Remicade

Generic Name: infliximab
Dosage Form: injection

Remicade Description

Remicade is a chimeric IgG1κ monoclonal antibody with an approximate molecular weight of 149,100 daltons. It is composed of human constant and murine variable regions. Infliximab binds specifically to human tumor necrosis factor alpha (TNFα) with an association constant of 1010 M-1. Infliximab is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses.

Remicade is supplied as a sterile, white, lyophilized powder for intravenous infusion. Following reconstitution with 10 mL of Sterile Water for Injection, USP, the resulting pH is approximately 7.2. Each single-use vial contains 100 mg infliximab, 500 mg sucrose, 0.5 mg polysorbate 80, 2.2 mg monobasic sodium phosphate, monohydrate, and 6.1 mg dibasic sodium phosphate, dihydrate. No preservatives are present.

Remicade - Clinical Pharmacology

General

Infliximab neutralizes the biological activity of TNFα by binding with high affinity to the soluble and transmembrane forms of TNFα and inhibits binding of TNFα with its receptors.3,4 Infliximab does not neutralize TNFβ (lymphotoxin α), a related cytokine that utilizes the same receptors as TNFα. Biological activities attributed to TNFα include: induction of pro-inflammatory cytokines such as interleukins (IL) 1 and 6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or chondrocytes. Cells expressing transmembrane TNFα bound by infliximab can be lysed in vitro4 or in vivo.5 Infliximab inhibits the functional activity of TNFα in a wide variety of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils, B and T lymphocytes and epithelial cells. The relationship of these biological response markers to the mechanism(s) by which Remicade exerts its clinical effects is unknown. Anti-TNFα antibodies reduce disease activity in the cotton-top tamarin colitis model, and decrease synovitis and joint erosions in a murine model of collagen-induced arthritis. Infliximab prevents disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFα, and when administered after disease onset, allows eroded joints to heal.

Pharmacodynamics

Elevated concentrations of TNFα have been found in involved tissues and fluids of patients with rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. In rheumatoid arthritis, treatment with Remicade reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion [E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)], chemoattraction [IL-8 and monocyte chemotactic protein (MCP-1)] and tissue degradation [matrix metalloproteinase (MMP) 1 and 3]. In Crohn's disease, treatment with Remicade reduced infiltration of inflammatory cells and TNFα production in inflamed areas of the intestine, and reduced the proportion of mononuclear cells from the lamina propria able to express TNFα and interferon. After treatment with Remicade, patients with rheumatoid arthritis or Crohn's disease exhibited decreased levels of serum IL-6 and C-reactive protein (CRP) compared to baseline. Peripheral blood lymphocytes from Remicade-treated patients showed no significant decrease in number or in proliferative responses to in vitro mitogenic stimulation when compared to cells from untreated patients. In psoriatic arthritis, treatment with Remicade resulted in a reduction in the number of T-cells and blood vessels in the synovium and psoriatic skin lesions as well as a reduction of macrophages in the synovium. In plaque psoriasis, Remicade treatment may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which Remicade exerts its clinical effects is unknown.

Pharmacokinetics

In adults, single intravenous (IV) infusions of 3 mg/kg to 20 mg/kg showed a linear relationship between the dose administered and the maximum serum concentration. The volume of distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment. Pharmacokinetic results for single doses of 3 mg/kg to 10 mg/kg in rheumatoid arthritis, 5 mg/kg in Crohn's disease, and 3 mg/kg to 5 mg/kg in plaque psoriasis indicate that the median terminal half-life of infliximab is 7.7 to 9.5 days.

Following an initial dose of Remicade, repeated infusions at 2 and 6 weeks resulted in predictable concentration-time profiles following each treatment. No systemic accumulation of infliximab occurred upon continued repeated treatment with 3 mg/kg or 10 mg/kg at 4- or 8-week intervals. Development of antibodies to infliximab increased infliximab clearance. At 8 weeks after a maintenance dose of 3 to 10 mg/kg of Remicade, median infliximab serum concentrations ranged from approximately 0.5 to 6 mcg/mL; however, infliximab concentrations were not detectable (<0.1 mcg/mL) in patients who became positive for antibodies to infliximab. No major differences in clearance or volume of distribution were observed in patient subgroups defined by age, weight, or gender. It is not known if there are differences in clearance or volume of distribution in patients with marked impairment of hepatic or renal function.

Infliximab peak and trough concentrations were similar in pediatric (aged 6 to 17 years old) and adult patients with Crohn's disease following the administration of the recommended regimen (see DOSAGE AND ADMINISTRATION, Crohn's Disease or Fistulizing Crohn's Disease).

Population pharmacokinetic analysis showed that in children with juvenile rheumatoid arthritis (JRA) with a body weight of up to 35 kg receiving 6 mg/kg Remicade and children with JRA with body weight greater than 35 kg up to adult body weight receiving 3mg/kg Remicade, the steady state area under the concentration curve (AUCss) was similar to that observed in adults receiving 3 mg/kg of Remicade.

