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Data Sheet

HUMIRA^®

Adalimumab

NAME OF THE MEDICINE

Adalimumab (rch)

DESCRIPTION

Humira (adalimumab) is a recombinant human immunoglobulin (IgG1) monoclonal antibody containing only human peptide sequences. Humira was created using phage display technology resulting in fully human heavy and light chain variable regions, which confer specificity to human tumour necrosis factor (TNF), and human IgG1 heavy chain and kappa light chain sequences. Humira binds with high affinity and specificity to soluble tumour necrosis factor (TNF-alpha) but not lymphotoxin (TNF-beta). Adalimumab is produced by recombinant DNA technology in a mammalian cell expression system. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.

Humira is supplied as a sterile, preservative-free solution of adalimumab for subcutaneous administration. The solution of Humira is clear and colourless with a pH of 5.2. The drug product is supplied as either a single-use prefilled glass syringe, vial or as a single use, prefilled pen (Humira Pen). Enclosed within the pen is a single-use, prefilled glass syringe. All presentations contain 40mg adalimumab per 0.8 mL (50 mg/mL).

Inactive ingredients include: 4.93 mg sodium chloride, 0.69 mg monobasic sodium phosphate dihydrate, 1.22 mg dibasic sodium phosphate dihydrate, 0.24 mg sodium citrate, 1.04 mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 80 and water for injections.

PHARMACOLOGY

General

Adalimumab binds to TNF and neutralises the biological function of TNF by blocking its interaction with the p55 and p75 cell surface TNF receptors. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients 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 (Ps) plaques, which contribute to the inflammatory response, to the proliferation and decreased maturation of keratinocytes and to the associated vascular damages that are characteristic of the disease.

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 X 10^-10 M).

Pharmacodynamics

After treatment with Humira, a rapid 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 RA. In patients with Crohn's disease, a decrease in CRP levels was observed by week 1. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodelling responsible for cartilage destruction were also decreased after Humira administration. Patients treated with Humira usually experienced improvement in haematological signs of chronic inflammation.

The serum adalimumab concentration-efficacy relationship as measured by the American College of Rheumatology response criteria (ACR20) appears to follow the Hill E_max equation as shown below:

EC₅₀ estimates ranging from 0.8 to 1.4 μg/mL were obtained through pharmacokinetic/ pharmacodynamic modelling of swollen joint count, tender joint count and ACR20 response from patients participating in Phase II and III trials.

Pharmacokinetics

Absorption

Following a single 40 mg subcutaneous (SC) administration of Humira to 59 healthy adult subjects, absorption of adalimumab was slow, with mean peak serum concentration being reached about five days after administration. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10 mg/kg following a single intravenous dose.

Distribution and Elimination

The single dose pharmacokinetics of adalimumab in rheumatoid arthritis (RA) patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The distribution volume (V_ss) ranged from 4.7 to 6.0 L. Adalimumab is slowly eliminated, with clearances typically under 12 mL/h. The mean terminal phase half-life was approximately two weeks, ranging from 10 to 20 days across studies. Adalimumab concentrations in the synovial fluid from several RA patients ranged from 31 to 96% of those in serum.

Steady-State

Accumulation of adalimumab was predictable based on the half-life following SC administration of 40 mg of Humira fortnightly to patients with RA, with mean steady-state trough concentrations of approximately 5 μg/mL (without concomitant methotrexate (MTX)) and 8 to 9 μg/mL (with concomitant MTX), respectively. These trough concentration levels are well above the EC₅₀ estimates of 0.8 to 1.4 μg/mL and consistent with those at which ACR20 responses appear to reach a maximum (Figure 1). The serum adalimumab trough levels at steady state increased approximately proportionally with dose following 20, 40 and 80 mg fortnightly and every week SC dosing. In long-term studies with dosing for more than two years, there was no evidence of changes in clearance over time.

In patients with Crohn's disease, the loading dose of 160mg Humira on Week 0 followed by 80mg Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 12 µg/mL at weeks 2 and 4. The mean steady state trough concentration at weeks 24 and 56 were 6.6 µg/mL and 7.2 µg/mL respectively. The range of trough concentrations in patients who received a maintenance dose of 40mg Humira every fortnight was 0 - 21.7 µg/mL

In patients with Psoriasis, the mean steady-state trough concentration was 5 mcg/mL during adalimumab 40 mg fortnightly monotherapy treatment.

Population pharmacokinetic analyses with data from over 1200 RA patients revealed a trend toward higher apparent clearance of adalimumab with increasing body weight and in patients who developed the presence of anti-adalimumab antibodies.

Minor increases in apparent clearance were predicted in RA patients receiving doses lower than the recommended dose, and in RA patients with high rheumatoid factor or CRP concentrations. These factors are not likely to be clinically important. However, there is a significant difference in mean apparent clearance in patients with Crohn's disease studied short term (4 weeks - 13.1 mL/hr) vs. long term (56 weeks - 16.8 mL/hr).

Special Populations

Pharmacokinetics in special populations were investigated using population pharmacokinetic analyses.

Geriatrics

Adalimumab's apparent clearance decreases slightly with increasing age. From the population analyses, the mean weight-adjusted clearances in patients 40 to 65 years (n=850) and ≥ 65 years (n=287) were 0.33 and 0.30 mL/h/kg, respectively.

Paediatrics

Humira has not been studied in children.

Gender

No gender-related pharmacokinetic differences were observed after correction for a patient's body weight.

Race

No differences in immunoglobulin clearance would be expected among races. From limited data in non-Caucasians, no important kinetic differences were observed for adalimumab.

Hepatic and Renal Insufficiency

No pharmacokinetic data are available in patients with hepatic or renal impairment.

Disease States

Healthy volunteers and patients with RA displayed similar adalimumab pharmacokinetics.

Drug Interactions, Methotrexate

When Humira was administered to 21 RA patients on stable methotrexate therapy, there were no statistically significant changes in the serum methotrexate concentration profiles. In contrast, after single and multiple dosing, methotrexate reduced adalimumab's apparent clearances by 29% and 44% respectively (see PRECAUTIONS - Drug Interactions). This is consistent with the higher trough concentrations of adalimumab found in patients treated with concomitant methotrexate (see Pharmacokinetics - Steady State).

CLINICAL TRIALS FOR RHEUMATOID ARTHRITIS

Description of Clinical Trials

Humira was evaluated in over 3000 patients in all rheumatoid arthritis clinical trials. Some patients were treated for greater than 60 months duration. The efficacy and safety of Humira were assessed in five randomised, double-blind and well-controlled studies.

The primary efficacy endpoint in those studies was ACR20 response, equating to an at least 20% improvement from baseline in tender joint count, swollen joint count, and at least 3 of the 5 remaining ACR core set measures: Patient assessment of pain, patient global assessment of disease activity, physician global assessment of disease activity, patient self-assessed disability (HAQ), and erythrocyte sedimentation rate or CRP.

Study I (DE009) evaluated 271 patients with moderately to severely active RA who were ≥18 years old, had failed therapy with at least one but no more than four disease - modifying anti-rheumatic drugs (DMARDs) and had insufficient efficacy with methotrexate at doses of 12.5 to 25 mg (10 mg if methotrexate-intolerant) every week and whose methotrexate dose remained constant at 10 to 25 mg every week. Patients had ≥ 6 swollen joints and ≥ 9 tender joints and RA diagnosed according to ACR criteria. Doses of 20, 40 or 80 mg of Humira or placebo were given fortnightly for 24 weeks.

Study II (DE011) evaluated 544 patients with moderately to severely active RA who were ≥18 years old and had failed therapy with at least one DMARD. Patients, who were not permitted methotrexate or other DMARDs during the study, had ≥ 10 swollen joints and ≥12 tender joints and were also diagnosed according to ACR criteria. Doses of 20 or 40 mg of Humira were given by subcutaneous injection fortnightly with placebo on alternative weeks or every week for 26 weeks; placebo was given every week for the same duration.

