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 2.Table 2. ACR Responses in Studies RA-II and RA-III (Percent of Patients) p<0.01, adalimumab vs. placeboStudy RA-IIMonotherapy(26 weeks)Study RA-IIIMethotrexate Combination(24 and 52 weeks)ResponsePlaceboAdalimumab40 mg everyother weekAdalimumab40 mg weeklyPlacebo/MTXAdalimumab/MTX40 mg everyother 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 3. 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 (EOW) 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 3. Components of ACR Response in Studies RA-II and RA-IIIa 40 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)PlaceboN=110Adalimumaba N=113 Placebo/MTXN=200Adalimumaba /MTX N=207 BaselineWk 26BaselineWk 26BaselineWk 24BaselineWk 24Number of tenderjoints (0-68)35263116 2615248 Number of swollenjoints (0-66)19161810 1711185 Physician global assessmentb 7.06.16.63.7 6.33.56.52.0 Patient global assessmentb 7.56.37.54.5 5.43.95.22.0 Painb 7.36.17.34.1 6.03.85.82.1 Disability index(HAQ)c 2.01.91.91.5 1.51.31.50.8 CRP (mg/dL)3.94.34.61.8 1.00.91.00.4 The 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 4).Table 4. 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/MTXN=268ACR20 Week 5263%54%73% Week 10456%49%69%ACR50 Week 5246%41%62% Week 10443%37%59%ACR70 Week 5227%26%46% Week 10428%28%47%Major Clinical Responsea 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 1. 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 5. Adalimumab/MTX treated patients demonstrated less radiographic progression than patients receiving MTX alone at 52 weeks.Table 5. Radiographic Mean Changes Over 12 Months in Study RA-III 95% 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% Confidence Interval)P-value Total 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 6).Table 6. 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/MTXN=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 study (Study JIA-I) 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.. 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 8). 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 7. ACR Response in Study PsA-I (Percent of Patients) p<0.001 for all comparisons between adalimumab and placeboPlaceboN=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 8. Components of Disease Activity in Study PsA-Ip<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/dLPlaceboN= 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)d 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 9).Table 9. Change in Modified Total Sharp Score in Psoriatic Arthritis <0.001 for the difference between adalimumab, Week 48 and Placebo, Week 24 (primary analysis)PlaceboN=141Adalimumab N=133 Week 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 10.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 10. 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 24PlaceboN=107Adalimumab N=208BaselinemeanWeek 24 meanBaselinemeanWeek 24 meanASAS 20 Response Criteria Patients Global Assessment of Disease Activitya 65606338Total back pain 67586537Inflammationb 6.75.66.73.6BASFIc 56515234BASDAId score 6.35.56.33.7BASMIe score 4.24.13.83.3Tragus to wall (cm)15.915.815.815.4Lumbar flexion (cm)4.14.04.24.4Cervical rotation (degrees)42.242.148.451.6Lumbar side flexion (cm)8.99.09.711.7Intermalleolar 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 2. 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 11).Table 11. 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-IIPlaceboN=74Adalimumab 160/80 mg N=76 PlaceboN=166Adalimumab 160/80 mg N=159 Week 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 12). 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 12. 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 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 the80/40 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 (eow).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 eow starting at Week through Week 50, or placebo starting at Week and eow 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 14).Table 14. 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-IIPlaceboN=130Adalimumab 160/80 mg N=130 TreatmentDifference(95% CI)PlaceboN=246Adalimumab160/80 mg N=248 Treatment Difference (95% CI)Induction of Clinical Remission (Clinical Remission at Week 8)9.2%18.5%9.3% (0.9%, 17.6%)9.3%16.5%7.2% (1.2%, 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.. 14.7 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 15 and 16).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 15. 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 minimal 506 (62%)17 (4%)PASI 75578 (71%)26 (7%)Table 16. 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 minimal 70 (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 eow beginning at week 1. At week 16, 69% (123/178) of subjects had response of PGA clear or minimal.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most serious adverse reactions described elsewhere in the labeling include the following:Serious Infections [see Warnings and Precautions (5.1)] Malignancies [see Warnings and Precautions (5.2)] Serious Infections [see Warnings and Precautions (5.1)] Malignancies [see Warnings and Precautions (5.2)] Most common adverse reactions (incidence >10%): infections (e.g. upper respiratory, sinusitis), injection site reactions, headache and rash (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., at 1-877-888-4231 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, HS and UV, 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, HS and UV 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 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.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 CD 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 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 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.. ImmunogenicityAs 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 to adalimumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult RA patients receiving adalimumab developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate (MTX) had lower rate of antibody development than patients on adalimumab monotherapy (1% versus 12%). 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.In patients with polyarticular JIA who were to 17 years of age, adalimumab antibodies were identified in 16% of adalimumab-treated patients. In patients receiving concomitant MTX, the incidence was 6% compared to 26% with adalimumab monotherapy.In patients with AS, the rate of development of antibodies to adalimumab in adalimumab-treated patients was comparable to patients with RA.In patients with PsA, the rate of antibody development in patients receiving adalimumab monotherapy was comparable to patients with RA; however, in patients receiving concomitant MTX the rate was 7% compared to 1% in RA.In adult patients with CD, the rate of antibody development was 3%.In patients with moderately to severely active UC, the rate of antibody development in patients receiving adalimumab was 5%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were 2 mcg/mL. Among the patients whose serum adalimumab levels were 2 mcg/mL (approximately 25% of total patients studied), the immunogenicity rate was 20.7%.In patients with Ps, the rate of antibody development with adalimumab monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were 2 mcg/mL. Among the patients whose serum adalimumab levels were 2 mcg/mL (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In Ps patients who were on adalimumab monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal.The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab or titers, and are highly dependent on the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to adalimumab with the incidence of antibodies to other products may be misleading.. 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.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 subcutaneousEvery 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) trial (Study JIA-I) 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 2years 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 levels decreased or returned to normal in all patients. Most patients were able to continue adalimumab without interruption.. 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. 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.. Adult Crohns Disease Clinical StudiesAdalimumab has been studied in 1478 adult patients with Crohns disease (CD) in four placebo- controlled and two open-label extension studies. The safety profile for adult patients with CD treated with adalimumab was similar to the safety profile seen in patients with RA.. Ulcerative Colitis Clinical StudiesAdalimumab has been studied in 1010 patients with ulcerative colitis (UC) in two placebo- controlled studies and one open-label extension study. The safety profile for patients with UC treated with adalimumab 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. 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 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 drug 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), alopeciaVascular disorders: Systemic vasculitis, deep vein thrombosis.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. IMRALDI (adalimumab-xxxx) is supplied as preservative-free, sterile solution for subcutaneous administration. The following packaging configurations are available.IMRALDI Pre-filled Pen Carton 40 mg/0.8 mL IMRALDI is dispensed in carton containing two dose packs, one package insert, one Medication Guide, and one Instructions for Use. Each pack consists of single-dose pre-filled pen, containing 1 mL pre-filled glass syringe with fixed 29 gauge, 1/2 inch needle, providing 40 mg/0.8 mL of IMRALDI. The NDC number is 71202-002-02.. IMRALDI Pre-filled Pen Carton 40 mg/0.8 mL IMRALDI is dispensed in carton containing two dose packs, one package insert, one Medication Guide, and one Instructions for Use. Each pack consists of single-dose pre-filled pen, containing 1 mL pre-filled glass syringe with fixed 29 gauge, 1/2 inch needle, providing 40 mg/0.8 mL of IMRALDI. The NDC number is 71202-002-02.. Storage and StabilityDo not use beyond the expiration date on the container. IMRALDI 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, IMRALDI may be stored at room temperature up to maximum of 77F (25C) for period of up to 14 days, with protection from light. IMRALDI should be discarded if not used within the 14-day period.Do not store IMRALDI in extreme heat or cold.