Clinical Studies

Rheumatoid Arthritis

The safety and efficacy of Remicade were assessed in two multicenter, randomized, double-blind, pivotal trials: ATTRACT (Study RA I) and ASPIRE (Study RA II). Concurrent use of stable doses of folic acid, oral corticosteroids (≤10 mg/day) and/or non-steroidal anti-inflammatory drugs was permitted.

Study RA I was a placebo-controlled study of 428 patients with active rheumatoid arthritis despite treatment with MTX. Patients enrolled had a median age of 54 years, median disease duration of 8.4 years, median swollen and tender joint count of 20 and 31 respectively, and were on a median dose of 15 mg/wk of MTX. Patients received either placebo + MTX or one of 4 doses/schedules of Remicade + MTX: 3 mg/kg or 10 mg/kg of Remicade by IV infusion at weeks 0, 2 and 6 followed by additional infusions every 4 or 8 weeks in combination with MTX.

Study RA II was a placebo-controlled study of three active treatment arms in 1004 MTX naive patients of 3 or fewer years duration active rheumatoid arthritis. Patients enrolled had a median age of 51 years with a median disease duration of 0.6 years, median swollen and tender joint count of 19 and 31, respectively, and >80% of patients had baseline joint erosions. At randomization, all patients received MTX (optimized to 20 mg/wk by week 8) and either placebo, 3mg/kg or 6 mg/kg Remicade at weeks 0, 2, and 6 and every 8 weeks thereafter.

Data on use of Remicade without concurrent MTX are limited (see ADVERSE REACTIONS, Immunogenicity). 6,7

Clinical response

In Study RA I, all doses/schedules of Remicade + MTX resulted in improvement in signs and symptoms as measured by the American College of Rheumatology response criteria (ACR 20) with a higher percentage of patients achieving an ACR 20, 50 and 70 compared to placebo + MTX (Table 1). This improvement was observed at week 2 and maintained through week 102. Greater effects on each component of the ACR 20 were observed in all patients treated with Remicade + MTX compared to placebo + MTX (Table 2). More patients treated with Remicade reached a major clinical response than placebo-treated patients (Table 1).

In Study RA II, after 54 weeks of treatment, both doses of Remicade + MTX resulted in statistically significantly greater response in signs and symptoms compared to MTX alone as measured by the proportion of patients achieving ACR 20, 50 and 70 responses (Table 1). More patients treated with Remicade reached a major clinical response than placebo-treated patients (Table 1).

Table 1 ACR RESPONSE (PERCENT OF PATIENTS)

	Study RA I												Study RA II
				Remicade + MTX											Remicade + MTX
						3 mg/kg			10 mg/kg							3 mg/kg	6 mg/kg
Response		Placebo + MTX			q 8 wks		q 4 wks	q 8 wks		q 4 wks				Placebo + MTX		q 8 wks	q 8 wks
		(n=88)			(n=86)		(n=86)	(n=87)		(n=81)				(n=274)		(n=351)	(n=355)
# A major clinical response was defined as a 70% ACR response for 6 consecutive months (consecutive visits spanning at least 26 weeks) through week 102 for Study RA I and week 54 for Study RA II.
ap ≤ 0.001
bp < 0.01
cp < 0.05
ACR 20
Week 30		20%			50%a		50%a	52%a		58%a				N/A		N/A	N/A
Week 54		17%			42%a		48%a	59%a		59%a				54%		62%c	66%a
ACR 50
Week 30		5%			27%a		29%a	31%a		26%a				N/A		N/A	N/A
Week 54		9%			21%c		34%a	40%a		38%a				32%		46%a	50%a
ACR 70
Week 30		0%			8%b		11%b	18%a		11%a				N/A		N/A	N/A
Week 54		2%			11%c		18%a	26%a		19%a				21%		33%b	37%a
Major clinical response#		0%			7% c		8% b	15% a		6% c				8%		12%	17% a

Table 2 COMPONENTS OF ACR 20 AT BASELINE AND 54 WEEKS (Study RA I)

	Placebo + MTX			Remicade + MTXa
Parameter (medians)	(n=88)			(n=340)
	Baseline	Week 54		Baseline	Week 54
aAll doses/schedules of Remicade + MTX
bVisual Analog Scale (0=best, 10=worst)
cHealth Assessment Questionnaire, measurement of 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities (0=best, 3=worst)
No. of Tender Joints	24	16		32	8
No. of Swollen Joints	19	13		20	7
Painb	6.7	6.1		6.8	3.3
Physician's Global Assessmentb	6.5	5.2		6.2	2.1
Patient's Global Assessmentb	6.2	6.2		6.3	3.2
Disability Index (HAQ-DI)c	1.8	1.5		1.8	1.3
CRP (mg/dL)	3.0	2.3		2.4	0.6

Radiographic response

Structural damage in both hands and feet was assessed radiographically at week 54 by the change from baseline in the van der Heijde-modified Sharp (vdH-S) score, a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing in hands/wrists and feet.8

In Study RA I, approximately 80% of patients had paired x-ray data at 54 weeks and approximately 70% at 102 weeks. The inhibition of progression of structural damage was observed at 54 weeks (Table 3) and maintained through 102 weeks.