Study III (DE019) evaluated 619 patients with moderately to severely active RA who were ≥ 18 years old, had insufficient efficacy to methotrexate at doses of 12.5 to 25 mg (10 mg if methotrexate-intolerant) every week and whose methotrexate dose remained constant at 12.5 to 25 mg every week. Patients had ≥ 6 swollen joints and ≥ 9 tender joints and RA diagnosed according to ACR criteria. There were three groups in this study. The first received placebo injections every week for 52 weeks. The second received 20 mg of Humira every week for 52 weeks. The third group received 40 mg of Humira fortnightly with placebo injections on alternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of Humira/MTX was administered fortnightly for up to 5 years. The objectives of this open-label extension were to evaluate the long-term safety and maintenance of efficacy of Humira in subjects with RA receiving concurrent MTX. The maintenance of efficacy was assessed by evaluating the effect of Humira on the signs and symptoms of RA, physical function, structural damage, rates of clinical remission and patient-reported outcomes. Of the 457 patients who entered the open-label extension, 53/457 (11.6%) subjects discontinued the study due to adverse events, and 16/457 (3.5%) subjects discontinued because of a lack of efficacy/disease progression.

Study IV (DE031) primarily assessed safety in 636 patients with moderately to severely active RA who were ≥ 18 years old. These patients met the ACR criteria for diagnosis of RA for at least three months and had at least 6 swollen joints and 9 tender joints. Patients were permitted to be either DMARD naïve or to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Patients were randomised to 40 mg of Humira or placebo fortnightly for 24 weeks.

Study V (DE013) was an active comparator trial of 2 years duration, which randomised 799 adult methotrexate (MTX)-naïve patients with early RA (mean disease duration less than 9 months) to treatment with adalimumab 40 mg fortnightly alone, methotrexate up to 20 mg/week alone, or the combination of the two, for 104 weeks. 31.5% of patients in the MTX group, 33.2% in the adalimumab group, and 32.5% in the combination group had taken previous DMARDs. The mean duration of RA was 0.8 years, 0.7 years, and 0.7 years in the MTX alone, adalimumab alone, and combination groups, respectively. The mean Tender Joint Count (TJC 68) at baseline was 32.3, 31.8 and 30.7 for the three groups, and the Erosion Score was 13.6, 11.3 and 11.0, respectively.

Results of all five trials were expressed in percentage of patients with improvement in RA using ACR response criteria. The primary endpoint in Studies I, II and III and the secondary endpoint in Study IV was the percent of patients who achieved an ACR20 response at Week 24 or 26. The primary endpoint in Study V was the percent of patients who achieved an ACR50 response at Week 52. Studies III and V had an additional primary endpoint at 52 weeks of retardation of disease progression (as detected by X-ray results). Study III also had a primary endpoint of changes in quality of life.

Clinical Response

Studies I, II and III

The percent of Humira-treated patients achieving ACR20, 50 and 70 responses was consistent across all three trials. The results for the 40 mg fortnightly dose are summarised in Table 1.

Table 1: ACR Responses in Placebo-Controlled Trials (Percent of Patients)
Response	Study Ia*		Study IIa*		Study IIIa, c*
	Placebo/ MTX N=60	Humirab/ MTX N=63	Placebo N=110	Humirab *N=113	Placebo/ MTX N=200	Humirab/ MTX N=207
ACR20
6 months	13.3%	65.1%	19.1%	46.0%	29.5%	63.3%
12 months	NA	NA	NA	NA	24.0%	58.9%
ACR50
6 months	6.7%	52.4%	8.2%	22.1%	9.5%	39.1%
12 months	NA	NA	NA	NA	9.5%	41.5%
ACR70
6 months	3.3%	23.8%	1.8%	12.4%	2.5%	20.8%
12 months	NA	NA	NA	NA	4.5%	23.2%

^a Study I at 24 weeks, Study II at 26 weeks, and Study III at 24 and 52 weeks

^b 40 mg Humira administered fortnightly

^c The 12 months placebo-controlled phase of Study III was followed by 12 months of open-label treatment with ACR responses at 24 months of 48.8% (ACR20), 36.2% (ACR50) and 22.7% (ACR70).

* p<0.01, Humira vs. placebo at all timepoints for ACR20, 50, 70

MTX Methotrexate

Patients receiving Humira 40 mg every week in Study II also achieved statistically significant ACR20, 50 and 70 response rates of 53.4%, 35.0% and 18.4%, respectively, at six months.

Figure 2: Study II ACR20 Responses over 26 Weeks

The results of the components of the ACR response criteria for Study III are shown in Table 2. ACR response rates and improvement in all ACR response criteria were maintained to Week 104. Over the 2 years in Study III, 20% of Humira patients achieved a major clinical response, defined as maintenance of an ACR70 response over a > 6 month period.

Table 2: Components of ACR Response in Study lll
Parameter (median)	Placebo/MTX (N = 200)			Humiraa /MTX (N = 207)
	Baseline	Week 24	Week 52	Baseline	Week 24	Week 52
Number of tender joints (0 - 68)	26.0	15.0	15.0	24.0	8.0*	6.0*
Number of swollen joints (0-66)	17.0	11.0	11.0	18.0	5.0*	4.0*
Physician global assessment disease activityb	63.0	35.0	38.0	65.0	20.0*	16.0*
Patient global assessment disease activityb	53.5	39.0	43.0	52.0	20.0*	18.0*
Painb	59.5	38.0	46.0	58.0	21.0*	19.0*
Disability index (HAQ)c	1.50	1.25	1.25	1.50	0.75*	0.75*
CRP (mg/L)	10.0	9.0	9.0	10.0	4.0*	4.0*

^a 40 mg Humira administered fortnightly

^b Visual analogue scale; 0 = best, 100 = worst

^c Disability Index of the Health Assessment Questionnaire ; 0 = best, 3 = worst, measures the patient's ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity

* p<0.001, Humira vs. placebo, based on mean change from baseline

In Study III, 84.7% of patients with ACR20 responses at Week 24 maintained the response at 52 weeks. Clinical responses were maintained for up to 5 years in the open-label portion of Study III.  ACR responses observed at week 52 were maintained or increased through 5 years of continuous HUMIRA treatment with 22% (115/534) of patients achieving major clinical response. A total of 372 (67.8%) subjects had no change in their methotrexate dose during the study. 141 (25.7%) subjects had a dose reduction and 36 (6.6%) subjects required a dose increase. A total of 149 (55.6%) subjects had no change in their corticosteroid dose during the study, 80 (29.9%) subejcts had a dose reduction and 39 (14.6%) subjects required a dose increase. The following figures illustrate the durability of ACR20 responses to Humira in Studies III and II.

Figure 3: Study III ACR20 Responses over 52 Weeks

Study IV

The ACR20 response of patients treated with Humira plus standard of care was statistically significantly better than patients treated with placebo plus standard of care (p<0.001).

In Studies I-IV, Humira-treated patients achieved statistically significant ACR20 and 50 responses compared to placebo as early as 1-2 weeks after initiation of treatment.

Study V

In Study V for early rheumatoid arthritis patients who were methotrexate naïve, combination therapy with Humira plus methotrexate led to significantly greater ACR responses than methotrexate monotherapy at Week 52 and responses were sustained at Week 104 (see Table 3).

At Week 52 all individual components of the ACR response criteria improved with Humira/methotrexate therapy and improvements were maintained to Week 104.

Over the two-year study, 48.5% patients who received Humira/methotrexate combination therapy achieved a major clinical response (ACR70 for > six continuous months) compared to 27.2% of patients who received methotrexate monotherapy (p<0.001).

