CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Rheumatoid Arthritis. The efficacy and safety of adalimumab were assessed in five randomized, double-blind studies in patients >=18 years of age with active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least swollen and tender joints. Adalimumab was administered subcutaneously in combination with methotrexate (MTX) (12.5 to 25 mg, Studies RA-I, RA-III and RA-V) or as monotherapy (Studies RA-II and RA-V) or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study RA-IV).Study RA-I evaluated 271 patients who had failed therapy with at least one but no more than four DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks.Study RA-II evaluated 544 patients who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of adalimumab were given as monotherapy every other week or weekly for 26 weeks.Study RA-III evaluated 619 patients who had an inadequate response to MTX. Patients received placebo, 40 mg of adalimumab every other week with placebo injections on alternate weeks, or 20 mg of adalimumab weekly for up to 52 weeks. Study RA-III had an additional primary endpoint at 52 weeks of inhibition of disease progression (as detected by X-ray results). Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was administered every other week for up to years.Study RA-IV assessed safety in 636 patients who were either DMARD-naive or were permitted to remain on their pre-existing rheumatologic therapy provided that therapy was stable for minimum of 28 days. Patients were randomized to 40 mg of adalimumab or placebo every other week for 24 weeks.Study RA-V evaluated 799 patients with moderately to severely active RA of less than years duration who were >=18 years old and MTX naive. Patients were randomized to receive either MTX (optimized to 20 mg/week by week 8), adalimumab 40 mg every other week or adalimumab/MTX combination therapy for 104 weeks. Patients were evaluated for signs and symptoms, and for radiographic progression of joint damage. The median disease duration among patients enrolled in the study was months. The median MTX dose achieved was 20 mg.. Clinical ResponseThe percent of adalimumab treated patients achieving ACR 20, 50 and 70 responses in Studies RA-II and III are shown in Table 3.Table 3. ACR Responses in Studies RA-II and RA-III (Percent of Patients) p<0.01, adalimumab vs. placeboStudy RA-II Monotherapy (26 weeks)Study RA-III Methotrexate Combination (24 and 52 weeks)ResponsePlaceboAdalimumabAdalimumabPlacebo/MTXAdalimumab/MTX40 mg every40 mg weekly40 mg everyother weekother weekN=110N=113N=103N=200N=207ACR20Month 619%46%53%30%63%Month 12NANANA24%59%ACR50Month 68%22%35%10%39%Month 12NANANA10%42%ACR70Month 62%12%18%3%21%Month 12NANANA5%23%The results of Study RA-I were similar to Study RA-III; patients receiving adalimumab 40 mg every other week in Study RA-I also achieved ACR 20, 50 and 70 response rates of 65%, 52% and 24%, respectively, compared to placebo responses of 13%, 7% and 3% respectively, at months (p<0.01).The results of the components of the ACR response criteria for Studies RA-II and RA-III are shown in Table 4. ACR response rates and improvement in all components of ACR response were maintained to week 104. Over the years in Study RA-III, 20% of adalimumab patients receiving 40 mg every other week achieved major clinical response, defined as maintenance of an ACR 70 response over 6-month period. ACR responses were maintained in similar proportions of patients for up to years with continuous adalimumab treatment in the open-label portion of Study RA-III.Table 4. Components of ACR Response in Studies RA-II and RA-III40 mg adalimumab administered every other weekb Visual analogue scale; = best, 10 worstc Disability Index of the Health Assessment Questionnaire; = best, = worst, measures the patients ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity p<0.001, adalimumab vs. placebo, based on mean change from baselineStudy RA-IIStudy RA-IIIParameter (median)Placebo N=110AdalimumabaN=113Placebo/MTX N=200Adalimumaba/MTX N=207BaselineWk 26BaselineWk 26BaselineWk 24BaselineWk 24Number of tender joints (0-68)352631162615248Number of swollen joints (0-66)191618101711185Physician global assessmentb 7.06.16.63.76.33.56.52.0Patient global assessmentb 7.56.37.54.55.43.95.22.0Painb 7.36.17.34.16.03.85.82.1Disability index (HAQ)c 2.01.91.91.51.51.31.50.8CRP (mg/dL)3.94.34.61.81.00.91.00.4The time course of ACR 20 response for Study RA-III is shown in Figure 1.In Study RA-III, 85% of patients with ACR 20 responses at week 24 maintained the response at 52 weeks. The time course of ACR 20 response for Study RA-I and Study RA-II were similar. Figure 1. Study RA-III ACR 20 Responses over 52 WeeksIn Study RA-IV, 53% of patients treated with adalimumab 40 mg every other week plus standard of care had an ACR 20 response at week 24 compared to 35% on placebo plus standard of care (p<0.001). No unique adverse reactions related to the combination of adalimumab and other DMARDs were observed.In Study RA-V with MTX naive patients with recent onset RA, the combination treatment with adalimumab plus MTX led to greater percentages of patients achieving ACR responses than either MTX monotherapy or adalimumab monotherapy at Week 52 and responses were sustained at Week 104 (see Table 5).Table 5. ACR Response in Study RA-V (Percent of Patients)a Major clinical response is defined as achieving an ACR70 response for continuous six month periodb p<0.05, adalimumab/MTX vs. MTX for ACR 20p<0.001, adalimumab/MTX vs. MTX for ACR 50 and 70, and Major Clinical Responsec p<0.001, adalimumab/MTX vs. adalimumabResponseMTXbN=257AdalimumabcN=274Adalimumab/MTX N=268ACR20 Week 52 Week 10463%56%54%49%73%69%ACR50 Week 52 Week 10446%43%41%37%62%59%ACR70 Week 52 Week 10427%28%26%28%46%47%Major Clinical Response 28%25%49%At Week 52, all individual components of the ACR response criteria for Study RA-V improved in the adalimumab/MTX group and improvements were maintained to Week 104.. Figure. Radiographic ResponseIn Study RA-III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score, at month 12 compared to baseline. At baseline, the median TSS was approximately 55 in the placebo and 40 mg every other week groups. The results are shown in Table 6. Adalimumab/MTX treated patients demonstrated less radiographic progression than patients receiving MTX alone at 52 weeks.Table 6. Radiographic Mean Changes Over 12 Months in Study RA-III95% confidence intervals for the differences in change scores between MTX and adalimumab.Based on rank analysisPlacebo/MTXAdalimumab/MTX40 mg every other weekPlacebo/MTX-Adalimumab/MTX (95% ConfidenceInterval)P-valueTotal Sharp score2.70.12.6 (1.4, 3.8)<0.001Erosion score1.60.01.6 (0.9, 2.2)<0.001JSN score1.00.10.9 (0.3, 1.4)0.002In the open-label extension of Study RA-III, 77% of the original patients treated with any dose of adalimumab were evaluated radiographically at years. Patients maintained inhibition of structural damage, as measured by the TSS. Fifty-four percent had no progression of structural damage as defined by change in the TSS of zero or less. Fifty-five percent (55%) of patients originally treated with 40 mg adalimumab every other week have been evaluated radiographically at years. Patients had continued inhibition of structural damage with 50% showing no progression of structural damage defined by change in the TSS of zero or less.In Study RA-V, structural joint damage was assessed as in Study RA-III. Greater inhibition of radiographic progression, as assessed by changes in TSS, erosion score and JSN was observed in the adalimumab/MTX combination group as compared to either the MTX or adalimumab monotherapy group at Week 52 as well as at Week 104 (see Table 7).Table 7. Radiographic Mean Change in Study RA-V mean (95% confidence interval)a p<0.001, adalimumab /MTX vs. MTX at 52 and 104 weeks and for adalimumab /MTX vs adalimumab at 104 weeksb p<0.01, for adalimumab /MTX vs. adalimumab at 52 weeksMTXaN=257Adalimumaba,bN=274Adalimumab/MTX N=26852 WeeksTotal Sharp score5.7 (4.2, 7.3)3.0 (1.7, 4.3)1.3 (0.5, 2.1)Erosion score3.7 (2.7, 4.8)1.7 (1.0, 2.4)0.8 (0.4, 1.2)JSN score2.0 (1.2, 2.8)1.3 (0.5, 2.1)0.5 (0.0, 1.0)104 WeeksTotal Sharp score10.4 (7.7, 13.2)5.5 (3.6, 7.4)1.9 (0.9, 2.9)Erosion score6.4 (4.6, 8.2)3.0 (2.0, 4.0)1.0 (0.4, 1.6)JSN score4.1 (2.7, 5.4)2.6 (1.5, 3.7)0.9 (0.3, 1.5). Physical Function ResponseIn studies RA-I through IV, adalimumab showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire (HAQ-DI) from baseline to the end of study, and significantly greater improvement than placebo in the health-outcomes as assessed by The Short Form Health Survey (SF 36). Improvement was seen in both the Physical Component Summary (PCS) and the Mental Component Summary (MCS).In Study RA-III, the mean (95% CI) improvement in HAQ-DI from baseline at week 52 was 0.60 (0.55, 0.65) for the adalimumab patients and 0.25 (0.17, 0.33) for placebo/MTX (p<0.001) patients. Sixty-three percent of adalimumab-treated patients achieved 0.5 or greater improvement in HAQ-DI at week 52 in the double-blind portion of the study. Eighty-two percent of these patients maintained that improvement through week 104 and similar proportion of patients maintained this response through week 260 (5 years) of open-label treatment. Mean improvement in the SF-36 was maintained through the end of measurement at week 156 (3 years).In Study RA-V, the HAQ-DI and the physical component of the SF-36 showed greater improvement (p<0.001) for the adalimumab/MTX combination therapy group versus either the MTX monotherapy or the adalimumab monotherapy group at Week 52, which was maintained through Week 104.. 14.2 Juvenile Idiopathic Arthritis. The safety and efficacy of adalimumab was assessed in two studies (Studies JIA-I and JIA-II) in patients with active polyarticular juvenile idiopathic arthritis (JIA).. Study JIA-IThe safety and efficacy of adalimumab were assessed in multicenter, randomized, withdrawal, double-blind, parallel-group study in 171 patients who were to 17 years of age with polyarticular JIA. In the study, the patients were stratified into two groups: MTX-treated or non-MTX-treated. All patients had to show signs of active moderate or severe disease despite previous treatment with NSAIDs, analgesics, corticosteroids, or DMARDS. Patients who received prior treatment with any biologic DMARDS were excluded from the study.The study included four phases: an open-label lead in phase (OL-LI; 16 weeks), double-blind randomized withdrawal phase (DB; 32 weeks), an open-label extension phase (OLE-BSA; up to 136 weeks), and an open-label fixed dose phase (OLE-FD; 16 weeks). In the first three phases of the study, adalimumab was administered based on body surface area at dose of 24 mg/m2 up to maximum total body dose of 40 mg subcutaneously (SC) every other week. In the OLE-FD phase, the patients were treated with 20 mg of adalimumab SC every other week if their weight was less than 30 kg and with 40 mg of adalimumab SC every other week if their weight was 30 kg or greater. Patients remained on stable doses of NSAIDs and or prednisone (<=0.2 mg/kg/day or 10 mg/day maximum).Patients demonstrating Pediatric ACR 30 response at the end of OL-LI phase were randomized into the double blind (DB) phase of the study and received either adalimumab or placebo every other week for 32 weeks or until disease flare. Disease flare was defined as worsening of >=30% from baseline in >=3 of Pediatric ACR core criteria, >=2 active joints, and improvement of >30% in no more than of the criteria. After 32 weeks or at the time of disease flare during the DB phase, patients were treated in the open-label extension phase based on the BSA regimen (OLE- BSA), before converting to fixed dose regimen based on body weight (OLE-FD phase).. Study JIA-I Clinical ResponseAt the end of the 16-week OL-LI phase, 94% of the patients in the MTX stratum and 74% of the patients in the non-MTX stratum were Pediatric ACR 30 responders. In the DB phase significantly fewer patients who received adalimumab experienced disease flare compared to placebo, both without MTX (43% vs. 71%) and with MTX (37% vs. 65%). More patients treated with adalimumab continued to show pediatric ACR 30/50/70 responses at Week 48 compared to patients treated with placebo. Pediatric ACR responses were maintained for up to two years in the OLE phase in patients who received adalimumab throughout the study.. Study JIA-IIAdalimumab was assessed in an open-label, multicenter study in 32 patients who were to <4 years of age or years of age and older weighing <15 kg with moderately to severely active polyarticular JIA. Most patients (97%) received at least 24 weeks of adalimumab treatment dosed 24 mg/m2 up to maximum of 20 mg every other week as single SC injection up to maximum of 120 weeks duration. During the study, most patients used concomitant MTX, with fewer reporting use of corticosteroids or NSAIDs. The primary objective of the study was evaluation of safety [see Adverse Reactions (6.1)].. 14.3 Psoriatic Arthritis. The safety and efficacy of adalimumab was assessed in two randomized, double-blind, placebo controlled studies in 413 patients with psoriatic arthritis (PsA). Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg adalimumab was administered every other week.Study PsA-I enrolled 313 adult patients with moderately to severely active PsA (>3 swollen and>3 tender joints) who had an inadequate response to NSAID therapy in one of the following forms: (1) distal interphalangeal (DIP) involvement (N=23); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of plaque psoriasis) (N=210); (3) arthritis mutilans (N=1); (4) asymmetric PsA (N=77); or (5) AS-like (N=2). Patients on MTX therapy (158 of 313 patients) at enrollment (stable dose of <=30 mg/week for >1 month) could continue MTX at the same dose. Doses of adalimumab 40 mg or placebo every other week were administered during the 24-week double-blind period of the study.Compared to placebo, treatment with adalimumab resulted in improvements in the measures of disease activity (see Tables and 9). Among patients with PsA who received adalimumab, the clinical responses were apparent in some patients at the time of the first visit (two weeks) and were maintained up to 88 weeks in the ongoing open-label study. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline.Patients with psoriatic involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses. At 24 weeks, the proportions of patients achieving 75% or 90% improvement in the PASI were 59% and 42% respectively, in the adalimumab group (N=69), compared to 1% and 0% respectively, in the placebo group (N=69) (p<0.001). PASI responses were apparent in some patients at the time of the first visit (two weeks). Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline.Table 8. ACR Response in Study PsA-I (Percent of Patients) p<0.001 for all comparisons between adalimumab and placeboPlacebo N=162Adalimumab N=151ACR20 Week 12 Week 2414%15%58%57%ACR50 Week 12 Week 244%6%36%39%ACR70 Week 12 Week 241%1%20%23%Table 9. Components of Disease Activity in Study PsA-I p<0.001 for adalimumab vs. placebo comparisons based on median changesa Scale 0-78b Scale 0-76c Visual analog scale; 0=best, 100=worstd Disability Index of the Health Assessment Questionnaire; 0=best, 3=worst; measures the patients ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.e Normal range: 0-0.287 mg/dLPlacebo N=162Adalimumab N=151Parameter: medianBaseline24 weeksBaseline24 weeksNumber of tender jointsa 23.017.020.05.0Number of swollen jointsb 11.09.011.03.0Physician global assessmentc 53.049.055.016.0Patient global assessmentc 49.549.048.020.0Painc 49.049.054.020.0Disability index (HAQ) 1.00.91.00.4CRP (mg/dL)e 0.80.70.80.2Similar results were seen in an additional, 12-week study in 100 patients with moderate to severe psoriatic arthritis who had suboptimal response to DMARD therapy as manifested by >=3 tender joints and >=3 swollen joints at enrollment.. Radiographic ResponseRadiographic changes were assessed in the PsA studies. Radiographs of hands, wrists, and feet were obtained at baseline and Week 24 during the double-blind period when patients were on adalimumab or placebo and at Week 48 when all patients were on open-label adalimumab. modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e., not identical to the TSS used for rheumatoid arthritis), was used by readers blinded to treatment group to assess the radiographs.Adalimumab-treated patients demonstrated greater inhibition of radiographic progression compared to placebo-treated patients and this effect was maintained at 48 weeks (see Table 10).Table 10. Change in Modified Total Sharp Score in Psoriatic Arthritis <0.001 for the difference between adalimumab, Week 48 and Placebo, Week 24 (primary analysis)Placebo N=141Adalimumab N=133Week 24Week 24Week 48Baseline mean22.123.423.4Mean Change +- SD0.9 +- 3.1-0.1 +- 1.7-0.2 +- 4.9 Physical Function ResponseIn Study PsA-I, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 40 mg of adalimumab every other week showed greater improvement from baseline in the HAQ-DI score (mean decreases of 47% and 49% at Weeks 12 and 24 respectively) in comparison to placebo (mean decreases of 1% and 3% at Weeks 12 and 24 respectively). At Weeks 12 and 24, patients treated with adalimumab showed greater improvement from baseline in the SF-36 Physical Component Summary score compared to patients treated with placebo, and no worsening in the SF-36 Mental Component Summary score. Improvement in physical function based on the HAQ-DI was maintained for up to 84 weeks through the open-label portion of the study.. 