In Study RA II, >90% of patients had at least two evaluable x-rays. Inhibition of progression of structural damage was observed at weeks 30 and 54 (Table 3) in the Remicade + MTX groups compared to MTX alone. Patients treated with Remicade + MTX demonstrated less progression of structural damage compared to MTX alone, whether baseline acute phase reactants (ESR and CRP) were normal or elevated: patients with elevated baseline acute phase reactants treated with MTX alone demonstrated a mean progression in vdH-S score of 4.2 units compared to patients treated with Remicade + MTX who demonstrated 0.5 units of progression; patients with normal baseline acute phase reactants treated with MTX alone demonstrated a mean progression in vdH-S score of 1.8 units compared to Remicade + MTX who demonstrated 0.2 units of progression. Of patients receiving Remicade + MTX, 59% had no progression (vdH-S score ≤ 0 unit) of structural damage compared to 45% patients receiving MTX alone. In a subset of patients who began the study without erosions, Remicade + MTX maintained an erosion free state at 1 year in a greater proportion of patients than MTX alone, 79% (77/98) vs. 58% (23/40), respectively (p<0.01). Fewer patients in the Remicade + MTX groups (47%) developed erosions in uninvolved joints compared to MTX alone (59%).

Table 3 RADIOGRAPHIC CHANGE FROM BASELINE TO WEEK 54

	Study RA I				Study RA II
		Remicade + MTX				Remicade + MTX
		3 mg/kg	10 mg/kg			3 mg/kg	6 mg/kg
	Placebo   + MTX	q 8     wks	q 8     wks		Placebo   + MTX	q 8     wks	q 8     wks
	(n=64)	(n=71)	(n=77)		(n=282)	(n=359)	(n=363)
a P <0.001 for each outcome against placebo.
Total Score
Baseline
Mean	79	78	65		11.3	11.6	11.2
Median	55	57	56		5.1	5.2	5.3
Change from baseline
Mean	6.9	1.3a	0.2a		3.7	0.4a	0.5a
Median	4.0	0.5	0.5		0.4	0.0	0.0
Erosion Score
Baseline
Mean	44	44	33		8.3	8.8	8.3
Median	25	29	22		3.0	3.8	3.8
Change from baseline
Mean	4.1	0.2a	0.2a		3.0	0.3a	0.1a
Median	2.0	0.0	0.5		0.3	0.0	0.0
JSN Score
Baseline
Mean	36	34	31		3.0	2.9	2.9
Median	26	29	24		1.0	1.0	1.0
Change from baseline
Mean	2.9	1.1a	0.0a		0.6	0.1a	0.2
Median	1.5	0.0	0.0		0.0	0.0	0.0

Physical function response

Physical function and disability were assessed using the Health Assessment Questionnaire (HAQ-DI) and the general health-related quality of life questionnaire SF-36.

In Study RA I, all doses/schedules of Remicade + MTX showed significantly greater improvement from baseline in HAQ-DI and SF-36 physical component summary score averaged over time through week 54 compared to placebo + MTX, and no worsening in the SF-36 mental component summary score. The median (interquartile range) improvement from baseline to week 54 in HAQ-DI was 0.1 (-0.1, 0.5) for the placebo + MTX group and 0.4 (0.1, 0.9) for Remicade + MTX (p<0.001). Both HAQ-DI and SF-36 effects were maintained through week 102. Approximately 80% of patients in all doses/schedules of Remicade + MTX remained in the trial through 102 weeks.

In Study RA II, both Remicade treatment groups showed greater improvement in HAQ-DI from baseline averaged over time through week 54 compared to MTX alone; 0.7 for Remicade + MTX vs. 0.6 for MTX alone (p≤0.001). No worsening in the SF-36 mental component summary score was observed.

Active Crohn's Disease

The safety and efficacy of single and multiple doses of Remicade were assessed in two randomized, double-blind, placebo-controlled clinical studies in 653 patients with moderate to severely active Crohn's disease [Crohn's Disease Activity Index (CDAI) ≥220 and ≤400] with an inadequate response to prior conventional therapies. Concomitant stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents were permitted and 92% of patients continued to receive at least one of these medications.

In the single-dose trial9 of 108 patients, 16% (4/25) of placebo patients achieved a clinical response (decrease in CDAI ≥70 points) at week 4 vs. 81% (22/27) of patients receiving 5 mg/kg Remicade (p<0.001, two-sided, Fisher's Exact test). Additionally, 4% (1/25) of placebo patients and 48% (13/27) of patients receiving 5 mg/kg Remicade achieved clinical remission (CDAI<150) at week 4.