Table 3. ACR20/50/70 Response at Weeks 26, 52, 76 and 104 (All Randomised Subjects) in Study V
	MTX N=257	Adalimumab N=274	Adalimumab + MTX N=268
	N (%)			p-valuea	p-valueb
ACR20
Week 26	158 (61.5)	146 (53.3)	184 (68.7)	0.084	< 0.001
Week 52	161 (62.6)	149 (54.4)	195 (72.8)	0.013	< 0.001
Week 76	154 (59.9)	137 (50.0)	185 (69.0)	0.029	< 0.001
Week 104	144 (56.0)	135 (49.3)	186 (69.4)	0.002	< 0.001
ACR50
Week 26	104 (40.5)	96 (35.0)	157 (58.6)	< 0.001	< 0.001
Week 52	118 (45.9)	113 (41.2)	165 (61.6)	< 0.001	< 0.001
Week 76	114 (44.4)	114 (41.6)	161 (60.1)	< 0.001	< 0.001
Week 104	110 (42.8)	101 (36.9)	158 (59.0)	< 0.001	< 0.001
ACR70
Week 26	57 (22.2)	54 (19.7)	114 (42.5)	< 0.001	< 0.001
Week 52	70 (27.2)	71 (25.9)	122 (45.5)	< 0.001	< 0.001
Week 76	75 (29.2)	79 (28.8)	127 (47.4)	< 0.001	< 0.001
Week 104	73 (28.4)	77 (28.1)	125 (46.6)	< 0.001	< 0.001

Note: Subjects with missing values were counted as non-responders.

a. P-value is from the pairwise comparison of MTX monotherapy and adalimumab + MTX combination therapy using Pearson's chi-square test.

b. P-value is from the pairwise comparison of adalimumab monotherapy and adalimumab + MTX combination therapy using Pearson's chi-square test.

In Study V, Humira/methotrexate combination therapy was superior to methotrexate monotherapy in achieving clinical remission defined as Disease Activity Score (DAS28) <2.6 at Week 52 (Table 4).

Table 4: Subjects in Remission as Defined by DAS28 < 2.6 at Week 52 (All Randomised Subjects) in Study V
	MTX N=257	Adalimumab N=274	Adalimumab + MTX N=268
	N (%)			p-valuea	p-valueb
Subjects in Remission at Week 52	53 (20.6)	64 (23.4)	115 (42.9)	< 0.001	< 0.001

^a. P-value is from the pairwise comparison of MTX monotherapy and adalimumab + MTX combination therapy using Pearson's chi-square test.

^b. P-value is from the pairwise comparison of adalimumab monotherapy and adalimumab + MTX combination therapy using Pearson's chi-square test.

MTX Methotrexate

Radiographic Response

In Study III, Humira-treated patients had a mean duration of rheumatoid arthritis for approximately 11 years and a mean ± standard deviation baseline modified Total Sharp Score for the 40 mg fortnightly group of 72.1 ± 60.7 and placebo group of 66.4 ± 47.4. Structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (TSS) and its components, erosion score and joint space narrowing score (JSN) at month 12 compared to baseline. Humira/methotrexate-treated patients demonstrated less radiographic progression than patients receiving placebo/methotrexate (Table 5).

In the open-label extension of Study III, 77% of the original patients treated with any dose of Humira were evaluated radiographically at 2 years. Patients maintained inhibition of structural damage, as measured by the TSS; 54% had no progression of structural damage as defined by a change in the TSS of zero or less.

Fifty-five percent (113/207) of patients originally treated with 40 mg HUMIRA fortnightly have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage with approximately 50% (57/113) showing no progression of structural damage defined by a change in the TSS of zero or less.

Table 5: Radiographic Mean Changes Over 12 Months in Study III with Background MTX
	Placebo/MTX N=200	Humiraa/MTX N=207	Difference Between Humiraa/MTX and Placebo/MTX (95% Confidence Interval*)	p-value
Total Sharp Score	2.7	0.1	2.6 (1.4, 3.8)	≤ 0.001b
Erosions	1.6	0.0	1.6 (0.9, 2.2)	≤ 0.001
No New Erosions (% of Patients)	46.2	62.9	16.7	≤ 0.001
JSN Score	1.0	0.1	0.9 (0.3, 1.4)	0.002

^a 40 mg administered fortnightly

^b Based on rank analysis

MTX Methotrexate

* 95% confidence intervals for the differences in change scores between MTX and Humira

In Study V, Humira-treated patients had a mean duration of rheumatoid arthritis of less than 9 months and had not previously received methotrexate. Structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score. The Week 52 results are shown in Table 6. A statistically significant difference for change in modified Total Sharp Score and the erosion score was observed at Week 52 and maintained at Week 104.

Table 6: Change in Modified Total Sharp Score from Baseline at Weeks 52 and 104 (All Randomised Subjects) in Study V
	MTX N=257	Adalimumab N=274	Adalimumab + MTX N=268	p-valuea	p-valueb
Week 52
Baseline (mean)	21.8 ± 22.2	18.8 ± 19.0	18.1 ± 20.1
Week 52 (mean)	27.6 ± 24.6	21.8 ± 19.7	19.4 ± 19.9
Change at Week 52 (mean ± SD)	5.7 ± 12.7	3.0 ± 11.2	1.3 ± 6.5	< 0.001	0.002
Week 104
Baseline (mean)	21.8 ± 22.2	18.8 ± 19.0	18.1 ± 20.1
Week 104 (mean)	32.3 ± 30.0	24.3 ± 23.2	20.0 ± 20.5
Change at Week 104 (mean ± SD)	10.4 ± 21.7	5.5 ± 15.8	1.9 ± 8.3	< 0.001	< 0.001

Note: Primary analysis imputation used for missing data.

^a. P-value is from the pairwise comparison of MTX monotherapy and adalimumab + MTX combination therapy using the Mann-Whitney U test.

^b. P-value is from the pairwise comparison of adalimumab monotherapy and adalimumab + MTX combination therapy using the Mann-Whitney U test.

Physical Function

Health-related quality of life and physical function was assessed using the disability index of the Stanford Health Assessment Questionnaire (HAQ), which was a pre-specified primary endpoint at Week 52 in Study III.

The HAQ was developed as a disease-specific outcome measure for rheumatoid arthritis and has been extensively studied in RA. HAQ has been shown to correlate with mortality, work disability, functional limitations, pain, fatigue and psychological relief. The score is based on 8 questions and normalised to a scale of 0 to 3, where higher scores indicate more disability, and lower scores indicate less disability. Studies have shown that a change in HAQ score of 0.22 or greater represents an improvement in disability that is perceptible and meaningful to the patient. All doses/schedules of Humira in Study III showed statistically significantly greater improvement in the disability index of the HAQ from baseline to Month 6 compared to placebo and the same was seen at Week 52.

There were 619 patients enrolled in Study III also known as the DE019 study. The patients were divided into three groups. The first group received placebo injections every week for 52 weeks. The second group received 20 mg of Humira every week for 52 weeks. The third group received 40 mg of Humira fortnightly with placebo injections on alternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase (DE019OLE) in which 40 mg of Humira/MTX was administered fortnightly. Maintenance of physical function was defined as maintaining a reduction in HAQ of -0.5 over the second year of active treatment.

Results

In Study III, the mean (95% CI) improvement in HAQ from baseline at Week 52 was -0.60 (-0.65, -0.55) for the Humira patients and -0.25 (-0.33, -0.17) for the placebo/MTX (p<0.001) patients. At Week 104, the mean improvement in HAQ from baseline was -0.70 (-0.8, -0.6) for the Humira patients.

Table 7: Percentage of Patients Achieving Improvement in physical Function After One and Two Years of Treatment In Study III
Reduction in HAQ from Baseline	Proportion of patients who achieved HAQ reduction at Week 52		Proportion of patients who received adalimumab 40 mg fortnightly and who achieved HAQ reduction at Week 104	Proportion of all adalimumab-treated patients with HAQ reduction at Week 52 that was maintained at Week 104
Treatment arm	Adalimumab 40 mg fortnightly	Placebo	Adalimumab 40 mg fortnightly	All adalimumab
-0.22	150/207 (72.5%)	96/200 (48%)	123/207 (59.4%)	231/258 (89.5%)
-0.5	114/207 (55.1%)	56/200 (28%)	94/207 (45.4%)	167/204 (81.9%)
-0.75	82/207 (39.6%)	40/200 (20%)	71/207 (34.3%)	124/149 (83.2%)
-1.0	56/207 (27.1%)	22/200 (11%)	40/207 (19.3%)	69/103 (67.0%)

At Year 2, 94/207 (45.4%) of patients who originally entered the study achieved a -0.5 reduction in HAQ. 79.5% (115/195) of the patients who achieved a reduction in HAQ of -0.5 at the end of one year of Humira treatment maintained this response over 5 years of active treatment.