14.4 Ankylosing Spondylitis. The safety and efficacy of adalimumab 40 mg every other week was assessed in 315 adult patients in randomized, 24 week double-blind, placebo-controlled study in patients with active ankylosing spondylitis (AS) who had an inadequate response to glucocorticoids, NSAIDs, analgesics, methotrexate or sulfasalazine. Active AS was defined as patients who fulfilled at least two of the following three criteria: (1) Bath AS disease activity index (BASDAI) score >=4 cm, (2) visual analog score (VAS) for total back pain >= 40 mm, and (3) morning stiffness >= hour. The blinded period was followed by an open-label period during which patients received adalimumab 40 mg every other week subcutaneously for up to an additional 28 weeks.Improvement in measures of disease activity was first observed at Week and maintained through 24 weeks as shown in Figure and Table 11.Responses of patients with total spinal ankylosis (n=11) were similar to those without total ankylosis. Figure 2. ASAS 20 Response By Visit, Study AS-IAt 12 weeks, the ASAS 20/50/70 responses were achieved by 58%, 38%, and 23%, respectively, of patients receiving adalimumab, compared to 21%, 10%, and 5% respectively, of patients receiving placebo (p <0.001). Similar responses were seen at Week 24 and were sustained in patients receiving open-label adalimumab for up to 52 weeks.A greater proportion of patients treated with adalimumab (22%) achieved low level of disease activity at 24 weeks (defined as value <20 [on scale of to 100 mm] in each of the four ASAS response parameters) compared to patients treated with placebo (6%).Table 11. Components of Ankylosing Spondylitis Disease Activitya Percent of subjects with at least 20% and 10-unit improvement measured on Visual Analog Scale (VAS) with = none and 100 severeb mean of questions and of BASDAI (defined in d)c Bath Ankylosing Spondylitis Functional Indexd Bath Ankylosing Spondylitis Disease Activity Indexe Bath Ankylosing Spondylitis Metrology Indexf C-Reactive Protein (mg/dL) statistically significant for comparisons between adalimumab and placebo at Week 24Placebo N=107Adalimumab N=208Baseline meanWeek 24 meanBaseline meanWeek 24 meanASAS 20 Response Criteria Patients Global Assessment of Disease Activitya 65606338 Total back pain67586537 Inflammationb 6.75.66.73.6BASFIc 56515234BASDAId score6.35.56.33.7BASMIe score4.24.13.83.3 Tragus to wall (cm)15.915.815.815.4 Lumbar flexion (cm)4.14.04.24.4 Cervical rotation (degrees)42.242.148.451.6 Lumbar side flexion (cm)8.99.09.711.7 Intermalleolar distance (cm)92.994.093.5100.8CRPf 2.22.01.80.6A second randomized, multicenter, double-blind, placebo-controlled study of 82 patients with ankylosing spondylitis showed similar results.Patients treated with adalimumab achieved improvement from baseline in the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score (-3.6 vs. -1.1) and in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) score (7.4 vs. 1.9) compared to placebo-treated patients at Week 24.. Figure. 14.5 Adult Crohns Disease. The safety and efficacy of multiple doses of adalimumab were assessed in adult patients with moderately to severely active Crohns disease, CD, (Crohns Disease Activity Index (CDAI) >= 220 and <= 450) in randomized, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted, and 79% of patients continued to receive at least one of these medications.Induction of clinical remission (defined as CDAI 150) was evaluated in two studies. In Study CD-I, 299 TNF-blocker naive patients were randomized to one of four treatment groups: the placebo group received placebo at Weeks and 2, the 160/80 group received 160 mg adalimumab at Week and 80 mg at Week 2, the 80/40 group received 80 mg at Week and 40 mg at Week 2, and the 40/20 group received 40 mg at Week and 20 mg at Week 2. Clinical results were assessed at Week 4.In the second induction study, Study CD-II, 325 patients who had lost response to, or were intolerant to, previous infliximab therapy were randomized to receive either 160 mg adalimumab at Week and 80 mg at Week 2, or placebo at Weeks and 2. Clinical results were assessed at Week 4.Maintenance of clinical remission was evaluated in Study CD-III. In this study, 854 patients with active disease received open-label adalimumab, 80 mg at week and 40 mg at Week 2. Patients were then randomized at Week to 40 mg adalimumab every other week, 40 mg adalimumab every week, or placebo. The total study duration was 56 weeks. Patients in clinical response (decrease in CDAI >=70) at Week were stratified and analyzed separately from those not in clinical response at Week 4.. Induction of Clinical RemissionA greater percentage of the patients treated with 160/80 mg adalimumab achieved induction of clinical remission versus placebo at Week regardless of whether the patients were TNF blocker naive (CD-I), or had lost response to or were intolerant to infliximab (CD-II) (see Table 12).Table 12. Induction of Clinical Remission in Studies CD-I and CD-II (Percent of Patients)Clinical remission is CDAI score 150; clinical response is decrease in CDAI of at least 70 points. p<0.001 for adalimumab vs. placebo pairwise comparison of proportions p<0.01 for adalimumab vs. placebo pairwise comparison of proportionsCD-ICD-IIPlacebo N=74Adalimumab 160/80 mg N=76Placebo N=166Adalimumab 160/80 mg N=159Week 4Clinical remission12%36% 7%21% Clinical response34%58% 34%52% Maintenance of Clinical RemissionIn Study CD-III at Week 4, 58% (499/854) of patients were in clinical response and were assessed in the primary analysis. At Weeks 26 and 56, greater proportions of patients who were in clinical response at Week achieved clinical remission in the adalimumab 40 mg every other week maintenance group compared to patients in the placebo maintenance group (see Table 13). The group that received adalimumab therapy every week did not demonstrate significantly higher remission rates compared to the group that received adalimumab every other week.Table 13. Maintenance of Clinical Remission in CD-III (Percent of Patients)Clinical remission is CDAI score 150; clinical response is decrease in CDAI of at least 70 points.p<0.001 for adalimumab vs. placebo pairwise comparisons of proportionsPlacebo40 mg Adalimumabevery other weekN=170N=172Week 26Clinical remission17%40%Clinical response28%54%Week 56Clinical remission12%36%Clinical response18%43%Of those in response at Week who attained remission during the study, patients in the adalimumab every other week group maintained remission for longer time than patients in the placebo maintenance group. Among patients who were not in response by Week 12, therapy continued beyond 12 weeks did not result in significantly more responses.. 14.6 Pediatric Crohns Disease. randomized, double-blind, 52-week clinical study of dose concentrations of adalimumab (Study PCD-I) was conducted in 192 pediatric patients (6 to 17 years of age) with moderately to severely active Crohns disease (defined as Pediatric Crohns Disease Activity Index (PCDAI) score 30). Enrolled patients had over the previous two year period an inadequate response to corticosteroids or an immunomodulator (i.e., azathioprine, 6-mercaptopurine, or methotrexate). Patients who had previously received TNF blocker were allowed to enroll if they had previously had loss of response or intolerance to that TNF blocker.Patients received open-label induction therapy at dose based on their body weight (>=40 kg and <40 kg). Patients weighing >=40 kg received 160 mg (at Week 0) and 80 mg (at Week 2). Patients weighing <40 kg received 80 mg (at Week 0) and 40 mg (at Week 2). At Week 4, patients within each body weight category (>=40 kg and <40 kg) were randomized 1:1 to one of two maintenance dose regimens (high dose and low dose). The high dose was 40 mg every other week for patients weighing >=40 kg and 20 mg every other week for patients weighing <40 kg. The low dose was 20 mg every other week for patients weighing >=40 kg and 10 mg every other week for patients weighing <40 kg.Concomitant stable dosages of corticosteroids (prednisone dosage <=40 mg/day or equivalent) and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted throughout the study.At Week 12, patients who experienced disease flare (increase in PCDAI of >= 15 from Week and absolute PCDAI 30) or who were non-responders (did not achieve decrease in the PCDAI of >= 15 from baseline for consecutive visits at least weeks apart) were allowed to dose-escalate (i.e., switch from blinded every other week dosing to blinded every week dosing); patients who dose-escalated were considered treatment failures.At baseline, 38% of patients were receiving corticosteroids, and 62% of patients were receiving an immunomodulator. Forty-four percent (44%) of patients had previously lost response or were intolerant to TNF blocker. The median baseline PCDAI score was 40.Of the 192 patients total, 188 patients completed the week induction period, 152 patients completed 26 weeks of treatment, and 124 patients completed 52 weeks of treatment. Fifty-one percent (51%) (48/95) of patients in the low maintenance dose group dose-escalated, and 38% (35/93) of patients in the high maintenance dose group dose-escalated.At Week 4, 28% (52/188) of patients were in clinical remission (defined as PCDAI <= 10).The proportions of patients in clinical remission (defined as PCDAI <= 10) and clinical response (defined as reduction in PCDAI of at least 15 points from baseline) were assessed at Weeks 26 and 52.At both Weeks 26 and 52, the proportion of patients in clinical remission and clinical response was numerically higher in the high dose group compared to the low dose group (Table 14). The recommended maintenance regimen is 20 mg every other week for patients weighing 40 kg and 40 mg every other week for patients weighing >= 40 kg. Every week dosing is not the recommended maintenance dosing regimen [see Dosage and Administration (2.3)].Table 14. Clinical Remission and Clinical Response in Study PCD-I+The low maintenance dose was 20 mg every other week for patients weighing >= 40 kg and 10mg every other week for patients weighing 40 kg.The high maintenance dose was 40 mg every other week for patients weighing >= 40 kg and 20mg every other week for patients weighing 40 kg.Clinical remission defined as PCDAI <= 10.Clinical response defined as reduction in PCDAI of at least 15 points from baseline.Low Maintenance Dose+(20 or 10 mg every other week)N 95High Maintenance Dose(40 or 20 mg every other week)N 93Week 26Clinical Remission 28%39%Clinical Response 48%59%Week 52Clinical Remission 23%33%Clinical Response 28%42%. 14.7 Adult Ulcerative Colitis. The safety and efficacy of adalimumab were assessed in adult patients with moderately to severely active ulcerative colitis (Mayo score to 12 on 12 point scale, with an endoscopy subscore of to on scale of to 3) despite concurrent or prior treatment with immunosuppressants such as corticosteroids, azathioprine, or 6-MP in two randomized, double-blind, placebo-controlled clinical studies (Studies UC-I and UC-II). Both studies enrolled TNF-blocker naive patients, but Study UC-II also allowed entry of patients who lost response to or were intolerant to TNF- blockers. Forty percent (40%) of patients enrolled in Study UC-II had previously used another TNF-blocker.Concomitant stable doses of aminosalicylates and immunosuppressants were permitted. In Studies UC-I and II, patients were receiving aminosalicylates (69%), corticosteroids (59%) and/or azathioprine or 6-MP (37%) at baseline. In both studies, 92% of patients received at least one of these medications.Induction of clinical remission (defined as Mayo score <= with no individual subscores 1) at Week was evaluated in both studies. Clinical remission at Week 52 and sustained clinical remission (defined as clinical remission at both Weeks and 52) were evaluated in Study UC-II.In Study UC-I, 390 TNF-blocker naive patients were randomized to one of three treatment groups for the primary efficacy analysis. The placebo group received placebo at Weeks 0, 2, and 6. The 160/80 group received 160 mg adalimumab at Week and 80 mg at Week 2, and the 80/40 group received 80 mg adalimumab at Week and 40 mg at Week 2. After Week 2, patients in both adalimumab treatment groups received 40 mg every other week.In Study UC-II, 518 patients were randomized to receive either adalimumab 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week starting at Week through Week 50, or placebo starting at Week and every other week through Week 50. Corticosteroid taper was permitted starting at Week 8.In both Studies UC-I and UC-II, greater percentage of the patients treated with 160/80 mg of adalimumab compared to patients treated with placebo achieved induction of clinical remission. In Study UC-II, greater percentage of the patients treated with 160/80 mg of adalimumab compared to patients treated with placebo achieved sustained clinical remission (clinical remission at both Weeks and 52) (Table 15).Table 15. Induction of Clinical Remission in Studies UC-I and UC-II and Sustained Clinical Remission in Study UC-II (Percent of Patients)Clinical remission is defined as Mayo score <= with no individual subscores 1.CI=Confidence interval p<0.05 for adalimumab vs. placebo pairwise comparison of proportionsStudy UC-IStudy UC-IIPlacebo N=130Adalimumab 160/80mg N=130Treatment Difference (95% CI)Placebo N=246Adalimumab 160/80mg N=248Treatment Difference (95% CI)Induction of Clinical9.2%18.5%9.3%9.3%16.5%7.2%Remission (Clinical(0.9%,(1.2%,Remission at Week 8)17.6%)12.9%)Sustained Clinical Remission (Clinical Remission at both Weeks and 52)N/AN/AN/A4.1%8.5%4.4% (0.1%, 8.6%)In Study UC-I, there was no statistically significant difference in clinical remission observed between the adalimumab 80/40 mg group and the placebo group at Week 8.In Study UC-II, 17.3% (43/248) in the adalimumab group were in clinical remission at Week 52 compared to 8.5% (21/246) in the placebo group (treatment difference: 8.8%; 95% confidence interval (CI): [2.8%, 14.5%]; p<0.05).In the subgroup of patients in Study UC-II with prior TNF-blocker use, the treatment difference for induction of clinical remission appeared to be lower than that seen in the whole study population, and the treatment differences for sustained clinical remission and clinical remission at Week 52 appeared to be similar to those seen in the whole study population. The subgroup of patients with prior TNF-blocker use achieved induction of clinical remission at 9% (9/98) in the adalimumab group versus 7% (7/101) in the placebo group, and sustained clinical remission at 5% (5/98) in the adalimumab group versus 1% (1/101) in the placebo group. In the subgroup of patients with prior TNF-blocker use, 10% (10/98) were in clinical remission at Week 52 in the adalimumab group versus 3% (3/101) in the placebo group.. 14.8 Plaque Psoriasis. The safety and efficacy of adalimumab were assessed in randomized, double-blind, placebo- controlled studies in 1696 adult subjects with moderate to severe chronic plaque psoriasis (Ps) who were candidates for systemic therapy or phototherapy.Study Ps-I evaluated 1212 subjects with chronic Ps with >=10% body surface area (BSA) involvement, Physicians Global Assessment (PGA) of at least moderate disease severity, and Psoriasis Area and Severity Index (PASI) >=12 within three treatment periods. In period A, subjects received placebo or adalimumab at an initial dose of 80 mg at Week followed by dose of 40 mg every other week starting at Week 1. After 16 weeks of therapy, subjects who achieved at least PASI 75 response at Week 16, defined as PASI score improvement of at least 75% relative to baseline, entered period and received open-label 40 mg adalimumab every other week.After 17 weeks of open label therapy, subjects who maintained at least PASI 75 response at Week 33 and were originally randomized to active therapy in period were re-randomized in period to receive 40 mg adalimumab every other week or placebo for an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 19 and the baseline Physicians Global Assessment score ranged from moderate (53%) to severe (41%) to very severe (6%).Study Ps-II evaluated 99 subjects randomized to adalimumab and 48 subjects randomized to placebo with chronic plaque psoriasis with >=10% BSA involvement and PASI >=12. Subjects received placebo, or an initial dose of 80 mg adalimumab at Week followed by 40 mg every other week starting at Week for 16 weeks. Across all treatment groups the mean baseline PASI score was 21 and the baseline PGA score ranged from moderate (41%) to severe (51%) to very severe (8%).Studies Ps-I and II evaluated the proportion of subjects who achieved clear or minimal disease on the 6-point PGA scale and the proportion of subjects who achieved reduction in PASI score of at least 75% (PASI 75) from baseline at Week 16 (see Table 17 and 18).Additionally, Study Ps-I evaluated the proportion of subjects who maintained PGA of clear or minimal disease or PASI 75 response after Week 33 and on or before Week 52.Table 17. Efficacy Results at 16 Weeks in Study Ps-I Number of Subjects (%) Clear no plaque elevation, no scale, plus or minus hyperpigmentation or diffuse pink or red colorationMinimal possible but difficult to ascertain whether there is slight elevation of plaque above normal skin, plus or minus surface dryness with some white coloration, plus or minus up to red colorationAdalimumab 40 mg every other weekPlaceboN 814N 398PGA: Clear or minimal506 (62%)17 (4%)PASI 75578 (71%)26 (7%)Table 18. Efficacy Results at 16 Weeks in Study Ps-II Number of Subjects (%) Clear no plaque elevation, no scale, plus or minus hyperpigmentation or diffuse pink or red colorationMinimal possible but difficult to ascertain whether there is slight elevation of plaque above normal skin, plus or minus surface dryness with some white coloration, plus or minus up to red colorationAdalimumab 40 mg every other weekPlaceboN 99N 48PGA: Clear or minimal70 (71%)5 (10%)PASI 7577 (78%)9 (19%)Additionally, in Study Ps-I, subjects on adalimumab who maintained PASI 75 were re- randomized to adalimumab (N 250) or placebo (N 240) at Week 33. After 52 weeks of treatment with adalimumab, more subjects on adalimumab maintained efficacy when compared to subjects who were re-randomized to placebo based on maintenance of PGA of clear or minimal disease (68% vs. 28%) or PASI 75 (79% vs. 43%).A total of 347 stable responders participated in withdrawal and retreatment evaluation in an open-label extension study. Median time to relapse (decline to PGA moderate or worse) was approximately months. During the withdrawal period, no subject experienced transformation to either pustular or erythrodermic psoriasis. total of 178 subjects who relapsed re-initiated treatment with 80 mg of adalimumab, then 40 mg every other week beginning at week 1. At week 16, 69% (123/178) of subjects had response of PGA clear or minimal.A randomized, double-blind study (Study Ps-III) compared the efficacy and safety of adalimumab versus placebo in 217 adult subjects. Subjects in the study had to have chronic plaque psoriasis of at least moderate severity on the PGA scale, fingernail involvement of at least moderate severity on 5-point Physicians Global Assessment of Fingernail Psoriasis (PGA-F) scale, Modified Nail Psoriasis Severity Index (mNAPSI) score for the target-fingernail of >= 8, and either BSA involvement of at least 10% or BSA involvement of at least 5% with total mNAPSI score for all fingernails of >= 20. Subjects received an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeks followed by open-label adalimumab treatment for an additional 26 weeks. This study evaluated the proportion of subjects who achieved clear or minimal assessment with at least 2-grade improvement on the PGA-F scale and the proportion of subjects who achieved at least 75% improvement from baseline in the mNAPSI score (mNAPSI 75) at Week 26.At Week 26, higher proportion of subjects in the adalimumab group than in the placebo group achieved the PGA-F endpoint. Furthermore, higher proportion of subjects in the adalimumab group than in the placebo group achieved mNAPSI 75 at Week 26 (see Table 19).Table 19. Efficacy Results at 26 WeeksSubjects received 80 mg of adalimumab at Week 0, followed by 40 mg every other week starting at Week 1.EndpointAdalimumab 40 mgevery other week N=109Placebo N=108PGA-F: >=2-grade improvement and clear or minimal 49%7%mNAPSI 7547%3%Nail pain was also evaluated and improvement in nail pain was observed in Study Ps-III.

