ETACEPT Injection (Etanercept)

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1 Published on: 10 Jul 2014 ETACEPT Injection (Etanercept) Blackbox Warnings Risk of Serious Infections Patients treated with etanercept are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate (MTX) or corticosteroids. Etanercept should be discontinued if a patient develops a serious infection or sepsis. Reported infections include the following: Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before etanercept use and during therapy. Treatment for latent infection should be initiated prior to etanercept use. Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. Bacterial, viral and other infections due to opportunistic pathogens, including legionella and listeria. The risks and benefits of treatment with etanercept should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with etanercept, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Malignancies Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumour necrosis factor (tnf)-blockers, including etanercept. Composition ETACEPT Injection Each vial contains: Etanercept. 25 mg (As a sterile lyophilized powder) Dosage Form Lyophilized powder for solution for subcutaneous injection Description Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) TNF-receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of etanercept contains the C H 2

2 domain, the C H 3 domain and hinge region, but not the C H 1 domain of IgG1. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. Pharmacology Pharmacodynamics Etanercept binds specifically to the TNF and blocks its interaction with cell surface TNFRs. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays an important role in the inflammatory processes of rheumatoid arthritis (RA), polyarticular-course juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), and the resulting joint pathology. In addition, TNF plays a role in the inflammatory process of plaque psoriasis. Elevated levels of TNF are found in the involved tissues and fluids of patients with RA, PsA, AS and plaque psoriasis. Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNFR. Etanercept is a dimeric soluble form of the p75 TNFR that can bind to two TNF molecules. It inhibits the activity of TNF in vitro and has been shown to affect several animal models of inflammation, including murine collagen-induced arthritis. Etanercept inhibits binding of both TNF-(alpha) and TNF-(beta) (lymphotoxin-alpha ) to cell surface TNFRs, rendering TNF biologically inactive. In in vitro studies, large complexes of etanercept with TNF-(alpha) were not detected and cells expressing transmembrane TNF (that binds etanercept) are not lysed in the presence or absence of complement. Etanercept can modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leucocyte migration (i.e. E-selectin and, to a lesser extent, intercellular adhesion molecule-1 ), serum levels of cytokines, and serum levels of matrix metalloproteinase-3 or stromelysin). Pharmacokinetics The clinical study results indicated etanercept was absorbed slowly at the injection site after subcutaneous injection. The peak blood concentration was achieved at 48 hours after single administration, and the absolute bioavailability was 76%. After administering twice weekly, the blood concentration at the steady state was two times of the peak concentration of single dose. When 11 active RA patients were injected with ETACEPT Injection 25 mg subcutaneously twice a week for consecutive 6 weeks, the time to steady state for etanercept was 480±20 h, C max (ss) was 3.0±0.2 μg/ml, C min (ss) was 2.6±0.2 μg/ml, the mean C ss was 2.8±0.3 μg/ml, and the fluctuation index (FI) was 12.8±3.3%. After the last administration of etanercept, the T 1/2 was 74±4 h, T max was 53±6 h and CL was ± 10.4 ml/h. No significant difference in blood concentration was observed among healthy persons, patients with acute renal failure and patients with abnormal liver functions; therefore, the dose does not need to be adjusted for patients with renal function impairment. The influence of MTX on the pharmacokinetics of etanercept was not observed in the above studies. Clinical Studies An open-label, prospective, non-comparative, multicentre study to assess the safety and efficacy of ETACEPT Injection 25 mg for subcutaneous injection was conducted in patients with moderate-to-severe, active RA who had shown inadequate response to DMARDs. Eligible patients received the treatment, etanercept powder for injection 25 mg twice weekly for 24 weeks. Efficacy assessment was carried out at the baseline visit (visit 3), 2 weeks, 6 weeks, 12 weeks, 18 weeks and