BOXED WARNING SECTION.

WARNING: SERIOUS INFECTIONS AND MALIGNANCY. 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 IMRALDI if patient develops serious infection or sepsis during treatment.Perform test for latent TB; if positive, start treatment for TB prior to starting IMRALDI.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 IMRALDI if patient develops serious infection or sepsis during treatment.. Perform test for latent TB; if positive, start treatment for TB prior to starting IMRALDI.. 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.. SERIOUS INFECTIONSPatients treated with adalimumab products 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 IMRALDI 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 IMRALDI use and during therapy. Initiate treatment for latent TB prior to IMRALDI 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 IMRALDI 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 IMRALDI, 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)].. 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 IMRALDI use and during therapy. Initiate treatment for latent TB prior to IMRALDI 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.. 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)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies of adalimumab 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 binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels 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 levels of TNF are also found in psoriasis plaques. In Ps, treatment with adalimumab may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab exerts its clinical effects is unknown.Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 10-10 M).. 12.2 Pharmacodynamics. After treatment with adalimumab, decrease in levels 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 levels was also observed in patients with Crohns disease and ulcerative colitis. Serum levels 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 maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 +- 1.6 ug/mL and 131 +- 56 hours respectively, following single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three studies following single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following single intravenous dose.The 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 distribution volume (Vss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/hr. The mean terminal half-life was approximately weeks, ranging from 10 to 20 days across studies. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum.In RA patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations of approximately ug/mL and to ug/mL, were observed without and with methotrexate (MTX), respectively. MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA. Mean serum adalimumab trough levels at steady state increased approximately proportionally with dose following 20, 40, and 80 mg every other week and every week subcutaneous dosing. In long- term studies with dosing more than two years, there was no evidence of changes in clearance over time.Adalimumab mean steady-state trough concentrations were slightly higher in psoriatic arthritis patients treated with 40 mg adalimumab every other week (6 to 10 ug/mL and 8.5 to 12 ug/mL, without and with MTX, respectively) compared to the concentrations in RA patients treated with the same dose.The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.In patients with CD, the loading dose of 160 mg adalimumab on Week followed by 80 mg adalimumab on Week achieves mean serum adalimumab trough levels of approximately 12 ug/mL at Week and Week 4. Mean steady-state trough levels of approximately ug/mL were observed at Week 24 and Week 56 in CD patients after receiving maintenance dose of 40 mg adalimumab every other week.In patients with UC, the loading dose of 160 mg adalimumab on Week followed by 80 mg adalimumab on Week achieves mean serum adalimumab trough levels of approximately 12 ug/mL at Week and Week 4. Mean steady-state trough level of approximately ug/mL was observed at Week 52 in UC patients after receiving dose of 40 mg adalimumab every other week, and approximately 15 ug/mL at Week 52 in UC patients who increased to dose of 40 mg adalimumab every week.In patients with Ps, the mean steady-state trough concentration was approximately to ug/mL during adalimumab 40 mg every other week monotherapy treatment.Population pharmacokinetic analyses in patients with RA revealed that there was trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies, and lower clearance with increasing age in patients aged 40 to >75 years.Minor increases in apparent clearance were also 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.No gender-related pharmacokinetic differences were observed after correction for patients body weight. Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.No pharmacokinetic data are available in patients with hepatic or renal impairment.In Study JIA-I for patients with polyarticular JIA who were to 17 years of age, the mean steady-state trough serum adalimumab concentrations for patients weighing <30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.8 ug/mL and 10.9 ug/mL, respectively. The mean steady-state trough serum adalimumab concentrations for patients weighing >=30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.6 ug/mL and 8.1 ug/mL, respectively.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Adalimumab is recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). Adalimumab is produced by recombinant DNA technology in mammalian cell 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.IMRALDI is supplied as sterile, preservative-free solution of adalimumab for subcutaneous administration. The drug product is supplied as single-dose, pre-filled pen (IMRALDI Pre-filled Pen). Enclosed within the pre-filled pen is single-dose, mL pre-filled glass syringe. The solution of IMRALDI is clear and colorless, with pH of about 5.2.Each 40 mg/0.8 mL pre-filled pen delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of IMRALDI contains adalimumab (40 mg), trisodium citrate dihydrate (1.6 mg), citric acid monohydrate (0.544 mg), histidine (0.96 mg), histidine monohydrochloride monohydrate (8.64 mg), sorbitol (20.0 mg), polysorbate 20 (0.64 mg), and Water for Injection.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. IMRALDI is administered by subcutaneous injection.. Administered by subcutaneous injection (2)Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis (2.1):40 mg every other week.Some patients with RA not receiving methotrexate may benefit from increasing the frequency to 40 mg every week.Juvenile Idiopathic Arthritis (2.2):>= 30 kg (66 lbs) and from to 17 years of age: 40 mg every other weekAdult Crohns Disease and Ulcerative Colitis (2.3, 2.4):Initial dose (Day 1): 160 mg (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days)Second dose two weeks later (Day 15): 80 mgTwo weeks later (Day 29): Begin maintenance dose of 40 mg every other week. For patients with Ulcerative Colitis only: Only continue IMRALDI in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy.Plaque Psoriasis (2.5):80 mg initial dose, followed by 40 mg every other week starting one week after initial dose.. Administered by subcutaneous injection (2). Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis (2.1):40 mg every other week.Some patients with RA not receiving methotrexate may benefit from increasing the frequency to 40 mg every week.. Some patients with RA not receiving methotrexate may benefit from increasing the frequency to 40 mg every week.. >= 30 kg (66 lbs) and from to 17 years of age: 40 mg every other week. Initial dose (Day 1): 160 mg (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days). Second dose two weeks later (Day 15): 80 mgTwo weeks later (Day 29): Begin maintenance dose of 40 mg every other week. Two weeks later (Day 29): Begin maintenance dose of 40 mg every other week.. For patients with Ulcerative Colitis only: Only continue IMRALDI in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy.. 