Quality of Life

Results from the Short Form Health Survey (SF-36) for all doses/schedules of Humira in all four studies support these findings, with statistically significant Physical Component Summary (PCS) scores, as well as statistically significant pain and vitality domain scores for the 40 mg fortnightly dose. A statistically significant decrease in fatigue as measured by Functional Assessment of Chronic Illness Therapy (FACIT) scores was seen in all three studies in which it was assessed (Studies I, III, IV). Improvement in SF-36 was measured up to week 156 (3 years) and improvement was maintained through this time.

In Study V, the active-comparator controlled study in early rheumatoid arthritis, the improvement in the HAQ disability index and the physical component of the SF-36 showed greater improvement (p<0.001) for Humira/methotrexate combination therapy versus methotrexate monotherapy at Week 52, which was maintained through Week 104.

CLINICAL TRIALS FOR PSORIATIC ARTHRITIS

Humira, 40 mg fortnightly, was studied in patients with moderately to severely active psoriatic arthritis in two placebo-controlled studies, Studies VI (M02-518) and VII (M02-570). Study VI with 24-week duration, treated 313 adult patients who had an inadequate response to non-steroidal anti-inflammatory drug therapy and of these, approximately 50% were taking methotrexate. Study VII with 12-week duration, treated 100 patients who had an inadequate response to DMARD therapy.

ACR and PASI response

Humira was superior to placebo in all measures of disease activity (p < 0.001) as shown in Table 8 and 9. Among patients with psoriatic arthritis who received Humira, the clinical responses were apparent at the time of the first visit (2 weeks), significant at 12 weeks and were maintained through 24 weeks of therapy. Patients with a psoriasis involvement of at least 3% Body Surface Areas (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) response. In these patients the skin lesions of psoriasis were improved with Humira, relative to placebo, as measured by PASI. Responses were similar with and without concomitant methotrexate therapy.

Table 8: ACR and PASI Response in Placebo-Controlled Psoriatic Arthritis Study (Percent of Patients)
Response*	Placebo N=162	Humira N=151
ACR20
Week 12	14%	58%
Week 24	15%	57%
ACR50
Week 12	4%	36%
Week 24	6%	39%
ACR70
Week 12	1%	20%
Week 24	1%	23%
	N=69	N=69
PASI 50
Week 12	15%	72%
Week 24	12%	75%
PASI 75
Week 12	4%	49%
Week 24	1%	59%

*  p<0.001 for all comparisons between Humira and placebo

Table 9: Components of Disease Activity in Psoriatic Arthritis
	Placebo N=162a		Humira N=151a
Parameter: mean (median)	Baseline	24 Weeks	Baseline	24 Weeks
Number of tender jointsb	25.8 (23.0)	22.3 (17.0)	23.3 (19.0)	11.8 (5.0)
Number of swollen jointsc	14.6 (11.0)	12.1 (8.0)	13.4 (10.0)	7.6 (3.0)
Physician global assessmentd	53.2 (53.0)	46.0 (48.0)	53.5 (54.0)	21.4 (16.0)
Patient global assessmentd	47.2 (49.0)	47.6 (49.0)	47.5 (48.0)	24.2 (18.5)
Paind	47.6 (47.5)	47.9 (49.0)	50.6 (53.0)	25.4 (19.0)
Disability index (HAQ)e	1.0 (1.0)	0.9 (0.8)	1.0 (0.9)	0.6 (0.4)
CRP (mg/L)f	13.9 (7.8)	14.3 (7.4)	14.3 (8.0)	5.5 (2.1)

^a As observed analysis presented. N at 24 weeks may be less than 162 for placebo or 151 for Humira.

^b Scale 0 - 78

^c Scale 0 - 76

^d Visual analog scale; 0 = best, 100 = worst.

^e Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst; measures the patient's ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.

^f Normal range: 0-2.87 mg/L.

* p< 0.001 for Humira vs. placebo comparisons based on mean changes.

Quality of Life and Physical Function

Health-related quality of life and physical function were assessed in the psoriatic arthritis study using the disability index of the Health Assessment Questionnaire (HAQ). The Humira-treated patients had significantly greater improvement in the disability index of the HAQ from baseline to Week 24 compared to placebo.

Results from the Short Form Health Survey (SF-36) support these findings, with statistically significant Physical Component Summary (PCS) scores, as well as statistically significant pain and vitality domain scores.

CLINICAL TRIALS FOR ANKYLOSING SPONDYLITIS

The safety and efficacy of Humira 40 mg fortnightly was assessed in 393 adult patients in two randomised, 24-week double-blind, placebo-controlled studies in patients with active ankylosing spondylitis (AS). The larger study (Study VIII or M03-607) enrolled 315 adult patients with active AS (defined as fulfilling at least two of the following three criteria: (1) a Bath AS disease activity index (BASDAI) score ≥4 cm, (2) a visual analog score (VAS) for total back pain ≥ 40 mm, (3) morning stiffness ≥ 1 hour), who had an inadequate response to conventional therapy. Seventy-nine (20.1%) patients were treated concomitantly with disease modifying anti-rheumatic drugs, and 37 (9.4%) patients with glucocorticoids. The blinded period was followed by an open-label period. Subjects (N=215, 54.7%) who failed to achieve ASAS 20 at Weeks 12, or 16 or 20 received early escape open-label adalimumab 40mg fortnightly SC and were subsequently treated as non-responders in double-blind statistical analyses.

Results showed statistically significant improvement of signs and symptoms of AS in patients treated with Humira compared to placebo. Significant improvement in measures of disease activity was first observed at Week 2 and maintained through 24 weeks as shown in Figure 4 and Table 10.

Patients with total spinal ankylosis were included in the larger study (n=11). Responses of these patients were similar to those without total ankylosis.

Figure 4. ASAS 20 Response By Visit, Study V

Table 10. ASASa Responses in Placebo-Controlled AS Study
Response	Placebo N=107	Humira N=208
ASAS 20
Week 12	21%	58%*
Week 24	19%	51%*
ASAS 50
Week 12	10%	38%*
Week 24	11%	35%*
ASAS 70
Week 12	5%	23%*
Week 24	8%	24%*

* Statistically significant at p<0.001 for all comparisons between Humira and placebo at Weeks 12 and 24

^a Assessments in Ankylosing Spondylitis

A low level of disease activity (defined as a value <20 [on a scale of 0-100mm] in each of the four ASAS response parameters) was achieved at 24 weeks in 22% of Humira-treated patients vs. 6% in placebo-treated patients (p<0.001).

Table 11. Components of Ankylosing Spondylitis Disease Activity
	Placebo N=107		Humira N=208
	Baseline mean	Week 24 mean	Baseline mean	Week 24 mean
ASAS 20 Response Criteria*
Patient's Global Assessment of Disease Activitya	65	60	63	38
Total back pain	67	58	65	37
Inflammationb	6.7	5.6	6.7	3.6
BASFIc	56	51	52	34
BASDAId score	6.3	5.5	6.3	3.7
CRPe	2.2	2.0	1.8	0.6

^a Percent of subjects with at least a 20% and 10-unit improvement measured on a Visual Analog Scale (VAS) with 0 = "none" and 100 = "severe"

^b mean of questions 5 and 6 of BASDAI (defined in 'd')

^c Bath Ankylosing Spondylitis Functional Index

^d Bath Ankylosing Spondylitis Disease Activity Index

^e C-Reactive Protein (mg/dL)

* Statistically significant as p<0.001 for all comparisons between Humira and placebo at Week 24

Results of this study were similar to those seen in the second randomised trial (Study IX or M03-606), a multicenter, double-blind, placebo-controlled study of 82 patients with ankylosing spondylitis. Patient Reported Outcomes were assessed in both ankylosing spondylitis studies using the generic health status questionnaire SF-36 and the disease specific Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL). The Humira-treated patients had significantly greater improvement in SF-36 Physical Component Score (mean change: 6.93) compared to placebo-treated patients (mean change: 1.55; p<0.001) at Week 12, which was maintained through Week 24.