3 24 weeks after visit 3. The primary efficacy criterion was set as ACR20. The secondary efficacy criterion was set as ACR 50. The safety of etanercept injection was assessed by recording the incidence of all adverse events, the incidence of drug-related adverse events, and the results of safety laboratory examinations: haematology, biochemistry and urinalysis, and the global assessment of tolerability. Subjects completing at least 12 weeks (visit 6) of treatment were considered for the statistical evaluation of the efficacy parameters. Subjects receiving at least one dose of the study medication were considered for safety evaluation. Table 1: Number and percentage of patients satisfying the primary efficacy endpoint (ACR20) Parameter Visit 4 (N=98) Visit 5 (N=98) Visit 6 (N=98) Visit 7 (N=98) Visit 8 (N=98) n (%) Number of patients satisfying at least five parameters, including tender and swollen joint counts 15 (15.31) 27 (27.55) 56 (57.14) 66 (67.35) 74 (75.51) Tender joints count 47 (47.96) Swollen joints count 49 (50.00) 58 (59.18) 73 (74.49) 80 (81.63) 91 (92.86) 55 (56.12) 68 (69.39) 80 (81.63) 91 (92.86) Physician's global assessment of disease activity Patient's global assessment of disease activity Patient s assessment of pain 38 (38.78) 25 (25.51) 26 (26.53) 56 (57.14) 80 (81.63) 86 (87.76) 87 (88.78) 46 (46.94) 65 (66.33) 72 (73.47) 76 (77.55) 54 (55.10) 73 (74.49) 74 (75.51) 79 (80.61) Patient's assessment of physical function using the disability domain of the HAQ index Acute-phase reactant erythrocyte sedimentation rate (75.51) 79 (80.61) 78 (79.59) (56.12) - 48 (48.98) At visit 4, 15 (15.31%) patients; at visit 5, 27 (27.55 %) patients; at visit 6, 56 (57.14%) patients; at visit 7, 66 (67.35%) patients and at visit 8, 74 (75.51%) patients satisfied the criteria of at least 5 parameters including tender and swollen joints respectively. When analysed for the secondary efficacy endpoint set at ACR50, the following number of patients satisfied the criteria of at least five parameters, including tender and swollen joints: at visit 4, 2 (2.04%) patients; at visit 5, 9 (8.16%) patients; at visit 6, 16 (16.33%) patients; at visit 7, 22 (22.45%) patients; and, at visit 8, 27 (27.55%) patients.

4 After evaluating the safety data it was found that Etanercept injection, administered over a period of 24 weeks, was well tolerated in patients with moderate to severe rheumatoid arthritis. Adverse events were reported in 55.77% of the patients while AEs related to Etanercept were reported in 25.96% patients. Adverse events reported were; 18(17.31%) patients had Injection site reaction, 14(13.46%) patients had Pyrexia, 9(8.65%) patients of each had cough and upper respiratory tract infection, 7 (6.73%) patients had Urinary Tract Infection, 6(5.77%) patients of each had Diarrhoea and Mouth Ulceration, 5 (4.81%) patients had Nasopharyngitis, 4(3.85%) patients of each had Dysuria and Productive Cough. Total of 9 serious adverse events in 3 patients were reported out of which only 1 SAE was related to the study medication. There were no significant deviations observed from the pre-study screening values for the vital signs examination, ECG, physical examination and laboratory evaluation performed during the post-study examination. In a MTX-controlled multicentre clinical trial conducted in 238 patients with moderate-to-severe, active RA, the patients in the study drug group received 25 mg ETACEPT Injection as a subcutaneous injection twice weekly for 24 weeks and the patients in the control group received MTX orally for 24 weeks. The ACR20/50/70 criteria were used for efficacy assessment. Percentage of patients achieving ACR20 in the ETACEPT Injection group was 35.59% at 2 weeks and significantly higher than that in the MTX (22.5%) control group (P<0.05). At 12 weeks, the percentage of patients achieving ACR20 in the ETACEPT Injection group was 66.10% and also significantly superior to the MTX (51.67%) control group (P<0.05). The adverse reactions mainly observed were injection site reactions, rash, elevated transaminase, infections and so on. There was no significant difference between the two groups in the incidence of infections. In a double-blind, randomized, placebo-controlled, multicentre clinical study, 141 patients with active AS were treated for 12 weeks. The study was divided into two stages: in the double-blind and placebo-controlled stage for the first 6 weeks of the study, patients in the etanercept group received 25 mg ETACEPT Injection as a subcutaneous injection twice a week and patients in the control group received placebo twice a week. After the completion of the first stage, patients entered into the second open-treatment stage for 6 weeks, wherein patients in both groups received ETACEPT Injection 25 mg twice a week. The ASAS20 criteria were used to assess the efficacy. In the first stage, the percentages of patients achieving ASAS20 in the ETACEPT Injection group were 55.07% and 68.12%, respectively, at 2 weeks and 6 weeks after the treatment, and they were significantly higher than those of the placebo group (P<0.001). After 12 weeks of continuous treatment, the percentage of patients achieving ASAS20 in the ETACEPT Injection group was 78.26%. After 6 weeks of open-label treatment with ETACEPT Injection, the percentage of patients achieving ASAS20 in the placebo control group was 75%, which was significant. ETACEPT Injection was well tolerated in the study. There was no significant difference in the incidence of adverse events between the ETACEPT Injection and placebo groups. The adverse reactions were mild and self-resolved without needing treatment. Indications Rheumatoid Arthritis ETACEPT Injection can be used alone or in combination with MTX to treat active RA refractory to DMARDs, including MTX. Severe, active RA in adults not previously treated with MTX Polyarticular-course JIA Active polyarticular Juvenile chronic arthritis refractory to MTX. Psoriatic Arthritis Active and progressive PsA refractory to DMARDs.