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 dose of IMRALDI 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 IMRALDI. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosing frequency of IMRALDI to 40 mg every week.. 2.2 Juvenile Idiopathic Arthritis. The recommended dose of IMRALDI for patients from years of age and >= 30 kg(66 lbs) with polyarticular juvenile idiopathic arthritis (JIA) is 40 mg administered every other week via subcutaneous injection. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with IMRALDI.Adalimumab has not been studied in patients with polyarticular JIA less than years of age or in patients with weight below 10 kg.. 2.3 Adult Crohns Disease. The recommended IMRALDI dose regimen for adult patients with Crohns disease (CD) is 160 mg initially on Day (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) begin maintenance dose of 40 mg every other week. Aminosalicylates and/or corticosteroids may be continued during treatment with IMRALDI. Azathioprine, 6- mercaptopurine (6-MP) [see Warnings and Precautions (5.2)] or MTX may be continued during treatment with IMRALDI if necessary. The use of adalimumab in CD beyond one year has not been evaluated in controlled clinical studies.. 2.4 Ulcerative Colitis. The recommended IMRALDI dose regimen for adult patients with ulcerative colitis (UC) is 160 mg initially on Day (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) continue with dose of 40 mg every other week.Only continue IMRALDI in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy. Aminosalicylates and/or corticosteroids may be continued during treatment with IMRALDI. Azathioprine and 6-mercaptopurine (6-MP) [see Warnings and Precautions (5.2)] may be continued during treatment with IMRALDI if necessary.. 2.5 Plaque Psoriasis. The recommended dose of IMRALDI 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 in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies.. 2.6 Monitoring to Assess Safety. Prior to initiating IMRALDI and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions (5.1)]. 2.7 General Considerations for Administration. IMRALDI is intended for use under the guidance and supervision of physician. patient may self-inject IMRALDI or caregiver may inject IMRALDI using the IMRALDI Pre-filled Pen if physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique.You may leave IMRALDI at room temperature for about 15 to 30 minutes before injecting. Do not remove the cap while allowing it to reach room temperature. Carefully inspect the solution in the IMRALDI Pre-filled Pen for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. IMRALDI does not contain preservatives; therefore, discard unused portions of drug remaining from the pen.Instruct patients using the IMRALDI Pre-filled Pen to inject the full amount in the pen, 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Pre-filled Pen Injection: 40 mg/0.8 mL of IMRALDI is provided by single-dose pre-filled pen (IMRALDI Pre-filled Pen), containing 1 mL pre-filled glass syringe with fixed 29 gauge and 1/2 inch needle.. Pre-filled Pen Injection: 40 mg/0.8 mL of IMRALDI is provided by single-dose pre-filled pen (IMRALDI Pre-filled Pen), containing 1 mL pre-filled glass syringe with fixed 29 gauge and 1/2 inch needle.. Injection: 40 mg/0.8 mL in single-dose pre-filled pen (IMRALDI Pre-filled Pen) (3). Injection: 40 mg/0.8 mL in single-dose pre-filled pen (IMRALDI Pre-filled Pen) (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 IMRALDI (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 IMRALDI (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 adalimumab 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 seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of IMRALDI with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions (5.7 and 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 adalimumab and other biologic products for the treatment of RA, PsA, AS, CD, UC and Ps. Concomitant administration of IMRALDI 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 IMRALDI [see Warnings and Precautions (5.10)]. 7.4 Cytochrome P450 Substrates. The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNF, IL-6) during chronic inflammation. It is possible for molecule that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of IMRALDI 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 over 65 years of age was higher than for those under 65 years of age. Because there is higher incidence of infections and malignancies in the elderly population, use caution when treating the elderly.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. IMRALDI is tumor necrosis factor (TNF) blocker indicated for treatment of: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 from to 17 years of age and >=30 kg (66 lbs).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.Adult Crohns Disease (CD) (1.5): Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohns disease who have had an inadequate response to conventional therapy. Reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.Ulcerative Colitis (UC) (1.6): Inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP). The effectiveness of adalimumab products has not been established in patients who have lost response to or were intolerant to TNF blockers.Plaque Psoriasis (Ps) (1.7): 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.. 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 from to 17 years of age and >=30 kg (66 lbs).. 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.. Adult Crohns Disease (CD) (1.5): Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohns disease who have had an inadequate response to conventional therapy. Reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.. Ulcerative Colitis (UC) (1.6): Inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP). The effectiveness of adalimumab products has not been established in patients who have lost response to or were intolerant to TNF blockers.. Plaque Psoriasis (Ps) (1.7): 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.. 1.1 Rheumatoid Arthritis. IMRALDI 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. IMRALDI can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).. 1.2 Juvenile Idiopathic Arthritis. IMRALDI is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients from to 17 years of age and >= 30 kg (66 lbs). IMRALDI can be used alone or in combination with methotrexate.. 1.3 Psoriatic Arthritis. IMRALDI is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. IMRALDI can be used alone or in combination with non-biologic DMARDs.. 1.4 Ankylosing Spondylitis. IMRALDI is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.. 1.5 Adult Crohns Disease. IMRALDI is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohns disease who have had an inadequate response to conventional therapy. IMRALDI is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.. 1.6 Ulcerative Colitis. IMRALDI is indicated for inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP). The effectiveness of adalimumab has not been established in patients who have lost response to or were intolerant to TNF blockers [see Clinical Studies (14.7)].. 