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2013年5月15日，杨森生物技术公司宣布，美国食品药品管理局(FDA)已批准Simponi(戈利木单抗)用于已证实对皮质类固醇依赖或对口服氨基水杨酸、口服类固醇皮质激素、咪唑硫嘌呤或6-巯基嘌呤无充分应答或不能耐受的中至重度活动性溃疡性结肠炎(UC)患者的治疗。 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis SIMPONI, in combination with methotrexate, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis. 1.2 Psoriatic Arthritis SIMPONI, alone or in combination with methotrexate, is indicated for the treatment of adult patients with active psoriatic arthritis. 1.3 Ankylosing Spondylitis SIMPONI is indicated for the treatment of adult patients with active ankylosing spondylitis. 2 DOSAGE AND ADMINISTRATION 2.1 Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis The SIMPONI dose regimen is 50 mg administered by subcutaneous injection once a month. For patients with rheumatoid arthritis (RA), SIMPONI should be given in combination with methotrexate and for patients with psoriatic arthritis (PsA) or ankylosing spondylitis (AS), SIMPONI may be given with or without methotrexate or other non-biologic Disease Modifying Antirheumatic Drugs (DMARDs). For patients with RA, PsA, or AS, corticosteroids, non-biologic DMARDs, and/or NSAIDs may be continued during treatment with SIMPONI. 2.2 Monitoring to Assess Safety
2.3 General Considerations for Administration SIMPONI is intended for use under the guidance and supervision of a physician. After proper training in subcutaneous injection technique, a patient may self inject with SIMPONI if a physician determines that it is appropriate. Patients should be instructed to follow the directions provided in the Medication Guide (see Medication Guide). To ensure proper use, allow the prefilled syringe or autoinjector to sit at room temperature outside the carton for 30 minutes prior to subcutaneous injection. Do not warm SIMPONI in any other way. Prior to administration, visually inspect the solution for particles and discoloration through the viewing window. SIMPONI should be clear to slightly opalescent and colorless to light yellow. The solution should not be used if discolored, or cloudy, or if foreign particles are present. Any leftover product remaining in the prefilled syringe or prefilled autoinjector should not be used. NOTE: The needle cover on the prefilled syringe as well as the prefilled syringe in the autoinjector contains dry natural rubber (a derivative of latex), which should not be handled by persons sensitive to latex. Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red, or hard. 3 DOSAGE FORMS AND STRENGTHS SmartJect® Autoinjector Each single dose SmartJect autoinjector contains a prefilled glass syringe (27 gauge ½ inch) providing 50 mg of SIMPONI per 0.5 mL of solution. Prefilled Syringe Each single dose prefilled glass syringe (27 gauge ½ inch) contains 50 mg of SIMPONI per 0.5 mL of solution. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS (see Boxed WARNING) 5.1Serious Infections Patients treated with SIMPONI are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
Treatment with SIMPONI should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating SIMPONI in patients:
Monitoring Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with SIMPONI. SIMPONI should be discontinued if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with SIMPONI should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored. Serious Infection in Clinical Trials In controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, serious infections were observed in 1.4% of SIMPONI-treated patients and 1.3% of control-treated patients. In the controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, the incidence of serious infections per 100 patient-years of follow-up was 5.7 (95% CI: 3.8, 8.2) for the SIMPONI group and 4.2 (95% CI: 1.8, 8.2) for the placebo group. Serious infections observed in SIMPONI-treated patients included sepsis, pneumonia, cellulitis, abscess, tuberculosis, invasive fungal infections, and hepatitis B infection. Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving TNF-blockers, including patients who have previously received treatment for latent or active tuberculosis. Patients should be eva luated for tuberculosis risk factors and tested for latent infection prior to initiating SIMPONI and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF-blockers 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 SIMPONI, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). Anti-tuberculosis therapy should also be considered prior to initiation of SIMPONI 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. Patients should be closely monitored for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tuberculosis should be strongly considered in patients who develop a new infection during SIMPONI treatment, especially in patients who have previously or recently traveled to countries with a high preva lence of tuberculosis, or who have had close contact with a person with active tuberculosis. In the controlled and uncontrolled portions of the Phase 2 RA and Phase 3 RA, PsA, and AS trials, the incidence of active TB was 0.23 and 0 per 100 patient-years in 2347 SIMPONI-treated patients and 674 placebo-treated patients, respectively. Cases of TB included pulmonary and extra pulmonary TB. The overwhelming majority of the TB cases occurred in countries with a high incidence rate of TB. Invasive Fungal Infections For SIMPONI-treated 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. Hepatitis B Virus Reactivation The use of TNF-blockers including SIMPONI has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers (i.e., surface antigen positive). In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants. All patients should be tested for HBV infection before initiating TNF-blocker therapy. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended before initiating TNF-blocker therapy. The risks and benefits of treatment should be considered prior to prescribing TNF-blockers, including SIMPONI, to patients who are carriers of HBV. Adequate data are not available on whether anti-viral therapy can reduce the risk of HBV reactivation in HBV carriers who are treated with TNF-blockers. Patients who are carriers of HBV and require treatment with TNF-blockers 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, TNF-blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF-blockers after HBV reactivation has been controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF-blockers in this situation and monitor patients closely. 5.2 Malignancies Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤ 18 years of age), of which SIMPONI is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression, and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports. The risks and benefits of TNF-blocker treatment including SIMPONI should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF-blocker in patients who develop a malignancy. In the controlled portions of clinical trials of TNF-blockers including SIMPONI, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. During the controlled portions of the Phase 2 trials in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI group compared with an incidence of 0 (95% CI: 0., 0.96) in the placebo group. In the controlled and uncontrolled portions of these clinical trials in 2347 SIMPONI-treated patients with a median follow-up of 1.4 years, the incidence of lymphoma was 3.8-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 Patients with RA and other chronic inflammatory diseases, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. During the controlled portions of the Phase 2 trial in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of malignancies other than lymphoma per 100 patient-years of follow-up was not elevated in the combined SIMPONI group compared with the placebo group. In the controlled and uncontrolled portions of these trials, the incidence of malignancies, other than lymphoma, in SIMPONI-treated patients was similar to that expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 In controlled trials of other TNF-blockers in patients at higher risk for malignancies (e.g., patients with COPD, patients with Wegener's granulomatosis treated with concomitant cyclophosphamide) a greater portion of malignancies occurred in the TNF-blocker group compared to the controlled group. In an exploratory 1-year clinical trial eva luating the use of 50, 100 and 200 mg of SIMPONI in 309 patients with severe persistent asthma, 6 patients developed malignancies other than NMSC in the SIMPONI groups compared to none in the control group. Three of the 6 patients were in the 200 mg SIMPONI group. 5.3Congestive Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF-blockers, including SIMPONI. In several exploratory trials of other TNF-blockers in the treatment of CHF, there were greater proportions of TNF-blocker treated patients who had CHF exacerbations requiring hospitalization or increased mortality. SIMPONI has not been studied in patients with a history of CHF and SIMPONI should be used with caution in patients with CHF. If a decision is made to administer SIMPONI to patients with CHF, these patients should be closely monitored during therapy, and SIMPONI should be discontinued if new or worsening symptoms of CHF appear. 5.4 Demyelinating Disorders Use of TNF-blockers, of which SIMPONI is a member, has been associated with cases of new onset or exacerbation of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS) and peripheral demyelinating disorders, including Guillain-Barré syndrome. In clinical trials, cases of central demyelination, MS, and peripheral demyelinating polyneuropathy have been reported in patients treated with SIMPONI [see Adverse Reactions (6.1)]. Prescribers should exercise caution in considering the use of TNF-blockers, including SIMPONI, in patients with central or peripheral nervous system demyelinating disorders. Discontinuation of SIMPONI should be considered if these disorders develop. 5.5 Use with Abatacept In controlled trials, the concurrent administration of another TNF-blocker and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; and the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of TNF-blockers including SIMPONI and abatacept is not recommended [see Drug Interactions (7.2)]. 5.6 Use with Anakinra Concurrent administration of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater portion of serious infections and neutropenia and no additional benefits compared with the TNF-blocker alone. Therefore, the combination of anakinra with TNF-blockers, including SIMPONI, is not recommended [see Drug Interactions 7.2]. 5.7 Switching Between Biological Disease Modifying Antirheumatic Drugs (DMARDs) Care should be taken when switching from one biologic to another since overlapping biological activity may further increase the risk of infection. 