5 Ankylosing Spondylitis Severe, active AS refractory to conventional therapy. Plaque Psoriasis Treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates to systemic therapy or phototherapy. Treatment of chronic severe plaque psoriasis in children and adolescents from the age of 8 years who are inadequately controlled by or are intolerant to other systemic therapies or phototherapies. Dosage And Administration General The recommended dose for adult patients is a 25 mg dose given by subcutaneous injection twice weekly, 3 or 4 days apart. Sites for injection (thighs, abdomen or upper arms) should be rotated. Never inject into areas where the skin is tender, bruised, red or hard. Adult RA, AS and PsA Patients The recommended dose of etanercept for adult patients with RA, PsA or AS is 50 mg per week. MTX, glucocorticoids, salicylates, non-steroidal anti-inflammatory drugs (NSAIDs) or analgesics may be continued during treatment with etanercept. Based on a study of 50 mg etanercept twice weekly in patients with RA that suggested a higher incidence of adverse reactions but similar ACR response rates, doses higher than 50 mg per week are not recommended. Polyarticular-course JIA Patients The recommended dose of etanercept for paediatric patients aged 2 to 17 years with active polyarticular-course JIA is 0.8 mg/kg per week (up to a maximum of 50 mg per week). Paediatric Patients Weight Recommended Dose 63 kg (138 pounds) or more 50 mg weekly Less than 63 kg (138 pounds) 0.8 mg/kg weekly Glucocorticoids, NSAIDs or analgesics may be continued during treatment with etanercept. Higher doses of etanercept have not been studied in paediatric patients. Plaque Psoriasis The recommended dose of etanercept for plaque psoriasis is 50 mg twice weekly starting dose. In addition to this, starting doses of 25 mg or 50 mg per week were shown to be efficacious. Preparation of ETACEPT Injection ETACEPT Injection is intended for use under the guidance and supervision of a physician. Patients may self-inject when deemed appropriate and if they receive medical follow-up, as necessary. Patients should not self-administer until they receive proper training in how to prepare and administer the correct dose. Etanercept is reconstituted with 1 ml Water for Injection before use, and administered by subcutaneous injection. The reconstituted solution could be stored at 2 8 in a confined environment for 6 hours.

6 Etanercept contains no antibacterial preservative and, therefore, solutions prepared with Water for Injection should be administered as soon as possible and within 6 hours following reconstitution. The solution should be clear and colourless to pale yellow with no lumps, flakes or particles. Some white foam may remain in the vial this is normal. Etanercept should not be used if all the powder in the vial is not dissolved within 10 minutes. Start again with another vial. Contraindications Etanercept should not be administered to patients with sepsis or with a known hypersensitivity to etanercept or any of its components. Warnings And Precautions General Risk of Serious Infections Patients treated with etanercept are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic or other opportunistic pathogens, including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease. Treatment with etanercept should not be initiated in patients with an active infection, including clinically important localized infections. Patients more than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (such as corticosteroids or MTX), may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients with chronic or recurrent infection; who have been exposed to tuberculosis; with a history of an opportunistic infection; who have resided or travelled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or, with underlying conditions that may predispose them to infection such as advanced or poorly controlled diabetes. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with etanercept. Etanercept should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with etanercept should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated. Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving etanercept, including patients who have previously received treatment for latent or active tuberculosis. Data from clinical trials and preclinical studies suggest that the risk of reactivation of latent tuberculosis infection is lower with etanercept than with TNF-blocking monoclonal antibodies. Nonetheless, post-marketing cases of tuberculosis reactivation have been reported for TNF-blockers, including etanercept. Tuberculosis has developed in patients who tested negative for latent tuberculosis prior to initiation of therapy. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating etanercept and periodically during therapy. Tests for latent tuberculosis infection may be falsely negative while on therapy with etanercept.

