용량 및 투여 방법
2 DOSAGE AND ADMINISTRATION Administer by subcutaneous injection ( 2 ) Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis ( 2.2 ): Adults: 40 mg every other week. Some patients with RA not receiving methotrexate may benefit from increasing the dosage to 40 mg every week or 80 mg every other week. Juvenile Idiopathic Arthritis or Pediatric Uveitis ( 2.3 ): Pediatric Weight 2 Years of Age and Older Recommended Dosage 10 kg (22 lbs) to less than 15 kg (33 lbs) 10 mg every other week 15 kg (33 lbs) to less than 30 kg (66 lbs) 20 mg every other week 30 kg (66 lbs) and greater 40 mg every other week Crohn's Disease ( 2.4 ): Adults : 160 mg on Day 1 (given in one day or split over two consecutive days); 80 mg on Day 15; and 40 mg every other week starting on Day 29. Pediatric Patients 6 Years of Age and Older : Pediatric Weight Recommended Dosage Days 1 and 15 Starting on Day 29 17 kg (37 lbs) to less than 40 kg (88 lbs) Day 1: 80 mg Day 15: 40 mg 20 mg every other week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) Day 15: 80 mg 40 mg every other week Ulcerative Colitis ( 2.5 ): Adults : 160 mg on Day 1 (given in one day or split over two consecutive days), 80 mg on Day 15 and 40 mg every other week starting on Day 29. Discontinue in patients without evidence of clinical remission by eight weeks (Day 57). Plaque Psoriasis or Adult Uveitis ( 2.6 ): Adults: 80 mg initial dose followed by 40 mg every other week starting one week after initial dose. Hidradenitis Suppurativa ( 2.7 ): Adults: Day 1: 160 mg (given in one day or split over two consecutive days) Day 15: 80 mg Day 29 and subsequent doses: 40 mg every week or 80 mg every other week Adolescents 12 years of age and older: Adolescent Weight Recommended Dosage 30 kg (66 lbs) to less than 60 kg (132 lbs) Day 1: 80 mg Day 8 and subsequent doses: 40 mg every other week 60 kg (132 lbs) and greater Day 1: 160 mg (given in one day or split over two consecutive days) Day 15: 80 mg Day 29 and subsequent doses: 40 mg every week or 80 mg every other week 2.1 Recommended Tuberculosis Evaluation Prior to initiating YUFLYMA and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions ( 5.1 )] . 2.2 Recommended Dosage in Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis The recommended subcutaneous dosage of YUFLYMA for adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) [see Indications and Usage ( 1.1 , 1.3 , 1.4 )] is 40 mg administered every other week. Methotrexate (MTX), other non-biologic DMARDS, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with YUFLYMA. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosage of YUFLYMA to 40 mg every week or 80 mg every other week. 2.3 Recommended Dosage in Juvenile Idiopathic Arthritis or Pediatric Patients with Uveitis The recommended subcutaneous dosage of YUFLYMA for pediatric patients 2 years of age and older with polyarticular juvenile idiopathic arthritis (JIA) or pediatric uveitis [see Indications and Usage ( 1.2 , 1.9 )] , based on weight, is shown below. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with YUFLYMA. Pediatric Weight (2 years of age and older) Recommended Dosage 10 kg (22 lbs) to less than 15 kg (33 lbs) 10 mg every other week 15 kg (33 lbs) to less than 30 kg (66 lbs) 20 mg every other week 30 kg (66 lbs) and greater 40 mg every other week Adalimumab products have not been studied in patients with polyarticular JIA or pediatric uveitis less than 2 years of age or in patients with a weight below 10 kg. 2.4 Recommended Dosage in Crohn's Disease Subcutaneous Adult Dosage Regimen The recommended subcutaneous dosage of YUFLYMA for adult patients with moderately to severely active Crohn's disease (CD) is 160 mg initially on Day 1 (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) begin a dosage of 40 mg every other week. Aminosalicylates and/or corticosteroids may be continued during treatment with YUFLYMA. Azathioprine, 6-mercaptopurine (6-MP) [see Warnings and Precautions ( 5.2 )] or MTX may be continued during treatment with YUFLYMA if necessary. Subcutaneous Pediatric Dosage Regimen The recommended subcutaneous dosage of YUFLYMA for pediatric patients 6 years of age and older with moderately to severely active Crohn's disease (CD), based on body weight, is shown below: Pediatric Weight Recommended Dosage Days 1 through 15 Starting on Day 29 17 kg (37 lbs) to less than 40 kg (88 lbs) Day 1: 80 mg Day 15: 40 mg 20 mg every other week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) Day 15: 80 mg 40 mg every other week 2.5 Recommended Dosage in Ulcerative Colitis Subcutaneous Adult Dosage Regimen The recommended subcutaneous dosage of YUFLYMA for adult patients with moderately to severely active ulcerative colitis is 160 mg initially on Day 1 (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) continue with a dosage of 40 mg every other week. Discontinue YUFLYMA in adult patients without evidence of clinical remission by eight weeks (Day 57) of therapy. Aminosalicylates and/or corticosteroids may be continued during treatment with YUFLYMA. Azathioprine and 6-mercaptopurine (6-MP) [see Warnings and Precautions ( 5.2 )] may be continued during treatment with YUFLYMA if necessary. 