5.8 Hematologic Cytopenias There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. In clinical studies, cases of pancytopenia, leukopenia, neutropenia, and thrombocytopenia have also occurred in SIMPONI-treated patients. Caution should be exercised when using TNF-blockers, including SIMPONI, in patients who have or have had significant cytopenias. 5. 9 Vaccinations Patients treated with SIMPONI may receive vaccinations, except for live vaccines. No data are available on the response to live vaccination or the risk of infection, or transmission of infection after the administration of live vaccines to patients receiving SIMPONI. In the Phase 3 PsA study, after pneumococcal vaccination, a similar proportion of SIMPONI-treated and placebo-treated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine. In both SIMPONI-treated and placebo-treated patients, the proportions of patients with response to pneumococcal vaccine were lower among patients receiving MTX compared with patients not receiving MTX. The data suggest that SIMPONI does not suppress the humoral immune response to the pneumococcal vaccine. 5.10 Hypersensitivity Reactions In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported following SIMPONI administration. Some of these reactions occurred after the first administration of SIMPONI. If an anaphylactic or other serious allergic reaction occurs, administration of SIMPONI should be discontinued immediately and appropriate therapy instituted. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction 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 reflect the rates observed in clinical practice. 6.1 Clinical Studies Experience The safety data described below are based on 5 pooled, randomized, double-blind, controlled Phase 3 trials in patients with RA, PsA, and AS (Studies RA-1, RA-2, RA-3, PsA, and AS) [see Clinical Studies (14.1, 14.2 and 14.3)]. These 5 trials included 639 control-treated patients and 1659 SIMPONI-treated patients including 1089 with RA, 292 with PsA, and 278 with AS. The proportion of patients who discontinued treatment due to adverse reactions in the controlled Phase 3 trials through Week 16 in RA, PsA and AS was 2% for SIMPONI-treated patients and 3% for placebo-treated patients. The most common adverse reactions leading to discontinuation of SIMPONI in the controlled Phase 3 trials through Week 16 were sepsis (0.2%), alanine aminotransferase increased (0.2%), and aspartate aminotransferase increased (0.2%). The most serious adverse reactions were:
Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 RA, PsA and AS trials through Week 16, occurring in 7% and 6% of SIMPONI-treated patients as compared with 6% and 5% of control-treated patients, respectively. Infections In controlled Phase 3 trials through Week 16 in RA, PsA, and AS, infections were observed in 28% of SIMPONI-treated patients compared to 25% of control-treated patients [for Serious Infections, see Warnings and Precautions (5.1)]. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of SIMPONI in patients with RA, PsA, and AS through Week 16, ALT elevations ≥ 5 × ULN occurred in 0.2% of control-treated patients and 0.7% of SIMPONI-treated patients and ALT elevations ≥ 3 × ULN occurred in 2% of control-treated patients and 2% of SIMPONI-treated patients. Since many of the patients in the Phase 3 trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDs, MTX), the relationship between SIMPONI and liver enzyme elevation is not clear. Autoimmune Disorders and Autoantibodies The use of TNF-blockers, including SIMPONI, has been associated with the formation of autoantibodies and, rarely, with the development of a lupus-like syndrome. In the controlled Phase 3 trials in patients with RA, PsA, and AS through Week 14, there was no association of SIMPONI treatment and the development of newly positive anti-dsDNA antibodies. Injection Site Reactions In controlled Phase 3 trials through Week 16 in RA, PsA and AS, 6% of SIMPONI-treated patients had injection site reactions compared with 2% of control-treated patients. The majority of the injection site reactions were mild and the most frequent manifestation was injection site erythema. In controlled Phase 2 and 3 trials in RA, PsA, and AS, no patients treated with SIMPONI developed anaphylactic reactions. Immunogenicity Antibodies to SIMPONI were detected in 57 (4%) of SIMPONI-treated patients across the Phase 3 RA, PsA, and AS trials through Week 24. Similar rates were observed in each of the three indications. Patients who received SIMPONI with concomitant MTX had a lower proportion of antibodies to SIMPONI than patients who received SIMPONI without MTX (approximately 2% versus 7%, respectively). Of the patients with a positive antibody response to SIMPONI in the Phase 2 and 3 trials, most were determined to have neutralizing antibodies to golimumab as measured by a cell-based functional assay. The small number of patients positive for antibodies to SIMPONI limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures. The data above reflect the percentage of patients whose test results were considered positive for antibodies to SIMPONI in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SIMPONI with the incidence of antibodies to other products may be misleading. Other Adverse Reactions Table 1 summarizes the adverse drug reactions that occurred at a rate of at least 1% in the SIMPONI ± DMARD group and with a higher incidence than in the placebo ± DMARD group during the controlled period of the 5 pooled Phase 3 trials through Week 16 in patients with RA, PsA, and AS.