ADVERSE REACTIONS SECTION.

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 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)] Serious Infections [see Warnings and Precautions (5.1)] Malignancies [see Warnings and Precautions (5.2)] Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Hepatitis 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 Fresenius Kabi USA, LLC at 1-800-551-7176 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 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 patients treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in patients with RA (i.e., Studies RA-I, RA- II, RA-III and RA-IV) was 7% for patients taking adalimumab and 4% for placebo-treated patients. 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%).. InfectionsIn the controlled portions of the 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, and other indications the rate of serious infections was 4.3 per 100 patient-years in 7973 adalimumab-treated patients versus rate of 2.9 per 100 patient-years in 4848 control-treated patients. 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 InfectionsIn 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, and other indications that included 24,605 adalimumab-treated patients, 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 subgroup of 10,113 U.S. and Canadian adalimumab-treated patients, 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)].. AutoantibodiesIn the rheumatoid arthritis controlled trials, 12% of patients treated with adalimumab and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with adalimumab developed clinical signs suggestive of new- onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients 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 ElevationsThere have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase trials of adalimumab (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from to 104 weeks, ALT elevations >= x ULN occurred in 3.5% of adalimumab-treated patients and 1.5% of control- treated patients. Since many of these patients 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 controlled Phase trial of adalimumab in patients with polyarticular JIA who were to 17 years, ALT elevations >= x ULN occurred in 4.4% of adalimumab-treated patients and 1.5% of control-treated patients (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 >= x ULN occurred in the open-label study of adalimumab in patients with polyarticular JIA who were to <4 years.In controlled Phase trials of adalimumab (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days and 15, respectively, followed by 40 mg every other week) in adult patients with Crohns Disease with control period duration ranging from to 52 weeks, ALT elevations >= x ULN occurred in 0.9% of adalimumab-treated patients and 0.9% of control-treated patients. In the Phase trial of adalimumab in pediatric patients with Crohns 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 >= x ULN occurred in 2.6% (5/192) of patients, of whom were receiving concomitant immunosuppressants at baseline; none of these patients discontinued due to abnormalities in ALT tests. In controlled Phase trials of adalimumab (initial doses of 160 mg and 80 mg on Days and 15 respectively, followed by 40 mg every other week) in adult patients with UC with control period duration ranging from to 52 weeks, ALT elevations >=3 ULN occurred in 1.5% of adalimumab-treated patients and 1.0% of control-treated patients. In controlled Phase trials of adalimumab (initial dose of 80 mg then 40 mg every other week) in patients with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations >= x ULN occurred in 1.8% of adalimumab-treated patients and 1.8% of control-treated patients.. Other Adverse Reactions. Rheumatoid Arthritis Clinical StudiesThe data described below reflect exposure to adalimumab in 2468 patients, including 2073 exposed for 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 mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg adalimumab every other week [see Clinical Studies (14.1)]. Table summarizes reactions reported at rate of at least 5% in patients 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 Patients Treated with Adalimumab during Placebo-Controlled Period of Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV) Laboratory test abnormalities were reported as adverse reactions in European trials Does not include injection site erythema, itching, hemorrhage, pain or swellingAdalimumab40 mg subcutaneous Every Other WeekPlacebo(N=705)(N=690)Adverse Reaction (Preferred Term)Respiratory Upper respiratory infection17%13% Sinusitis11%9% Flu syndrome7%6%Gastrointestinal Nausea9%8% Abdominal pain7%4%Laboratory Tests Laboratory test abnormal8%7% Hypercholesterolemia6%4% Hyperlipidemia7%5% Hematuria5%4% Alkaline phosphatase increased5%3%Other Headache12%8% Rash12%6% Accidental injury10%8% Injection site reaction 8%1% Back pain6%4% Urinary tract infection8%5% Hypertension5%3%. Less Common Adverse Reactions in Rheumatoid Arthritis Clinical StudiesOther 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 patients in RA studies were:Body As Whole: Pain in extremity, pelvic pain, surgery, thorax painCardiovascular System: Arrhythmia, atrial fibrillation, chest pain, coronary artery disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, pericarditis, syncope, tachycardiaDigestive System: Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, hepatic necrosis, vomitingEndocrine System: Parathyroid disorderHemic And Lymphatic System: Agranulocytosis, polycythemiaMetabolic And Nutritional Disorders: Dehydration, healing abnormal, ketosis, paraproteinemia, peripheral edemaMusculo-Skeletal System: Arthritis, bone disorder, bone fracture (not spontaneous), bone necrosis, joint disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, tendon disorderNeoplasia: AdenomaNervous System: Confusion, paresthesia, subdural hematoma, tremorRespiratory System: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusionSpecial Senses: CataractThrombosis: Thrombosis legUrogenital System: Cystitis, kidney calculus, menstrual disorder. Juvenile Idiopathic Arthritis Clinical StudiesIn general, the adverse reactions in the adalimumab-treated patients 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 patients [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 patients who were 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 patients within approximately 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 patients 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 patients were generally similar to those commonly seen in polyarticular JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in this patient population treated with adalimumab were injection site pain and injection site reaction (19% and 16%, respectively). less commonly reported adverse event in patients 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 patients and included primarily localized allergic hypersensitivity reactions and allergic rash.In Study JIA-I, 10% of patients treated with adalimumab who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial.Approximately 15% of patients treated with adalimumab developed mild-to-moderate elevations of creatine phosphokinase (CPK) in Study JIA-I. Elevations exceeding times the upper limit of normal were observed in several patients. CPK concentrations decreased or returned to normal in all patients. Most patients were able to continue adalimumab without interruption.In Study JIA-II, adalimumab was studied in 32 patients who were to <4 years of age or years of age and older weighing <15 kg with polyarticular JIA. The safety profile for this patient population was similar to the safety profile seen in patients to 17 years of age with polyarticular JIA.In Study JIA-II, 78% of patients 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 patients 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 patients and included intermittent urticaria and rash, which were all mild in severity.. Psoriatic Arthritis and Ankylosing Spondylitis Clinical StudiesAdalimumab has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo- controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies [see Clinical Studies (14.3, 14.4)]. The safety profile for patients with PsA and AS treated with adalimumab 40 mg every other week was similar to the safety profile seen in patients with RA, adalimumab Studies RA-I through IV.. Crohns Disease Clinical StudiesAdults: The safety profile of adalimumab in 1478 adult patients with Crohns disease from four placebo-controlled and two open-label extension studies [see Clinical Studies (14.5)] was similar to the safety profile seen in patients with RA.Pediatric Patients Years to 17 Years: The safety profile of adalimumab in 192 pediatric patients 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 patients with Crohns 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 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 StudiesAdults: The safety profile of adalimumab in 1010 adult patients 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 patients with RA.. Plaque Psoriasis Clinical StudiesAdalimumab 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 higher incidence of arthralgia when compared to controls (3% vs. 1%).. 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other adalimumab products may be misleading.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 adalimumabn: 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 monotherapyb In patients receiving concomitant MTX, the incidence of anti-adalimumab antibody was 6% compared to 26% with adalimumab monotherapyc This patient received concomitant MTXd In patients receiving concomitant MTX, the incidence of antibody development was 7% compared to 1% in RAe Subjects enrolled after completing 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 withdrawalg One 12-week Phase study and one 52-week Phase studyIndicationsStudy DurationAnti-Adalimumab Antibody Incidence by ELISA (n/N)Anti-Adalimumab Antibody Incidence by ECL Assay (n/N)In all patients who received adalimumabIn patients with serum adalimumab concentrations< mcg/mLRheumatoid Arthritisa to 12 months5% (58/1062)NRNAJuvenile Idiopathic Arthritis (JIA)4 to 17 years of ageb 48 weeks16% (27/171)NRNA2 to years of age or >= years of age and weighing 15 kg24 weeks7% (1/15)c NRNAPsoriatic Arthritisd 48 weekse 13% (24/178)NRNAAnkylosing Spondylitis24 weeks9% (16/185)NRNAAdult Crohns Disease56 weeks3% (7/269)8% (7/86)NAPediatric Crohns Disease52 weeks3% (6/182)10% (6/58)NAAdult Ulcerative Colitis52 weeks5% (19/360)21% (19/92)NAPlaque Psoriasisf Up to 52 weeksg 8% (77/920)21% (77/372)NARheumatoid Arthritis and Psoriatic Arthritis: Patients 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, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to adalimumab products exposure.Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitisGeneral disorders and administration site conditions: PyrexiaHepato-biliary disorders: Liver failure, hepatitisImmune system disorders: SarcoidosisNeoplasms 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-Barre syndrome), cerebrovascular accidentRespiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolismSkin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia, lichenoid skin reactionVascular disorders: Systemic vasculitis, deep vein thrombosis.

BOXED WARNING SECTION.

WARNING: SERIOUS INFECTIONS AND MALIGNANCY. SERIOUS INFECTIONSPatients treated with adalimumab products including IDACIO are at increased risk for developing serious infections that may lead to hospitalization or death[see Warnings and Precautions (5.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.Discontinue IDACIO if patient develops serious infection or sepsis. Reported infections include:Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before IDACIO use and during therapy. Initiate treatment for latent TB prior to IDACIO use.Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti- fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria.Carefully consider the risks and benefits of treatment with IDACIO prior to initiating therapy in patients with chronic or recurrent infection.Monitor patients closely for the development of signs and symptoms of infection during and after treatment with IDACIO, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy[see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].MALIGNANCYLymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including adalimumab products[see Warnings and Precautions (5.2)]. Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including adalimumab products. These cases have had very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohns disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine (6-MP) concomitantly with TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of TNF blocker or TNF blocker in combination with these other immunosuppressants[see Warnings and Precautions (5.2)].. Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before IDACIO use and during therapy. Initiate treatment for latent TB prior to IDACIO use.. Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti- fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.. Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria.. WARNING: SERIOUS INFECTIONS AND MALIGNANCYSee full prescribing information for complete boxed warning.SERIOUS INFECTIONS (5.1, 6.1):Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens.Discontinue IDACIO if patient develops serious infection or sepsis during treatment.Perform test for latent TB; if positive, start treatment for TB prior to starting IDACIO.Monitor all patients for active TB during treatment, even if initial latent TB test is negative.MALIGNANCY (5.2):Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including adalimumab products.Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), rare type of T-cell lymphoma, have occurred in adolescent and young adults with inflammatory bowel disease treated with TNF blockers including adalimumab products.. Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens.. Discontinue IDACIO if patient develops serious infection or sepsis during treatment.. Perform test for latent TB; if positive, start treatment for TB prior to starting IDACIO.. Monitor all patients for active TB during treatment, even if initial latent TB test is negative.. Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including adalimumab products.. Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), rare type of T-cell lymphoma, have occurred in adolescent and young adults with inflammatory bowel disease treated with TNF blockers including adalimumab products.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies of adalimumab products have not been conducted to evaluate the carcinogenic potential or its effect on fertility.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Adalimumab products bind specifically to TNF-alpha and block its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab products also lyse surface TNF expressing cells in vitro in the presence of complement. Adalimumab products do not bind or inactivate lymphotoxin (TNF-beta). TNF is naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated concentrations of TNF are found in the synovial fluid of patients with RA, JIA, PsA, and AS and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased concentrations of TNF are also found in psoriasis plaques. In Ps, treatment with IDACIO may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab products exert their clinical effects is unknown.Adalimumab products also modulate biological responses that are induced or regulated by TNF, including changes in the concentrations of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 10-10M).. 12.2 Pharmacodynamics. After treatment with adalimumab, decrease in concentrations of acute phase reactants of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. decrease in CRP concentrations was also observed in patients with Crohns disease, and ulcerative colitis. Serum concentrations of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.. 12.3 Pharmacokinetics. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10 mg/kg following administration of single intravenous dose (adalimumab products are not approved for intravenous use). Following 20, 40, and 80 mg every other week and every week subcutaneous administration, adalimumab mean serum trough concentrations at steady state increased approximately proportionally with dose in RA patients. The mean terminal half-life was approximately weeks, ranging from 10 to 20 days across studies. Healthy subjects and patients with RA displayed similar adalimumab pharmacokinetics.Adalimumab exposure in patients treated with 80 mg every other week is estimated to be comparable with that in patients treated with 40 mg every week.. AbsorptionThe average absolute bioavailability of adalimumab following single 40 mg subcutaneous dose was 64%. The mean time to reach the maximum concentration was 5.5 days (131 +- 56 hours) and the maximum serum concentration was 4.7 +- 1.6 mcg/mL in healthy subjects following single 40 mg subcutaneous administration of adalimumab.. DistributionThe distribution volume (Vss) ranged from 4.7 to 6.0 following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients.. EliminationThe single dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients.. Patient Population. Rheumatoid Arthritis and Ankylosing Spondylitis: In patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations were approximately mcg/mL and to mcg/mL, without and with MTX concomitant treatment, respectively. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum. The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.. Psoriatic Arthritis: In patients receiving 40 mg every other week, adalimumab mean steady-state trough concentrations were to 10 mcg/mL and 8.5 to 12 mcg/mL, without and with MTX concomitant treatment, respectively.. Plaque Psoriasis: Adalimumab mean steady-state trough concentration was approximately to mcg/mL during adalimumab 40 mg every other week treatment.. Adult Crohns Disease: Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week and Week after receiving 160 mg on Week followed by 80 mg on Week 2. Mean steady-state trough concentrations were mcg/mL at Week 24 and Week 56 during adalimumab 40 mg every other week treatment.. Adult Ulcerative Colitis: Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week and Week after receiving 160 mg on Week followed by 80 mg on Week 2. Mean steady-state trough concentrations were approximately mcg/mL and 15 mcg/mL at Week 52 after receiving dose of adalimumab 40 mg every other week and 40 mg every week, respectively.. Anti-Drug Antibody Effects on Pharmacokinetics. Rheumatoid Arthritis: trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies was identified.. Specific Populations. Geriatric Patients: lower clearance with increasing age was observed in patients with RA aged 40 to >75 years.. Pediatric Patients:. Juvenile Idiopathic Arthritis:4 years to 17 years of age: The adalimumab mean steady-state trough concentrations were 6.8 mcg/mL and 10.9 mcg/mL in patients weighing <30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX, respectively. The adalimumab mean steady-state trough concentrations were 6.6 mcg/mL and 8.1 mcg/mL in patients weighing >=30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with MTX concomitant treatment, respectively.2 years to <4 years of age or years of age and older weighing <15 kg: The adalimumab mean steady-state trough adalimumab concentrations were 6.0 mcg/mL and 7.9 mcg/mL in patients receiving adalimumab subcutaneously every other week as monotherapy or with MTX concomitant treatment, respectively.. years to 17 years of age: The adalimumab mean steady-state trough concentrations were 6.8 mcg/mL and 10.9 mcg/mL in patients weighing <30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX, respectively. The adalimumab mean steady-state trough concentrations were 6.6 mcg/mL and 8.1 mcg/mL in patients weighing >=30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with MTX concomitant treatment, respectively.. years to <4 years of age or years of age and older weighing <15 kg: The adalimumab mean steady-state trough adalimumab concentrations were 6.0 mcg/mL and 7.9 mcg/mL in patients receiving adalimumab subcutaneously every other week as monotherapy or with MTX concomitant treatment, respectively.. Pediatric Crohns Disease: Adalimumab mean +- SD concentrations were 15.7+-6.5 mcg/mL at Week following 160 mg at Week and 80 mg at Week 2, and 10.5+-6.0 mcg/mL at Week 52 following 40 mg every other week dosing in patients weighing >= 40 kg. Adalimumab mean +- SD concentrations were 10.6+-6.1 mcg/mL at Week following dosing 80 mg at Week and 40 mg at Week 2, and 6.9+-3.6 mcg/mL at Week 52 following 20 mg every other week dosing in patients weighing 40 kg.. Male and Female Patients: No gender-related pharmacokinetic differences were observed after correction for patients body weight. Healthy subjects and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.. Patients with Renal or Hepatic Impairment: No pharmacokinetic data are available in patients with hepatic or renal impairment.. Rheumatoid factor or CRP concentrations: Minor increases in apparent clearance were predicted in RA patients receiving doses lower than the recommended dose and in RA patients with high rheumatoid factor or CRP concentrations. These increases are not likely to be clinically important.. Drug Interaction Studies:. Methotrexate: MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA [see Drug Interactions (7.1)].