1.7 Plaque Psoriasis. IMRALDI 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. IMRALDI should only be administered to patients who will be closely monitored and have regular follow-up visits with physician [see Boxed Warning and Warnings and Precautions (5)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Medication Guide and Instructions for Use).. Patient CounselingProvide the IMRALDI Medication Guide to patients or their caregivers, and provide them an opportunity to read it and ask questions prior to initiation of therapy and prior to each time the prescription is renewed. If patients develop signs and symptoms of infection, instruct them to seek medical evaluation immediately.Advise patients of the potential benefits and risks of IMRALDI.Infections Inform patients that IMRALDI 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.Malignancies Counsel patients about the risk of malignancies while receiving IMRALDI.Allergic Reactions Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions.Other Medical Conditions Advise 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.. Infections Inform patients that IMRALDI 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.. Malignancies Counsel patients about the risk of malignancies while receiving IMRALDI.. Allergic Reactions Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions.. Other Medical Conditions Advise 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.. 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 IMRALDI, instruct them in injection techniques and assess their ability to inject subcutaneously to ensure the proper administration of IMRALDI [see Instructions for Use]. For patients who will use the IMRALDI Pre-filled Pen, tell them that they:May hear 1 st click when they place the red base straight on their skin and push the entire pen down firmly. The click means the start of the injection.Must keep holding the IMRALDI Pre-filled Pen against their skin until all of the medicine is injected.Will know that the injection has finished when the yellow indicator fills the medication window and stops moving. Also they may hear 2 nd click several seconds after starting the injection.Instruct patients to dispose of their used pre-filled pen in FDA-cleared sharps disposal container immediately after use. Instruct patients not to dispose of pre-filled pen 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 pen. 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: Samsung Bioepis Co., Ltd., 107, Cheomdan-daero, Yeonsu-gu, Incheon, 21987, Republic of KoreaU.S. License No. 2046Manufactured for: Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., Kenilworth, NJ 07033 USA. May hear 1 st click when they place the red base straight on their skin and push the entire pen down firmly. The click means the start of the injection.. Must keep holding the IMRALDI Pre-filled Pen against their skin until all of the medicine is injected.. Will know that the injection has finished when the yellow indicator fills the medication window and stops moving. Also they may hear 2 nd click several seconds after starting the injection.. Samsung Bioepis Logo. Merck Logo.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEIMRALDI Pre-filled Pen (Im-RAL-di)(adalimumab-xxxx)40 mg/0.8 mLSingle-Dose Pre-filled penThe following instructions are for preparing and giving dose of IMRALDI Pre-filled Pen using single-dose pen. Read this Instructions for Use before you start using IMRALDI Pre-filled Pen.Your single-dose pre-filled pen:There is no button on your pre-filled pen. The needle is hidden below the green base. When you push the pre-filled pen firmly onto your skin, the injection will start automatically.Step 1: Gather suppliesPlace your pre-filled pen and alcohol swabs on clean, dry surface.Remember to wash your hands.Dont remove the cap just yet.Step 2: Wait 15-30 minutesWait 15-30 minutes for your pre-filled pen to reach to room temperature, which helps to reduce pain during injection.Dont remove the cap just yet.Step 3: Inspect medicine dateAlways make sure your medicine is clear, free of particles, and hasnt expired.You may see an air bubble, and thats okay.Dont remove the cap just yet.Step 4: Choose site clean skinChoose an injection site on your body.Your abdomen or thighs are best.Wipe the injection site with an alcohol swab.Avoid skin thats sore, bruised, scarred, scaly or has red patches.Step 5: Pull off the clear needle capCarefully pull off the needle cap with metal center from the pen.Step 6: Place green base, press down, and holdPlace the green base straight on your skin, and push the entire pre-filled pen down firmly to start the injection.When you push down, the injection starts.You may hear 1st click.Step 7: Continue to holdHold the pen against your skin until the yellow indicator fills the medication window and stops moving.Several seconds later you may hear 2nd click.Step 8: Confirm completion dispose penConfirm that the entire medication window is yellow.Discard your pre-filled pen in sharps container.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by: Samsung Bioepis Co., Ltd., 107, Cheomdan-daero, Yeonsu-gu, Incheon, 21987, Republic of KoreaU.S. License No. 2046Manufactured for: Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., Kenilworth, NJ 07033 USALast Revised <MM/YYYY>. Place your pre-filled pen and alcohol swabs on clean, dry surface.. Remember to wash your hands.. Dont remove the cap just yet.. Wait 15-30 minutes for your pre-filled pen to reach to room temperature, which helps to reduce pain during injection.. Dont remove the cap just yet.. Always make sure your medicine is clear, free of particles, and hasnt expired.. You may see an air bubble, and thats okay.. Dont remove the cap just yet.. Choose an injection site on your body.. Your abdomen or thighs are best.. Wipe the injection site with an alcohol swab.. Avoid skin thats sore, bruised, scarred, scaly or has red patches.. Carefully pull off the needle cap with metal center from the pen.. Place the green base straight on your skin, and push the entire pre-filled pen down firmly to start the injection.. When you push down, the injection starts.. You may hear 1st click.. Hold the pen against your skin until the yellow indicator fills the medication window and stops moving.. Several seconds later you may hear 2nd click.. Confirm that the entire medication window is yellow.. Discard your pre-filled pen in sharps container.. 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 level. There are no reports of adverse effects of adalimumab 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 adalimumab and any potential adverse effects on the breastfed child from adalimumab or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels 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 levels of TNF are also found in psoriasis plaques. In Ps, treatment with adalimumab may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab exerts its clinical effects is unknown.Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 10-10 M).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies of adalimumab 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 Imraldi Pre-filled Pen LabelNDC 71202-002-02ImraldiEXP:(adalimumab-xxxx) injectionLOT:40 mg/0.8 mLSingle-Dose Pre-filled PenFor Subcutaneous Use only Rx only Manuf by: Samsung Bioepis Co., Ltd.Incheon, 21987 Republic of KoreaLicense No. 2046Manuf for: Merck Sharp Dohme Corp.,a subsidiary of Merck Co., Inc.. Principal Display Panel Imraldi Pre-filled Pen Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and efficacy of adalimumab products in pediatric patients for uses other than polyarticular juvenile idiopathic arthritis (JIA) and pediatric Crohns disease have not been established. Due to its 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 levels 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 Boxed Warning and Warnings and Precautions (5.2)].. 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)]. 