Adverse drug reactions that occurred <1% in SIMPONI-treated patients during the SIMPONI clinical trials that do not appear in the Warnings and Precautions section included the following events listed by system organ class: Infections and infestations: Septic shock, atypical mycobacterial infection, pyelonephritis, arthritis bacterial, bursitis infective Neoplasms benign, malignant and unspecified: leukemia Skin and subcutaneous tissue disorders: psoriasis (new onset or worsening, palmar/plantar and pustular), vasculitis (cutaneous) Vascular disorders: Vasculitis (systemic) 6.2Post-marketing Experience The following adverse reactions have been identified during post-approval use of SIMPONI. 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 SIMPONI exposure. Immune System Disorders: Serious systemic hypersensitivity reactions (including anaphylactic reaction) [see Warnings and Precautions (5.10)]. 7 DRUG INTERACTIONS 7.1 Methotrexate For the treatment of RA, SIMPONI should be used with methotrexate (MTX) [see Clinical Studies (14.1)]. Since the presence or absence of concomitant MTX did not appear to influence the efficacy or safety of SIMPONI in the treatment of PsA or AS, SIMPONI can be used with or without MTX in the treatment of PsA and AS [see Clinical Studies (14.1) and Clinical Pharmacology (12.3)]. 7.2 Biologic Products for RA, PsA, and/or AS An increased risk of serious infections has been seen in clinical RA studies of other TNF-blockers used in combination with anakinra or abatacept, with no added benefit; therefore, use of SIMPONI with abatacept or anakinra is not recommended [see Warnings and Precautions (5.5 and 5.6)]. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF-blocker. There is insufficient information to provide recommendations regarding the concomitant use of SIMPONI and other biologic products approved to treat RA, PsA, or AS. 7.3 Live Vaccines Live vaccines should not be given concurrently with SIMPONI [see Warnings and Precautions (5.9)]. Infants born to women treated with SIMPONI during their pregnancy may be at increased risk of infection for up to 6 months. Administration of live vaccines to infants exposed to SIMPONI in utero is not recommended for 6 months following the mother's last SIMPONI injection during pregnancy (see Use in Specific Populations (8.1)]. 7.4 Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as golimumab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of SIMPONI in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B – There are no adequate and well-controlled studies of SIMPONI in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, it is not known whether SIMPONI can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. SIMPONI should be used during pregnancy only if clearly needed. An embryofetal developmental toxicology study was performed in which pregnant cynomolgus monkeys were treated subcutaneously with golimumab during the first trimester with doses up to 50 mg/kg twice weekly (360 times greater than the maximum recommended human dose-MHRD) and has revealed no evidence of harm to maternal animals or fetuses. Umbilical cord blood samples collected at the end of the second trimester showed that fetuses were exposed to golimumab during gestation. In this study, in utero exposure to golimumab produced no developmental defects to the fetus. A pre- and post-natal developmental study was performed in which pregnant cynomolgus monkeys were treated with golimumab during the second and third trimesters, and during lactation at doses up to 50 mg/kg twice weekly (860 times and 310 times greater than the maximal steady state human blood levels for maternal animals and neonates, respectively) and has revealed no evidence of harm to maternal animals or neonates. Golimumab was present in the neonatal serum from the time of birth and for up to six months postpartum. Exposure to golimumab during gestation and during the postnatal period caused no developmental defects in the infants. IgG antibodies are known to cross the placenta during pregnancy and have been detected in the serum of infants born to patients treated with these antibodies. Since SIMPONI is an IgG antibody, infants born to women treated with SIMPONI during their pregnancy may be at increased risk of infection for up to 6 months. Administration of live vaccines to infants exposed to SIMPONI in utero is not recommended for 6 months following the mother's last SIMPONI injection during pregnancy [see Warnings and Precautions (5.9)]. 8.3 Nursing Mothers It is not known whether SIMPONI 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 adverse reactions in nursing infants from SIMPONI, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In the pre- and post-natal development study in cynomolgus monkeys in which golimumab was administered subcutaneously during pregnancy and lactation, golimumab was detected in the breast milk at concentrations that were approximately 400-fold lower than the maternal serum concentrations. 8.4 Pediatric Use Safety and effectiveness of SIMPONI in pediatric patients less than 18 years of age have not been established. 