7 Treatment of latent tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating etanercept, even for patients previously vaccinated with Bacille Calmette- Guérin (BCG). Anti-tuberculosis therapy should also be considered prior to initiation of etanercept in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Tuberculosis should be strongly considered in patients who develop a new infection during etanercept treatment, especially in patients who have previously or recently travelled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. Invasive Fungal Infections Cases of serious and, sometimes, fatal fungal infections, including histoplasmosis, have been reported with TNF-blockers, including etanercept. For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy. In 38 etanercept clinical trials and 4 cohort studies in all approved indications representing 27,169 patient years of exposure (17,696 patients) from the United States and Canada, no histoplasmosis infections were reported among patients treated with etanercept. In a 24-week study of concurrent etanercept and anakinra therapy, the rate of serious infections in the combination arm (7%) was higher than with etanercept alone (0%). The combination of etanercept and anakinra did not result in higher ACR response rates compared to etanercept alone. Concurrent therapy with etanercept and anakinra is not recommended. Etanercept should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with etanercept should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated. Malignancies Lymphomas In the controlled portions of clinical trials of TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF-blocker compared to control patients. During the controlled portions of etanercept trials in adult patients with RA, AS and PsA, two lymphoma were observed among 3,306 etanercept -treated patients versus zero incidence among 1,521 control patients (duration of controlled treatment ranged from 3 to 36 months). Among 6,543 adult rheumatology (RA, PsA, AS) patients treated with etanercept in controlled and uncontrolled portions of clinical trials, representing approximately 12,845 patient-years of therapy, the observed rate of lymphoma was 0.10 cases per 100 patient-years. This was 3-fold higher than the rate of lymphoma expected in the general US population based on the Surveillance, Epidemiology and End Results (SEER) Database. An increased rate of lymphoma up to several-fold has been reported in the RA patient population, and may be further increased in patients with more severe disease activity. Among 4,410 adult PsO patients treated with etanercept in clinical trials up to 36 months, representing approximately 4,278 patient-years of therapy, the observed rate of lymphoma was 0.05 cases per 100 patient-years, which is

8 comparable to the rate in the general population. No cases were observed in etanercept - or placebo-treated patients during the controlled portions of these trials. Leukaemia Cases of acute and chronic leukaemia have been reported in association with post-marketing TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at higher risk (approximately 2- fold) than the general population for the development of leukaemia. During the controlled portions of etanercept trials, two instances of leukaemia were observed among 5,445 (0.06 cases per 100 patient-years) etanercept -treated patients versus zero incidence among 2,890 (0%) control patients (duration of controlled treatment ranged from 3 to 48 months). Among 15,401 patients treated with etanercept in the controlled and open portions of clinical trials representing approximately 23,325 patient-years of therapy, the observed rate of leukaemia was 0.03 cases per 100 patient-years. Other Malignancies Information is available from 10,953 adult patients with 17,123 patient-years and 696 paediatric patients with 1,282 patient- years of experience across 45 etanercept clinical studies. For malignancies other than lymphoma and non-melanoma skin cancer, there was no difference in the exposureadjusted rates between the etanercept and control arms in the controlled portions of clinical studies for all indications. Analysis of the malignancy rate in combined controlled and uncontrolled portions of studies has demonstrated that types and rates are similar to what is expected in the general US population, based on the SEER database, and suggests no increase in rates over time. Whether treatment with etanercept might influence the development and course of malignancies in adults is unknown. Melanoma and Non-Melanoma Skin Cancer (NMSC) Melanoma and NMSC has been reported in patients treated with TNF-antagonists, including etanercept. Among 15,401 patients treated with etanercept in the controlled and open portions of clinical trials representing approximately 23,325 patient-years of therapy, the observed rate of melanoma was cases per 100 patient-years. Among 3,306 adult rheumatology (RA, PsA, AS) patients treated with etanercept in controlled clinical trials representing approximately 2,669 patient-years of therapy, the observed rate of NMSC was 0.41 cases per 100 patient-years versus 0.37 cases per 100 patient-years among 1,521 control-treated patients representing 1,077 patient-years. Among 1,245 adult psoriasis patients treated with etanercept in controlled clinical trials, representing approximately 283 patient-years of therapy, the observed rate of NMSC was 3.54 cases per 100 patient-years versus 1.28 cases per 100 patient-years among 720 control-treated patients representing 156 patient-years. Postmarketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with Etanercept. Periodic skin examinations should be considered for all patients at increased risk for skin cancer. Neurologic Events Treatment with TNF-blocking agents, including etanercept, has been associated with rare (<0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barré syndrome, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with etanercept therapy. Prescribers should exercise caution in considering the use of etanercept in patients with pre-existing or recentonset central or peripheral nervous system demyelinating disorders. Haematologic Events Rare (<0.1%) reports of pancytopenia, including very rare (<0.01%) aplastic anaemia, some with a fatal outcome, have been reported in patients treated with etanercept. The causal relationship to etanercept therapy remains unclear. Although no high-risk group has been identified, caution should be exercised in patients being treated with etanercept