2.6 Recommended Dosage in Plaque Psoriasis or Adults with Uveitis The recommended subcutaneous dosage of YUFLYMA for adult patients with plaque psoriasis (Ps) or uveitis (UV) [see Indications and Usage ( 1.7 , 1.9 )] is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. The use of adalimumab products in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies. 2.7 Recommended Dosage in Hidradenitis Suppurativa Subcutaneous Adult Dosage Regimen The recommended subcutaneous dosage of YUFLYMA for adult patients with moderate to severe hidradenitis suppurativa (HS) is an initial dose of 160 mg (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15). Begin 40 mg weekly or 80 mg every other week dosing two weeks later (Day 29). Subcutaneous Pediatric Dosage Regimen The recommended subcutaneous dosage of YUFLYMA for pediatric patients 12 years of age and older weighing at least 30 kg with moderate to severe hidradenitis suppurativa (HS), based on body weight, is shown below [see Use in Specific Populations ( 8.4 ) and Clinical Pharmacology ( 12.3 )] : Body Weight of Pediatric Patients (12 years of age and older) Recommended Dosage 30 kg (66 lbs) to less than 60 kg (132 lbs) Day 1: 80 mg Day 8 and subsequent doses: 40 mg every other week 60 kg (132 lbs) and greater Day 1: 160 mg (given in one day or split over two consecutive days) Day 15: 80 mg Day 29 and subsequent doses: 40 mg every week or 80 mg every other week 2.8 General Considerations for Administration YUFLYMA is intended for use under the guidance and supervision of a physician. A patient may self-inject YUFLYMA or a caregiver may inject YUFLYMA using either the YUFLYMA AI or YUFLYMA prefilled syringe if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique. YUFLYMA can be taken out of the refrigerator for about 15 to 30 minutes before injecting to allow the liquid to come to room temperature. Do not remove the cap or cover while allowing it to reach room temperature. Do not shake. Carefully inspect the solution in the YUFLYMA AI or YUFLYMA prefilled syringe for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. YUFLYMA does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe. Instruct patients using the YUFLYMA AI or YUFLYMA prefilled syringe to inject the full amount in the syringe, according to the directions provided in the Instructions for Use [see Instructions for Use]. Injections should occur at separate sites in the thigh or abdomen. Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red or hard. If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.
Side Effects Overview
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions ( 5.1 )] Malignancies [see Warnings and Precautions ( 5.2 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.3 )] Hepatitis B Virus Reactivation [see Warnings and Precautions ( 5.4 )] Neurologic Reactions [see Warnings and Precautions ( 5.5 )] Hematological Reactions [see Warnings and Precautions ( 5.6 )] Heart Failure [see Warnings and Precautions ( 5.8 )] Autoimmunity [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (> 10%) are: infections (e.g. upper respiratory, sinusitis), injection site reactions, headache and rash ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact CELLTRION USA Inc., at 1-800-560-9414 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 practice. The most common adverse reaction with adalimumab was injection site reactions. In placebo-controlled trials, 20% of subjects treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of subjects receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation. The proportion of subjects who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in subjects with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for subjects taking adalimumab and 4% for placebo-treated subjects. The most common adverse reactions leading to discontinuation of adalimumab in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%). Infections In the controlled portions of the 39 global adalimumab clinical trials in adult subjects with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate of serious infections was 4.3 per 100 patient-years in 7973 adalimumab-treated subjects versus a rate of 2.9 per 100 patient-years in 4848 control-treated subjects. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions ( 5.1 )]. Tuberculosis and Opportunistic Infections In 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, HS and UV that included 24,605 adalimumab-treated subjects, the rate of reported active tuberculosis was 0.20 per 100 patient-years and the rate of positive PPD conversion was 0.09 per 100 patient-years. In a subgroup of 10,113 U.S. and Canadian adalimumab-treated subjects, the rate of reported active TB was 0.05 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.05 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see Warnings and Precautions ( 5.1 )]. Autoantibodies In the rheumatoid arthritis-controlled trials, 12% of subjects treated with adalimumab and 7% of placebo-treated subjects that had negative baseline ANA titers developed positive titers at week 24. Two subjects out of 3046 treated with adalimumab developed clinical signs suggestive of new-onset lupus-like syndrome. The subjects improved following discontinuation of therapy. No subjects developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with adalimumab products on the development of autoimmune diseases is unknown. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in subjects receiving TNF-blockers. In controlled Phase 3 trials of adalimumab (40 mg SC every other week) in subjects with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 × ULN occurred in 3.5% of adalimumab-treated subjects and 1.5% of control-treated subjects. Since many of these subjects in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between adalimumab and the liver enzyme elevations is not clear. In a controlled Phase 3 trial of adalimumab in subjects with polyarticular JIA who were 4 to 17 years, ALT elevations ≥ 3 × ULN occurred in 4.4% of adalimumab-treated subjects and 1.5% of control-treated subjects (ALT more common than AST); liver enzyme test elevations were more frequent among those treated with the combination of adalimumab and MTX than those treated with adalimumab alone. In general, these elevations did not lead to discontinuation of adalimumab treatment. No ALT elevations ≥ 3 × ULN occurred in the open-label study of adalimumab in subjects with polyarticular JIA who were 2 to < 4 years. In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in adult subjects with Crohn's disease with a control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 × ULN occurred in 0.9% of adalimumab-treated subjects and 0.9% of control-treated subjects. In the Phase 3 trial of adalimumab in pediatric subjects with Crohn's disease which evaluated efficacy and safety of two body weight based maintenance dose regimens following body weight based induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 × ULN occurred in 2.6% (5/192) of subjects, of whom 4 were receiving concomitant immunosuppressants at baseline; none of these subjects discontinued due to abnormalities in ALT tests. In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in adult subjects with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥ 3 × ULN occurred in 1.5% of adalimumab-treated subjects and 1.0% of control-treated subjects. In controlled Phase 3 trials of adalimumab (initial dose of 80 mg then 40 mg every other week) in subjects with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 × ULN occurred in 1.8% of adalimumab-treated subjects and 1.8% of control-treated subjects. In controlled trials of adalimumab (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in subjects with HS with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 × ULN occurred in 0.3% of adalimumab-treated subjects and 0.6% of control-treated subjects. In controlled trials of adalimumab (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult subjects with uveitis with an exposure of 165.4 PYs and 119.8 PYs in adalimumab-treated and control-treated subjects, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of adalimumab-treated subjects and 2.4% of control-treated subjects. Other Adverse Reactions Rheumatoid Arthritis Clinical Studies The data described below reflect exposure to adalimumab in 2468 subjects, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). Adalimumab was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most subjects received 40 mg adalimumab every other week [see Clinical Studies ( 14.1 )] . Table 1 summarizes reactions reported at a rate of at least 5% in subjects treated with adalimumab 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion. Table 1. Adverse Reactions Reported by ≥ 5% of Subjects with Adalimumab During Placebo-Controlled Period of Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV) Adalimumab 40 mg subcutaneous Every Other Week Placebo (N=705) (N=690) Adverse Reaction (Preferred Term) Respiratory Upper respiratory infection 17% 13% Sinusitis 11% 9% Flu syndrome 7% 6% Gastrointestinal Nausea 9% 8% Abdominal pain 7% 4% Laboratory Tests* Laboratory test abnormal 8% 7% Hypercholesterolemia 6% 4% Hyperlipidemia 7% 5% Hematuria 5% 4% Alkaline phosphatase increased 5% 3% Other Headache 12% 8% Rash 12% 6% Accidental injury 10% 8% Injection site reaction ** 8% 1% Back pain 6% 4% Urinary tract infection 8% 5% Hypertension 5% 3% * Laboratory test abnormalities were reported as adverse reactions in European trials ** Does not include injection site erythema, itching, hemorrhage, pain or swelling Less Common Adverse Reactions in Rheumatoid Arthritis Clinical Studies Other infrequent serious adverse reactions that do not appear in the Warnings and Precautions or Adverse Reaction sections that occurred at an incidence of less than 5% in adalimumab-treated subjects in RA studies (RA-I, RA-II, RA-III, and RA-IV) were: Body As A Whole: Pain in extremity, pelvic pain, surgery, thorax pain Cardiovascular System: Arrhythmia, atrial fibrillation, chest pain, coronary artery disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, pericarditis, syncope, tachycardia Digestive System: Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, hepatic necrosis, vomiting Endocrine System: Parathyroid disorder Hemic And Lymphatic System: Agranulocytosis, polycythemia Metabolic And Nutritional Disorders: Dehydration, healing