8.5 Geriatric Use In the Phase 3 trials in RA, PsA, and AS, there were no overall differences in SAEs, serious infections, and AEs in SIMPONI-treated patients ages 65 or older (N = 155) compared with younger SIMPONI-treated patients. Because there is a higher incidence of infections in the geriatric population in general, caution should be used in treating geriatric patients with SIMPONI. 10 OVERDOSAGE In a clinical study, 5 patients received protocol-directed single infusions of 10 mg/kg of intravenous SIMPONI without serious adverse reactions or other significant reactions. The highest weight patient was 100 kg, and therefore received a single intravenous infusion of 1000 mg of SIMPONI. There were no SIMPONI overdoses in the clinical studies. 11 DESCRIPTION SIMPONI (golimumab) is a human IgG1κ monoclonal antibody specific for human tumor necrosis factor alpha (TNFα) that exhibits multiple glycoforms with molecular masses of approximately 150 to 151 kilodaltons. SIMPONI was created using genetically engineered mice immunized with human TNF, resulting in an antibody with human-derived antibody variable and constant regions. SIMPONI is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses. The SIMPONI drug product is a sterile solution of the golimumab antibody supplied as either a single dose prefilled syringe (with a passive needle safety guard) or a single dose prefilled autoinjector. The Type 1 glass syringe has a coated stopper. The fixed stainless steel needle (5 bevel, 27G, half-inch) is covered with a needle shield to prevent leakage of the solution through the needle and to protect the needle during handling prior to administration. The needle shield is made of a dry natural rubber containing latex. SIMPONI does not contain preservatives. The solution is clear to slightly opalescent, colorless to light yellow with a pH of approximately 5.5. SIMPONI is provided in one strength: 50 mg of the golimumab antibody in 0.5 mL of solution. Each 0.5 mL of SIMPONI contains 50 mg of the golimumab antibody, 0.44 mg of L-histidine and L-histidine monohydrochloride monohydrate, 20.5 mg of sorbitol, 0.08 mg of polysorbate 80, and Water for Injection. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Golimumab is a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNFα. This interaction prevents the binding of TNFα to its receptors, thereby inhibiting the biological activity of TNFα (a cytokine protein). There was no evidence of the golimumab antibody binding to other TNF superfamily ligands; in particular, the golimumab antibody did not bind or neutralize human lymphotoxin. Golimumab did not lyse human monocytes expressing transmembrane TNF in the presence of complement or effector cells. Elevated TNFα levels in the blood, synovium, and joints have been implicated in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. TNFα is an important mediator of the articular inflammation that is characteristic of these diseases. Golimumab modulated the in vitro biological effects mediated by TNF in several bioassays, including the expression of adhesion proteins responsible for leukocyte infiltration (E-selectin, ICAM-1 and VCAM-1) and the secretion of proinflammatory cytokines (IL-6, IL-8, G-CSF and GM-CSF). 12.2 Pharmacodynamics In clinical studies, decreases in C-reactive protein (CRP), interleukin (IL)-6, matrix metalloproteinase 3 (MMP-3), intercellular adhesion molecule (ICAM)-1 and vascular endothelial growth factor (VEGF) were observed following SIMPONI administration in patients with RA, PsA, and AS. 12.3 Pharmacokinetics Following subcutaneous administration of SIMPONI to healthy subjects and patients with active RA, the median time to reach maximum serum concentrations (Tmax) ranged from 2 to 6 days. A subcutaneous injection of 50 mg SIMPONI to healthy subjects produced a mean maximum serum concentration (Cmax) of approximately 2.5 µg/mL. SIMPONI exhibited dose-proportional pharmacokinetics (PK) in patients with active RA over the dose range of 0.1 to 10.0 mg/kg following a single intravenous (IV) dose. Following a single IV administration over the same dose range in patients with active RA, mean systemic clearance of SIMPONI was estimated to be 4.9 to 6.7 mL/day/kg, and mean volume of distribution ranged from 58 to 126 mL/kg. The volume of distribution for SIMPONI indicates that SIMPONI is distributed primarily in the circulatory system with limited extravascular distribution. Median terminal half-life values were estimated to be approximately 2 weeks in healthy subjects and patients with active RA, PsA or AS. By cross-study comparisons of mean AUCinf values following an IV or subcutaneous administration of SIMPONI, the absolute bioavailability of subcutaneous SIMPONI was estimated to be approximately 53%. When 50 mg SIMPONI was administered subcutaneous to patients with RA, PsA, or AS every 4 weeks, serum concentrations appeared to reach steady state by Week 12. With concomitant use of methotrexate (MTX), treatment with 50 mg SIMPONI subcutaneous every 4 weeks resulted in a mean steady-state trough serum concentration of approximately 0.4–0.6 µg/mL in patients with active