9 who have a previous history of significant haematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g. persistent fever, bruising, bleeding, pallor) while on etanercept. Discontinuation of etanercept therapy should be considered in patients with confirmed significant haematologic abnormalities. Neutropenia (ANC < /L) developed in 2% of patients treated concurrently with etanercept and anakinra. While neutropenic, 1 patient developed cellulitis, which resolved with antibiotic therapy. Paediatric Patients Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (initiation of therapy at 18 years of age), including etanercept. Approximately half the cases were lymphomas, including Hodgkin's and non-hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range, 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and are derived from a variety of sources, including registries and spontaneous post-marketing reports. In clinical trials of 696 patients representing 1,282 patient-years of therapy, no malignancies, including lymphoma or NMSC, have been reported. Post-marketing Use In global post-marketing adult and paediatric use, lymphoma and other malignancies have been reported. Hepatitis B Virus Reactivation Use of TNF-blockers, including etanercept, has been associated with reactivation of the hepatitis B virus (HBV), including very rare cases (<0.01%) with etanercept, in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF-blocker therapy. Prescribers should exercise caution in prescribing TNF-blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with antiviral therapy in conjunction with TNF-blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with etanercept should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, consideration should be given to stopping etanercept and initiating antiviral therapy with appropriate supportive treatment. The safety of resuming etanercept therapy after HBV reactivation is controlled is not known. Therefore, prescribers should weigh the risks and benefits when considering resumption of therapy in this situation. Use in Patients with Moderate-to-Severe Alcoholic Hepatitis In a study of 48 hospitalized patients treated with etanercept or placebo for moderate-to-severe alcoholic hepatitis, the mortality rate in patients treated with etanercept was similar to patients treated with placebo at 1 month, but significantly higher after 6 months. Physicians should use caution when using etanercept in patients with moderate-t- -severe alcoholic hepatitis. Allergic Reactions Allergic reactions associated with the administration of etanercept during clinical trials have been reported in <2% of patients. If an anaphylactic reaction or other serious allergic reaction occurs, administration of etanercept should be discontinued immediately and appropriate therapy initiated. Patients with Heart Failure Two clinical trials evaluating the use of etanercept in the treatment of heart failure were terminated early due to lack of

10 efficacy. The results of one study suggested a higher mortality in patients treated with etanercept compared to placebo. The results of the second study did not corroborate these observations. Analysis did not identify specific factors associated with an increased risk of adverse outcomes in heart failure patients treated with etanercept. There have been postmarketing reports of the worsening of congestive heart failure (CHF), with and without identifiable precipitating factors, in patients taking etanercept. There have also been rare (<0.1%) reports of new onset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some of these patients have been below 50 years of age. Physicians should exercise caution when using etanercept in patients who also have heart failure, and monitor such patients carefully. Immunosuppression Anti-TNF therapies, including etanercept, affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 49 patients with RA treated with etanercept, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels or change in enumeration of effector cell populations. The impact of treatment with etanercept on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood. The safety and efficacy of etanercept in patients with immunosuppression or chronic infections have not been evaluated. Immunizations Most PsA patients receiving etanercept were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine, but the titres, in aggregate, were moderately lower and fewer patients had two-fold rises in titres compared to patients not receiving etanercept. The clinical significance of this is unknown. Patients receiving etanercept may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving etanercept. It is recommended that polyarticular-course JIA patients, if possible, should be brought up-to-date with all immunizations in agreement with the current immunization guidelines prior to initiating etanercept therapy. Patients with a significant exposure to the varicella virus should temporarily discontinue etanercept therapy and be considered for prophylactic treatment with Varicella Zoster Immuneglobulin. Autoimmunity Treatment with etanercept may result in the formation of auto-antibodies and, rarely (<0.1%), in the development of a lupus-like syndrome or autoimmune hepatitis, which may resolve following the withdrawal of etanercept. If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with etanercept, treatment should be discontinued and the patient should be carefully evaluated. Carcinogenesis, Mutagenesis and Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of etanercept or its effect on fertility. Mutagenesis studies were conducted in vitro and in vivo, and no evidence of mutagenic activity was observed. Drug Interactions Specific drug interaction studies have not been conducted with etanercept. However, it was observed that the pharmacokinetics of etanercept was unaltered by concomitant MTX in RA patients. In a study in which patients with active RA were treated for up to 24 weeks with concurrent etanercept and anakinra therapy, a 7% rate of serious infections was observed, which was higher than that observed with etanercept alone (0%). The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases). One patient with pulmonary fibrosis and pneumonia died due to respiratory failure. Neutropenia (ANC < /L) developed in 2% of patients treated concurrently with etanercept and anakinra. In clinical studies, concurrent administration of abatacept and etanercept resulted in increased incidences of serious adverse events, including infections, and did not demonstrate increased clinical benefit. Use of etanercept with anakinra or abatacept is not recommended.