Results from the ASQoL support these findings demonstrating improvement in overall quality of life. The Humira-treated patients had statistically significant improvement (mean change: - 3.15) compared to placebo-treated patients (mean change: - 0.95; p<0.001) at Week 12, which was maintained through Week 24.

CLINICAL TRIALS FOR CROHN'S DISEASE

The safety and efficacy of multiple doses of Humira were assessed in over 1400 patients with moderately to severely active Crohn's disease (Crohn's 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, Study CD-I (M02-403) and Study CD-II (M04-691). In Study CD-I, 299 TNF-antagonist naïve patients were randomized to one of four treatment groups; the placebo group received placebo at weeks 0 to 2, the 160/80 group received 160mg Humira at Week 0 and 80mg at Week 2, the 80/40 group received 80mg at Week 0 and 40mg at Week 2, and the 40/20 group received 40mg at Week 0 and 20mg at Week 2. In CD-II, 325 patients who had lost response or were intolerant to infliximab were randomized to receive either 160mg Humira at Week 0 and 80mg at Week 2, or placebo at Weeks 0 and 2.

Maintenance of clinical remission was evaluated in a third study, Study CD-III (M02-404). In Study CD-III, 854 patients received open-label 80 mg Humira at Week 0 and 40 mg Humira at Week 2. Patients were then randomized at Week 4 to 40 mg Humira fortnightly, 40 mg Humira every week or placebo with a total study duration of 56 weeks. Patients in clinical response (decrease in CDAI ≥70) at Week 4 were stratified and analysed separately from those not in clinical response at Week 4. Corticosteroid taper was permitted after Week 8.

Clinical Results

Study CD-I / Study CD-II

A statistically significantly greater percentage of the groups treated with 160/80mg Humira achieved induction of clinical remission versus placebo at Week 4 regardless of whether the patients were TNF antagonist naïve (Study CD-I) or had been previously exposed to infliximab (Study CD-II) (see table 12)

Clinical remission is CDAI score <150; clinical response (CR-100) is decrease in CDAI ≥ 100 points; clinical response (CR-70) is decrease in CDAI ≥ 70 points
All p-values are pairwise comparisons of proportions for Humira vs. placebo
^* p<0.001
^** p<0.01

Study CD-III (M02-404)

At Week 4, 58% (499/854) patients were in clinical response (decrease in CDAI ≥ 70 points) and were assessed in the primary analysis. Of those in clinical response at Week 4, 48% had been previously exposed to other anti-TNF therapy. At Weeks 26 and 56, statistically significantly greater proportions of patients who were in clinical response at Week 4 achieved clinical remission in the Humira maintenance groups compared to patients in the placebo maintenance group. Additionally, statistically significantly greater proportions of patients receiving concomitant corticosteroids at baseline were in clinical remission and were able to discontinue corticosteroid use for at least 90 days in the Humira maintenance groups compared to patients in the placebo maintenance group at Weeks 26 and 56 (see table 13).

Clinical remission results presented in Table 13 remained relatively constant irrespective of previous TNF antagonist exposure.

Of those in response at Week 4 who attained remission during the study, patients in Humira maintenance groups maintained remission for a significantly longer time that patients in the placebo maintenance group (see Figure 5). Among patients who were not in response by Week 12, therapy continued beyond 12 weeks did not result in significantly more responses. The group that received Humira every week did not show significantly higher remission rates than the group that received Humira fortnightly.

Clinical remission is CDAI score <150; clinical response (CR-100) is decrease in CDAI ≥ 100 points; clinical response (CR-70) is decrease in CDAI ≥ 70 points
* p<0.001 for Humira vs. placebo pairwise comparisons of proportions
** p<0.02 for Humira vs. placebo pairwise comparisons of proportions
^a Of those receiving corticosteroids at baseline

Figure 5: Days in Clinical Remission for Patients Who Achieved Clinical Remission in Study CD-III

Patient Reported Outcomes

In Study CD-I and Study CD-II, statistically significant improvement in disease-specific inflammatory bowel disease questionnaire (IBDQ) total score was achieved at Week 4 in patients randomized to Humira 160/80 mg compared to placebo. Statistically significant improvement from baseline in IBDQ scores was seen at Weeks 26 and 56 in CD-III among the adalimumab treatment groups compared to the placebo group.

CLINICAL TRIALS FOR PSORIASIS

The safety and efficacy of Humira were assessed in over 1,600 patients 18 years of age or older with moderate to severe chronic plaque psoriasis who were candidates for systemic therapy or phototherapy in randomized, double-blind, well-controlled studies.

Ps Study I (Ps-I) evaluated 1212 patients with chronic plaque psoriasis with ≥ 10% BSA involvement and Psoriasis Area and Severity Index (PASI) ≥ 12 within three treatment periods. In period A, patients received placebo or Humira subcutaneously at an initial dose of 80 mg at week 0 followed by a dose of 40 mg every other week starting at week 1. After 16 weeks of therapy, patients who achieved at least a PASI 75 response at week 16, defined as a PASI score improvement of at least 75% relative to baseline, entered period B and received open label 40 mg Humira every other week. After 17 weeks of open label therapy, patients who maintained at least a PASI 75 response at week 33 and were originally randomized to active therapy in Period A were re-randomized in period C to receive 40 mg Humira every other week or placebo for an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 18.9 and the baseline Physician's Global Assessment (PGA) score ranged from "moderate" (52.6%) to "severe" (41.3%) to "very severe" (6.1%).

Ps Study II (Ps-II) compared the efficacy and safety of Humira versus methotrexate and placebo in 271 patients with chronic plaque psoriasis with 10% BSA involvement and PASI > 10. Patients received placebo, MTX (7.5 - 25.0 mg) or an initial dose of 80 mg Humira subcutaneously at week 0 followed by a dose of 40 mg every other week starting at week 1 for 16 weeks. Across all treatment groups the mean baseline PASI score was 19.7 and the baseline PGA score ranged from "mild" (0.4%) to "moderate" (47.8%) to "severe" (45.6%) to "very severe" (6.3%).

Ps Study III (Ps-III) evaluated 148 patients with chronic plaque psoriasis with ≥ 5% BSA involvement for at least 1 year. Patients received placebo or Humira subcutaneously at a dose of 40 mg every other week starting at week 1 after an initial dose of 80 mg at week 0 or Humira at an initial dose of 80 mg at week 0 followed by a dose of 40 mg weekly.

Clinical Results

In Ps Studies I, II and III, the primary endpoint was the proportion of patients who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at week 16 for studies I and II and week 12 for study III. Other evaluated outcomes in Ps Studies I, II, and III included the PGA and other PASI measures. Ps Study I had an additional primary endpoint of loss of adequate response after week 33 and on or before week 52. Loss of adequate response is defined as a PASI score after week 33 and on or before week 52 that resulted in a <PASI 50 response relative to baseline with a minimum of a 6-point increase in PASI score relative to week 33. In Ps Studies I and II, more patients randomized to Humira than to placebo achieved at least a 75% reduction from baseline of PASI score at week 16. Other relevant clinical parameters including PASI 100 (i.e. complete clearance of psoriasis skin signs) and PGA of "clear or minimal" were also improved over placebo. In Ps Study II, superior results were achieved for PASI 75, PASI 100 and PGA of "clear or minimal" in patients randomized to the Humira treatment group versus those randomized to receive methotrexate (see Tables 14 and 15).

Results from Ps Study III supported the efficacy demonstrated in Ps Studies I and II.

In Ps Study I, patients who were PASI 75 responders and were re-randomized to continue Humira therapy at week 33 were less likely to experience a loss of adequate response on or before week 52 than the PASI 75 responders who were re-randomized to placebo at week 33 (4.9% versus 28.4%, p<0.001).