RA, approximately 0.5 µg/mL in patients with active PsA, and approximately 0.8 µg/mL in patients with active AS. Patients with RA, PsA, and AS treated with SIMPONI 50 mg and MTX had approximately 52%, 36% and 21% higher mean steady-state trough concentrations of golimumab, respectively compared with those treated with SIMPONI 50 mg without MTX. The presence of MTX also decreased anti-golimumab antibody incidence from 7% to 2% [see Adverse Reactions (6.1)]. For RA, SIMPONI should be used with MTX. In the PsA and AS trials, the presence or absence of concomitant MTX did not appear to influence clinical efficacy and safety parameters [see Drug Interactions (7.1) and Clinical Studies (14.1)]. Population PK analyses indicated that concomitant use of NSAIDs, oral corticosteroids, or sulfasalazine did not influence the apparent clearance of SIMPONI. Population PK analyses showed there was a trend toward higher apparent clearance of SIMPONI with increasing weight. However, across the PsA and AS populations, no meaningful differences in clinical efficacy were observed among the subgroups by weight quartile. The RA trial in MTX-experienced and TNF-blocker-naïve patients (Study RA-2) did show evidence of a reduction in clinical efficacy with increasing body weight, but this effect was observed for both tested doses of SIMPONI (50 mg and 100 mg). Therefore, there is no need to adjust the dosage of SIMPONI based on a patient's weight. Population PK analyses suggested no PK differences between male and female patients after body weight adjustment in the RA and PsA trials. In the AS trial, female patients showed 13% higher apparent clearance than male patients after body weight adjustment. Subgroup analysis based on gender showed that both female and male patients achieved clinically significant response at the proposed clinical dose. Dosage adjustment based on gender is not needed. Population PK analyses indicated that PK parameters of SIMPONI were not influenced by age in adult patients. Patients with age ≥ 65 years had apparent clearance of SIMPONI similar to patients with age < 65 years. No ethnicity-related PK differences were observed between Caucasians and Asians, and there were too few patients of other races to assess for PK differences. Patients who developed anti-SIMPONI antibodies generally had lower steady-state serum trough concentrations of SIMPONI. No formal study of the effect of renal or hepatic impairment on the PK of golimumab was conducted. 13NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies of golimumab have not been conducted to eva luate its carcinogenic potential. Mutagenicity studies have not been conducted with golimumab. A fertility study conducted in mice using an analogous anti-mouse TNFα antibody showed no impairment of fertility. 14CLINICAL STUDIES 14.1 Rheumatoid Arthritis The efficacy and safety of SIMPONI were eva luated in 3 multicenter, randomized, double-blind, controlled trials (Studies RA-1, RA-2, and RA-3) in 1542 patients ≥ 18 years of age with moderately to severely active RA, diagnosed according to the American College of Rheumatology (ACR) criteria, for at least 3 months prior to administration of study agent. Patients were required to have at least 4 swollen and 4 tender joints. SIMPONI was administered subcutaneously at doses of 50 mg or 100 mg every 4 weeks. Double-blinded controlled efficacy data were collected and analyzed through Week 24. Patients were allowed to continue stable doses of concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and/or NSAIDs and patients may have received oral MTX during the trials. Study RA-1 eva luated 445 patients who were previously treated (at least 8 to 12 weeks prior to administration of study agent) with one or more doses of a biologic TNF-blocker without a serious adverse reaction. Patients may have discontinued the biologic TNF-blocker for a variety of reasons. Patients were randomized to receive placebo (n = 150), SIMPONI 50 mg (n = 147), or SIMPONI 100 mg (n = 148). Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), and/or hydroxychloroquine (HCQ) during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited. Study RA-2 eva luated 444 patients who had active RA despite a stable dose of at least 15 mg/week of MTX and who had not been previously treated with a biologic TNF-blocker. Patients were randomized to receive background MTX (n = 133), SIMPONI 50 mg + background MTX (n = 89), SIMPONI 100 mg + background MTX (n = 89), or SIMPONI 100 mg monotherapy (n = 133). The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited. Study RA-3 eva luated 637 patients with active RA who were MTX-naïve and had not previously been treated with a biologic TNF-blocker. Patients were randomized to receive MTX (n = 160), SIMPONI 50 mg + MTX (n = 159), SIMPONI 100 mg + MTX (n = 159), or SIMPONI 100 mg monotherapy (n = 159). For patients receiving MTX, MTX was administered at a dose of 10 mg/week beginning at Week 0 and increased to 20 mg/week by Week 8. The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited. The primary endpoint in Study RA-1 and Study RA-2 was the percentage of patients