11 In a study of patients with Wegener's granulomatosis, the addition of etanercept to standard therapy (including cyclophosphamide) was associated with a higher incidence of non-cutaneous solid malignancies and was not associated with improved clinical outcomes when compared with standard therapy alone. The use of etanercept in patients with Wegener s granulomatosis receiving immunosuppressive agents is not recommended. The use of etanercept in patients receiving concurrent cyclophosphamide therapy is not recommended. Patients in a clinical study who were on established therapy with sulphasalazine, to which etanercept was added, were noted to develop a mild decrease in mean neutrophil counts in comparison to groups treated with either etanercept or sulphasalazine alone. The clinical significance of this observation is unknown. Pregnancy Pregnancy Category B Developmental toxicity studies have been performed in rats and rabbits at doses ranging from 60- to 100-fold higher than the human dose and have revealed no evidence of harm to the foetus due to etanercept. There are, however, no studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Lactation It is not known whether etanercept is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from etanercept, a decision should be made whether to discontinue nursing or to discontinue the drug. Paediatric Use Etanercept is indicated for treatment of polyarticular-course JIA in patients aged 2 years and older. Etanercept has not been studied in children below 2 years of age. The safety and efficacy of etanercept in paediatric patients with plaque psoriasis have not been studied. Rare (<0.1%) cases of IBD have been reported in JIA patients receiving etanercept, which is not effective for the treatment of IBD. Geriatric Use A total of 480 RA patients aged 65 years or older have been studied in clinical trials. In PsO randomized clinical trials, a total of 138 out of 1,965 patients treated with etanercept or placebo were aged 65 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients but the number of geriatric PsO patients is too small to determine whether they respond differently from younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly. Use in Diabetics There have been reports of hypoglycaemia following initiation of etanercept therapy in patients receiving medication for diabetes, necessitating a reduction in the anti-diabetic medication in some of these patients. Undesirable Effects Across clinical studies and postmarketing experience, the most serious adverse reactions with etanercept were infections, neurologic events, CHF and haematologic events. The most common adverse reactions with etanercept were infections and injection site reactions. Adverse reactions in adult patients with RA, PsA, AS or plaque psoriasis The data described below reflect the exposure to etanercept in 2,219 adult patients with RA followed for up to 80