abnormal, ketosis, paraproteinemia, peripheral edema Musculo-Skeletal System: Arthritis, bone disorder, bone fracture (not spontaneous), bone necrosis, joint disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, tendon disorder Neoplasia: Adenoma Nervous System: Confusion, paresthesia, subdural hematoma, tremor Respiratory System: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion Special Senses: Cataract Thrombosis: Thrombosis leg Urogenital System: Cystitis, kidney calculus, menstrual disorder Juvenile Idiopathic Arthritis Clinical Studies In general, the adverse reactions in the adalimumab-treated subjects in the polyarticular juvenile idiopathic arthritis (JIA) trials (Studies JIA-I and JIA-II) [see Clinical Studies ( 14.2 )] were similar in frequency and type to those seen in adult subjects [see Warnings and Precautions ( 5 ), Adverse Reactions ( 6 )] . Important findings and differences from adults are discussed in the following paragraphs. In Study JIA-I, adalimumab was studied in 171 subjects who were 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, and appendicitis. Serious infections were observed in 4% of subjects within approximately 2 years of initiation of treatment with adalimumab and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. In Study JIA-I, 45% of subjects experienced an infection while receiving adalimumab with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in adalimumab-treated subjects were generally similar to those commonly seen in polyarticular JIA subjects who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in this population treated with adalimumab were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in subjects receiving adalimumab was granuloma annulare which did not lead to discontinuation of adalimumab treatment. In the first 48 weeks of treatment in Study JIA-I, non-serious hypersensitivity reactions were seen in approximately 6% of subjects and included primarily localized allergic hypersensitivity reactions and allergic rash. In Study JIA-I, 10% of subjects treated with adalimumab who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No subject developed clinical signs of autoimmunity during the clinical trial. Approximately 15% of subjects treated with adalimumab developed mild-to-moderate elevations of creatine phosphokinase (CPK) in Study JIA-I. Elevations exceeding 5 times the upper limit of normal were observed in several subjects. CPK concentrations decreased or returned to normal in all subjects. Most subjects were able to continue adalimumab without interruption. In Study JIA-II, adalimumab was studied in 32 subjects who were 2 to < 4 years of age or 4 years of age and older weighing < 15 kg with polyarticular JIA. The safety profile for this population was similar to the safety profile seen in subjects 4 to 17 years of age with polyarticular JIA. In Study JIA-II, 78% of subjects experienced an infection while receiving adalimumab. These included nasopharyngitis, bronchitis, upper respiratory tract infection, otitis media, and were mostly mild to moderate in severity. Serious infections were observed in 9% of subjects receiving adalimumab in the study and included dental caries, rotavirus gastroenteritis, and varicella. In Study JIA-II, non-serious allergic reactions were observed in 6% of subjects and included intermittent urticaria and rash, which were all mild in severity. Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies Adalimumab has been studied in 395 subjects with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 subjects with ankylosing spondylitis (AS) in two placebo-controlled studies [see Clinical Studies ( 14.3 , 14.4 )] . The safety profile for subjects with PsA and AS treated with adalimumab 40 mg every other week was similar to the safety profile seen in subjects with RA, adalimumab Studies RA-I through IV. Crohn's Disease Clinical Studies Adults: The safety profile of adalimumab in 1478 adult subjects with Crohn's disease from four placebo-controlled and two open-label extension studies [see Clinical Studies ( 14.5 )] was similar to the safety profile seen in subjects with RA. Pediatric Patients 6 Years to 17 Years : The safety profile of adalimumab in 192 pediatric subjects from one double-blind study (Study PCD-I) and one open-label extension study [see Clinical Studies ( 14.6 )] was similar to the safety profile seen in adult subjects with Crohn's disease. During the 4-week open label induction phase of Study PCD-I, the most common adverse reactions occurring in the pediatric population treated with adalimumab were injection site pain and injection site reaction (6% and 5%, respectively). A total of 67% of children experienced an infection while receiving adalimumab in Study PCD-I. These included upper respiratory tract infection and nasopharyngitis. A total of 5% of children experienced a serious infection while receiving adalimumab in Study PCD-I. These included viral infection, device related sepsis (catheter), gastroenteritis, H1N1 influenza, and disseminated histoplasmosis. In Study PCD-I, allergic reactions were observed in 5% of children which were all non-serious and were primarily localized reactions. Ulcerative Colitis Clinical