10 %); uncommon (u2265 0,1 %; < 1 %); rare (u2265 0,01 %; < 0,1 %).

Side Effects in Placebo-Controlled Trials Infections and infestations Very common Upper respiratory tract infection (including tracheitis, nasopharyngitis, sinusitis) Common Lower respiratory tract infection (including bronchitis), urinary tract infection, herpes infections (including herpes simplex, oral herpes, and herpes zoster, pneumonia Uncommon Tooth infection, infected skin ulcer, onychomycosis, pelvic inflammatory disease, rhinitis, ear infection, pyelonephritis Neoplasms benign, malignant, and unspecified (including cysts and polyps) Uncommon Basal cell carcinoma Blood and the lymphatic system disorders Uncommon Thrombocytopenia, leukopenia Immune system disorders Uncommon Hypersensitivity Psychiatric disorders Uncommon Depression, anxiety, sleep disorder (including insomnia) Nervous system disorders Common Headache, dizziness Uncommon Paraesthesia Eye disorders Uncommon Conjunctivitis, reduced visual acuity Ear and labyrinth disorders Uncommon Vertigo Cardiac disorders Uncommon Tachycardia, bradycardia, palpitations Vascular disorders Common Hypertension Uncommon Hypotension, hot flush, flushing Respiratory, thoracic and mediastinal disorders Common Cough Uncommon Chronic obstructive pulmonary disease exacerbation Gastrointestinal disorders Common Abdominal pain, diarrhoea, nausea, dyspepsia, mouth ulceration, aphthous stomatitis Uncommon Gastritis Skin and subcutaneous tissue disorders Common Rash (including dermatitis) Uncommon Increased tendency to bruise, alopecia, dry skin, hyperhidrosis, erythema, acne Musculoskeletal, connective tissue and bone disorders Uncommon Arthralgia, pain in extremity Reproductive system and breast disorders Uncommon Amenorrhoea, menorrhagia General disorders and administration site conditions Common Fatigue, asthenia, local injection site reactions Uncommon Influenza-like illness Investigations Common Increased blood pressure, abnormal liver function test (including increased transaminases) Uncommon Decreased blood pressure, increased weight

Infections In the placebo-controlled trials with durations of 6 to 14 months, infections at least possibly related to treatment were reported in 22,7 % of ORENCIA-treated patients and 20,5 % of placebo patients. Serious infections at least possibly related to treatment were reported in 1,5 % of ORENCIA-treated patients and 1,1 % of placebo patients. The type and frequency of serious infections was similar between the ORENCIA and placebo treatment groups.

Malignancies In placebo-controlled clinical trials with durations of up to 14 months, malignancies were reported in 1,2 % (31/2653) of ORENCIA-treated patients and in 0,9 % (14/1485) of placebo-treated patients. In the cumulative period in 7044 patients treated with ORENCIA during 21011 patient-years the incidence rate of malignancy was 1,2 (1,1, 1,4) per 100 patient-years, and the annualised incidence rate remained stable. The most frequently reported malignancy in the placebo-controlled clinical trials was non-melanoma skin cancer; 0,6 (0,3, 1,0) per 100 patient-years for abatacept-treated patients, 0,4 (0,1, 0,9) per 100 patient-years for placebo-treated patients, and 0,5 (0,4, 0,6) per 100 patient-years in the cumulative period. The most frequently reported solid organ cancer in the placebo-controlled clinical trials was lung cancer (0,17 (0,05, 0,43) per 100 patient-years) for abatacept-treated patients, 0 for placebo-treated patients, and 0,12 (0,08, 0,17) per 100 patient-years in the cumulative period. The most common haematologic malignancy was lymphoma (0,04 (0, 0,24) per 100 patient-years) for abatacept-treated patients, 0 for placebo-treated patients, and 0,06 (0,03, 0,1) per 100 patient-years in the cumulative period.

Adverse medicine reactions in patients with chronic obstructive pulmonary disease (COPD) In one study, there were 37 patients with COPD treated with ORENCIA and 17 treated with placebo. The adult COPD patients treated with ORENCIA developed adverse drug reactions more frequently than those treated with placebo (51,4 % vs. 47,1 %, respectively). Respiratory disorders occurred more frequently in ORENCIA-treated patients than in placebo-treated patients (10,8 % vs. 5,9 %, respectively); these included COPD exacerbation and dyspnoea.

Doses up to 50 mg/kg have been administered intravenously without apparent toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.