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 products in patients in the polyarticular JIA trials was generally similar to that observed in adults with certain exceptions [see Adverse Reactions (6.1)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. After treatment with adalimumab, decrease in levels 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 levels was also observed in patients with Crohns disease and ulcerative colitis. Serum levels 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 maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 +- 1.6 ug/mL and 131 +- 56 hours respectively, following single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three studies following single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following single intravenous dose.The 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 distribution volume (Vss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/hr. The mean terminal half-life was approximately weeks, ranging from 10 to 20 days across studies. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum.In RA patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations of approximately ug/mL and to ug/mL, were observed without and with methotrexate (MTX), respectively. MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA. Mean serum adalimumab trough levels at steady state increased approximately proportionally with dose following 20, 40, and 80 mg every other week and every week subcutaneous dosing. In long- term studies with dosing more than two years, there was no evidence of changes in clearance over time.Adalimumab mean steady-state trough concentrations were slightly higher in psoriatic arthritis patients treated with 40 mg adalimumab every other week (6 to 10 ug/mL and 8.5 to 12 ug/mL, without and with MTX, respectively) compared to the concentrations in RA patients treated with the same dose.The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.In patients with CD, the loading dose of 160 mg adalimumab on Week followed by 80 mg adalimumab on Week achieves mean serum adalimumab trough levels of approximately 12 ug/mL at Week and Week 4. Mean steady-state trough levels of approximately ug/mL were observed at Week 24 and Week 56 in CD patients after receiving maintenance dose of 40 mg adalimumab every other week.In patients with UC, the loading dose of 160 mg adalimumab on Week followed by 80 mg adalimumab on Week achieves mean serum adalimumab trough levels of approximately 12 ug/mL at Week and Week 4. Mean steady-state trough level of approximately ug/mL was observed at Week 52 in UC patients after receiving dose of 40 mg adalimumab every other week, and approximately 15 ug/mL at Week 52 in UC patients who increased to dose of 40 mg adalimumab every week.In patients with Ps, the mean steady-state trough concentration was approximately to ug/mL during adalimumab 40 mg every other week monotherapy treatment.Population pharmacokinetic analyses in patients with RA revealed that there was trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies, and lower clearance with increasing age in patients aged 40 to >75 years.Minor increases in apparent clearance were also 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.No gender-related pharmacokinetic differences were observed after correction for patients body weight. Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.No pharmacokinetic data are available in patients with hepatic or renal impairment.In Study JIA-I for patients with polyarticular JIA who were to 17 years of age, the mean steady-state trough serum adalimumab concentrations for patients weighing <30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.8 ug/mL and 10.9 ug/mL, respectively. The mean steady-state trough serum adalimumab concentrations for patients weighing >=30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.6 ug/mL and 8.1 ug/mL, respectively.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryLimited clinical data are available from the Humira Pregnancy Registry. Excluding lost-to follow-up, data from the registry reports rate of 5.6% for major birth defects with first trimester use of adalimumab in pregnant women with rheumatoid arthritis (RA), and rate of 7.8% and 5.5% for major birth defects in the disease-matched and non-diseased comparison groups [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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and miscarriage is 15-20%, respectively.. Clinical Considerations. 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 (8.4)].. Data. Human DataIn prospective cohort pregnancy exposure registry conducted in the U.S. and Canada between 2004 and 2013, 74 women with RA treated with adalimumab at least during the first trimester, 80 women with RA not treated with adalimumab and 218 women without RA (non-diseased) were enrolled. Excluding lost-to-follow-up, the rate of major defects in the adalimumab-exposed pregnancies (N=72), disease-matched (N=77), and non-diseased comparison groups (N=201) was 5.6%, 7.8% and 5.5%, respectively. However, this study cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and nonrandomized study design. Data from the Crohns disease portion of the study is in the follow-up phase and the analysis is ongoing.In an independent clinical study conducted in ten pregnant women with inflammatory bowel disease 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 ug/mL in cord blood, 4.28-17.7 ug/mL in infant serum, and 0-16.1 ug/mL in maternal serum. In all but one case, the cord blood level of adalimumab was higher than the maternal serum level, suggesting adalimumab actively crosses the placenta. In addition, one infant had serum levels at each of the following: weeks (1.94 ug/mL), weeks (1.31 ug/mL), weeks (0.93 ug/mL), and 11 weeks (0.53 ug/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.Hyams JS, Ferry GD, Mandel FS, et al. Development and validation of pediatric Crohns disease activity index. Pediatr Gastroenterol Nutr. 1991;12:439-447.. National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Incidence Crude Rates, 17 Registries, 2000-2007.. Hyams JS, Ferry GD, Mandel FS, et al. Development and validation of pediatric Crohns disease activity index. Pediatr Gastroenterol Nutr. 1991;12:439-447.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Issued: MM/YYYYMEDICATION GUIDEIMRALDI (Im-RAL-di)(adalimumab-xxxx)injectionRead the Medication Guide that comes with IMRALDI 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 doctor about your medical condition or treatment.What is the most important information should know about IMRALDIIMRALDI is medicine that affects your immune system. IMRALDI can lower the ability of your immune system to fight infections. Serious infections have happened in people taking TNF blockers including 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 doctor should test you for TB before starting IMRALDI.Your doctor should check you closely for signs and symptoms of TB during treatment with IMRALDI. You should not start taking IMRALDI if you have any kind of infection unless your doctor says it is okay. Before starting IMRALDI, tell your doctor if you: think you have an infection or have symptoms of 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 tired weight loss are being treated for an infectionget lot of infections or have infections that keep coming backhave diabeteshave TB, or have been in close contact with someone with TBwere born in, lived in, or traveled to countries where there is more risk for getting TB. Ask your doctor 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 IMRALDI. Ask your doctor 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(R) (abatacept), KINERET(R) (anakinra), RITUXAN(R) (rituximab), IMURAN(R) (azathioprine), or PURINETHOL(R) (6-mercaptopurine, 6-MP).are scheduled to have major surgery After starting IMRALDI, call your doctor right away if you have an infection, or any sign of an infection.IMRALDI can make you more likely to get infections or make any infection that you may have worse. Cancer For children and adults taking TNF-blockers, including adalimumab products, 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 RA, especially more serious RA, may have higher chance for getting kind of cancer called lymphoma.If you use TNF blockers including adalimumab product 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 