For patients who dose escalated from 40 mg every other week to 40 mg weekly due to a PASI response below 50 and were evaluated at 12 weeks after dose escalation in an open-label extension study, PASI response rates partially recovered. At week 12 after dose escalation, 47.7% of patients regained at least a PASI 50 response; among these, 12.5% achieved a PASI 75 response.

Quality of Life

Patient Reported Outcomes (PRO) were evaluated by several measures. Quality of Life was assessed using the disease-specific Dermatology Life Quality Index (DLQI) in Ps Study I and Ps Study II. In Ps Study I, patients receiving Humira demonstrated clinically meaningful improvement in the DLQI total score, disease severity, pain, and pruritus compared to the placebo group at both weeks 4 & 16. The DLQI result was maintained at week 52. In Ps Study II, patients receiving Humira demonstrated clinically meaningful improvement in the DLQI total score, disease severity, and pruritus compared to the placebo and methotrexate groups at week 16, and clinically meaningful improvement in pain compared to the placebo group at week 16.

The Short Form Health Survey (SF-36) was used to assess general health-related quality of life in Ps Study I. The Humira-treated patients had significantly greater improvement in the SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores.

IMMUNOGENICITY

Patients in Studies I, II, and III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5.5% (58 of 1,062) of adult rheumatoid arthritis patients receiving Humira developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant MTX had a lower rate of antibody development than patients on Humira monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse events was observed. With monotherapy, patients receiving fortnightly dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg fortnightly as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of Humira is unknown.

In patients with ankylosing spondylitis, the rate of development of antibodies to adalimumab in Humira-treated patients was comparable to patients with rheumatoid arthritis. In patients with psoriatic arthritis, the rate of antibody development in patients receiving Humira monotherapy was comparable to patients with rheumatoid arthritis; however, in patients receiving concomitant methotrexate the rate was 7% compared to 1% in rheumatoid arthritis. In patients with Crohn's disease, the rate of antibody development was 2.6%. The immunogenicity rate was 8% for psoriasis patients who were treated with Humira monotherapy.

The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. For these reasons, comparison of the incidence of antibodies to adalimumab with the incidence of antibodies to other products may be misleading.

INDICATIONS

Rheumatoid Arthritis

Humira is indicated for reducing signs and symptoms, as well as inhibiting the progression of structural damage in adult patients with moderate to severely active rheumatoid arthritis. This includes the treatment of patients with recently diagnosed moderate to severely active disease who have not received methotrexate.

Humira can be used alone or in combination with methotrexate.

Psoriatic Arthritis

Humira is indicated for the treatment of signs and symptoms of moderate to severely active psoriatic arthritis in patients where response to previous DMARDS has been inadequate.

Ankylosing Spondylitis

Humira is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

Crohn's Disease

Humira is indicated for the treatment of moderate to severe Crohn's disease in adults to reduce the signs and symptoms of the disease and to induce and maintain clinical remission in patients who have had an inadequate response to conventional therapies, or who have lost response to or are intolerant of infliximab.

Psoriasis

Humira is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.

CONTRAINDICATIONS

Humira should not be administered to patients with known hypersensitivity to Humira or any of its excipients.

Humira is contraindicated in severe infections including sepsis, active tuberculosis and opportunistic infections (see PRECAUTIONS).

Concurrent administration of Humira and anakinra (interleukin-1 receptor antagonist) is contraindicated (see PRECAUTIONS).

Moderate to severe heart failure (NYHA class III/IV).

PRECAUTIONS

Infections

Serious infections, sepsis, tuberculosis and other opportunistic infections, including fatalities, have been reported with the use of Humira. Other serious infections seen in clinical trials include pneumonia, pyelonephritis, septic arthritis and septicaemia. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their RA could predispose them to infections. Tuberculosis and invasive opportunistic fungal infection have been observed in patients treated with Humira.

Treatment with Humira should not be initiated in patients with active infections including chronic or localised infections. Patients should be monitored closely for infections - including tuberculosis before, during and after treatment with Humira.

Patients who develop a new infection while undergoing treatment with Humira should be monitored closely. Administration of Humira should be discontinued if a patient develops a new serious infection. Physicians should exercise caution when considering the use of Humira in patients with a history of recurring infection or with underlying conditions, which may predispose patients to infections. A patient who requires surgery while on Humira should be closely monitored for infections, and appropriate actions should be taken.

Hepatitis B Virus

Use of TNF blockers has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients at risk for HBV infection should be evaluated for evidence of prior HBV infection before initiating TNF blocker therapy. Prescribers should exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Patients who are carriers of HBV and require treatment with TNF blockers should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. 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. In patients who develop HBV reactivation, Humira should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.

Tuberculosis and Other Opportunistic Infections

As observed with other TNF-antagonists, tuberculosis associated with administration of Humira in clinical trials has been reported.

While cases were observed at all doses, the incidence of tuberculosis reactivations was particularly increased at doses of Humira that were higher than the recommended dose.

Invasive fungal infections, and other opportunistic infections have been observed in patients receiving Humira. Some of these infections, including tuberculosis, have been fatal.

Before initiation of therapy with Humira, all patients should be evaluated for both active or inactive (latent) tuberculosis infection. This evaluation should include a detailed medical history with possible previous exposure to patients with active tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests (e.g., chest X-ray or tuberculin test) should be performed in accordance with local recommendations. Treatment of latent tuberculosis infections should be initiated prior to therapy with Humira. When tuberculin skin testing is performed for latent tuberculosis infection, an induration size of 5mm or greater should be considered positive, even if vaccinated previously with Bacille Calmette-Guerin (BCG).

The possibility of undetected latent tuberculosis should be considered especially in patients who have immigrated from or travelled to countries with a high prevalence of tuberculosis or who had close contact with a person with active tuberculosis.

If active tuberculosis is diagnosed, Humira therapy must not be initiated.

If latent tuberculosis is diagnosed, appropriate anti-tuberculosis prophylaxis in accordance with local recommendations should be initiated before starting treatment with Humira. Anti-tuberculosis therapy prior initiating Humira should also be considered in patients who have a negative test for latent tuberculosis but have risk factors for TB infection. The decision to initiate anti-tuberculosis therapy in these patients should only be made after taking into account both the risk for latent tuberculosis infection and the risks of anti-tuberculosis therapy. If necessary, consultation should occur with a physician with expertise in the treatment of tuberculosis. The benefit/risk balance of therapy with Humira should be very carefully considered.

Anti-tuberculosis treatment of patients with latent tuberculosis infection reduces the risk of reactivation in patients receiving treatment with Humira. However, active tuberculosis has developed in patients receiving Humira whose screening for latent tuberculosis infection was negative and some patients who have previously received treatment for latent or active tuberculosis have developed active tuberculosis while being treated with TNF blocking agents.

Patients receiving Humira should be monitored for signs and symptoms of active tuberculosis, particularly because tests for latent tuberculosis infection may be falsely negative. The risk of false negative tuberculin skin test results should be considered especially in patients who are severely ill or immunocompromised.

Patients should be instructed to seek medical advice if signs/symptoms (e.g., persistent cough, wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur.

Neurologic Events

Humira has been associated in rare cases with new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease, including multiple sclerosis. Prescribers should exercise caution in considering the use of Humira in patients with pre-existing or recent-onset central nervous system demyelinating disorders.

Hypersensitivity Reactions

Serious allergic reactions associated with Humira were rare during clinical trials. Allergic reactions overall (e.g., allergic rash, anaphylactoid reaction, fixed-drug reaction, non-specific drug reaction, urticaria) have been observed in approximately 1% of patients. In post-marketing, serious allergic reactions including anaphylaxis have been reported rarely following Humira administration. If an anaphylactic reaction or other serious allergic reaction occurs, administration of Humira should be discontinued immediately and appropriate therapy initiated.

The needle cover of the syringe contains natural rubber (latex). This may cause severe allergic reactions in patients sensitive to latex.