achieving an ACR 20 response at Week 14 and the primary endpoint in Study RA-3 was the percentage of patients achieving an ACR 50 response at Week 24. In Studies RA-1, RA-2, and RA-3, the median duration of RA disease was 9.4, 5.7, and 1.2 years; and 99%, 75%, and 54% of the patients used at least one DMARD in the past, respectively. Approximately 77% and 57% of patients received concomitant NSAIDs and low dose corticosteroids, respectively, in the 3 pooled RA trials. Clinical Response In the 3 RA trials, a greater percentage of patients treated with the combination of SIMPONI and MTX achieved ACR responses at Week 14 (Studies RA-1 and RA-2) and Week 24 (Studies RA-1, RA-2, and RA-3) versus patients treated with the MTX alone. There was no clear evidence of improved ACR response with the higher SIMPONI dose group (100 mg) compared to the lower SIMPONI dose group (50 mg). In Studies RA-2 and RA-3, the SIMPONI monotherapy groups were not statistically different from the MTX monotherapy groups in ACR responses. Table 2 shows the proportion of patients with the ACR response for the SIMPONI 50 mg and control groups in Studies RA-1, RA-2, and RA-3. In the subset of patients who received SIMPONI in combination with MTX in Study RA-1, the proportion of patients achieving ACR 20, 50 and 70 responses at week 14 were 40%, 18%, and 12%, respectively, in the SIMPONI 50 mg + MTX group (N = 101) compared with 17%, 6%, and 2%, respectively, in the placebo + MTX group (N = 103). Table 3 shows the percent improvement in the components of the ACR response criteria for the SIMPONI 50 mg + MTX and MTX groups in Study RA-2. The percent of patients achieving ACR 20 responses by visit for Study RA-2 is shown in Figure 1. ACR 20 responses were observed in 38% of patients in the SIMPONI 50 mg + MTX group at the first assessment (Week 4) after the initial SIMPONI administration.
In Studies RA-1 and RA-2, the SIMPONI 50 mg groups demonstrated a greater improvement compared to the control groups in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24: 0.23 vs. 0.03 in RA-1, 0.47 vs. 0.13 in RA-2, respectively. Also in Studies RA-1 and RA-2, the SIMPONI 50 mg groups compared to the control groups had a greater proportion of HAQ responders (change from baseline > 0.22) at Week 24: 43% vs. 27%, 65% vs. 35%, respectively. 14.2 Psoriatic Arthritis The safety and efficacy of SIMPONI were eva luated in a multi-center, randomized, double-blind, placebo-controlled trial in 405 adult patients with moderately to severely active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite NSAID or DMARD therapy (Study PsA). Patients in this study had a diagnosis of PsA for at least 6 months with a qualifying psoriatic skin lesion of at least 2 cm in diameter. Previous treatment with a biologic TNF-blocker was not allowed. Patients were randomly assigned to placebo (n = 113), SIMPONI 50 mg (n = 146), or SIMPONI 100 mg (n = 146) given subcutaneously every 4 weeks. Patients were allowed to receive stable doses of concomitant MTX (≤ 25 mg/week), low dose oral corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and/or NSAIDs during the trial. The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited. The primary endpoint was the percentage of patients achieving ACR 20 response at Week 14. Placebo-controlled efficacy data were collected and analyzed through Week 24. Patients with each subtype of PsA were enrolled, including polyarticular arthritis with no rheumatoid nodules (43%), asymmetric peripheral arthritis (30%), distal interphalangeal (DIP) joint arthritis (15%), spondylitis with peripheral arthritis (11%), and arthritis mutilans (1%). The median duration of PsA disease was 5.1 years, 78% of patients received at least one DMARD in the past, and approximately 48% of patients received MTX, and 16% received low dose oral steroids. Clinical Response in Patients with PsA SIMPONI ± MTX, compared with placebo ± MTX, resulted in significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ACR 20 response at Week 14 in Study PsA (see Table 4). There was no clear evidence of improved ACR response with the higher SIMPONI dose group (100 mg) compared to the lower SIMPONI dose group (50 mg). ACR responses observed in the SIMPONI-treated groups were similar in patients receiving and not receiving concomitant MTX. Similar ACR 20 responses at Week 14 were observed in patients with different PsA subtypes. However, the number of patients with arthritis mutilans was too small to allow meaningful assessment. SIMPONI 50 mg treatment also resulted in significantly greater improvement compared with placebo for each ACR component in Study PsA (Table 5). Treatment with SIMPONI resulted in improvement in enthesitis and skin manifestations in patients with PsA. However, the safety and efficacy of SIMPONI in the treatment of patients with plaque psoriasis has not been established. The percent of patients achieving ACR 20 responses by visit for Study PsA is shown in Figure 2. ACR 20 responses were observed in 31% of patients in the SIMPONI 50 mg + MTX group at the first assessment (Week 4) after the initial SIMPONI administration.