doctor if you have bump or open sore that doesnt heal.Some people receiving TNF blockers including adalimumab products 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(R) (azathioprine) or PURINETHOL(R) (6-mercaptopurine, 6-MP). What is IMRALDIIMRALDI is medicine called Tumor Necrosis Factor (TNF) blocker. IMRALDI is used:To reduce the signs and symptoms of:moderate to severe rheumatoid arthritis (RA) in adults. IMRALDI can be used alone, with methotrexate, or with certain other medicines.moderate to severe polyarticular juvenile idiopathic arthritis (JIA) in children from years of age and >= 30 kg (66 lbs). IMRALDI can be used alone, with methotrexate, or with certain other medicines.psoriatic arthritis (PsA) in adults. IMRALDI can be used alone or with certain other medicines.ankylosing spondylitis (AS) in adults.moderate to severe Crohns disease (CD) in adults when other treatments have not worked well enough. In adults, to help get moderate to severe ulcerative colitis (UC) under control (induce remission) and keep it under control (sustain remission) when certain other medicines have not worked well enough. It is not known if IMRALDI is 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 doctor before taking IMRALDIIMRALDI may not be right for you. Before starting IMRALDI, tell your doctor about all of your health conditions, including if you:have an infection. See What is the most important information should know about IMRALDI 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 IMRALDI. Children should be brought up to date with all vaccines before starting IMRALDI.are allergic to IMRALDI or to any of its ingredients. See the end of this Medication Guide for list of ingredients in IMRALDI.are pregnant or plan to become pregnant. It is not known if IMRALDI will harm your unborn baby. IMRALDI should only be used during pregnancy if needed.have baby and you were using IMRALDI during your pregnancy. Tell your babys doctor before your baby receives any vaccines.breastfeeding or plan to breastfeed. You and your doctor should decide if you will breastfeed or use IMRALDI. You should not do both.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your doctor if you use: ORENCIA(R) (abatacept), KINERET(R) (anakinra), REMICADE(R) (infliximab), ENBREL(R) (etanercept), CIMZIA(R) (certolizumab pegol) or SIMPONI(R) (golimumab), because you should not use IMRALDI while you are also using one of these medicines.RITUXAN(R) (rituximab). Your doctor may not want to give you IMRALDI if you have received RITUXAN(R) (rituximab) recently.IMURAN(R) (azathioprine) or PURINETHOL(R) (6-mercaptopurine, 6-MP). Keep list of your medicines with you to show your doctor and pharmacist each time you get new medicine.How should take IMRALDIIMRALDI is given by an injection under the skin. Your doctor will tell you how often to take an injection of IMRALDI. This is based on your condition to be treated. Do not inject IMRALDI 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 IMRALDI.Make sure you have been shown how to inject IMRALDI before you do it yourself. You can call your doctor or 1-877-888-4231 if you have any questions about giving yourself an injection. Someone you know can also help you with your injection after they have been shown how to prepare and inject IMRALDI.Do not try to inject IMRALDI yourself until you have been shown the right way to give the injections. If your doctor decides that you or caregiver may be able to give your injections of IMRALDI at home, you should receive training on the right way to prepare and inject IMRALDI.Do not miss any doses of IMRALDI unless your doctor says it is okay. If you forget to take IMRALDI, 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 IMRALDI, call your doctor or pharmacist.If you take more IMRALDI than you were told to take, call your doctor.What are the possible side effects of IMRALDIIMRALDI can cause serious side effects, including:See What is the most important information should know about IMRALDISerious Infections. Your doctor will examine you for TB and perform test to see if you have TB. If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with IMRALDI and during treatment with IMRALDI. Even if your TB test is negative your doctor should carefully monitor you for TB infections while you are taking IMRALDI. People who had negative TB skin test before receiving adalimumab have developed active TB. Tell your doctor if you have any of the following symptoms while taking or after taking IMRALDI:cough that does not go awaylow grade feverweight lossloss 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 IMRALDI. Your doctor should do blood tests before you start treatment, while you are using IMRALDI, and for several months after you stop treatment with IMRALDI. Tell your doctor 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 rashclay-colored bowel movementsAllergic reactions. Allergic reactions can happen in people who use adalimumab products. Call your doctor 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 doctor right away if you get new worsening symptoms of heart failure while taking IMRALDI, 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 IMRALDI.Liver Problems. Liver problems can happen in people who use TNF-blocker medicines. These problems can lead to liver failure and death. Call your doctor 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 doctor if you develop red scaly patches or raised bumps that are filled with pus. Your doctor may decide to stop your treatment with IMRALDI.Call your doctor or get medical care right away if you develop any of the above symptoms. Your treatment with IMRALDI may be stopped. Common side effects with adalimumab products include:injection site reactions: redness, rash, swelling, itching, or bruising. These symptoms usually will go away within few days. Call your doctor 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)headachesrash These are not all the possible side effects with IMRALDI. Tell your doctor if you have any side effect that bothers you or that does not go away. Ask your doctor or pharmacist for more information.Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.How should store IMRALDIStore IMRALDI in the refrigerator at 36oF to 46oF (2oC to 8oC). Store IMRALDI in the original carton until use to protect it from light.Do not freeze IMRALDI. Do not use IMRALDI if frozen, even if it has been thawed.Refrigerated IMRALDI may be used until the expiration date printed on the IMRALDI carton, dose pack, pre-filled pen. Do not use IMRALDI after the expiration date.If needed, for example when you are traveling, you may also store IMRALDI at room temperature up to 77F (25C) for up to 14 days. Store IMRALDI in the original carton until use to protect it from light.Throw away IMRALDI if it has been kept at room temperature and not been used within 14 days.Record the date you first remove IMRALDI from the refrigerator in the spaces provided on the carton and dose tray.Do not store IMRALDI in extreme heat or cold.Do not use pre-filled pen if the liquid is cloudy, discolored, or has flakes or particles in it.Do not drop or crush IMRALDI. Keep IMRALDI, injection supplies, and all other medicines out of the reach of children.General information about the safe and effective use of IMRALDIMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use IMRALDI for condition for which it was not prescribed. Do not give IMRALDI to other people, even if they have the same condition. It may harm them.This Medication Guide summarizes the most important information about IMRALDI. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about IMRALDI that is written for health professionals. For more information go to www.XXXXXXX.com or call Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc. at 1-877-888-4231.What are the ingredients in IMRALDIActive ingredient: adalimumab IMRALDI Pre-filled Pen 40 mg/0.8 mL: Inactive ingredients: trisodium citrate dihydrate, citric acid monohydrate, histidine, histidine monohydrochloride monohydrate, sorbitol, polysorbate 20, and Water for Injection. Manufactured by: Samsung Bioepis Co., Ltd., 107, Cheomdan-daero, Yeonsu-gu, Incheon, 21987, Republic of Korea Manufactured for: Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., Kenilworth, NJ 07033 USAUS License Number 2046 Your doctor should test you for TB before starting IMRALDI.. Your doctor should check you closely for signs and symptoms of TB during treatment with IMRALDI. think you have an infection or have symptoms of 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 doctor 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 IMRALDI. Ask your doctor 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(R) (abatacept), KINERET(R) (anakinra), RITUXAN(R) (rituximab), IMURAN(R) (azathioprine), or PURINETHOL(R) (6-mercaptopurine, 6-MP).. are scheduled to have major surgery For children and adults taking TNF-blockers, including adalimumab products, 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 RA, especially more serious RA, may have higher chance for getting kind of cancer called lymphoma.. If you use TNF blockers including adalimumab product 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 doctor if you have bump or open sore that doesnt heal.. Some people receiving TNF blockers including adalimumab products 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(R) (azathioprine) or PURINETHOL(R) (6-mercaptopurine, 6-MP).. To reduce the signs and symptoms of:moderate to severe rheumatoid arthritis (RA) in adults. IMRALDI can be used alone, with methotrexate, or with certain other medicines.moderate to severe polyarticular juvenile idiopathic arthritis (JIA) in children from years of age and >= 30 kg (66 lbs). IMRALDI can be used alone, with methotrexate, or with certain other medicines.psoriatic arthritis (PsA) in adults. IMRALDI can be used alone or with certain other medicines.ankylosing spondylitis (AS) in adults.moderate to severe Crohns disease (CD) in adults when other treatments have not worked well enough. moderate to severe rheumatoid arthritis (RA) in adults. IMRALDI can be used alone, with methotrexate, or with certain other medicines.. moderate to severe polyarticular juvenile idiopathic arthritis (JIA) in children from years of age and >= 30 kg (66 lbs). IMRALDI can be used alone, with methotrexate, or with certain other medicines.. psoriatic arthritis (PsA) in adults. IMRALDI can be used alone or with certain other medicines.. ankylosing spondylitis (AS) in adults.. moderate to severe Crohns disease (CD) in adults when other treatments have not worked well enough.. In adults, to help get moderate to severe ulcerative colitis (UC) under control (induce remission) and keep it under control (sustain remission) when certain other medicines have not worked well enough. It is not known if IMRALDI is 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 IMRALDI 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 IMRALDI. Children should be brought up to date with all vaccines before starting IMRALDI.. are allergic to IMRALDI or to any of its ingredients. See the end of this Medication Guide for list of ingredients in IMRALDI.. are pregnant or plan to become pregnant. It is not known if IMRALDI will harm your unborn baby. IMRALDI should only be used during pregnancy if needed.. have baby and you were using IMRALDI during your pregnancy. Tell your babys doctor before your baby receives any vaccines.. breastfeeding or plan to breastfeed. You and your doctor should decide if you will breastfeed or use IMRALDI. You should not do both.. ORENCIA(R) (abatacept), KINERET(R) (anakinra), REMICADE(R) (infliximab), ENBREL(R) (etanercept), CIMZIA(R) (certolizumab pegol) or SIMPONI(R) (golimumab), because you should not use IMRALDI while you are also using one of these medicines.. RITUXAN(R) (rituximab). Your doctor may not want to give you IMRALDI if you have received RITUXAN(R) (rituximab) recently.. IMURAN(R) (azathioprine) or PURINETHOL(R) (6-mercaptopurine, 6-MP). IMRALDI is given by an injection under the skin. Your doctor will tell you how often to take an injection of IMRALDI. This is based on your condition to be treated. Do not inject IMRALDI 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 IMRALDI.. Make sure you have been shown how to inject IMRALDI before you do it yourself. You can call your doctor or 1-877-888-4231 if you have any questions about giving yourself an injection. Someone you know can also help you with your injection after they have been shown how to prepare and inject IMRALDI.. Do not try to inject IMRALDI yourself until you have been shown the right way to give the injections. If your doctor decides that you or caregiver may be able to give your injections of IMRALDI at home, you should receive training on the right way to prepare and inject IMRALDI.. Do not miss any doses of IMRALDI unless your doctor says it is okay. If you forget to take IMRALDI, 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 IMRALDI, call your doctor or pharmacist.. If you take more IMRALDI than you were told to take, call your doctor.. Serious Infections. Your doctor will examine you for TB and perform test to see if you have TB. If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with IMRALDI and during treatment with IMRALDI. Even if your TB test is negative your doctor should carefully monitor you for TB infections while you are taking IMRALDI. People who had negative TB skin test before receiving adalimumab have developed active TB. Tell your doctor if you have any of the following symptoms while taking or after taking IMRALDI:. cough that does not go away. low grade fever. weight loss. 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 IMRALDI. Your doctor should do blood tests before you start treatment, while you are using IMRALDI, and for several months after you stop treatment with IMRALDI. Tell your doctor 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. clay-colored bowel movements. Allergic reactions. Allergic reactions can happen in people who use adalimumab products. Call your doctor 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 doctor right away if you get new worsening symptoms of heart failure while taking IMRALDI, 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 IMRALDI.. Liver Problems. Liver problems can happen in people who use TNF-blocker medicines. These problems can lead to liver failure and death. Call your doctor 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 doctor if you develop red scaly patches or raised bumps that are filled with pus. Your doctor may decide to stop your treatment with IMRALDI.. injection site reactions: redness, rash, swelling, itching, or bruising. These symptoms usually will go away within few days. Call your doctor 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 IMRALDI in the refrigerator at 36oF to 46oF (2oC to 8oC). Store IMRALDI in the original carton until use to protect it from light.. Do not freeze IMRALDI. Do not use IMRALDI if frozen, even if it has been thawed.. Refrigerated IMRALDI may be used until the expiration date printed on the IMRALDI carton, dose pack, pre-filled pen. Do not use IMRALDI after the expiration date.. If needed, for example when you are traveling, you may also store IMRALDI at room temperature up to 77F (25C) for up to 14 days. Store IMRALDI in the original carton until use to protect it from light.. Throw away IMRALDI if it has been kept at room temperature and not been used within 14 days.. Record the date you first remove IMRALDI from the refrigerator in the spaces provided on the carton and dose tray.. Do not store IMRALDI in extreme heat or cold.. Do not use pre-filled pen if the liquid is cloudy, discolored, or has flakes or particles in it.. Do not drop or crush IMRALDI.