Studies Adults : The safety profile of adalimumab in 1010 adult subjects with ulcerative colitis (UC) from two placebo-controlled studies and one open-label extension study [see Clinical Studies ( 14.7 )] was similar to the safety profile seen in subjects with RA. Plaque Psoriasis Clinical Studies Adalimumab has been studied in 1696 subjects with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies [see Clinical Studies ( 14.8 )] . The safety profile for subjects with Ps treated with adalimumab was similar to the safety profile seen in subjects with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in Ps subjects, adalimumab-treated subjects had a higher incidence of arthralgia when compared to controls (3% vs. 1%). Hidradenitis Suppurativa Clinical Studies Adalimumab has been studied in 727 subjects with hidradenitis suppurativa (HS) in three placebo-controlled studies and one open-label extension study [see Clinical Studies ( 14.9 )] . The safety profile for subjects with HS treated with adalimumab weekly was consistent with the known safety profile of adalimumab. Flare of HS, defined as ≥ 25% increase from baseline in abscesses and inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects who were withdrawn from adalimumab treatment following the primary efficacy timepoint in two studies. Uveitis Clinical Studies Adalimumab has been studied in 464 adult subjects with uveitis (UV) in placebo-controlled and open-label extension studies and in 90 pediatric subjects with uveitis (Study PUV-I) [see Clinical Studies ( 14.10 , 14.11 )] . The safety profile for subjects with UV treated with adalimumab was similar to the safety profile seen in subjects with RA. 6.2 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of adalimumab or of other adalimumab products. There are two assays that have been used to measure anti-adalimumab antibodies. With the ELISA, antibodies to adalimumab could be detected only when serum adalimumab concentrations were < 2 mcg/mL. The ECL assay can detect anti-adalimumab antibody titers independent of adalimumab concentrations in the serum samples. The incidence of anti-adalimumab antibody (AAA) development in patients treated with adalimumab are presented in Table 2. Table 2: Anti-Adalimumab Antibody Development Determined by ELISA and ECL Assay in Patients Treated with Adalimumab Indications Study Duration Anti-Adalimumab Antibody Incidence by ELISA (n/N) Anti-Adalimumab Antibody Incidence by ECL Assay (n/N) In all patients who received adalimumab In patients with serum adalimumab concentrations < 2 mcg/mL Rheumatoid Arthritis a 6 to 12 months 5% (58/1062) NR NA Juvenile Idiopathic Arthritis (JIA) 4 to 17 years of age b 48 weeks 16% (27/171) NR NA 2 to 4 years of age or ≥ 4 years of age and weighing < 15 kg 24 weeks 7% (1/15) c NR NA Psoriatic Arthritis d 48 weeks e 13% (24/178) NR NA Ankylosing Spondylitis 24 weeks 9% (16/185) NR NA Adult Crohn’s Disease 56 weeks 3% (7/269) 8% (7/86) NA Pediatric Crohn’s Disease 52 weeks 3% (6/182) 10% (6/58) NA Adult Ulcerative Colitis 52 weeks 5% (19/360) 21% (19/92) NA Plaque Psoriasis f Up to 52 weeks g 8% (77/920) 21% (77/372) NA Hidradenitis Suppurativa 36 weeks 7% (30/461) 28% (58/207) h 61% (272/445) i Non-infectious Uveitis 52 weeks 5% (12/249) 21% (12/57) 40% (99/249) j n: number of patients with anti-adalimumab antibody; NR: not reported; NA: Not applicable (not performed) a In patients receiving concomitant methotrexate (MTX), the incidence of anti-adalimumab antibody was 1% compared to 12% with adalimumab monotherapy b In patients receiving concomitant MTX, the incidence of anti-adalimumab antibody was 6% compared to 26% with adalimumab monotherapy c This patient received concomitant MTX d In patients receiving concomitant MTX, the incidence of antibody development was 7% compared to 1% in RA e Subjects enrolled after completing 2 previous studies of 24 weeks or 12 weeks of treatments. f In plaque psoriasis patients who were on adalimumab monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal g One 12-week Phase 2 study and one 52-week Phase 3 study h Among subjects in the 2 Phase 3 studies who stopped adalimumab treatment for up to 24 weeks and in whom adalimumab serum levels subsequently declined to <2 mcg/mL (approximately 22% of total subjects studied) i No apparent association between antibody development and safety was observed j No correlation of antibody development to safety or efficacy outcomes was observed Rheumatoid Arthritis and Psoriatic Arthritis : Subjects in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab using the ELISA during the 6- to 12-month period. No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, subjects receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In subjects receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive subjects than among antibody-negative subjects. The long-term immunogenicity of adalimumab products is unknown. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of adalimumab products. 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 adalimumab products exposure. Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis General disorders and administration site conditions: Pyrexia Hepato-biliary disorders: Liver failure, hepatitis, autoimmune hepatitis Immune system disorders: Sarcoidosis Neoplasms benign, malignant and unspecified (including cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin) Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia, lichenoid skin reaction Vascular disorders: Systemic vasculitis, deep vein thrombosis