12 months, in 182 patients with PsA for up to 24 months, in 138 patients with AS for up to 6 months, and in 1,204 adult patients with PsO for up to 18 months. In controlled trials, the proportion of etanercept-treated patients who discontinued treatment due to adverse events was approximately 4% in the indications studied. Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the 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 clinical practice. Infections Infections, including viral, bacterial and fungal infections, have been observed in adult and paediatric patients. Infections have been noted in all body systems and have been reported in patients receiving etanercept alone or in combination with other immunosuppressive agents. In controlled portions of the trials, the types and severity of infection were similar between etanercept and the respective control group (placebo or MTX for RA and PsA patients) in RA, PsA, AS and PsO patients. Rates of infections in RA and PsO patients are provided in Table 2 and Table 3, respectively. Infections consisted primarily of upper respiratory tract infection, sinusitis and influenza. In controlled portions of the trials in RA, PsA, AS and PsO, the rates of serious infection were similar (0.8% in placebo, 3.6% in MTX, and 1.4% in etanercept /etanercept plus MTX-treated groups). In clinical trials in rheumatologic indications, serious infections experienced by patients have included, but are not limited to, pneumonia, cellulitis, septic arthritis, bronchitis, gastroenteritis, pyelonephritis, sepsis, abscess and osteomyelitis. In clinical trials in PsO, serious infections experienced by patients have included, but are not limited to, pneumonia, cellulitis, gastroenteritis, abscess and osteomyelitis. The rate of serious infections was not increased in open-label extension trials and was similar to that observed in etanercept- and placebo-treated patients from controlled trials. In 66 global clinical trials of 17,505 patients (21,015 patient-years of therapy), tuberculosis was observed in approximately 0.02% of patients. In 17,696 patients (27,169 patient-years of therapy) from 38 clinical trials and 4 cohort studies in the US and Canada, tuberculosis was observed in approximately 0.006% of patients. These studies include reports of pulmonary and extrapulmonary tuberculosis. Injection Site Reactions In controlled trials in rheumatologic indications, approximately 37% of patients treated with etanercept developed injection site reactions. In controlled trials in patients with plaque psoriasis, 15% of patients treated with etanercept developed injection site reactions during the first 3 months of treatment. All injection site reactions were described as mild to moderate (erythema and/or itching, pain, or swelling, bleeding, bruising) and generally did not necessitate drug discontinuation. Injection site reactions generally occurred in the first month and subsequently decreased in frequency. The mean duration of injection site reactions was 3 to 5 days. In 7% of patients, redness was experienced at a previous injection site when subsequent injections were given. In postmarketing experience, injection site bleeding and bruising have also been observed in conjunction with etanercept therapy. Malignancies Patients have been observed in clinical trials with etanercept for over 5 years. Among 4,462 RA patients treated with etanercept in clinical trials for a mean of 27 months (approximately 10,000 patient-years of therapy), nine lymphomas were observed for a rate of 0.09 cases per 100 patient-years. This is 3-fold higher than the rate of lymphomas expected in the general population based on the SEER Database. An increased rate of lymphoma up to several-fold has been reported in the RA patient population, and may be further increased in patients with more severe disease activity. Sixtyseven malignancies, other than lymphoma, were observed. Of these, the most common malignancies were of the colon, breasts, lungs and prostate, which were similar in type and number to what would be expected in the general population. Analysis of the cancer rates at 6-month intervals suggests constant rates over 5 years of observation. In the placebo-controlled portions of the psoriasis studies, 8 of 933 patients who received etanercept at any dose were

13 diagnosed with a malignancy compared to 1 of 414 patients who received placebo. Among the 1,261 patients with psoriasis who received etanercept at any dose in the controlled and uncontrolled portions of the psoriasis studies (1,062 patient-years), a total of 22 patients were diagnosed with 23 malignancies; 9 patients with non-cutaneous solid tumours, 12 patients with thirteen non-melanoma skin cancers (eight basal, five squamous), and 1 patient with non-hodgkin's lymphoma. Among the placebo-treated patients (90 patient-years of observation), 1 patient was diagnosed with two squamous cell cancers. The size of the placebo group and limited duration of the controlled portions of studies precludes the ability to draw firm conclusions. Among 89 patients with Wegener's granulomatosis receiving etanercept in a randomized, placebo-controlled trial, 5 experienced a variety of non-cutaneous solid malignancies compared with none receiving placebo. Immunogenicity Patients with RA, PsA, AS or plaque psoriasis were tested at multiple timepoints for antibodies to etanercept. Antibodies to the TNF-receptor portion or other protein components of the etanercept drug product were detected at least once in the sera of approximately 6% of adult patients with RA, PsA, AS or plaque psoriasis. These antibodies were all nonneutralizing. Results from polyarticular-course JIA patients were similar to those seen in adult RA patients treated with etanercept. In PsO studies that evaluated the exposure of etanercept for up to 120 weeks, the percentage of patients testing positive at the assessed time points of 24, 48, 72 and 96 weeks ranged from 3.6% to 8.7% and were all non-neutralizing. The percentage of patients testing positive increased with an increase in the duration of study; however, the clinical significance of this finding is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed. The long-term immunogenicity data of etanercept beyond 120 weeks of exposure are unknown. The data reflect the percentage of patients whose test results were considered positive for antibodies to etanercept in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of any 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 medications and underlying disease. For these reasons, comparison of the incidence of antibodies to etanercept with the incidence of antibodies to other products may be misleading. Auto-antibodies Patients with RA had serum samples tested for auto-antibodies at multiple timepoints. In RA Studies I and II, the percentage of patients evaluated for antinuclear antibodies (ANA) who developed new positive ANA (titre 1:40) was higher in patients treated with etanercept (11%) than in placebo-treated patients (5%). The percentage of patients who developed new positive anti-double-stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with etanercept compared to 4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treated with etanercept compared to none of placebo-treated patients). The proportion of patients treated with etanercept who developed anti-cardiolipin antibodies was similarly increased compared to placebo-treated patients. In Study III, no pattern of increased auto-antibody development was seen in etanercept patients compared to MTX patients. The impact of long-term treatment with etanercept on the development of autoimmune diseases is unknown. Rare adverse event reports have described patients with rheumatoid factor-positive and/or erosive RA who have developed additional auto-antibodies in conjunction with rash and other features suggesting a lupus-like syndrome. Other Adverse Reactions Table 2 summarizes adverse reactions reported in adult RA patients. The types of adverse reactions seen in patients with PsA or AS were similar to the types of adverse reactions seen in patients with RA. Table 2: Percent of adult RA patients reporting adverse events in controlled clinical trials