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 patients treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in patients with RA (i.e., Studies RA-I, RA- II, RA-III and RA-IV) was 7% for patients taking adalimumab and 4% for placebo-treated patients. 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%).. InfectionsIn the controlled portions of the 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, and other indications the rate of serious infections was 4.3 per 100 patient-years in 7973 adalimumab-treated patients versus rate of 2.9 per 100 patient-years in 4848 control-treated patients. 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 InfectionsIn 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, and other indications that included 24,605 adalimumab-treated patients, 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 subgroup of 10,113 U.S. and Canadian adalimumab-treated patients, 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)].. AutoantibodiesIn the rheumatoid arthritis controlled trials, 12% of patients treated with adalimumab and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with adalimumab developed clinical signs suggestive of new- onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients 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 ElevationsThere have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase trials of adalimumab (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from to 104 weeks, ALT elevations >= x ULN occurred in 3.5% of adalimumab-treated patients and 1.5% of control- treated patients. Since many of these patients 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 controlled Phase trial of adalimumab in patients with polyarticular JIA who were to 17 years, ALT elevations >= x ULN occurred in 4.4% of adalimumab-treated patients and 1.5% of control-treated patients (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 >= x ULN occurred in the open-label study of adalimumab in patients with polyarticular JIA who were to <4 years.In controlled Phase trials of adalimumab (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days and 15, respectively, followed by 40 mg every other week) in adult patients with Crohns Disease with control period duration ranging from to 52 weeks, ALT elevations >= x ULN occurred in 0.9% of adalimumab-treated patients and 0.9% of control-treated patients. In the Phase trial of adalimumab in pediatric patients with Crohns 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 >= x ULN occurred in 2.6% (5/192) of patients, of whom were receiving concomitant immunosuppressants at baseline; none of these patients discontinued due to abnormalities in ALT tests. In controlled Phase trials of adalimumab (initial doses of 160 mg and 80 mg on Days and 15 respectively, followed by 40 mg every other week) in adult patients with UC with control period duration ranging from to 52 weeks, ALT elevations >=3 ULN occurred in 1.5% of adalimumab-treated patients and 1.0% of control-treated patients. In controlled Phase trials of adalimumab (initial dose of 80 mg then 40 mg every other week) in patients with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations >= x ULN occurred in 1.8% of adalimumab-treated patients and 1.8% of control-treated patients.. Other Adverse Reactions. Rheumatoid Arthritis Clinical StudiesThe data described below reflect exposure to adalimumab in 2468 patients, including 2073 exposed for 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 mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg adalimumab every other week [see Clinical Studies (14.1)]. Table summarizes reactions reported at rate of at least 5% in patients 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 Patients Treated with Adalimumab during Placebo-Controlled Period of Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV) Laboratory test abnormalities were reported as adverse reactions in European trials Does not include injection site erythema, itching, hemorrhage, pain or swellingAdalimumab40 mg subcutaneous Every Other WeekPlacebo(N=705)(N=690)Adverse Reaction (Preferred Term)Respiratory Upper respiratory infection17%13% Sinusitis11%9% Flu syndrome7%6%Gastrointestinal Nausea9%8% Abdominal pain7%4%Laboratory Tests Laboratory test abnormal8%7% Hypercholesterolemia6%4% Hyperlipidemia7%5% Hematuria5%4% Alkaline phosphatase increased5%3%Other Headache12%8% Rash12%6% Accidental injury10%8% Injection site reaction 8%1% Back pain6%4% Urinary tract infection8%5% Hypertension5%3%. Less Common Adverse Reactions in Rheumatoid Arthritis Clinical StudiesOther 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 patients in RA studies were:Body As Whole: Pain in extremity, pelvic pain, surgery, thorax painCardiovascular System: Arrhythmia, atrial fibrillation, chest pain, coronary artery disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, pericarditis, syncope, tachycardiaDigestive System: Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, hepatic necrosis, vomitingEndocrine System: Parathyroid disorderHemic And Lymphatic System: Agranulocytosis, polycythemiaMetabolic And Nutritional Disorders: Dehydration, healing abnormal, ketosis, paraproteinemia, peripheral edemaMusculo-Skeletal System: Arthritis, bone disorder, bone fracture (not spontaneous), bone necrosis, joint disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, tendon disorderNeoplasia: AdenomaNervous System: Confusion, paresthesia, subdural hematoma, tremorRespiratory System: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusionSpecial Senses: CataractThrombosis: Thrombosis legUrogenital System: Cystitis, kidney calculus, menstrual disorder. Juvenile Idiopathic Arthritis Clinical StudiesIn general, the adverse reactions in the adalimumab-treated patients 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 patients [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 patients who were 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 patients within approximately 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 patients 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 patients were generally similar to those commonly seen in polyarticular JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in this patient population treated with adalimumab were injection site pain and injection site reaction (19% and 16%, respectively). less commonly reported adverse event in patients 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 patients and included primarily localized allergic hypersensitivity reactions and allergic rash.In Study JIA-I, 10% of patients treated with adalimumab who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial.Approximately 15% of patients treated with adalimumab developed mild-to-moderate elevations of creatine phosphokinase (CPK) in Study JIA-I. Elevations exceeding times the upper limit of normal were observed in several patients. CPK concentrations decreased or returned to normal in all patients. Most patients were able to continue adalimumab without interruption.In Study JIA-II, adalimumab was studied in 32 patients who were to <4 years of age or years of age and older weighing <15 kg with polyarticular JIA. The safety profile for this patient population was similar to the safety profile seen in patients to 17 years of age with polyarticular JIA.In Study JIA-II, 78% of patients 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 patients 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 patients and included intermittent urticaria and rash, which were all mild in severity.. Psoriatic Arthritis and Ankylosing Spondylitis Clinical StudiesAdalimumab has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo- controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies [see Clinical Studies (14.3, 14.4)]. The safety profile for patients with PsA and AS treated with adalimumab 40 mg every other week was similar to the safety profile seen in patients with RA, adalimumab Studies RA-I through IV.. Crohns Disease Clinical StudiesAdults: The safety profile of adalimumab in 1478 adult patients with Crohns disease from four placebo-controlled and two open-label extension studies [see Clinical Studies (14.5)] was similar to the safety profile seen in patients with RA.Pediatric Patients Years to 17 Years: The safety profile of adalimumab in 192 pediatric patients 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 patients with Crohns 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 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 StudiesAdults: The safety profile of adalimumab in 1010 adult patients 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 patients with RA.. Plaque Psoriasis Clinical StudiesAdalimumab 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 higher incidence of arthralgia when compared to controls (3% vs. 1%).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Adalimumab-aacf is tumor necrosis factor blocker. Adalimumab-aacf is recombinant human IgG1 monoclonal antibody created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1:k constant regions. Adalimumab-aacf is produced by recombinant DNA technology in mammalian cell (Chinese Hamster Ovary (CHO)) expression system and is purified by process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has molecular weight of approximately 148 kilodaltons.IDACIO (adalimumab-aacf) injection is supplied as sterile, preservative-free solution for subcutaneous administration. The drug product is supplied as either single-dose, prefilled pen (IDACIO Pen), or as single-dose, mL prefilled glass syringe. Enclosed within the pen is single-dose, mL prefilled glass syringe. The solution of IDACIO is clear and colorless to pale yellow, with pH of about 5.2.Each 40 mg/0.8 mL prefilled syringe or prefilled pen delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of IDACIO contains adalimumab-aacf (40 mg) and glacial acetic acid (0.5 mg), trehalose (54.8 mg), polysorbate 80 (0.8 mg), sodium chloride (2.3 mg), and Water for Injection. Sodium hydroxide is added to adjust pH.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer by subcutaneous injection (2)Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis (2.1):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 (2.2):Pediatric Weight2 Years of Age and OlderRecommended Dosage30 kg (66 lbs) and greater40 mg every other weekCrohns Disease (2.3):Adults: 160 mg on Day (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 Years of Age and Older:Pediatric WeightRecommended DosageDays and 15Starting on Day 2940 kg (88 lbs) and greaterDay 1: 160 mg (single dose or split over two consecutive days) Day 15: 80 mg40 mg every other weekUlcerative Colitis (2.4):Adults: 160 mg on Day (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 (2.5):Adults: 80 mg initial dose, followed by 40 mg every other week starting one week after initial dose.. Administer by subcutaneous injection (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. Some patients with RA not receiving methotrexate may benefit from increasing the dosage to 40 mg every week or 80 mg every other week.. Adults: 160 mg on Day (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 Years of Age and Older:. Adults: 160 mg on Day (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).. Adults: 80 mg initial dose, followed by 40 mg every other week starting one week after initial dose.. 2.1 Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis. The recommended subcutaneous dosage of IDACIO for adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) 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 IDACIO. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosage of IDACIO to 40 mg every week or 80 mg every other week.. 2.2 Juvenile Idiopathic Arthritis. The recommended subcutaneous dosage of IDACIO for patients years of age and older with polyarticular juvenile idiopathic arthritis (JIA) is based on weight as shown below. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with IDACIO.Pediatric Weight (2 Years of Age and older)Recommended Dosage30 kg (66 lbs) and greater40 mg every other weekThere is no dosage form for IDACIO that allows weight-based dosing for pediatric patients below 30 kg.Adalimumab products have not been studied in patients with polyarticular JIA less than years of age or in patients with weight below 10 kg.. 2.3 Crohns Disease. AdultsThe recommended subcutaneous dosage of IDACIO for adult patients with Crohns disease (CD) is 160 mg initially on Day (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 dosage of 40 mg every other week. Aminosalicylates and/or corticosteroids may be continued during treatment with IDACIO. Azathioprine, 6-mercaptopurine (6-MP) [see Warnings and Precautions (5.2)] or MTX may be continued during treatment with IDACIO if necessary.. PediatricsThe recommended subcutaneous dosage of IDACIO for pediatric patients years of age and older with Crohns disease (CD) is based on body weight as shown below:Pediatric WeightRecommended DosageDays through 15Starting on Day 2940 kg (88 lbs) and greaterDay 1: 160 mg (single dose or split over two consecutive days)Day 15: 80 mg40 mg every other weekThere is no dosage form for IDACIO that allows weight-based dosing for pediatric patients below 40 kg.. 2.4 Ulcerative Colitis. AdultsThe recommended subcutaneous dosage of IDACIO for adult patients with ulcerative colitis is 160 mg initially on Day (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 dosage of 40 mg every other week.Discontinue IDACIO 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 IDACIO. Azathioprine and 6-mercaptopurine (6-MP) [see Warnings and Precautions (5.2)] may be continued during treatment with IDACIO if necessary.. 2.5 Plaque Psoriasis. The recommended subcutaneous dosage of IDACIO for adult patients with plaque psoriasis (Ps) 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 Monitoring to Assess Safety. Prior to initiating IDACIO and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions (5.1)].. 2.8 General Considerations for Administration. IDACIO is intended for use under the guidance and supervision of physician. patient may self-inject IDACIO or caregiver may inject IDACIO using either the IDACIO Pen or prefilled syringe if physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique.IDACIO may be taken out of the refrigerator for 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. Carefully inspect the solution in the IDACIO Pen, or prefilled syringe for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. IDACIO does not contain preservatives. Therefore, discard unused portions of drug remaining from the syringe.Instruct patients using the IDACIO Pen or 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 dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.The IDACIO syringe plunger stopper and needle cover are not made with natural rubber latex.. DOSAGE FORMS AND STRENGTHS. IDACIO is clear and colorless to pale yellow solution available as:Pen (IDACIO Pen)Injection: 40 mg/0.8 mL in single-dose pen.Prefilled Syringe Injection: 40 mg/0.8 mL in single-dose prefilled glass syringe.. Pen (IDACIO Pen)Injection: 40 mg/0.8 mL in single-dose pen.. Prefilled Syringe Injection: 40 mg/0.8 mL in single-dose prefilled glass syringe.. Injection:Single-dose prefilled pen (IDACIO Pen): 40 mg/0.8 mL (3)Single-dose prefilled glass syringe: 40 mg/0.8 mL (3). Single-dose prefilled pen (IDACIO Pen): 40 mg/0.8 mL (3). Single-dose prefilled glass syringe: 40 mg/0.8 mL (3).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. IDACIO is clear and colorless to pale yellow solution available as:Pen (IDACIO Pen)Injection: 40 mg/0.8 mL in single-dose pen.Prefilled Syringe Injection: 40 mg/0.8 mL in single-dose prefilled glass syringe.. Pen (IDACIO Pen)Injection: 40 mg/0.8 mL in single-dose pen.. Prefilled Syringe Injection: 40 mg/0.8 mL in single-dose prefilled glass syringe.. Injection:Single-dose prefilled pen (IDACIO Pen): 40 mg/0.8 mL (3)Single-dose prefilled glass syringe: 40 mg/0.8 mL (3). Single-dose prefilled pen (IDACIO Pen): 40 mg/0.8 mL (3). Single-dose prefilled glass syringe: 40 mg/0.8 mL (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Abatacept: Increased risk of serious infection. (5.1, 5.11, 7.2)Anakinra: Increased risk of serious infection. (5.1, 5.7, 7.2)Live vaccines: Avoid use with IDACIO. (5.10, 7.3). Abatacept: Increased risk of serious infection. (5.1, 5.11, 7.2). Anakinra: Increased risk of serious infection. (5.1, 5.7, 7.2). Live vaccines: Avoid use with IDACIO. (5.10, 7.3). 7.1 Methotrexate. Adalimumab has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either IDACIO or MTX [see Clinical Pharmacology (12.3)].. 7.2 Biological Products. In clinical studies in patients with RA, an increased risk of serious infections has been observed with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of IDACIO with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions (5.7, 5.11)]. higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with TNF blocker. There is insufficient information regarding the concomitant use of IDACIO and other biologic products for the treatment of RA, PsA, AS, CD, UC, and Ps. Concomitant administration of IDACIO with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions.. 7.3 Live Vaccines. Avoid the use of live vaccines with IDACIO [see Warnings and Precautions (5.10)].. 7.4 Cytochrome P450 Substrates. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF, IL-6) during chronic inflammation. It is possible for products that antagonize cytokine activity, such as adalimumab products, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of IDACIO in patients being treated with CYP450 substrates with 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.

GERIATRIC USE SECTION.