Haematologic Events

Rare reports of pancytopenia including aplastic anaemia have been reported with TNF blocking agents. Adverse events of the haematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with Humira (see ADVERSE REACTIONS). The causal relationship of these reports to Humira remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on Humira. Discontinuation of Humira therapy should be considered in patients with confirmed significant haematologic abnormalities.

Immunosuppression

The possibility exists for TNF blocking agents, including Humira, to affect host defenses against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 64 patients with rheumatoid arthritis treated with Humira, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T- and B-cells and NK-cells, monocyte/macrophages, and neutrophils. The impact of treatment with Humira on the development and course of malignancies, as well as active and/or chronic infections is not fully understood. The safety and efficacy of Humira in patients with immunosuppression have not been evaluated. See PRECAUTIONS - Infections and ADVERSE REACTIONS - Infections and Malignancies.

Vaccinations

In a randomised, double-blind, placebo-controlled study in 226 adult rheumatoid arthritis patients treated with Humira, antibody responses to concomitant pneumococcal and influenza vaccines were assessed. Protective antibody levels to the pneumococcal antigens were achieved by 86% of patients in the Humira group compared to 82% in the placebo group. A total of 37% of Humira-treated subjects and 40% of placebo-treated subjects achieved at least a 2-fold increase in at least 3 out of 5 pneumococcal antigens. In the same study 98% of patients in the Humira group and 95% in the placebo group achieved protective antibody levels to the influenza antigens. A total of 52% of Humira-treated subjects and 63% of placebo-treated subjects achieved at least a 4-fold increase in at least 2 out of 3 influenza antigens.

Patients on Humira may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving Humira.

Congestive Heart Failure

In a clinical trial with another TNF antagonist worsening congestive heart failure and increased mortality due to congestive heart failure have been observed. Cases of worsening congestive heart failure have been reported in patients receiving Humira. Humira should be used with caution in patients with mild heart failure (NYHA class I/II). Humira is contraindicated in moderate or severe heart failure. Treatment with Humira must be discontinued in patients who develop new or worsening symptoms of congestive heart failure.

Malignancies

In the controlled portions of clinical trials of TNF-antagonists, more cases of malignancies including lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients (see ADVERSE REACTIONS - Malignancies). However, the occurrence was rare. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with long-standing, highly active inflammatory disease, which complicates the risk estimation.

With the current knowledge, a possible risk for the development of lymphomas or other malignancies in patients treated with a TNF-antagonist cannot be excluded.

No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving Humira. Thus, additional caution should be exercised in considering Humira treatment of these patients.

In an exploratory clinical trial evaluating the use of another anti-TNF agent, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lung or head and neck, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Therefore, caution should be exercised when using any TNF-antagnoist in COPD patients, as well as in patients with an increased risk for malignancy due to heavy smoking.

Autoimmune Processes

Treatment with Humira may result in the formation of autoantibodies and rarely in the development of a lupus-like syndrome. The impact of long-term treatment with Humira on the development of autoimmune disease is unknown. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Humira, treatment should be discontinued (see ADVERSE REACTIONS - Autoantibodies).

Concurrent Administration of TNF-alpha Inhibitor and Anakinra

Concurrent administration of etanercept and anakinra has been associated with an increased risk of serious infections, an increased risk of neutropenia and no additional benefit compared to these medicinal products alone. The safety and efficacy of anakinra used in combination with adalimumab has not been established. Therefore, combination of adalimumab and anakinra is contraindicated.

Concurrent Administration of TNF-alpha Inhibitor and Abatacept

Concurrent administration of TNF antagonists and abatacept has been associated with an increased risk of infections including serious infections compared to TNF antagonists alone. This combination has not demonstrated increased clinical benefit. Thus, the combined use of TNF antagonists and abatacept is not recommended.

Renal and Hepatic Impairment

Humira has not been studied in these patient populations. No dose recommendations can be made.

Effects on Fertility

The effect of adalimumab on fertility has not been investigated.

Use in Pregnancy (Category C)

Results obtained with a very high intravenous adalimumab dose (100 mg/kg/week) in an embryofoetal toxicity study in cynomolgus monkeys were inconclusive. No developmental toxicity was observed with an intravenous dose of 30 mg/kg/week, which resulted in a serum drug concentration greater than 100-fold higher than the maximum value expected during therapy during 40 mg fortnightly. Parturition was unaffected by both doses.

There are no clinical data for pregnant women being treated with Humira. Because animal studies are not always predictive of human responses, the use of Humira during pregnancy is not recommended. Women of child bearing potential should be advised to use adequate contraception during Humira therapy. The long half-life of Humira should also be considered when discontinuing therapy.

Use In Lactation

It is not known whether adalimumab is excreted in animal or human milk or whether it would be absorbed by neonates after ingestion.

Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in breastfeeding infants from Humira, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother. The long half-life of Humira should also be considered when discontinuing therapy.

Paediatric Use

Safety and effectiveness in paediatric patients have not been studied.

Use in the Elderly

A total of 519 RA patients 65 years of age and older, including 107 patients 75 years and older, received Humira in clinical studies I-IV. No overall difference in effectiveness was observed between these subjects and younger subjects. The frequency of serious infection and malignancy among Humira-treated subjects over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.

Carcinogenicity

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of adalimumab.

Genotoxicity

No genotoxicity was observed in an in-vitro test for bacterial gene mutation or in an in-vivo mouse micronucleus test for clastogenicity.

Interactions with other Medicines

Humira has been studied in RA patients taking concomitant methotrexate (see CLINICAL STUDIES and Pharmacokinetics - Steady State). The data do not suggest the need for dose adjustment of either Humira or methotrexate. Interactions between Humira and drugs other than methotrexate have not been evaluated in formal pharmacokinetic studies.

Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

Effects on Laboratory Tests

There is no known interference between Humira and laboratory tests.

ADVERSE EFFECTS

Rheumatoid Arthritis Clinical Trials

Humira was studied in 2334 patients in placebo-controlled trials and in long-term follow-up studies, for up to 5 years, including 2073 patients exposed for six months and 1497 patients exposed for greater than one year. The data in the table is based on the adequate and well-controlled studies I, II, III and IV involving 1380 patients receiving adalimumab during the placebo-controlled period by randomised treatment. The population had a mean age of 54.5 years, 77% were female, 91% were Caucasian and had moderate to severely active RA. Most patients received 40 mg Humira fortnightly.

The proportion of patients who discontinued treatment due to adverse events during the double-blind, placebo-controlled portion of Studies I, II, III and IV was 6.6% for patients taking Humira and 4.2% for placebo-treated patients. Overall discontinuation rates were 12.7% for patients taking Humira and 16.8% for placebo-treated patients. The most common reasons for discontinuation with Humira were adverse events (6.6%), lack of efficacy (2.4%) and withdrawal of consent (1.9%). The most common adverse events leading to discontinuation of Humira were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).

Adverse events at least possibly causally-related to adalimumab, both clinical and laboratory, are displayed by system organ class and frequency (very common >1/10; common >1/100 ≤ 1/10; uncommon >1/1000 ≤1/100) in Table 16 below.