경고 및 주의 사항
5 WARNINGS AND PRECAUTIONS Serious infections: Do not start YUFLYMA during an active infection. If an infection develops, monitor carefully, and stop YUFLYMA if infection becomes serious ( 5.1 ) Invasive fungal infections: For patients who develop a systemic illness on YUFLYMA, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic ( 5.1 ) Malignancies: Incidence of malignancies was greater in adalimumab-treated patients than in controls ( 5.2 ) Anaphylaxis or serious hypersensitivity reactions may occur ( 5.3 ) Hepatitis B virus reactivation: Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop YUFLYMA and begin anti-viral therapy ( 5.4 ) Demyelinating disease: Exacerbation or new onset, may occur ( 5.5 ) Cytopenias, pancytopenia: Advise patients to seek immediate medical attention if symptoms develop, and consider stopping YUFLYMA ( 5.6 ) Heart failure: Worsening or new onset, may occur ( 5.8 ) Autoimmunity: Stop YUFLYMA if lupus-like syndrome or autoimmune hepatitis develop ( 5.9 ) 5.1 Serious Infections Patients treated with adalimumab products, including YUFLYMA, 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. The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of YUFLYMA and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions ( 5.7 , 5.11 ) and Drug Interactions ( 7.2 )] . Treatment with YUFLYMA should not be initiated in patients with an active infection, including localized infections. Patients 65 years of age and older, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. Consider the risks and benefits of treatment 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 traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or with underlying conditions that may predispose them to infection. Tuberculosis Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients receiving adalimumab products, including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating YUFLYMA and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating YUFLYMA, assess if treatment for latent tuberculosis is needed; and consider an induration of ≥ 5 mm a positive tuberculin skin test result, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). Consider anti-tuberculosis therapy prior to initiation of YUFLYMA 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. Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with adalimumab products. 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. Strongly consider tuberculosis in the differential diagnosis in patients who develop a new infection during YUFLYMA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. Monitoring Closely monitor patients for the development of signs and symptoms of infection during and after treatment with YUFLYMA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with YUFLYMA. Discontinue YUFLYMA if a patient develops a serious infection or sepsis. For a patient who develops a new infection during treatment with YUFLYMA, closely monitor them, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy. Invasive Fungal Infections If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider appropriate empiric antifungal therapy, taking into account both the risk for severe fungal infection and the risks of antifungal therapy, while a diagnostic workup is being performed. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections. 5.2 Malignancies Consider the risks and benefits of TNF-blocker treatment including YUFLYMA 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. Malignancies in Adults In the controlled portions of clinical trials of some TNF-blockers, including adalimumab products, more cases of malignancies have been observed among TNF-blocker-treated adult subjects compared to control-treated adult subjects. During the controlled portions of 39 global adalimumab clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD), ulcerative colitis (UC), plaque psoriasis (Ps), hidradenitis suppurativa (HS) and uveitis (UV), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.7 (0.48, 1.03) per 100 patient-years among 7973 adalimumab-treated subjects versus a rate of 0.7 (0.41, 1.17) per 100 patient-years among 4848 control-treated subjects (median duration of treatment of 4 months for adalimumab-treated subjects and 4 months for control-treated subjects). In 52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in adalimumab-treated subjects in the controlled and uncontrolled portions of the studies were similar in type and number to what would be 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 adult patients at higher risk for malignancies (i.e., subjects with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener's granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group. Non-Melanoma Skin Cancer During the controlled portions of 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate (95% confidence