14 Placebo-Controlled* (Studies I, II and a Phase 2 Study) Percent of Patients Active-Controlled (Study III) Percent of Patients Event Placebo (N = 152) Etanercept (N = 349) MTX (N = 217) Etanercept (N = 415) Injection site reaction Infection (total) Non-upper respiratory infections Upper respiratory infection Diarrhoea Pruritus Pyrexia Urticaria Hypersensitivity Rash *Includes data from the 6-month study in which patients received concurrent MTX therapy in both arms. Study duration of 2 years Any dose Includes bacterial, viral and fungal infections Most frequent upper respiratory infections were upper respiratory tract infections, sinusitis and influenza In placebo-controlled PsO trials, the percentages of patients reporting adverse reactions in the 50 mg twice-a-week dose group were similar to those observed in the 25 mg twice-a-week dose group or the placebo group. Table 3 summarizes adverse reactions reported in adult PsO patients from Studies I and II. Table 3: Percent of adult PsO patients experiencing adverse reactions in placebo-controlled portions of clinical trials (Studies I and II) Percent of Patients Reaction Placebo (N = 359) Etanercept * (N = 876) Injection site reaction 6 15 Infection (total) 28 27

15 Non-upper respiratory infections Upper respiratory infection Diarrhoea 2 3 Pruritus 2 1 Pyrexia 1 - Urticaria - 1 Hypersensitivity - 1 Rash 1 1 *Includes 25 mg subcutaneous once weekly, 25 mg SC twice weekly, 50 mg subcutaneous once weekly, and 50 mg subcutaneous twice weekly doses. Includes bacterial, viral and fungal infections. Most frequent upper respiratory infections were upper respiratory tract infection, nasopharyngitis and sinusitis. Adverse Reactions in Patients with Polyarticular-course JIA In general, the adverse events in paediatric patients were similar in frequency and type as those seen in adult patients. Differences from adults and other special considerations are discussed in the following paragraphs. Severe adverse reactions reported in 69 polyarticular-course JIA patients aged 4 to 17 years included varicella, gastroenteritis, depression/personality disorder, cutaneous ulcer, oesophagitis/gastritis, group A streptococcal septic shock, Type 1 diabetes mellitus, and soft tissue and post-operative wound infection. Of 69 (62%) children with JIA, 43 experienced an infection while receiving etanercept during the 3 months of the study (part 1 open-label), and the frequency and severity of infections was similar in 58 patients completing 12 months of open-label extension therapy. The types of infections reported in JIA patients were generally mild and consistent with those commonly seen in outpatient paediatric populations. Two JIA patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae. The following adverse events were reported more commonly in 69 JIA patients receiving 3 months of etanercept compared to the 349 adult RA patients in placebo-controlled trials. These included headache (19% of patients, 1.7 events per patient-year), nausea (9%, 1.0 events per patient-year), abdominal pain (19%, 0.74 events per patient-year), and vomiting (13%, 0.74 events per patient-year). In open-label clinical studies of children with JIA, adverse events reported in those aged 2 to 4 years were similar to adverse events reported in older children. In post-marketing experience, the following additional serious adverse events have been reported in paediatric patients: abscess with bacteraemia, optic neuritis, pancytopenia, seizures, tuberculous arthritis, urinary tract infection, coagulopathy, cutaneous vasculitis and transaminase elevations. The frequency of these events and their causal relationship to etanercept therapy are unknown. Patients with Heart Failure Two randomized placebo-controlled studies have been performed in patients with CHF. In one study, patients received either etanercept 25 mg twice weekly, 25 mg three times weekly or placebo. In a second study, patients received either