SPL UNCLASSIFIED SECTION.

SERIOUS INFECTIONSPatients treated with adalimumab products 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 IMRALDI 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 IMRALDI use and during therapy. Initiate treatment for latent TB prior to IMRALDI 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 IMRALDI 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 IMRALDI, 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)].. 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 IMRALDI use and during therapy. Initiate treatment for latent TB prior to IMRALDI 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.

STORAGE AND HANDLING SECTION.

Storage and StabilityDo not use beyond the expiration date on the container. IMRALDI 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, IMRALDI may be stored at room temperature up to maximum of 77F (25C) for period of up to 14 days, with protection from light. IMRALDI should be discarded if not used within the 14-day period.Do not store IMRALDI in extreme heat or cold.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryLimited clinical data are available from the Humira Pregnancy Registry. Excluding lost-to follow-up, data from the registry reports rate of 5.6% for major birth defects with first trimester use of adalimumab in pregnant women with rheumatoid arthritis (RA), and rate of 7.8% and 5.5% for major birth defects in the disease-matched and non-diseased comparison groups [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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and miscarriage is 15-20%, respectively.. Clinical Considerations. 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 (8.4)].. Data. Human DataIn prospective cohort pregnancy exposure registry conducted in the U.S. and Canada between 2004 and 2013, 74 women with RA treated with adalimumab at least during the first trimester, 80 women with RA not treated with adalimumab and 218 women without RA (non-diseased) were enrolled. Excluding lost-to-follow-up, the rate of major defects in the adalimumab-exposed pregnancies (N=72), disease-matched (N=77), and non-diseased comparison groups (N=201) was 5.6%, 7.8% and 5.5%, respectively. However, this study cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and nonrandomized study design. Data from the Crohns disease portion of the study is in the follow-up phase and the analysis is ongoing.In an independent clinical study conducted in ten pregnant women with inflammatory bowel disease 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 ug/mL in cord blood, 4.28-17.7 ug/mL in infant serum, and 0-16.1 ug/mL in maternal serum. In all but one case, the cord blood level of adalimumab was higher than the maternal serum level, suggesting adalimumab actively crosses the placenta. In addition, one infant had serum levels at each of the following: weeks (1.94 ug/mL), weeks (1.31 ug/mL), weeks (0.93 ug/mL), and 11 weeks (0.53 ug/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 level. There are no reports of adverse effects of adalimumab 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 adalimumab and any potential adverse effects on the breastfed child from adalimumab or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and efficacy of adalimumab products in pediatric patients for uses other than polyarticular juvenile idiopathic arthritis (JIA) and pediatric Crohns disease have not been established. Due to its 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 levels 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 Boxed Warning and Warnings and Precautions (5.2)].. 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)]. 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 products in patients in the polyarticular JIA trials was generally similar to that observed in adults with certain exceptions [see Adverse Reactions (6.1)].. 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 over 65 years of age was higher than for those under 65 years of age. Because there is higher incidence of infections and malignancies in the elderly population, use caution when treating the elderly.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Serious infections: Do not start IMRALDI during an active infection. If an infection develops, monitor carefully, and stop IMRALDI if infection becomes serious (5.1)Invasive fungal infections: For patients who develop systemic illness on IMRALDI, 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 allergic reactions may occur (5.3)Hepatitis virus reactivation: Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop IMRALDI 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 IMRALDI (5.6)Heart failure: Worsening or new onset, may occur (5.8)Lupus-like syndrome: Stop IMRALDI if syndrome develops (5.9). Serious infections: Do not start IMRALDI during an active infection. If an infection develops, monitor carefully, and stop IMRALDI if infection becomes serious (5.1). Invasive fungal infections: For patients who develop systemic illness on IMRALDI, 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 allergic reactions may occur (5.3). Hepatitis virus reactivation: Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop IMRALDI 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 IMRALDI (5.6). Heart failure: Worsening or new onset, may occur (5.8). Lupus-like syndrome: Stop IMRALDI if syndrome develops (5.9). 5.1 Serious Infections. Patients treated with adalimumab products are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death [see Boxed Warning]. 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 IMRALDI 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 IMRALDI should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. 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 IMRALDI 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 IMRALDI, 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 IMRALDI 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 IMRALDI 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 IMRALDI, 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 IMRALDI.Discontinue IMRALDI if patient develops serious infection or sepsis. For patient who develops new infection during treatment with IMRALDI, 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 adalimumab products 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), hidradenitis suppurativa (HS) and uveitis (UV), 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, HS and UV the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in adalimumab-treated 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, HS and UV, 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 adalimumab.. 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, HS and UV, 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, HS and UV with median duration of approximately 0.7 years, including 24,605 patients and over 40,125 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 adalimumab products are member [see Boxed Warning]. 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 [see Boxed Warning]. 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 IMRALDI 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 IMRALDI and institute appropriate therapy. In clinical trials of adalimumab products in adults, allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed.. 5.4 Hepatitis Virus Reactivation. Use of TNF blockers, including adalimumab products, 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 IMRALDI 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 IMRALDI 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 IMRALDI in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of IMRALDI 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. The causal relationship of these reports to adalimumab 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 IMRALDI. Consider discontinuation of IMRALDI therapy in patients with confirmed significant hematologic abnormalities.. 5.7 Use 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 IMRALDI 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 has 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 IMRALDI in patients who have heart failure and monitor them carefully.. 5.9 Autoimmunity. Treatment with IMRALDI 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 IMRALDI, 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 IMRALDI 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 IMRALDI therapy. Patients on IMRALDI 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 Use 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 adalimumab products is not recommended [see Drug Interactions (7.2)].