8.5 Geriatric Use. total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received adalimumab in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these patients and younger patients. The frequency of serious infection and malignancy among adalimumab treated patients 65 years of age and older was higher than for those less than 65 years of age. Consider the benefits and risks of IDACIO in patients 65 years of age and older. In patients treated with IDACIO, closely monitor for the development of infection or malignancy [see Warnings and Precautions (5.1, 5.2)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. IDACIO (adalimumab-aacf) injection is supplied as preservative-free, sterile, clear and colorless to pale yellow solution for subcutaneous administration. The following packaging configurations are available.IDACIO Pen Carton 40 mg/0.8 mL (2 count) IDACIO is supplied in carton containing alcohol preps and one tray. The tray contains two single-dose pens, each containing 1 mL prefilled glass syringe with 29 gauge staked 1/2 inch needle, providing 40 mg/0.8 mL of IDACIO. The syringe plunger stopper and needle cover are not made with natural rubber latex. The NDC number is 65219-554-08IDACIO Pen 40 mg/0.8 mL Starter Package for Plaque Psoriasis IDACIO is supplied in carton containing alcohol preps and trays (Starter Package for Plaque Psoriasis). Each tray contains two single-dose pens, each pen containing 1 mL prefilled glass syringe with 29 gauge staked 1/2 inch needle, providing 40 mg/0.8 mL of IDACIO. The syringe plunger stopper and needle cover are not made with natural rubber latex. The NDC number is 65219-554-28.IDACIO Pen 40 mg/0.8 mL Starter Package for Crohns Disease, Ulcerative Colitis IDACIO is supplied in carton containing alcohol preps and trays (Starter Package for Crohns Disease, Ulcerative Colitis). Each tray contains two single-dose pens, each pen containing 1 mL prefilled glass syringe with 29 gauge staked 1/2 inch needle, providing 40 mg/0.8 mL of IDACIO. The syringe plunger stopper and needle cover are not made with natural rubber latex.The NDC number is 65219-554-38.IDACIO Prefilled Syringe Carton 40 mg/0.8 mL (2 count) IDACIO is supplied in carton containing alcohol preps and one tray. The tray contains two single-dose mL prefilled glass syringes with 29 gauge staked 1/2 inch needle, each syringe providing 40 mg/0.8 mL of IDACIO. The syringe plunger stopper and needle cover are not made with natural rubber latex.. IDACIO Pen Carton 40 mg/0.8 mL (2 count) IDACIO is supplied in carton containing alcohol preps and one tray. The tray contains two single-dose pens, each containing 1 mL prefilled glass syringe with 29 gauge staked 1/2 inch needle, providing 40 mg/0.8 mL of IDACIO. The syringe plunger stopper and needle cover are not made with natural rubber latex. The NDC number is 65219-554-08. IDACIO Pen 40 mg/0.8 mL Starter Package for Plaque Psoriasis IDACIO is supplied in carton containing alcohol preps and trays (Starter Package for Plaque Psoriasis). Each tray contains two single-dose pens, each pen containing 1 mL prefilled glass syringe with 29 gauge staked 1/2 inch needle, providing 40 mg/0.8 mL of IDACIO. The syringe plunger stopper and needle cover are not made with natural rubber latex. The NDC number is 65219-554-28.. IDACIO Pen 40 mg/0.8 mL Starter Package for Crohns Disease, Ulcerative Colitis IDACIO is supplied in carton containing alcohol preps and trays (Starter Package for Crohns Disease, Ulcerative Colitis). Each tray contains two single-dose pens, each pen containing 1 mL prefilled glass syringe with 29 gauge staked 1/2 inch needle, providing 40 mg/0.8 mL of IDACIO. The syringe plunger stopper and needle cover are not made with natural rubber latex.The NDC number is 65219-554-38.. IDACIO Prefilled Syringe Carton 40 mg/0.8 mL (2 count) IDACIO is supplied in carton containing alcohol preps and one tray. The tray contains two single-dose mL prefilled glass syringes with 29 gauge staked 1/2 inch needle, each syringe providing 40 mg/0.8 mL of IDACIO. The syringe plunger stopper and needle cover are not made with natural rubber latex.. Storage and StabilityDo not use beyond the expiration date on the container. IDACIO must be refrigerated at 36F to 46F (2C to 8C). DO NOT FREEZE. Do not use if frozen even if it has been thawed.Store in original carton until time of administration to protect from light.If needed, for example when traveling, IDACIO may be stored at room temperature up to maximum of 77F (25C) for period of up to 28 days, with protection from light. IDACIO should be discarded if not used within the 28-day period. Record the date when IDACIO is first removed from the refrigerator in the spaces provided on the carton.Do not store IDACIO in extreme heat or cold.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. IDACIO is tumor necrosis factor (TNF) blocker indicated for:Rheumatoid Arthritis (RA) (1.1): reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA.Juvenile Idiopathic Arthritis (JIA) (1.2): reducing signs and symptoms of moderately to severely active polyarticular JIA in patients years of age and older.Psoriatic Arthritis (PsA) (1.3): reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active PsA.Ankylosing Spondylitis (AS) (1.4): reducing signs and symptoms in adult patients with active AS.Crohns Disease (CD) (1.5): treatment of moderately to severely active Crohns disease in adults and pediatric patients years of age and older.Ulcerative Colitis (UC) (1.6): treatment of moderately to severely active ulcerative colitis in adult patients.Limitations of Use: Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers.Plaque Psoriasis (Ps) (1.7): treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate.. Rheumatoid Arthritis (RA) (1.1): reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA.. Juvenile Idiopathic Arthritis (JIA) (1.2): reducing signs and symptoms of moderately to severely active polyarticular JIA in patients years of age and older.. Psoriatic Arthritis (PsA) (1.3): reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active PsA.. Ankylosing Spondylitis (AS) (1.4): reducing signs and symptoms in adult patients with active AS.. Crohns Disease (CD) (1.5): treatment of moderately to severely active Crohns disease in adults and pediatric patients years of age and older.. Ulcerative Colitis (UC) (1.6): treatment of moderately to severely active ulcerative colitis in adult patients.Limitations of Use: Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers.. Plaque Psoriasis (Ps) (1.7): treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate.. 1.1 Rheumatoid Arthritis. IDACIO is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. IDACIO can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).. 1.2 Juvenile Idiopathic Arthritis. IDACIO is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients years of age and older. IDACIO can be used alone or in combination with methotrexate.. 1.3 Psoriatic Arthritis. IDACIO is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis.IDACIO can be used alone or in combination with non-biologic DMARDs.. 1.4 Ankylosing Spondylitis. IDACIO is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.. 1.5 Crohns Disease. IDACIO is indicated for the treatment of moderately to severely active Crohns disease in adults and pediatric patients years of age and older.. 1.6 Ulcerative Colitis. IDACIO is indicated for the treatment of moderately to severely active ulcerative colitis in adult patients.. Limitations of UseThe effectiveness of adalimumab products has not been established in patients who have lost response to or were intolerant to TNF blockers [see Clinical Studies (14.7, 14.8)].. 1.7 Plaque Psoriasis. IDACIO is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. IDACIO should only be administered to patients who will be closely monitored and have regular follow-up visits with physician [see Warnings and Precautions (5)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).. InfectionsInform patients that IDACIO may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis virus infections [see Warnings and Precautions (5.1, 5.2, 5.4)].. MalignanciesCounsel patients about the risk of malignancies while receiving IDACIO [see Warnings and Precautions (5.2)] Hypersensitivity ReactionsAdvise patients to seek immediate medical attention if they experience any symptoms of severe hypersensitivity reactions.. Other Medical ConditionsAdvise patients to report any signs of new or worsening medical conditions such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of cytopenia such as bruising, bleeding, or persistent fever [see Warnings and Precautions (5.5, 5.6, 5.8, 5.9)].. Instructions on Injection TechniqueInform patients that the first injection is to be performed under the supervision of qualified health care professional. If patient or caregiver is to administer IDACIO, instruct them in injection techniques and assess their ability to inject subcutaneously to ensure the proper administration of IDACIO [see Instructions for Use]. For patients who will use the IDACIO Pen, tell them to :Remove the needle cap of the Pen and push and hold the Pen firmly against the skin on the chosen injection site.Activate Pen by pressing the injection button. The click means the start of the injection.Keep holding the IDACIO Pen against their skin until the injection has finished.Will know that the injection has finished when the syringe plunger moves all the way down to the bottom of the transparent syringe housing to enable the safety guard to cover the needleInstruct patients to dispose of their used needles and syringes or used Pen in FDA-cleared sharps disposal container immediately after use. Instruct patients not to dispose of loose needles and syringes or Pens in their household trash. Instruct patients that if they do not have FDA-cleared sharps disposal container, they may use household container that is made of heavy-duty plastic, can be closed with tight-fitting and puncture-resistant lid without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container.Instruct patients that when their sharps disposal container is almost full, they will need to follow their community guidelines for the correct way to dispose of their sharps disposal container. Instruct patients that there may be state or local laws regarding disposal of used needles and syringes. Refer patients to the FDAs website at http://www.fda.gov/safesharpsdisposal for more information about safe sharps disposal, and for specific information about sharps disposal in the state that they live in.Instruct patients not to dispose of their used sharps disposal container in their household trash unless their community guidelines permit this. Instruct patients not to recycle their used sharps disposal container.Manufactured by: Fresenius Kabi USA, LLCLake Zurich, IL 60047, U.S.A US License Number 2146. Remove the needle cap of the Pen and push and hold the Pen firmly against the skin on the chosen injection site.. Activate Pen by pressing the injection button. The click means the start of the injection.. Keep holding the IDACIO Pen against their skin until the injection has finished.. Will know that the injection has finished when the syringe plunger moves all the way down to the bottom of the transparent syringe housing to enable the safety guard to cover the needle.

INSTRUCTIONS FOR USE SECTION.

This Instruction for Use has been approved by the U.S. Food and Drug Administration Approved 12/2022Important informationRead the Medication Guide that comes with your IDACIO prefilled syringe for important information you need to know before using it.Do not try to inject IDACIO yourself until you have been shown the right way to give the injections and have read and understand this Instructions for Use. If your doctor decides that you or caregiver may be able to give your injections of IDACIO at home, you should receive training on the right way to prepare and inject IDACIO. It is important that you read, understand, and follow these instructions so that you inject IDACIO the right way. It is also important to talk to your doctor to be sure you understand your IDACIO dosing instructions. To help you remember when to inject IDACIO, you can mark your calendar ahead of time. Call your healthcare provider if you or your caregiver have any questions about the right way to inject IDACIO.How should store IDACIOStore IDACIO in the refrigerator between 36F to 46F (2C to 8C). Store IDACIO in the original carton until use to protect it from light.Do not freeze IDACIO. Do not use IDACIO if frozen, even if it has been thawed.Refrigerated IDACIO may be used until the expiration date printed on the IDACIO carton, or prefilled syringe. Do not use IDACIO after the expiration date.If needed, for example when traveling, you may also store IDACIO at room temperature up to 77F (25C) for up to 28 days. Store IDACIO in the original carton until use to protect it from light.Throw away IDACIO if it has been kept at room temperature and not been used within 28 days.Record the date you first remove IDACIO from the refrigerator in the spaces provided on the carton.Do not store IDACIO in extreme heat or cold.Do not use prefilled syringe if the liquid is cloudy, discolored, or has flakes or particles in it.Do not drop or crush IDACIO. The prefilled syringe is glass.Keep IDACIO, injection supplies, and all other medicines out of the reach of children.How should use IDACIOOnly use IDACIO prefilled syringe if your healthcare provider has instructed you on how to use it.Do not try to reuse the IDACIO prefilled syringe.Before injecting, let IDACIO sit at room temperature for 15-30 minutes after removing it from the refrigerator.Do not use an IDACIO prefilled syringe to give IDACIO to child who weighs less than 66 pounds (30 kg).1.1 Gather the supplies for your injection. You will need the following supplies for each injection of IDACIO (Figure D). Find clean, flat surface to place the supplies on.1 alcohol prep1 cotton ball or gauze pad (not included in your IDACIO carton)1 IDACIO prefilled syringe (See Figures and B)Puncture-resistant sharps disposal container for IDACIO prefilled syringe disposal (not included in your IDACIO carton). See Step Dispose of used prefilled syringes. If you do not have all the supplies you need to give yourself an injection, go to pharmacy or call your pharmacist.1.2 Remove the carton of IDACIO prefilled syringes from the refrigerator (Figure E).1.3 Check the expiration date (EXP:) on the side of the carton (Figure E). Do not use if the expiration date has passed. 1.4 Take one IDACIO prefilled syringe out of the original carton: Place two fingers on the middle of the clear needle guardPull the syringe straight up and out of the packaging (Figure F)Put the syringe on clean flat surface.Do not pick up the syringe by the plunger or the needle cap. Doing this could damage the syringe or activate the clear needle guard. 1.5 Return the remaining syringe in its original carton to the refrigerator (Figure G). See How should store IDACIO for information on how to store your unused syringe. 1.6 Take your IDACIO prefilled syringe out of the refrigerator 15-30 minutes before injecting to allow the liquid to reach room temperature (Figure H). Do not remove the needle cap while allowing it to reach room temperature.Do not warm the syringe in any other way (for example, do not warm it in microwave or in hot water). 2.1 Make sure that: the name IDACIO appears on the prefilled syringe label (Figure I).the syringe, the clear needle guard, and the needle cap are not cracked or damaged (Figure K).the needle cap is securely attached (Figure L).the needle guard spring is not extended (Figure M). 2.2Do not use and do call your doctor or pharmacist if: the IDACIO labeling has an expired date. Check the expiration date (EXP:) on the prefilled syringe label and do not use if the date has passed (Figure I).the prefilled syringe has been frozen or left in direct sunlight.IDACIO has been kept at room temperature for longer than 28 days or IDACIO has been stored above 77F (25C).the liquid in the prefilled syringe is cloudy, discolored or has flakes or particles in it. Make sure the liquid is clear and colorless to pale yellow. (Figure J). See How should store IDACIO section at the beginning of this Instructions for Use. 3.1 Wash and dry your hands well (Figure N).4.1 Choose an injection site on (Figure O): your lower abdomen (belly). If you choose your abdomen, do not use the area inches around your belly button (navel) orthe front of your thighsChoose different site each time to reduce redness, irritation or other skin problems. Each new injection should be given at least inch from site you used before.Do not inject into skin that is:sore (tender)bruisedredhardscarred or where you have stretch marks. If you have psoriasis, do not inject directly into any raised, thick, red or scaly skin patches or lesions on your skin.Do not inject through your clothes. 5.1 Wipe the injection site with an alcohol prep using circular motion (Figure P). Do not touch this area again before giving the injection. 5.2 Allow the skin to dry before injecting. Do not fan or blow on the clean area. 6.1 Remove the needle cap: Hold the syringe in one hand. With the other hand gently remove the needle cap (Figure Q).Throw away the needle cap.Do not touch the needle with your fingers or let the needle touch anything. 6.2 Position the syringe Hold the body of the prefilled syringe in one hand between the thumb and index finger. Hold the syringe in your hand like pencil (Figure R).Do not pull back on the plunger at any time.With your other hand, gently squeeze the area of the cleaned skin and hold it firmly (Figure S). 6.3 Insert the needle Using quick dart-like motion, insert the needle into the squeezed skin at 45-degree angle (Figure T). 6.4 Inject IDACIO Slowly push the plunger all the way in until all the liquid is injected, and the syringe is empty (Figure T).The plunger must be pushed all the way down to be sure the full dose has been injected and the safety system is activated (Figure U).Do not remove the needle from the skin when the plunger is pushed all the way down. 6.5 Finish Injection Slowly remove your thumb upwards off of the plunger. This will allow the needle to move up into the clear needle guard and cover the entire needle (Figure V).Release the squeezed skin.Call your healthcare provider or pharmacist right away if:you did not inject the full dose orthe clear needle guard does not activate after injecting. Do not reuse syringe even if all of the medicine was not injected.Do not try to recap the needle as it could lead to needle stick injury.Press cotton ball or gauze pad over the injection site and hold it for 10 seconds (Figure W). Do not rub the injection site. You may have slight bleeding. This is normal. 7.1 Put your used prefilled syringes in FDA-cleared sharps disposal container right away after use (Figure X). Do not throw away (dispose of) prefilled syringes in your household trash.If you do not have FDA-cleared sharps disposal container, you may use household container that is:-made of heavy-duty plastic,-can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,-upright and stable during use,-leak resistant, and-properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposalFor the safety and health of you and others, used syringes must never be re-used.The used alcohol prep, cotton balls, dose trays and packaging may be placed in your household trash.Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.Always keep the sharps container out of the reach of children.8.1 To help you remember when and where on your body to give your next injection, keep record of the dates and injection sites used for your injections (Figure Y). Manufactured by:Fresenius Kabi USA, LLCLake Zurich, Illinois 60047U.S. License No. 2146. Store IDACIO in the refrigerator between 36F to 46F (2C to 8C). Store IDACIO in the original carton until use to protect it from light.. Do not freeze IDACIO. Do not use IDACIO if frozen, even if it has been thawed.. Refrigerated IDACIO may be used until the expiration date printed on the IDACIO carton, or prefilled syringe. Do not use IDACIO after the expiration date.. If needed, for example when traveling, you may also store IDACIO at room temperature up to 77F (25C) for up to 28 days. Store IDACIO in the original carton until use to protect it from light.. Throw away IDACIO if it has been kept at room temperature and not been used within 28 days.. Record the date you first remove IDACIO from the refrigerator in the spaces provided on the carton.. Do not store IDACIO in extreme heat or cold.. Do not use prefilled syringe if the liquid is cloudy, discolored, or has flakes or particles in it.. Do not drop or crush IDACIO. The prefilled syringe is glass.. Keep IDACIO, injection supplies, and all other medicines out of the reach of children.. Only use IDACIO prefilled syringe if your healthcare provider has instructed you on how to use it.. Do not try to reuse the IDACIO prefilled syringe.. Before injecting, let IDACIO sit at room temperature for 15-30 minutes after removing it from the refrigerator.. Do not use an IDACIO prefilled syringe to give IDACIO to child who weighs less than 66 pounds (30 kg).. You will need the following supplies for each injection of IDACIO (Figure D). Find clean, flat surface to place the supplies on.1 alcohol prep1 cotton ball or gauze pad (not included in your IDACIO carton)1 IDACIO prefilled syringe (See Figures and B)Puncture-resistant sharps disposal container for IDACIO prefilled syringe disposal (not included in your IDACIO carton). See Step Dispose of used prefilled syringes. 1 alcohol prep. cotton ball or gauze pad (not included in your IDACIO carton). IDACIO prefilled syringe (See Figures and B). Puncture-resistant sharps disposal container for IDACIO prefilled syringe disposal (not included in your IDACIO carton). See Step Dispose of used prefilled syringes.. Do not use if the expiration date has passed. Place two fingers on the middle of the clear needle guard. Pull the syringe straight up and out of the packaging (Figure F). Put the syringe on clean flat surface.. Do not pick up the syringe by the plunger or the needle cap. Doing this could damage the syringe or activate the clear needle guard.. See How should store IDACIO for information on how to store your unused syringe. Do not remove the needle cap while allowing it to reach room temperature.. Do not warm the syringe in any other way (for example, do not warm it in microwave or in hot water).. the name IDACIO appears on the prefilled syringe label (Figure I).. the syringe, the clear needle guard, and the needle cap are not cracked or damaged (Figure K).. the needle cap is securely attached (Figure L).. the needle guard spring is not extended (Figure M).. the IDACIO labeling has an expired date. Check the expiration date (EXP:) on the prefilled syringe label and do not use if the date has passed (Figure I).. the prefilled syringe has been frozen or left in direct sunlight.. IDACIO has been kept at room temperature for longer than 28 days or IDACIO has been stored above 77F (25C).. the liquid in the prefilled syringe is cloudy, discolored or has flakes or particles in it. Make sure the liquid is clear and colorless to pale yellow. (Figure J). your lower abdomen (belly). If you choose your abdomen, do not use the area inches around your belly button (navel) or. the front of your thighs. Choose different site each time to reduce redness, irritation or other skin problems. Each new injection should be given at least inch from site you used before.. Do not inject into skin that is:sore (tender)bruisedredhardscarred or where you have stretch marks. sore (tender). bruised. red. hard. scarred or where you have stretch marks.. If you have psoriasis, do not inject directly into any raised, thick, red or scaly skin patches or lesions on your skin.. Do not inject through your clothes.. Do not touch this area again before giving the injection.. Do not fan or blow on the clean area.. Hold the syringe in one hand. With the other hand gently remove the needle cap (Figure Q).. Throw away the needle cap.. Do not touch the needle with your fingers or let the needle touch anything.. Hold the body of the prefilled syringe in one hand between the thumb and index finger. Hold the syringe in your hand like pencil (Figure R).. Do not pull back on the plunger at any time.. With your other hand, gently squeeze the area of the cleaned skin and hold it firmly (Figure S).. Using quick dart-like motion, insert the needle into the squeezed skin at 45-degree angle (Figure T).. Slowly push the plunger all the way in until all the liquid is injected, and the syringe is empty (Figure T).. The plunger must be pushed all the way down to be sure the full dose has been injected and the safety system is activated (Figure U).. Do not remove the needle from the skin when the plunger is pushed all the way down.. Slowly remove your thumb upwards off of the plunger. This will allow the needle to move up into the clear needle guard and cover the entire needle (Figure V).. Release the squeezed skin.. Call your healthcare provider or pharmacist right away if:you did not inject the full dose orthe clear needle guard does not activate after injecting. you did not inject the full dose or. the clear needle guard does not activate after injecting.. Do not reuse syringe even if all of the medicine was not injected.. Do not try to recap the needle as it could lead to needle stick injury.. Press cotton ball or gauze pad over the injection site and hold it for 10 seconds (Figure W). Do not rub the injection site. You may have slight bleeding. This is normal.. If you do not have FDA-cleared sharps disposal container, you may use household container that is:-made of heavy-duty plastic,-can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,-upright and stable during use,-leak resistant, and-properly labeled to warn of hazardous waste inside the container. -made of heavy-duty plastic,. -can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. -upright and stable during use,. -leak resistant, and. -properly labeled to warn of hazardous waste inside the container.. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal. For the safety and health of you and others, used syringes must never be re-used.. The used alcohol prep, cotton balls, dose trays and packaging may be placed in your household trash.. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.. Always keep the sharps container out of the reach of children.. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