In a multidose trial (ACCENT I [Study Crohn's I])10, 545 patients received 5 mg/kg at week 0 and were then randomized to one of three treatment groups; the placebo maintenance group received placebo at weeks 2 and 6, and then every 8 weeks; the 5 mg/kg maintenance group received 5 mg/kg at weeks 2 and 6, and then every 8 weeks; and the 10 mg/kg maintenance group received 5 mg/kg at weeks 2 and 6, and then 10 mg/kg every 8 weeks. Patients in response at week 2 were randomized and analyzed separately from those not in response at week 2. Corticosteroid taper was permitted after week 6.

At week 2, 57% (311/545) of patients were in clinical response. At week 30, a significantly greater proportion of these patients in the 5 mg/kg and 10 mg/kg maintenance groups achieved clinical remission compared to patients in the placebo maintenance group (Table 4).

Additionally, a significantly greater proportion of patients in the 5 mg/kg and 10 mg/kg Remicade maintenance groups were in clinical remission and were able to discontinue corticosteroid use compared to patients in the placebo maintenance group at week 54 (Table 4).

Table 4 CLINICAL REMISSION AND STEROID WITHDRAWAL

	Single 5 mg/kg Dosea	Three Dose Inductionb
	Placebo Maintenance	Remicade Maintenance q 8 wks
		5 mg/kg	10 mg/kg
a Remicade at week 0
b Remicade 5 mg/kg administered at weeks 0, 2 and 6
c p-values represent pairwise comparisons to placebo
d Of those receiving corticosteroids at baseline
Week 30 Clinical remission	25/102 25%	41/104 39%	48/105 46%
p-valuec		0.022	0.001
Week 54 Patients in remission able to discontinue corticosteroid used	6/54 11%	14/56 25%	18/53 34%
p-valuec		0.059	0.005

Patients in the Remicade maintenance groups (5 mg/kg and 10 mg/kg) had a longer time to loss of response than patients in the placebo maintenance group ( Figure 1). At weeks 30 and 54, significant improvement from baseline was seen among the 5 mg/kg and 10 mg/kg Remicade-treated groups compared to the placebo group in the disease specific inflammatory bowel disease questionnaire (IBDQ), particularly the bowel and systemic components, and in the physical component summary score of the general health-related quality of life questionnaire SF-36.

In a subset of 78 patients who had mucosal ulceration at baseline and who participated in an endoscopic substudy, 13 of 43 patients in the Remicade maintenance group had endoscopic evidence of mucosal healing compared to 1 of 28 patients in the placebo group at week 10. Of the Remicade-treated patients showing mucosal healing at week 10, 9 of 12 patients also showed mucosal healing at week 54.

Patients who achieved a response and subsequently lost response were eligible to receive Remicade on an episodic basis at a dose that was 5 mg/kg higher than the dose to which they were randomized. The majority of such patients responded to the higher dose. Among patients who were not in response at week 2, 59% (92/157) of Remicade maintenance patients responded by week 14 compared to 51% (39/77) of placebo maintenance patients. Among patients who did not respond by week 14, additional therapy did not result in significantly more responses (see DOSAGE AND ADMINISTRATION).

Fistulizing Crohn's Disease

The safety and efficacy of Remicade were assessed in 2 randomized, double-blind, placebo-controlled studies in patients with fistulizing Crohn's disease with fistula(s) that were of at least 3 months duration. Concurrent use of stable doses of corticosteroids, 5-aminosalicylates, antibiotics, MTX, 6-mercaptopurine (6-MP) and/or azathioprine (AZA) was permitted.

In the first trial,11 94 patients received three doses of either placebo or Remicade at weeks 0, 2 and 6. Fistula response (≥50% reduction in number of enterocutaneous fistulas draining upon gentle compression on at least two consecutive visits without an increase in medication or surgery for Crohn's disease) was seen in 68% (21/31) of patients in the 5 mg/kg Remicade group (p=0.002) and 56% (18/32) of patients in the 10 mg/kg Remicade group (p=0.021) vs. 26% (8/31) of patients in the placebo arm. The median time to onset of response and median duration of response in Remicade-treated patients was 2 and 12 weeks, respectively. Closure of all fistula was achieved in 52% of Remicade-treated patients compared with 13% of placebo-treated patients (p<0.001).

In the second trial (ACCENT II [Study Crohn's II]), patients who were enrolled had to have at least one draining enterocutaneous (perianal, abdominal) fistula. All patients received 5 mg/kg Remicade at weeks 0, 2 and 6. Patients were randomized to placebo or 5 mg/kg Remicade maintenance at week 14. Patients received maintenance doses at week 14 and then every eight weeks through week 46. Patients who were in fistula response (fistula response was defined the same as in the first trial) at both weeks 10 and 14 were randomized separately from those not in response. The primary endpoint was time from randomization to loss of response among those patients who were in fistula response.

Among the randomized patients (273 of the 296 initially enrolled), 87% had perianal fistulas and 14% had abdominal fistulas. Eight percent also had rectovaginal fistulas. Greater than 90% of the patients had received previous immunosuppressive and antibiotic therapy.