Table 16: Very Common and Common Adverse Drug Reactions in Rheumatoid Arthritis Clinical Studies
Body system	Adverse Reaction	Adalimumab (N=1380) (%)	Placebo (N=690) (%)
Haemic and Lymphatic system	Decreased haemoglobin	1.2	1.2
Metabolic and Nutritional Disorders	Hyperlipidaemia	1.2	0.3
Nervous System	Headache	5.5	2.2
	Dizziness	1.2	0.9
Respiratory System	Upper respiratory infection	5.3	2.5
	Rhinitis	4.3	1.6
	Sinusitis	2.9	3.2
	Bronchitis	1.7	1.3
	Cough increased	1.7	0.7
	Pneumonia	1.2	0.4
Digestive System	Nausea	4.0	1.7
	Diarrhoea	2.3	2.3
	Sore throat	1.5	1.3
Skin and appendages	Rash	5.7	2.2
	Pruritus	2.6	0.4
	Herpes simplex	1.7	0.9
Urogenital System	Urinary tract infection	2.0	1.2
Body as a whole	Laboratory test abnormal	3.8	1.9
	Asthenia	3.3	1.4
	Clinical flare reaction	2.2	1.3
	Flu syndrome	1.9	1.3
	Abdominal pain	1.4	1.3
	Infection	1.4	0.3
Injection site reaction	Injection site pain	11.2	12.2
	Injection site reaction	7.0	1.0
	Injection site haemorrhage	1.7	1.2
	Injection site eruption	1.4	0.3

Uncommon adverse drug reactions are line listed by system organ class in the following:

Neoplasia:

Skin benign neoplasm

Haemic and Lymphatic System:

Granulocytopenia, coagulation time increased, antinuclear antibody present, leukopenia, lymphadenopathy, lymphocytosis, platelet count decreased, purpura

Metabolic and Nutritional Disorders:

Hypercholesterolaemia, alkaline phosphatase increased, BUN increased, hyperuricaemia, peripheral oedema, weight gain, creatinine phosphokinase increased, healing abnormal, hypokalaemia, lactic dehydrogenase increased

Psychiatric Disorders:

Depression, somnolence, insomnia, agitation

Nervous System:

Paraesthesia, vertigo, hypaesthesia, neuralgia, tremor

Special Senses:

Conjunctivitis, eye disorder, otitis media, taste perversion, abnormal vision, blurred vision, dry eye, ear disorder, eye pain

Cardiovascular System:

Hypertension, vasodilation, chest pain, migraine

Haemorrhage:

Ecchymosis

Respiratory System:

Pharyngitis, dyspnoea, lung disorder, asthma

Digestive System:

Liver function test abnormal, ALT/SGPT increased, AST/SGOT increased, mouth ulceration, oesophagitis, vomiting, dyspepsia, constipation, gastrointestinal pain, tooth disorder, gastritis, gastroenteritis, tongue disorder, oral moniliasis, aphthous stomatitis, dysphagia, stomatitis, ulcerative stomatitis

Skin and Appendages:

Skin disorder, herpes zoster, maculopapular rash, nail disorder, dry skin, sweating increased, alopecia, fungal dermatitis, urticaria, skin nodule, skin ulcer, eczema, subcutaneous haematoma

Musculo-skeletal System:

Arthralgia, muscle cramps, myalgia, joint disorder, synovitis, tendon disorder

Urogenital System:

Vaginal moniliasis, haematuria, cystitis, menorrhagia, proteinuria, increased urinary frequency

Body as a Whole:

Fever, mucous membrane disorder, pain in extremity, face oedema, back pain, cellulitis, chills, sepsis, surgery, invasive fungal infection

Hypersensitivity:

Allergic reaction

Other serious adverse events occurring at an incidence of less than 1% in clinical studies

Adenoma, carcinomas such as breast, gastrointestinal, skin, urogenital and others, lymphoma and melanoma, agranulocytosis, pancytopenia, arrhythmia, atrial fibrillation, cardiovascular disorder, congestive heart failure, coronary artery disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, pericarditis, syncope, tachycardia, vascular disorder, hepatic necrosis, cholecystitis, tuberculosis reactivated, lupus erythematosus syndrome, pelvic pain, thorax pain, cholelithiasis, gastrointestinal disorder, gastrointestinal haemorrhage, parathyroid disorder, lymphoma like reaction, polycythaemia, ketosis, paraproteinaemia, arthritis, bone disorder, bone fracture, bone necrosis, myasthenia, pyogenic arthritis, confusion, multiple sclerosis, subdural haematoma, bronchospasm, lung function decreased, pleural effusion, cellulitis, erysipelas, cataract, thrombosis leg, kidney calculus, menstrual disorder, pyelonephritis

Rare adverse drug reactions are line listed by system organ class in the following:

Nervous System

Rarely, demyelinating disorders have been noted.

A comparison of adverse events for patients on adalimumab versus patients on adalimumab with concomitant methotrexate is provided in Table 17 below. Differences seen are in part due to regional methodological variations in parts of the world where studies were conducted and may not be clinically meaningful.

Table 17: Overview of adverse events during treatment with 40 mg fortnightly adalimumab with and without methotrexate. Study group: all studies in patients with RA (DE001/3, 004, 005/X, 010, 009/X. 011, 019, 031, 018, 020)
	Adalimumab 40 mg fortnightly sc
	With MTX (N=1198)	Without MTX (N=1005)
Patients with any	%	%
AE *	91.2	96.7
Clinical AE *	90.2	91.3
Laboratory AE *	24.2	72.6
Fatal AE *	0.7	0.7
SAE *	17.4	24.4
AE leading to withdrawal *	6.8	7.8
AE leading to dose interruption *	21.5	24.1
AE leading to dose reduction *	0.3	0.1
Severe or life-threatening/ intractable AE *	20.9	30.4
At least possibly drug-related AE *	48.8	61.2
Infection (serious and non-serious) *	62.9	59.8
Serious infection *	3.8	3.8
Malignancy *	2.7	2.1
Immunologic reaction *	0.7	1.2
* This data is from clinical trial information through 29-Mar-2002

Injection Site Reactions

In placebo-controlled trials, 20% of patients treated with Humira developed injection site reactions (erythema and/or itching, haemorrhage, 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.

Infections

In placebo-controlled trials, the rate of infection was 1 per patient year in the Humira-treated patients and 0.9 per patient year in the placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, bronchitis and urinary tract infections. Most patients continued on Humira after the infection resolved. The incidence of serious infections was 0.04 per patient year in Humira-treated patients and 0.02 per patient year in placebo-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis.

Uncommonly, cases of tuberculosis, including miliary, lymphatic, peritoneal, and pulmonary were reported in clinical trials. Most of the cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. Uncommonly, cases of invasive opportunistic infections caused by histoplasma, aspergillus, and nocardia were reported in clinical trials.

Malignancies

During the controlled portions of Humira trials in patients with moderately to severely active rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease and psoriasist, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 5.9 (3.5, 9.9) per 1000 patient-years among 3853 Humira treated patients versus a rate of 4.3 (1.8, 10.4) per 1000 patient years among 2183 control patients (median duration of treatment was 5.5 months for Humira and 3.9 months for control-treated patients). The rate (95% confidence interval) of non-melanoma skin cancers was 8.8 (5.7, 13.5) per 1000 patient-years among Humira treated patients and 2.6 (0.8, 8.0) per 1000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at a rate (95% confidence interval) of 2.5 (1.1, 5.6) per 1000 patient-years among Humira-treated patients and 0.9 (0.1, 6.1) per 1000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.8 (0.2, 3.3) per 1000 patient-years among Humira-treated patients and 0.9 (0.1, 6.1) per 1000 patient-years among control patients (see PRECAUTIONS - Malignancies).

When combining controlled trials and ongoing open label extension studies with a median duration of approximately 1.7 years, including 6539 patients and over 16,000 patient-years of therapy, the observed rate (95% confidence interval) of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 10.1 (8.6, 11.8) per 1000 patient years. The observed rate (95% confidence interval) of non-melanoma skin cancers is approximately 9.0 (7.7, 10.6) per 1000 patient years. The observed rate (95% confidence interval) of lymphomas is approximately 1.1 (0.7, 1.8) per 1000 patient years, which is approximately 3.0-fold higher than expected in the general population.

In post-marketing experience from January 2003, predominantly in patients with rheumatoid arthritis, the reported rate of amlignancies other than lymphomas and non-melanoma skin cancers is approximately 1.7 per 1000 patients years. The reported rates for non-melanoma skins cancers and lymphomas are approximately 0.5 and 0.4 per 1000 patients years, respectively.

Autoantibodies

Patients had serum samples tested for autoantibodies at multiple time points. In the adequate and well-controlled rheumatoid arthritis trials, 12.6% of patients treated with Humira and 7.3% of placebo-treated patients that had negative baseline antinuclear antibody titres reported positive titres at Week 24. Two patients out of >3000 treated with Humira de