LACTATION SECTION.

8.2 Lactation. Risk SummaryLimited data from case reports in the published literature describe the presence of adalimumab in human milk at infant doses of 0.1% to 1% of the maternal serum concentration. Published data suggest that the systemic exposure to breastfed infant is expected to be low because adalimumab is large molecule and is degraded in the gastrointestinal tract. However, the effects of local exposure in the gastrointestinal tract are unknown. There are no reports of adverse effects of adalimumab products on the breastfed infant and no effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for IDACIO and any potential adverse effects on the breastfed child from IDACIO or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Adalimumab products bind specifically to TNF-alpha and block its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab products also lyse surface TNF expressing cells in vitro in the presence of complement. Adalimumab products do not bind or inactivate lymphotoxin (TNF-beta). TNF is naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated concentrations of TNF are found in the synovial fluid of patients with RA, JIA, PsA, and AS and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased concentrations of TNF are also found in psoriasis plaques. In Ps, treatment with IDACIO may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab products exert their clinical effects is unknown.Adalimumab products also modulate biological responses that are induced or regulated by TNF, including changes in the concentrations of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 10-10M).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies of adalimumab products have not been conducted to evaluate the carcinogenic potential or its effect on fertility.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display Panel 0.8.mL Carton LabelIdacio(R) adalimumab-aacfInjection40 mg 0.8 mLNDC 65219-556-18Rx Only29GaugeNeedleFor subcutaneous use only2 single-dose prefilled syringesCarton contains:2 Single-dose prefilled syringes with 29 gauge1/2 inch length staked needle2 Alcohol preps1 Prescribing Information1 Medication Guide1 Instruction For UseFRESENIUSKABIATTENTION PHARMACIST:Each patient is required to receive the enclosed Medication Guide.Needle cover for syringe is not made with natural rubber latex.The entire carton is to be dispensed as unit.. Principal Display Panel 0.8.mL Carton Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of IDACIO have been established for:reducing signs and symptoms of moderately to severely active polyarticular JIA in pediatric patients years of age and older.the treatment of moderately to severely active Crohns disease in pediatric patients years of age and older.A pediatric assessment for IDACIO demonstrates that IDACIO is safe and effective for pediatric patients in an indication for which HUMIRA (adalimumab) is approved. However, IDACIO is not approved for such indication due to marketing exclusivity for HUMIRA (adalimumab).Due to their inhibition of TNF, adalimumab products administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to adalimumab in utero suggest adalimumab crosses the placenta [see Use in Specific Populations (8.1)]. The clinical significance of elevated adalimumab concentrations in infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants.Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including adalimumab products [see Warnings and Precautions (5.2)].. reducing signs and symptoms of moderately to severely active polyarticular JIA in pediatric patients years of age and older.. the treatment of moderately to severely active Crohns disease in pediatric patients years of age and older.. Juvenile Idiopathic ArthritisIn Study JIA-I, adalimumab was shown to reduce signs and symptoms of active polyarticular JIA in patients to 17 years of age [see Clinical Studies (14.2)]. In Study JIA-II, the safety profile for patients to <4 years of age was similar to the safety profile for patients to 17 years of age with polyarticular JIA [see Adverse Reactions (6.1)]. Adalimumab products have not been studied in patients with polyarticular JIA less than years of age or in patients with weight below 10 kg.The safety of adalimumab in patients in the polyarticular JIA trials was generally similar to that observed in adults with certain exceptions [see Adverse Reactions (6.1)].The safety and effectiveness of adalimumab products have not been established in pediatric patients with JIA less than years of age.. Pediatric Crohns DiseaseThe safety and effectiveness of adalimumab products for the treatment of moderately to severely active Crohns disease have been established in pediatric patients years of age and older. Use of adalimumab products for this indication is supported by evidence from adequate and well-controlled studies in adults with additional data from randomized, double-blind, 52-week clinical study of two dose concentrations of adalimumab in 192 pediatric patients (6 years to 17 years of age) [see Adverse Reactions (6.1), Clinical Pharmacology (12.2, 12.3), Clinical Studies (14.6)]. The adverse reaction profile in patients years to 17 years of age was similar to adults.The safety and effectiveness of adalimumab products have not been established in pediatric patients with Crohns disease less than years of age.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. After treatment with adalimumab, decrease in concentrations of acute phase reactants of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. decrease in CRP concentrations was also observed in patients with Crohns disease, and ulcerative colitis. Serum concentrations of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10 mg/kg following administration of single intravenous dose (adalimumab products are not approved for intravenous use). Following 20, 40, and 80 mg every other week and every week subcutaneous administration, adalimumab mean serum trough concentrations at steady state increased approximately proportionally with dose in RA patients. The mean terminal half-life was approximately weeks, ranging from 10 to 20 days across studies. Healthy subjects and patients with RA displayed similar adalimumab pharmacokinetics.Adalimumab exposure in patients treated with 80 mg every other week is estimated to be comparable with that in patients treated with 40 mg every week.. AbsorptionThe average absolute bioavailability of adalimumab following single 40 mg subcutaneous dose was 64%. The mean time to reach the maximum concentration was 5.5 days (131 +- 56 hours) and the maximum serum concentration was 4.7 +- 1.6 mcg/mL in healthy subjects following single 40 mg subcutaneous administration of adalimumab.. DistributionThe distribution volume (Vss) ranged from 4.7 to 6.0 following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients.. EliminationThe single dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients.. Patient Population. Rheumatoid Arthritis and Ankylosing Spondylitis: In patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations were approximately mcg/mL and to mcg/mL, without and with MTX concomitant treatment, respectively. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum. The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.. Psoriatic Arthritis: In patients receiving 40 mg every other week, adalimumab mean steady-state trough concentrations were to 10 mcg/mL and 8.5 to 12 mcg/mL, without and with MTX concomitant treatment, respectively.. Plaque Psoriasis: Adalimumab mean steady-state trough concentration was approximately to mcg/mL during adalimumab 40 mg every other week treatment.. Adult Crohns Disease: Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week and Week after receiving 160 mg on Week followed by 80 mg on Week 2. Mean steady-state trough concentrations were mcg/mL at Week 24 and Week 56 during adalimumab 40 mg every other week treatment.. Adult Ulcerative Colitis: Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week and Week after receiving 160 mg on Week followed by 80 mg on Week 2. Mean steady-state trough concentrations were approximately mcg/mL and 15 mcg/mL at Week 52 after receiving dose of adalimumab 40 mg every other week and 40 mg every week, respectively.. Anti-Drug Antibody Effects on Pharmacokinetics. Rheumatoid Arthritis: trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies was identified.. Specific Populations. Geriatric Patients: lower clearance with increasing age was observed in patients with RA aged 40 to >75 years.. Pediatric Patients:. Juvenile Idiopathic Arthritis:4 years to 17 years of age: The adalimumab mean steady-state trough concentrations were 6.8 mcg/mL and 10.9 mcg/mL in patients weighing <30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX, respectively. The adalimumab mean steady-state trough concentrations were 6.6 mcg/mL and 8.1 mcg/mL in patients weighing >=30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with MTX concomitant treatment, respectively.2 years to <4 years of age or years of age and older weighing <15 kg: The adalimumab mean steady-state trough adalimumab concentrations were 6.0 mcg/mL and 7.9 mcg/mL in patients receiving adalimumab subcutaneously every other week as monotherapy or with MTX concomitant treatment, respectively.. years to 17 years of age: The adalimumab mean steady-state trough concentrations were 6.8 mcg/mL and 10.9 mcg/mL in patients weighing <30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX, respectively. The adalimumab mean steady-state trough concentrations were 6.6 mcg/mL and 8.1 mcg/mL in patients weighing >=30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with MTX concomitant treatment, respectively.. years to <4 years of age or years of age and older weighing <15 kg: The adalimumab mean steady-state trough adalimumab concentrations were 6.0 mcg/mL and 7.9 mcg/mL in patients receiving adalimumab subcutaneously every other week as monotherapy or with MTX concomitant treatment, respectively.. Pediatric Crohns Disease: Adalimumab mean +- SD concentrations were 15.7+-6.5 mcg/mL at Week following 160 mg at Week and 80 mg at Week 2, and 10.5+-6.0 mcg/mL at Week 52 following 40 mg every other week dosing in patients weighing >= 40 kg. Adalimumab mean +- SD concentrations were 10.6+-6.1 mcg/mL at Week following dosing 80 mg at Week and 40 mg at Week 2, and 6.9+-3.6 mcg/mL at Week 52 following 20 mg every other week dosing in patients weighing 40 kg.. Male and Female Patients: No gender-related pharmacokinetic differences were observed after correction for patients body weight. Healthy subjects and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.. Patients with Renal or Hepatic Impairment: No pharmacokinetic data are available in patients with hepatic or renal impairment.. Rheumatoid factor or CRP concentrations: Minor increases in apparent clearance were predicted in RA patients receiving doses lower than the recommended dose and in RA patients with high rheumatoid factor or CRP concentrations. These increases are not likely to be clinically important.. Drug Interaction Studies:. Methotrexate: MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA [see Drug Interactions (7.1)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable studies with use of adalimumab during pregnancy do not reliably establish an association between adalimumab and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry in pregnant women with rheumatoid arthritis (RA) or Crohns disease (CD) treated with adalimumab. Registry results showed rate of 10% for major birth defects with first trimester use of adalimumab in pregnant women with RA or CD and rate of 7.5% for major birth defects in the disease-matched comparison cohort. The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects (see Data).Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in-utero exposed infant (see Clinical Considerations). In an embryo-fetal perinatal development study conducted in cynomolgus monkeys, no fetal harm or malformations were observed with intravenous administration of adalimumab during organogenesis and later in gestation, at doses that produced exposures up to approximately 373 times the maximum recommended human dose (MRHD) of 40 mg subcutaneous without methotrexate (see Data).The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical Considerations. Disease-associated maternal and embryo/fetal riskPublished data suggest that the risk of adverse pregnancy outcomes in women with RA or inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.. Fetal/Neonatal Adverse ReactionsMonoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester (see Data). Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to adalimumab products in utero [see Use in Specific Populations (8.5)].. Data. Human DataA prospective cohort pregnancy exposure registry conducted by OTIS/MotherToBaby in the U.S. and Canada between 2004 and 2016 compared the risk of major birth defects in live-born infants of 221 women (69 RA, 152 CD) treated with adalimumab during the first trimester and 106 women (74 RA, 32 CD) not treated with adalimumab.The proportion of major birth defects among live-born infants in the adalimumab-treated and untreated cohorts was 10% (8.7% RA, 10.5% CD) and 7.5% (6.8% RA, 9.4% CD), respectively. The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects. This study cannot reliably establish whether there is an association between adalimumab and major birth defects because of methodological limitations of the registry, including small sample size, the voluntary nature of the study, and the non-randomized design.In an independent clinical study conducted in ten pregnant women with IBD treated with adalimumab, adalimumab concentrations were measured in maternal serum as well as in cord blood (n=10) and infant serum (n=8) on the day of birth. The last dose of adalimumab was given between and 56 days prior to delivery. Adalimumab concentrations were 0.16-19.7 mcg/mL in cord blood, 4.28-17.7 mcg/mL in infant serum, and 0-16.1 mcg/mL in maternal serum. In all but one case, the cord blood concentration of adalimumab was higher than the maternal serum concentration, suggesting adalimumab actively crosses the placenta. In addition, one infant had serum concentrations at each of the following: weeks (1.94 mcg/mL), weeks (1.31 mcg/mL), weeks (0.93 mcg/mL), and 11 weeks (0.53 mcg/mL), suggesting adalimumab can be detected in the serum of infants exposed in utero for at least months from birth.. Animal DataIn an embryo-fetal perinatal development study, pregnant cynomolgus monkeys received adalimumab from gestation days 20 to 97 at doses that produced exposures up to 373 times that achieved with the MRHD without methotrexate (on an AUC basis with maternal IV doses up to 100 mg/kg/week). Adalimumab did not elicit harm to the fetuses or malformations.