At week 14, 65% (177/273) of patients were in fistula response. Patients randomized to Remicade maintenance had a longer time to loss of fistula response compared to the placebo maintenance group ( Figure 2). At week 54, 38% (33/87) of Remicade-treated patients had no draining fistulas compared with 22% (20/90) of placebo-treated patients (p=0.02). Compared to placebo maintenance, patients on Remicade maintenance had a trend toward fewer hospitalizations.

Patients who achieved a fistula response and subsequently lost response were eligible to receive Remicade maintenance therapy at a dose that was 5 mg/kg higher than the dose to which they were randomized. Of the placebo maintenance patients, 66% (25/38) responded to 5 mg/kg Remicade, and 57% (12/21) of Remicade maintenance patients responded to 10 mg/kg.

Patients who had not achieved a response by week 14 were unlikely to respond to additional doses of Remicade.

Similar proportions of patients in either group developed new fistulas (17% overall) and similar numbers developed abscesses (15% overall).

Active Crohn's Disease in Pediatric Patients

The safety and efficacy of Remicade were assessed in a randomized, open-label study (Study Peds Crohn's) in 112 pediatric patients 6 to 17 years old with moderately to severely active Crohn's disease and an inadequate response to conventional therapies. The median age was 13 years and the median Pediatric Crohn's Disease Activity Index (PCDAI) was 40 (on a scale of 0 to 100). All patients were required to be on a stable dose of 6-mercaptopurine, azathioprine, or methotrexate; 35% were also receiving corticosteroids at baseline.

All patients received induction dosing of 5 mg/kg Remicade at Weeks 0, 2, and 6. At Week 10, 103 patients were randomized to a maintenance regimen of 5 mg/kg Remicade given either every 8 weeks or every 12 weeks.

At Week 10, 88% of patients were in clinical response (defined as a decrease from baseline in the PCDAI score of 15 points and total PCDAI score of 30 points), and 59% were in clinical remission (defined as PCDAI score of 10 points).

The proportion of pediatric patients achieving clinical response at Week 10 compared favorably with the proportion of adults achieving a clinical response in Study Crohn's I. The study definition of clinical response in Study Peds Crohn's was based on the PCDAI score, whereas the CDAI score was used in the adult Study Crohn's I.

At both Week 30 and Week 54, the proportion of patients in clinical response was greater in the every 8 week treatment group than in the every 12 week treatment group (73% vs. 47% at Week 30, and 64% vs. 33% at Week 54). At both Week 30 and Week 54, the proportion of patients in clinical remission was also greater in the every 8 week treatment group than in the every 12 week treatment group (60% vs. 35% at Week 30, and 56% vs. 24% at Week 54), (Table 5).

For patients in Study Peds Crohn's receiving corticosteroids at baseline, the proportion of patients able to discontinue corticosteroids while in remission at Week 30 was 46% for the every 8 week maintenance group and 33% for the every 12 week maintenance group. At Week 54, the proportion of patients able to discontinue corticosteroids while in remission was 46% for the every 8 week maintenance group and 17% for the every 12 week maintenance group.

Table 5 RESPONSE AND REMISSION IN STUDY PEDS CROHN'S

1Defined as a decrease from baseline in the PCDAI score of ≥ 15 points and total score of ≤ ࿠30 points.
2Defined as a PCDAI score of ≤ 10 points.
* p-value < 0.05
**p-value < 0.01
		5 mg/kg Remicade
	Every 8 Week		Every 12 Week
	Treatment Group		Treatment Group
Patients randomized	52		51
Clinical Response1
Week 30	73%**		47%
Week 54	64%**		33%
Clinical Remission2
Week 30	60%*		35%
Week 54	56%**		24%

Ankylosing Spondylitis

The safety and efficacy of Remicade were assessed in a randomized, multicenter, double-blind, placebo-controlled study in 279 patients with active ankylosing spondylitis. Patients were between 18 and 74 years of age, and had ankylosing spondylitis as defined by the modified New York criteria for Ankylosing Spondylitis.12 Patients were to have had active disease as evidenced by both a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score >4 (possible range 0-10) and spinal pain >4 (on a Visual Analog Scale [VAS] of 0-10). Patients with complete ankylosis of the spine were excluded from study participation, and the use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) and systemic corticosteroids were prohibited. Doses of Remicade 5 mg/kg or placebo were administered intravenously at Weeks 0, 2, 6, 12 and 18.

At 24 weeks, improvement in the signs and symptoms of ankylosing spondylitis, as measured by the proportion of patients achieving a 20% improvement in ASAS response criteria (ASAS 20), was seen in 60% of patients in the Remicade-treated group vs. 18% of patients in the placebo group (p<0.001). Improvement was observed at week 2 and maintained through week 24 ( Figure 3 and Table 6).