Physical Function Response in Patients with PsA In Study PsA, SIMPONI 50 mg demonstrated a greater improvement compared to placebo in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24 (0.33 and -0.01, respectively). In addition, the SIMPONI 50 mg group compared to the placebo group had a greater proportion of HAQ responders (≥ 0.3 change from baseline) at Week 24: 43% vs. 22%, respectively. 14.3 Ankylosing Spondylitis The safety and efficacy of SIMPONI were eva luated in a multi-center, randomized, double-blind, placebo-controlled trial in 356 adult patients with active ankylosing spondylitis according to modified New York criteria for at least 3 months (Study AS). Patients had symptoms of active disease [defined as a Bath AS Disease Activity Index (BASDAI) ≥ 4 and VAS for total back pain of ≥ 4, on scales of 0 to 10 cm] despite current or previous NSAID therapy. Patients were excluded if they were previously treated with a biologic TNF-blocker or if they had complete ankylosis of the spine. Patients were randomly assigned to placebo (n = 78), SIMPONI 50 mg (n = 138), or SIMPONI 100 mg (n = 140) administered subcutaneously every 4 weeks. Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), hydroxychloroquine (HCQ), low dose corticosteroids (equivalent to < 10 mg of prednisone a day), and/or NSAIDs during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited. The primary endpoint was the percentage of patients achieving an ASsessment in Ankylosing Spondylitis (ASAS) 20 response at Week 14. Placebo-controlled efficacy data were collected and analyzed through Week 24. In Study AS, the median duration of AS disease was 5.6 years, median duration of inflammatory back pain was 12 years, 83% were HLA-B27 positive, 24% had prior joint surgery or procedure, and 55% received at least one DMARD in the past. During the trial, the use of concomitant DMARDs and/or NSAIDs was as follows: MTX (20%), SSZ (26%), HCQ (1%), low dose oral steroids (16%), and NSAIDs (90%). Clinical Response in Patients with AS In Study AS, SIMPONI ± DMARDs treatment, compared with placebo ± DMARDs, resulted in a significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ASAS 20 response at Week 14 (see Table 6). There was no clear evidence of improved ASAS response with the higher SIMPONI dose group (100 mg) compared to the lower SIMPONI dose group (50 mg). Table 7 shows the percent improvement in the components of the ASAS response criteria for the SIMPONI 50 mg ± DMARDs and placebo ± DMARDs groups in Study AS. The percent of patients achieving ASAS 20 responses by visit for Study AS is shown in Figure 3. ASAS 20 responses were observed in 48% of patients in the SIMPONI 50 mg + MTX group at the first assessment (Week 4) after the initial SIMPONI administration.
16HOW SUPPLIED/STORAGE AND HANDLING Each SIMPONI prefilled autoinjector or prefilled syringe is packaged in a light-blocking, cardboard outer carton. SIMPONI is available in packs of 1 prefilled syringe NDC 57894-070-01 or 1 prefilled SmartJect autoinjector NDC 57894-070-02. Prefilled SmartJect Autoinjector Each single dose SmartJect autoinjector contains a prefilled glass syringe (27 gauge ½ inch) providing 50 mg of SIMPONI per 0.5 mL of solution. Prefilled Syringe Each single dose prefilled glass syringe (27 gauge ½ inch) contains 50 mg of SIMPONI per 0.5 mL of solution. Storage and Stability SIMPONI must be refrigerated at 2°C to 8°C (36°F to 46°F) and protected from light. Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. Do not use SIMPONI beyond the expiration date (EXP) on the carton or the expiration date on the prefilled syringe (observed through the viewing window) or the prefilled SmartJect autoinjector.
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戈利木单抗注射剂|Simponi(Golimumab)Injection简介：
2013年5月15日，杨森生物技术公司宣布，美国食品药品管理局(FDA)已批准Simponi(戈利木单抗)用于已证实对皮质类固醇依赖或对口服氨基水杨酸、口服类固醇皮质激素、咪唑硫嘌呤或6-巯基嘌呤无充分应答或不 ... 责任编辑：admin |
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