REFERENCES SECTION.

15 REFERENCES. National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Incidence Crude Rates, 17 Registries, 2000-2007.. National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Incidence Crude Rates, 17 Registries, 2000-2007.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration Approved: 12/2022MEDICATION GUIDE IDACIO(R) (i-DAS-i-oh) (adalimumab-aacf) injection, for subcutaneous useRead the Medication Guide that comes with IDACIO before you start taking it and each time you get refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment.What is the most important information should know about IDACIOIDACIO is medicine that affects your immune system. IDACIO can lower the ability of your immune system to fight infections. Serious infections have happened in people taking adalimumab products. These serious infections include tuberculosis (TB) and infections caused by viruses, fungi or bacteria that have spread throughout the body. Some people have died from these infections.Your healthcare provider should test you for TB before starting IDACIO.Your healthcare provider should check you closely for signs and symptoms of TB during treatment with IDACIO.You should not start taking IDACIO if you have any kind of infection unless your healthcare provider says it is okay. Before starting IDACIO, tell your healthcare provider if you: think you have an infection or have symptoms of an infection such as: fever, sweats, or chillsmuscle achescoughshortness of breathblood in phlegmwarm, red, or painful skin or sores on your bodydiarrhea or stomach painburning when you urinate or urinate more often than normalfeel very tiredweight lossare being treated for an infection.get lot of infections or have infections that keep coming back.have diabeteshave TB or have been in close contact with someone with TB.were born in, lived in, or traveled to countries where there is more risk for getting TB. Ask your healthcare provider if you are not sure.live or have lived in certain parts of the country (such as the Ohio and Mississippi River valleys) where there is an increased risk for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, or blastomycosis). These infections may happen or become more severe if you use IDACIO. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common.have or have had hepatitis Buse the medicine ORENCIA (abatacept), KINERET (anakinra), RITUXAN (rituximab), IMURAN (azathioprine), or PURINETHOL (6-mercaptopurine, 6-MP).are scheduled to have major surgery.After starting IDACIO, call your healthcare provider right away if you have an infection, or any sign of an infection.IDACIO can make you more likely to get infections or make any infection that you may have worse. Cancer For children and adults taking Tumor Necrosis Factor (TNF)-blockers, including IDACIO, the chances of getting cancer may increase.There have been cases of unusual cancers in children, teenagers, and young adults using TNF-blockers.People with rheumatoid arthritis (RA), especially more serious RA, may have higher chance for getting kind of cancer called lymphoma.If you use TNF blockers including IDACIO your chance of getting two types of skin cancer may increase (basal cell cancer and squamous cell cancer of the skin). These types of cancer are generally not life-threatening if treated. Tell your healthcare provider if you have bump or open sore that does not heal.Some people receiving TNF blockers including IDACIO developed rare type of cancer called hepatosplenic T-cell lymphoma. This type of cancer often results in death. Most of these people were male teenagers or young men. Also, most people were being treated for Crohns disease or ulcerative colitis with another medicine called IMURAN (azathioprine) or PURINETHOL (6-mercaptopurine, 6-MP). What is IDACIOIDACIO is medicine called Tumor Necrosis Factor (TNF) blocker. IDACIO is used:To reduce the signs and symptoms of:moderate to severe RA in adults. IDACIO can be used alone, with methotrexate, or with certain other medicines.moderate to severe polyarticular juvenile idiopathic arthritis (JIA) in children years and older. IDACIO can be used alone, or with methotrexate.psoriatic arthritis (PsA) in adults. IDACIO can be used alone or with certain other medicines.ankylosing spondylitis (AS) in adults. To treat moderate to severe Crohns disease (CD) in adults and children years of age and older.To treat moderate to severe ulcerative colitis (UC) in adults. It is not known if adalimumab products are effective in people who stopped responding to or could not tolerate TNF-blocker medicines.To treat moderate to severe chronic (lasting long time) plaque psoriasis (Ps) in adults who have the condition in many areas of their body and who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).What should tell my healthcare provider before taking IDACIOIDACIO may not be right for you. Before starting IDACIO, tell your healthcare provider about all of your medical conditions, including if you:have an infection. See What is the most important information should know about IDACIO have or have had cancer.have any numbness or tingling or have disease that affects your nervous system such as multiple sclerosis or Guillain-Barre syndrome.have or had heart failure.have recently received or are scheduled to receive vaccine. You may receive vaccines, except for live vaccines while using IDACIO. Children should be brought up to date with all vaccines before starting IDACIO.are allergic to IDACIO or to any of its ingredients. See the end of this Medication Guide for list of ingredients in IDACIO.are pregnant or plan to become pregnant, breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you should take IDACIO while you are pregnant or breastfeeding.have baby and you were using IDACIO during your pregnancy. Tell your babys healthcare provider before your baby receives any vaccines.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you use: ORENCIA (abatacept), KINERET (anakinra), REMICADE (infliximab), ENBREL (etanercept), CIMZIA (certolizumab pegol) or SIMPONI (golimumab), because you should not use IDACIO while you are also using one of these medicines.RITUXAN (rituximab). Your healthcare provider may not want to give you IDACIO if you have received RITUXAN (rituximab) recently.IMURAN (azathioprine) or PURINETHOL (6-mercaptopurine, 6-MP). Keep list of your medicines with you to show your healthcare provider and pharmacist each time you get new medicine.How should take IDACIOIDACIO is given by an injection under the skin. Your healthcare provider will tell you how often to take an injection of IDACIO. This is based on your condition to be treated. Do not inject IDACIO more often than you were prescribed. See the Instructions for Use inside the carton for complete instructions for the right way to prepare and inject IDACIO.Make sure you have been shown how to inject IDACIO before you do it yourself. If you have any questions about giving yourself an injection, you can call your healthcare provider or the patient support program at 1-833-522-4227. Someone you know can also help you with your injection after they have been shown how to prepare and inject IDACIO.Do not try to inject IDACIO yourself until you have been shown the right way to give the injections. If your healthcare provider decides that you or caregiver may be able to give your injections of IDACIO at home, you should receive training on the right way to prepare and inject IDACIO.Do not miss any doses of IDACIO unless your healthcare provider says it is okay. If you forget to take IDACIO, inject dose as soon as you remember. Then, take your next dose at your regular scheduled time. This will put you back on schedule. In case you are not sure when to inject IDACIO, call your healthcare provider or pharmacist.If you take more IDACIO than you were told to take, call your healthcare provider.What are the possible side effects of IDACIOIDACIO can cause serious side effects, including:See What is the most important information should know about IDACIOSerious Infections. Your healthcare provider will examine you for TB and perform test to see if you have TB. If your healthcare provider feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with IDACIO and during treatment with IDACIO. Even if your TB test is negative your healthcare provider should carefully monitor you for TB infections while you are taking IDACIO. People who had negative TB skin test before receiving adalimumab products have developed active TB. Tell your healthcare provider if you have any of the following symptoms while taking or after taking IDACIO:cough that does not go awayweight losslow grade feverloss of body fat and muscle (wasting)Hepatitis infection in people who carry the virus in their blood. If you are carrier of the hepatitis virus (a virus that affects the liver), the virus can become active while you use IDACIO. Your healthcare provider should do blood tests before you start treatment, while you are using IDACIO, and for several months after you stop treatment with IDACIO. Tell your healthcare provider if you have any of the following symptoms of possible hepatitis infection:muscle achesfeel very tireddark urineskin or eyes look yellowlittle or no appetitevomitingclay-colored bowel movementsfeverchillsstomach discomfortskin rashAllergic reactions. Allergic reactions can happen in people who use IDACIO. Call your healthcare provider or get medical help right away if you have any of these symptoms of serious allergic reaction:Hivestrouble breathingswelling of your face, eyes, lips or mouthNervous system problems. Signs and symptoms of nervous system problem include: numbness or tingling, problems with your vision, weakness in your arms or legs, and dizziness.Blood problems. Your body may not make enough of the blood cells that help fight infections or help to stop bleeding. Symptoms include fever that does not go away, bruising or bleeding very easily, or looking very pale.New heart failure or worsening of heart failure you already have. Call your healthcare provider right away if you get new worsening symptoms of heart failure while taking IDACIO, including:shortness of breathsudden weight gainswelling of your ankles or feetImmune reactions including lupus-like syndrome. Symptoms include chest discomfort or pain that does not go away, shortness of breath, joint pain, or rash on your cheeks or arms that gets worse in the sun. Symptoms may improve when you stop IDACIO.Liver Problems. Liver problems can happen in people who use TNF-blocker medicines. These problems can lead to liver failure and death. Call your healthcare provider right away if you have any of these symptoms:feel very tiredpoor appetite or vomitingskin or eyes look yellowpain on the right side of your stomach (abdomen)Psoriasis. Some people using adalimumab products had new psoriasis or worsening of psoriasis they already had. Tell your healthcare provider if you develop red scaly patches or raised bumps that are filled with pus. Your healthcare provider may decide to stop your treatment with IDACIO.Call your healthcare provider or get medical care right away if you develop any of the above symptoms. Your treatment withIDACIOmay be stopped.The most common side effects of IDACIO include:injection site reactions: redness, rash, swelling, itching, or bruising. These symptoms usually will go away within few days. Call your healthcare provider right away if you have pain, redness or swelling around the injection site that does not go away within few days or gets worse.upper respiratory infections (including sinus infections).headaches.rash.These are not all the possible side effects with IDACIO. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store IDACIOStore IDACIO in the refrigerator at 36oF to 46oF (2oC to 8oC). Store IDACIO in the original carton until use to protect it from light.Do not freeze IDACIO. Do not use IDACIO if frozen, even if it has been thawed.Refrigerated IDACIO may be used until the expiration date printed on the IDACIO carton. Pen or prefilled syringe. Do not use IDACIO after the expiration date.If needed, for example when you are traveling, you may also store IDACIO at room temperature up to 77F (25C) for up to 28 days. Store IDACIO in the original carton until use, to protect it from light.Throw away IDACIO if it has been kept at room temperature and not been used within 28 days.Record the date you first remove IDACIO from the refrigerator in the spaces provided on the carton.Do not store IDACIO in extreme heat or cold.Do not use Pen or prefilled syringe if the liquid is cloudy, discolored, or has flakes or particles in it.Do not drop or crush IDACIO. The prefilled syringe is glass.Keep IDACIO, injection supplies, and all other medicines out of the reach of children.General information about the safe and effective use of IDACIO.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use IDACIO for condition for which it was not prescribed. Do not give IDACIO to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about IDACIO. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about IDACIO that is written for health professionals.What are the ingredients in IDACIOActive ingredient: adalimumab-aacfIDACIO 40 mg/0.8 mL Pen, and IDACIO 40 mg/0.8 mL prefilled syringe. Inactive ingredients: glacial acetic acid, trehalose, polysorbate 80, sodium chloride and Water for Injection. Sodium hydroxide is added as necessary to adjust pH. Manufactured by: Fresenius Kabi USA, LLC, Lake Zurich, IL 60047, U.S.A.For more product information go to www. IDACIO .com. You can enroll in patient support program by calling 1-833-522-4227 or visiting the patient support program website: https://kabicare.us/.U.S. License number 2146. Your healthcare provider should test you for TB before starting IDACIO.. Your healthcare provider should check you closely for signs and symptoms of TB during treatment with IDACIO.. think you have an infection or have symptoms of an infection such as:. fever, sweats, or chills. muscle aches. cough. shortness of breath. blood in phlegm. warm, red, or painful skin or sores on your body. diarrhea or stomach pain. burning when you urinate or urinate more often than normal. feel very tired. weight loss. are being treated for an infection.. get lot of infections or have infections that keep coming back.. have diabetes. have TB or have been in close contact with someone with TB.. were born in, lived in, or traveled to countries where there is more risk for getting TB. Ask your healthcare provider if you are not sure.. live or have lived in certain parts of the country (such as the Ohio and Mississippi River valleys) where there is an increased risk for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, or blastomycosis). These infections may happen or become more severe if you use IDACIO. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common.. have or have had hepatitis B. use the medicine ORENCIA (abatacept), KINERET (anakinra), RITUXAN (rituximab), IMURAN (azathioprine), or PURINETHOL (6-mercaptopurine, 6-MP).. are scheduled to have major surgery.. For children and adults taking Tumor Necrosis Factor (TNF)-blockers, including IDACIO, the chances of getting cancer may increase.. There have been cases of unusual cancers in children, teenagers, and young adults using TNF-blockers.. People with rheumatoid arthritis (RA), especially more serious RA, may have higher chance for getting kind of cancer called lymphoma.. If you use TNF blockers including IDACIO your chance of getting two types of skin cancer may increase (basal cell cancer and squamous cell cancer of the skin). These types of cancer are generally not life-threatening if treated. Tell your healthcare provider if you have bump or open sore that does not heal.. Some people receiving TNF blockers including IDACIO developed rare type of cancer called hepatosplenic T-cell lymphoma. This type of cancer often results in death. Most of these people were male teenagers or young men. Also, most people were being treated for Crohns disease or ulcerative colitis with another medicine called IMURAN (azathioprine) or PURINETHOL (6-mercaptopurine, 6-MP).. To reduce the signs and symptoms of:moderate to severe RA in adults. IDACIO can be used alone, with methotrexate, or with certain other medicines.moderate to severe polyarticular juvenile idiopathic arthritis (JIA) in children years and older. IDACIO can be used alone, or with methotrexate.psoriatic arthritis (PsA) in adults. IDACIO can be used alone or with certain other medicines.ankylosing spondylitis (AS) in adults. moderate to severe RA in adults. IDACIO can be used alone, with methotrexate, or with certain other medicines.. moderate to severe polyarticular juvenile idiopathic arthritis (JIA) in children years and older. IDACIO can be used alone, or with methotrexate.. psoriatic arthritis (PsA) in adults. IDACIO can be used alone or with certain other medicines.. ankylosing spondylitis (AS) in adults.. To treat moderate to severe Crohns disease (CD) in adults and children years of age and older.. To treat moderate to severe ulcerative colitis (UC) in adults. It is not known if adalimumab products are effective in people who stopped responding to or could not tolerate TNF-blocker medicines.. To treat moderate to severe chronic (lasting long time) plaque psoriasis (Ps) in adults who have the condition in many areas of their body and who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).. have an infection. See What is the most important information should know about IDACIO . have or have had cancer.. have any numbness or tingling or have disease that affects your nervous system such as multiple sclerosis or Guillain-Barre syndrome.. have or had heart failure.. have recently received or are scheduled to receive vaccine. You may receive vaccines, except for live vaccines while using IDACIO. Children should be brought up to date with all vaccines before starting IDACIO.. are allergic to IDACIO or to any of its ingredients. See the end of this Medication Guide for list of ingredients in IDACIO.. are pregnant or plan to become pregnant, breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you should take IDACIO while you are pregnant or breastfeeding.. have baby and you were using IDACIO during your pregnancy. Tell your babys healthcare provider before your baby receives any vaccines.. ORENCIA (abatacept), KINERET (anakinra), REMICADE (infliximab), ENBREL (etanercept), CIMZIA (certolizumab pegol) or SIMPONI (golimumab), because you should not use IDACIO while you are also using one of these medicines.. RITUXAN (rituximab). Your healthcare provider may not want to give you IDACIO if you have received RITUXAN (rituximab) recently.. IMURAN (azathioprine) or PURINETHOL (6-mercaptopurine, 6-MP).. IDACIO is given by an injection under the skin. Your healthcare provider will tell you how often to take an injection of IDACIO. This is based on your condition to be treated. Do not inject IDACIO more often than you were prescribed. See the Instructions for Use inside the carton for complete instructions for the right way to prepare and inject IDACIO.. Make sure you have been shown how to inject IDACIO before you do it yourself. If you have any questions about giving yourself an injection, you can call your healthcare provider or the patient support program at 1-833-522-4227. Someone you know can also help you with your injection after they have been shown how to prepare and inject IDACIO.. Do not try to inject IDACIO yourself until you have been shown the right way to give the injections. If your healthcare provider decides that you or caregiver may be able to give your injections of IDACIO at home, you should receive training on the right way to prepare and inject IDACIO.. Do not miss any doses of IDACIO unless your healthcare provider says it is okay. If you forget to take IDACIO, inject dose as soon as you remember. Then, take your next dose at your regular scheduled time. This will put you back on schedule. In case you are not sure when to inject IDACIO, call your healthcare provider or pharmacist.. If you take more IDACIO than you were told to take, call your healthcare provider.. Serious Infections. Your healthcare provider will examine you for TB and perform test to see if you have TB. If your healthcare provider feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with IDACIO and during treatment with IDACIO. Even if your TB test is negative your healthcare provider should carefully monitor you for TB infections while you are taking IDACIO. People who had negative TB skin test before receiving adalimumab products have developed active TB. Tell your healthcare provider if you have any of the following symptoms while taking or after taking IDACIO:. cough that does not go away. weight loss. low grade fever. loss of body fat and muscle (wasting). Hepatitis infection in people who carry the virus in their blood. If you are carrier of the hepatitis virus (a virus that affects the liver), the virus can become active while you use IDACIO. Your healthcare provider should do blood tests before you start treatment, while you are using IDACIO, and for several months after you stop treatment with IDACIO. Tell your healthcare provider if you have any of the following symptoms of possible hepatitis infection:. muscle aches. feel very tired. dark urine. skin or eyes look yellow. little or no appetite. vomiting. clay-colored bowel movements. fever. chills. stomach discomfort. skin rash. Allergic reactions. Allergic reactions can happen in people who use IDACIO. Call your healthcare provider or get medical help right away if you have any of these symptoms of serious allergic reaction:. Hives. trouble breathing. swelling of your face, eyes, lips or mouth. Nervous system problems. Signs and symptoms of nervous system problem include: numbness or tingling, problems with your vision, weakness in your arms or legs, and dizziness.. Blood problems. Your body may not make enough of the blood cells that help fight infections or help to stop bleeding. Symptoms include fever that does not go away, bruising or bleeding very easily, or looking very pale.. New heart failure or worsening of heart failure you already have. Call your healthcare provider right away if you get new worsening symptoms of heart failure while taking IDACIO, including:. shortness of breath. sudden weight gain. swelling of your ankles or feet. Immune reactions including lupus-like syndrome. Symptoms include chest discomfort or pain that does not go away, shortness of breath, joint pain, or rash on your cheeks or arms that gets worse in the sun. Symptoms may improve when you stop IDACIO.. Liver Problems. Liver problems can happen in people who use TNF-blocker medicines. These problems can lead to liver failure and death. Call your healthcare provider right away if you have any of these symptoms:. feel very tired. poor appetite or vomiting. skin or eyes look yellow. pain on the right side of your stomach (abdomen). Psoriasis. Some people using adalimumab products had new psoriasis or worsening of psoriasis they already had. Tell your healthcare provider if you develop red scaly patches or raised bumps that are filled with pus. Your healthcare provider may decide to stop your treatment with IDACIO.. injection site reactions: redness, rash, swelling, itching, or bruising. These symptoms usually will go away within few days. Call your healthcare provider right away if you have pain, redness or swelling around the injection site that does not go away within few days or gets worse.. upper respiratory infections (including sinus infections).. headaches.. rash.. Store IDACIO in the refrigerator at 36oF to 46oF (2oC to 8oC). Store IDACIO in the original carton until use to protect it from light.. Do not freeze IDACIO. Do not use IDACIO if frozen, even if it has been thawed.. Refrigerated IDACIO may be used until the expiration date printed on the IDACIO carton. Pen or prefilled syringe. Do not use IDACIO after the expiration date.. If needed, for example when you are traveling, you may also store IDACIO at room temperature up to 77F (25C) for up to 28 days. Store IDACIO in the original carton until use, to protect it from light.. Throw away IDACIO if it has been kept at room temperature and not been used within 28 days.. Record the date you first remove IDACIO from the refrigerator in the spaces provided on the carton.. Do not store IDACIO in extreme heat or cold.. Do not use Pen or prefilled syringe if the liquid is cloudy, discolored, or has flakes or particles in it.. Do not drop or crush IDACIO. The prefilled syringe is glass.