At 24 weeks, the proportions of patients achieving a 50% and a 70% improvement in the signs and symptoms of ankylosing spondylitis, as measured by ASAS response criteria (ASAS 50 and ASAS 70, respectively), were 44% and 28%, respectively, for patients receiving Remicade, compared to 9% and 4%, respectively, for patients receiving placebo (p<0.001, Remicade vs. placebo). A low level of disease activity (defined as a value <20 [on a scale of 0-100 mm] in each of the four ASAS response parameters) was achieved in 22% of Remicade-treated patients vs. 1% in placebo-treated patients (p<0.001).

Table 6 Components of Ankylosing Spondylitis Disease Activity

	Placebo (n=78)		Remicade 5mg/kg (n=201)
	Baseline	24 Weeks	Baseline	24 Weeks	p-value
a measured on a VAS with 0=”none” and 10=”severe”
b Bath Ankylosing Spondylitis Functional Index (BASFI), average of 10 questions
c Inflammation, average of last 2 questions on the 6 question BASDAI
d CRP normal range 0-1.0 mg/dL
e Spinal mobility normal values: modified Schober's test: >4 cm; chest expansion:>6 cm; tragus to wall: <15 cm; lateral spinal flexion: >10 cm
ASAS 20 response Criteria (Mean)
Patient global assessmenta	6.6	6.0	6.8	3.8	<0.001
Spinal paina	7.3	6.5	7.6	4.0	<0.001
BASFIb	5.8	5.6	5.7	3.6	<0.001
Inflammationc	6.9	5.8	6.9	3.4	<0.001
Acute Phase Reactants
Median CRPd (mg/dL)	1.7	1.5	1.5	0.4	<0.001
Spinal Mobility (cm, Mean)
Modified Schober's teste	4.0	5.0	4.3	4.4	0.75
Chest expansione	3.6	3.7	3.3	3.9	0.04
Tragus to walle	17.3	17.4	16.9	15.7	0.02
Lateral spinal flexione	10.6	11.0	11.4	12.9	0.03

The median improvement from baseline in the general health-related quality of life questionnaire SF-36 physical component summary score at week 24 was 10.2 for the Remicade group vs. 0.8 for the placebo group (p<0.001). There was no change in the SF-36 mental component summary score in either the Remicade group or the placebo group.

Results of this study were similar to those seen in a multicenter double-blind, placebo-controlled study of 70 patients with ankylosing spondylitis.

Psoriatic Arthritis

Safety and efficacy of Remicade were assessed in a multicenter, double-blind, placebo-controlled study in 200 adult patients with active psoriatic arthritis despite DMARD or NSAID therapy (≥ 5 swollen joints and ≥ 5 tender joints) with one or more of the following subtypes: arthritis involving DIP joints (n=49), arthritis mutilans (n=3), asymmetric peripheral arthritis (n=40), polyarticular arthritis (n=100), and spondylitis with peripheral arthritis (n=8). Patients also had plaque psoriasis with a qualifying target lesion ≥ 2 cm in diameter. Forty-six percent of patients continued on stable doses of methotrexate (≤ 25 mg/week). During the 24-week double-blind phase, patients received either 5 mg/kg Remicade or placebo at weeks 0, 2, 6, 14, and 22 (100 patients in each group). At week 16, placebo patients with < 10% improvement from baseline in both swollen and tender joint counts were switched to Remicade induction (early escape). At week 24, all placebo-treated patients crossed over to Remicade induction. Dosing continued for all patients through week 46.

Clinical response

Treatment with Remicade resulted in improvement in signs and symptoms, as assessed by the ACR criteria, with 58% of Remicade-treated patients achieving ACR 20 at week 14, compared with 11% of placebo-treated patients (p < 0.001). The response was similar regardless of concomitant use of methotrexate. Improvement was observed as early as week 2. At 6 months, the ACR 20/50/70 responses were achieved by 54%, 41%, and 27%, respectively, of patients receiving Remicade compared to 16%, 4%, and 2%, respectively, of patients receiving placebo. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and spondylitis with peripheral arthritis subtypes.

Compared to placebo, treatment with Remicade resulted in improvements in the components of the ACR response criteria, as well as in dactylitis and enthesopathy (Table 7). The clinical response was maintained through week 54. Similar ACR responses were observed in an earlier randomized, placebo-controlled study of 104 psoriatic arthritis patients, and the responses were maintained through 98 weeks in an open label extension phase.