interval) of NMSC was 0.8 (0.52, 1.09) per 100 patient-years among adalimumab-treated subjects and 0.2 (0.10, 0.59) per 100 patient-years among control-treated subjects. Examine all patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment for the presence of NMSC prior to and during treatment with YUFLYMA. Lymphoma and Leukemia In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF-blocker-treated subjects compared to control-treated subjects. In the controlled portions of 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, 2 lymphomas occurred among 7973 adalimumab-treated subjects versus 1 among 4848 control-treated subjects. In 52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV with a median duration of approximately 0.7 years, including 24,605 subjects and over 40,215 patient-years of adalimumab, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). 1 Rates of lymphoma in clinical trials of adalimumab cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with RA and other chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. Malignancies in Pediatric Patients and Young Adults Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy ≤ 18 years of age), of which YUFLYMA is a member. 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 post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including adalimumab products. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. The potential risk with the combination of azathioprine or 6-mercaptopurine and YUFLYMA should be carefully considered. 5.3 Hypersensitivity Reactions Anaphylaxis and angioneurotic edema have been reported following administration of adalimumab products. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue administration of YUFLYMA and institute appropriate therapy. In clinical trials of adalimumab, hypersensitivity reactions (e.g., rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed. 5.4 Hepatitis B Virus Reactivation Use of TNF blockers, including YUFLYMA, may increase the risk of reactivation of hepatitis B virus (HBV) 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. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. 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 anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. For patients who are carriers of HBV and require treatment with TNF blockers, closely monitor such patients 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, stop YUFLYMA and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of YUFLYMA therapy in this situation and monitor patients closely. 5.5 Neurologic Reactions Use of TNF blocking agents, including adalimumab products, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of YUFLYMA in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of YUFLYMA should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders. 5.6 Hematological Reactions Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with adalimumab products. The causal relationship of these reports to adalimumab products remains unclear. Advise all patients 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 YUFLYMA. Consider discontinuation of YUFLYMA therapy in patients with confirmed significant hematologic abnormalities. 5.7 Increased Risk of Infection when Used with Anakinra Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of YUFLYMA and anakinra is not recommended [see Drug Interactions ( 7.2 )]. 5.8 Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with adalimumab products. Adalimumab products have not been formally studied in patients with CHF; however, in clinical trials of another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed. Exercise caution when using YUFLYMA in patients who have heart failure and monitor them carefully. 5.9 Autoimmunity Treatment with adalimumab products may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome or autoimmune hepatitis [see Adverse Reactions ( 6.1 , 6.3 )] . If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with YUFLYMA, discontinue treatment and evaluate the patient . 5.10 Immunizations In a placebo-controlled clinical trial of patients with RA, no difference was detected in anti-pneumococcal antibody response between adalimumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with adalimumab. Similar proportions of subjects developed protective levels of anti-influenza antibodies between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving adalimumab. The clinical significance of this is unknown. Patients on YUFLYMA may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving adalimumab products. It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating YUFLYMA therapy. Patients on YUFLYMA may receive concurrent vaccinations, except for live vaccines. The safety of administering live or live-attenuated vaccines in infants exposed to adalimumab products in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants [see Use in Specific Populations ( 8.1 , 8.4 )]. 5.11 Increased Risk of Infection When Used with Abatacept In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; 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 abatacept with TNF-blockers including YUFLYMA is not recommended [see Drug Interactions ( 7.2 )] .