SPL UNCLASSIFIED SECTION.

1.1 Rheumatoid Arthritis. IDACIO is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. IDACIO can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).

STORAGE AND HANDLING SECTION.

Storage and StabilityDo not use beyond the expiration date on the container. IDACIO must be refrigerated at 36F to 46F (2C to 8C). DO NOT FREEZE. Do not use if frozen even if it has been thawed.Store in original carton until time of administration to protect from light.If needed, for example when traveling, IDACIO may be stored at room temperature up to maximum of 77F (25C) for period of up to 28 days, with protection from light. IDACIO should be discarded if not used within the 28-day period. Record the date when IDACIO is first removed from the refrigerator in the spaces provided on the carton.Do not store IDACIO in extreme heat or cold.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable studies with use of adalimumab during pregnancy do not reliably establish an association between adalimumab and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry in pregnant women with rheumatoid arthritis (RA) or Crohns disease (CD) treated with adalimumab. Registry results showed rate of 10% for major birth defects with first trimester use of adalimumab in pregnant women with RA or CD and rate of 7.5% for major birth defects in the disease-matched comparison cohort. The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects (see Data).Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in-utero exposed infant (see Clinical Considerations). In an embryo-fetal perinatal development study conducted in cynomolgus monkeys, no fetal harm or malformations were observed with intravenous administration of adalimumab during organogenesis and later in gestation, at doses that produced exposures up to approximately 373 times the maximum recommended human dose (MRHD) of 40 mg subcutaneous without methotrexate (see Data).The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical Considerations. Disease-associated maternal and embryo/fetal riskPublished data suggest that the risk of adverse pregnancy outcomes in women with RA or inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.. Fetal/Neonatal Adverse ReactionsMonoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester (see Data). Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to adalimumab products in utero [see Use in Specific Populations (8.5)].. Data. Human DataA prospective cohort pregnancy exposure registry conducted by OTIS/MotherToBaby in the U.S. and Canada between 2004 and 2016 compared the risk of major birth defects in live-born infants of 221 women (69 RA, 152 CD) treated with adalimumab during the first trimester and 106 women (74 RA, 32 CD) not treated with adalimumab.The proportion of major birth defects among live-born infants in the adalimumab-treated and untreated cohorts was 10% (8.7% RA, 10.5% CD) and 7.5% (6.8% RA, 9.4% CD), respectively. The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects. This study cannot reliably establish whether there is an association between adalimumab and major birth defects because of methodological limitations of the registry, including small sample size, the voluntary nature of the study, and the non-randomized design.In an independent clinical study conducted in ten pregnant women with IBD treated with adalimumab, adalimumab concentrations were measured in maternal serum as well as in cord blood (n=10) and infant serum (n=8) on the day of birth. The last dose of adalimumab was given between and 56 days prior to delivery. Adalimumab concentrations were 0.16-19.7 mcg/mL in cord blood, 4.28-17.7 mcg/mL in infant serum, and 0-16.1 mcg/mL in maternal serum. In all but one case, the cord blood concentration of adalimumab was higher than the maternal serum concentration, suggesting adalimumab actively crosses the placenta. In addition, one infant had serum concentrations at each of the following: weeks (1.94 mcg/mL), weeks (1.31 mcg/mL), weeks (0.93 mcg/mL), and 11 weeks (0.53 mcg/mL), suggesting adalimumab can be detected in the serum of infants exposed in utero for at least months from birth.. Animal DataIn an embryo-fetal perinatal development study, pregnant cynomolgus monkeys received adalimumab from gestation days 20 to 97 at doses that produced exposures up to 373 times that achieved with the MRHD without methotrexate (on an AUC basis with maternal IV doses up to 100 mg/kg/week). Adalimumab did not elicit harm to the fetuses or malformations.. 8.2 Lactation. Risk SummaryLimited data from case reports in the published literature describe the presence of adalimumab in human milk at infant doses of 0.1% to 1% of the maternal serum concentration. Published data suggest that the systemic exposure to breastfed infant is expected to be low because adalimumab is large molecule and is degraded in the gastrointestinal tract. However, the effects of local exposure in the gastrointestinal tract are unknown. There are no reports of adverse effects of adalimumab products on the breastfed infant and no effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for IDACIO and any potential adverse effects on the breastfed child from IDACIO or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of IDACIO have been established for:reducing signs and symptoms of moderately to severely active polyarticular JIA in pediatric patients years of age and older.the treatment of moderately to severely active Crohns disease in pediatric patients years of age and older.A pediatric assessment for IDACIO demonstrates that IDACIO is safe and effective for pediatric patients in an indication for which HUMIRA (adalimumab) is approved. However, IDACIO is not approved for such indication due to marketing exclusivity for HUMIRA (adalimumab).Due to their inhibition of TNF, adalimumab products administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to adalimumab in utero suggest adalimumab crosses the placenta [see Use in Specific Populations (8.1)]. The clinical significance of elevated adalimumab concentrations in infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants.Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including adalimumab products [see Warnings and Precautions (5.2)].. reducing signs and symptoms of moderately to severely active polyarticular JIA in pediatric patients years of age and older.. the treatment of moderately to severely active Crohns disease in pediatric patients years of age and older.. Juvenile Idiopathic ArthritisIn Study JIA-I, adalimumab was shown to reduce signs and symptoms of active polyarticular JIA in patients to 17 years of age [see Clinical Studies (14.2)]. In Study JIA-II, the safety profile for patients to <4 years of age was similar to the safety profile for patients to 17 years of age with polyarticular JIA [see Adverse Reactions (6.1)]. Adalimumab products have not been studied in patients with polyarticular JIA less than years of age or in patients with weight below 10 kg.The safety of adalimumab in patients in the polyarticular JIA trials was generally similar to that observed in adults with certain exceptions [see Adverse Reactions (6.1)].The safety and effectiveness of adalimumab products have not been established in pediatric patients with JIA less than years of age.. Pediatric Crohns DiseaseThe safety and effectiveness of adalimumab products for the treatment of moderately to severely active Crohns disease have been established in pediatric patients years of age and older. Use of adalimumab products for this indication is supported by evidence from adequate and well-controlled studies in adults with additional data from randomized, double-blind, 52-week clinical study of two dose concentrations of adalimumab in 192 pediatric patients (6 years to 17 years of age) [see Adverse Reactions (6.1), Clinical Pharmacology (12.2, 12.3), Clinical Studies (14.6)]. The adverse reaction profile in patients years to 17 years of age was similar to adults.The safety and effectiveness of adalimumab products have not been established in pediatric patients with Crohns disease less than years of age.. 8.5 Geriatric Use. total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received adalimumab in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these patients and younger patients. The frequency of serious infection and malignancy among adalimumab treated patients 65 years of age and older was higher than for those less than 65 years of age. Consider the benefits and risks of IDACIO in patients 65 years of age and older. In patients treated with IDACIO, closely monitor for the development of infection or malignancy [see Warnings and Precautions (5.1, 5.2)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Serious infections: Do not start IDACIO during an active infection. If an infection develops, monitor carefully, and stop IDACIO if infection becomes serious. (5.1)Invasive fungal infections: For patients who develop systemic illness on IDACIO, 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 virus reactivation: Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop IDACIO 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 IDACIO. (5.6)Heart failure: Worsening or new onset, may occur. (5.8)Lupus-like syndrome: Stop IDACIO if syndrome develops. (5.9). Serious infections: Do not start IDACIO during an active infection. If an infection develops, monitor carefully, and stop IDACIO if infection becomes serious. (5.1). Invasive fungal infections: For patients who develop systemic illness on IDACIO, 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 virus reactivation: Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop IDACIO 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 IDACIO. (5.6). Heart failure: Worsening or new onset, may occur. (5.8). Lupus-like syndrome: Stop IDACIO if syndrome develops. (5.9). 5.1 Serious Infections. Patients treated with adalimumab products including IDACIO 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 TNF blocker and abatacept or anakinra was associated with higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of IDACIO 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 IDACIO 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 history of an opportunistic infection;who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; orwith underlying conditions that may predispose them to infection.. with chronic or recurrent infection;. who have been exposed to tuberculosis;. with 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.. TuberculosisCases 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 IDACIO 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 IDACIO, assess if treatment for latent tuberculosis is needed; and consider an induration of >= mm positive tuberculin skin test result, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).Consider anti-tuberculosis therapy prior to initiation of IDACIO in patients with past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with 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 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 new infection during IDACIO treatment, especially in patients who have previously or recently traveled to countries with high prevalence of tuberculosis, or who have had close contact with person with active tuberculosis.. MonitoringClosely monitor patients for the development of signs and symptoms of infection during and after treatment with IDACIO, 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 IDACIO.Discontinue IDACIO if patient develops serious infection or sepsis. For patient who develops new infection during treatment with IDACIO, closely monitor them, perform prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy.. Invasive Fungal InfectionsIf patients develop 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 diagnostic workup is being performed. To aid in the management of such patients, consider consultation with 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 IDACIO prior to initiating therapy in patients with known malignancy other than successfully treated non-melanoma skin cancer (NMSC) or when considering continuing TNF blocker in patients who develop malignancy.. Malignancies in AdultsIn 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 patients compared to control-treated adult patients. During the controlled portions of 39 global adalimumab clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohns disease (CD), ulcerative colitis (UC), plaque psoriasis (Ps), and other indications, malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at rate (95% confidence interval) of 0.7 (0.48, 1.03) per 100 patient-years among 7973 adalimumab-treated patients versus rate of 0.7 (0.41, 1.17) per 100 patient-years among 4848 control-treated patients (median duration of treatment of months for adalimumab-treated patients and months for control-treated patients). In 52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, and other indications, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in adalimumab-treated patients 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., patients with COPD with significant smoking history and cyclophosphamide-treated patients with Wegeners granulomatosis), greater portion of malignancies occurred in the TNF blocker group compared to the control group.. Non-Melanoma Skin CancerDuring the controlled portions of 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, and other indications, the rate (95% confidence interval) of NMSC was 0.8 (0.52, 1.09) per 100 patient-years among adalimumab-treated patients and 0.2 (0.10, 0.59) per 100 patient-years among control-treated patients. Examine all patients, and in particular patients with medical history of prior prolonged immunosuppressant therapy or psoriasis patients with history of PUVA treatment for the presence of NMSC prior to and during treatment with IDACIO.. Lymphoma and LeukemiaIn the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF-blocker-treated patients compared to control-treated patients. In the controlled portions of 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, and other indications, lymphomas occurred among 7973 adalimumab-treated patients versus among 4848 control-treated patients. In 52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, and other indications with median duration of approximately 0.7 years, including 24,605 patients 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 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 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 higher risk (approximately 2-fold) than the general population for the development of leukemia.. Malignancies in Pediatric Patients and Young AdultsMalignancies, 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 IDACIO is member. Approximately half the cases were lymphomas, including Hodgkins and non-Hodgkins lymphoma. The other cases represented 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 median of 30 months of therapy (range to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from variety of sources including registries and spontaneous postmarketing reports.Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including adalimumab products. These cases have had very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohns 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 TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of TNF blocker or TNF blocker in combination with these other immunosuppressants. The potential risk with the combination of azathioprine or 6-mercaptopurine and IDACIO 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 IDACIO 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 Virus Reactivation. Use of TNF blockers, including IDACIO, may increase the risk of reactivation of hepatitis 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 IDACIO 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 IDACIO 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-Barre syndrome. Exercise caution in considering the use of IDACIO in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of IDACIO should be considered if any of these disorders develop.. 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 IDACIO. Consider discontinuation of IDACIO 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 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 IDACIO 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, higher rate of serious CHF-related adverse reactions was observed. Exercise caution when using IDACIO 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 lupus-like syndrome. If patient develops symptoms suggestive of lupus-like syndrome following treatment with IDACIO, discontinue treatment [see Adverse Reactions (6.1)].. 5.10 Immunizations. In 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 patients 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 IDACIO 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 IDACIO therapy. Patients on IDACIO 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 greater proportion of serious infections than the use of TNF-blocker alone; the combination therapy, compared to the use of TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including IDACIO is not recommended [see Drug Interactions (7.2)].