Table 7 COMPONENTS OF ACR 20 AND PERCENTAGE OF PATIENTS WITH 1 OR MORE JOINTS WITH DACTYLITIS AND PERCENTAGE OF PATIENTS WITH ENTHESOPATHY AT BASELINE and WEEK 24

a p<0.001 for percent change from baseline in all components of ACR 20 at week 24, p<0.05 for % of patients with dactylitis, and p=0.004 for % of patients with enthesopathy at week 24
b Scale 0-68
c Scale 0-66
d Visual Analog Scale (0=best, 10=worst)
e Health Assessment Questionnaire, measurement of 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities (0=best, 3=worst)
f Normal range 0-0.6 mg/dL
	Placebo		Remicade 5mg/kga
Patients Randomized	(n=100)		(n=100)
	Baseline	Week 24	Baseline	Week 24
Parameter (medians)
No of Tender Jointsb	24	20	20	6
No. of Swollen Jointsc	12	9	12	3
Paind	6.4	5.6	5.9	2.6
Physician's Global Assessmentd	6.0	4.5	5.6	1.5
Patient's Global Assessmentd	6.1	5.0	5.9	2.5
Disability Index (HAQ-DI)e	1.1	1.1	1.1	0.5
CRP (mg/dL) f	1.2	0.9	1.0	0.4
% Patients with 1 or more digits with dactylitis	41	33	40	15
% Patients with enthesopathy	35	36	42	22

Improvement in Psoriasis Area and Severity Index (PASI) in psoriatic arthritis patients with baseline body surface area (BSA) ≥ 3% (n=87 placebo, n=83 Remicade) was achieved at week 14, regardless of concomitant methotrexate use, with 64% of Remicade-treated patients achieving at least 75% improvement from baseline vs. 2% of placebo-treated patients; improvement was observed in some patients as early as week 2. At 6 months, the PASI 75 and PASI 90 responses were achieved by 60% and 39%, respectively, of patients receiving Remicade compared to 1% and 0%, respectively, of patients receiving placebo. The PASI response was generally maintained through week 54. See also CLINICAL STUDIES: Plaque Psoriasis section below.

Radiographic response

Structural damage in both hands and feet was assessed radiographically by the change from baseline in the van der Heijde-Sharp (vdH-S) score, modified by the addition of hand DIP joints. The total modified vdH-S score is a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing (JSN) in the hands and feet. At Week 24, Remicade-treated patients had less radiographic progression than placebo-treated patients (mean change of -0.70 vs. 0.82, p<0.001). Remicade-treated patients also had less progression in their erosion scores (-0.56 vs. 0.51 and JSN scores (-0.14 vs. 0.31). The patients in the Remicade group demonstrated continued inhibition of structural damage at week 54. Most patients showed little or no change in the vdH-S score during this 12-month study (median change of 0 in both patients who initially received Remicade or placebo). More patients in the placebo group (12%) had readily apparent radiographic progression compared with the Remicade group (3%).

Physical function

Physical function status was assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Remicade-treated patients demonstrated significant improvement in physical function as assessed by HAQ-DI (median percent improvement in HAQ-DI score from baseline to week 14 and 24 of 43% for Remicade-treated patients vs. 0% for placebo-treated patients).

During the placebo-controlled portion of the trial (24 weeks), 54% of Remicade-treated patients achieved a clinically meaningful improvement in HAQ-DI (≥ 0.3 unit decrease) compared to 22% of placebo-treated patients. Remicade-treated patients also demonstrated greater improvement in the SF-36 physical and mental component summary scores than placebo-treated patients. The responses were maintained for up to 2 years in an open label extension study.

Plaque Psoriasis

The safety and efficacy of Remicade were assessed in three randomized, double-blind, placebo-controlled studies in patients 18 years of age and older with chronic, stable plaque psoriasis involving ≥ 10% BSA, a minimum PASI score of 12, and who were candidates for systemic therapy or phototherapy. Patients with guttate, pustular, or erythrodermic psoriasis were excluded from these studies. No concomitant anti-psoriatic therapies were allowed during the study, with the exception of low-potency topical corticosteroids on the face and groin after week 10 of study initiation.

Study I (EXPRESS) evaluated 378 patients who received placebo or Remicade at a dose of 5 mg/kg at weeks 0, 2, and 6 (induction therapy), followed by maintenance therapy every 8 weeks. At week 24, the placebo group crossed over to Remicade induction therapy (5 mg/kg), followed by maintenance therapy every 8 weeks. Patients originally randomized to Remicade continued to receive Remicade 5 mg/kg every 8 weeks through week 46. Across all treatment groups, the median baseline PASI score was 21 and the baseline Static Physician Global Assessment (sPGA) score ranged from moderate (52% of patients) to marked (36%) to severe (2%). In addition, 75% of patients had a BSA >20%. Seventy-one percent of patients previously received systemic therapy and 82% received phototherapy.

Study II (EXPRESS II) evaluated 835 patients who received placebo or Remicade at doses of 3 mg/kg or 5 mg/kg at Weeks 0, 2, and 6 (induction therapy). At week 14, within each Remicade dose group, patients were randomized to either scheduled (every 8 weeks) or as needed (PRN) maintenance treatment through week 46. At week 16, the placebo group crossed over to Remicade induction therapy (5 mg/kg), followed by maintenance therapy every 8 weeks. Across all treatment groups, the median baseline PASI score was 18 and 63% of patients had a BSA >20%. Fifty-five percent of patients previously received systemic therapy and 64% received a phototherapy.

Study III (SPIRIT) evaluated 249 patients who had previously received either psoralen plus ultraviolet A treatment (PUVA) or other systemic therapy for their psoriasis. These patients were randomized to receive either placebo or Remicade at doses of 3 mg/kg or 5 mg/kg at weeks 0, 2, and 6. At week 26, patients with a sPGA score of moderate or worse (greater than or equal to 3 on a scale of 0 to 5) received an additional dose of the randomized treatment. Across all treatment groups, the median baseline PASI score was 19 and the baseline sPGA score ranged from moderate (62% of patients) to marked (22%) to severe (3%). In addition, 75% of patients had a BSA >20%. Of the enrolled patients 114 (46%) received the week 26 additional dose.

In Studies I, II and III, the primary endpoint was the proportion of patients who achieved a reduction in score of at least 75% from baseline at week 10 by the PASI (PASI 75). In Study I and Study III, another evaluated outcome included the proportion of patients who achieved a score of "cleared" or "minimal" by the sPGA. The sPGA is a 6 category scale ranging from "5 = severe" to "0 = cleared" indicating the physician's overall assessment of the psoriasis severity focusing on induration, erythema, and scaling. Treatment success, defined as "cleared" or "minimal", consisted of none or minimal elevation in plaque, up to faint red coloration in erythema, and none or minimal fine scale over < 5% of the plaque.

Study II also evaluated the proportion of patients who achieved a score of “clear” or “excellent” by the relative Physician's Global Assessment (rPGA). The rPGA is a 6 category scale ranging from “6 = worse” to “1 = clear” that was assessed relative to baseline. Overall lesions were graded with consideration to the percent of body involvement as well as overall induration, scaling, and erythema. Treatment success, defined as "clear" or "excellent", consisted of some residual pinkness or pigmentation to marked improvement (nearly normal skin texture; some erythema may be present). The results of these studies are presented in Table 8.

Table 8 Psoriasis Studies I, II, and III, Week 10 Percentage of Patients Who Achieved PASI 75 and Percentage Who Achieved Treatment “Success” with Physician's Global Assessment

* p<0.001 compared with placebo
a Patients with missing data at week 10 were considered as nonresponders.
b Patients with missing data at week 10 were imputed by last observation.
	Placebo	Remicade
		3 mg/kg	5 mg/kg
Psoriasis Study I - patients randomizeda            PASI 75	77 2 (3%)	--- ---	301 242 (80%)*
sPGA	3 (4%)	---	242 (80%)*
Psoriasis Study II - patients randomizeda            PASI 75	208 4 (2%)	313 220 (70%)*	314 237 (75%)*
rPGA	2 (1%)	217 (69%)*	234 (75%)*
Psoriasis Study III - patients randomizedb            PASI 75	51 3 (6%)	99 71 (72%)*	99 87 (88%)*
sPGA	5 (10%)	71 (72%)*	89 (90%)*

In Study I, in the subgroup of patients with more extensive psoriasis who had previously received phototherapy, 85% of patients on 5 mg/kg Remicade achieved a PASI 75 at week 10 compared with 4% of patients on placebo.

In Study II, in the subgroup of patients with more extensive psoriasis who had previously received phototherapy, 72% and 77% of patients on 3 mg/kg and 5 mg/kg Remicade achieved a PASI 75 at week 10 respectively compared with 1% on placebo. In Study II, among patients with more extensive psoriasis who had failed or were intolerant to phototherapy, 70% and 78% of patients on 3 mg/kg and 5 mg/kg Remicade achieved a PASI 75 at week 10 respectively, compared with 2% on placebo.

Maintenance of response was studied in a subset of 292 and 297 Remicade treated patients in the 3 mg/kg and 5 mg/kg groups; respectively, in Study II. Stratified by PASI response at week 10 and investigational site, patients in the active treatment groups were re-randomized to either a scheduled or as needed maintenance (PRN) therapy, beginning on week 14.

The groups that received a maintenance dose every 8 weeks appear to have a greater percentage of patients maintaining a PASI 75 through week 50 as compared to patients who received the as needed or PRN doses and the best response was maintained with the 5 mg/kg every 8 week dose. These results are shown in Figure 4. At week 46, when Remicade serum concentrations were at trough level, in the every 8 week dose group, 54% of patients in the 5 mg/kg group compared to 36% in the 3 mg/kg group achieved PASI 75. The lower percentage of PASI 75 responders in the 3mg/kg every 8 week dose group compared to the 5mg/kg group was associated with a lower percentage of patients with detectable trough serum infliximab levels. This may be related in part to higher antibody rates (see ADVERSE REACTIONS: Immunogenicity). In addition, in a subset of patients who had achieved a response at week 10, maintenance of response appears to be greater in patients who received Remicade every 8 weeks at the 5 mg/kg dose. Regardless of whether the maintenance doses are PRN or every 8 weeks, there is a decline in response in a subpopulation of patients in each group over time. The results of Study I through Week 50 in the 5mg/kg every 8 weeks maintenance dose group were similar to the results from Study II.

Efficacy and safety of Remicade treatment beyond 50 weeks have not been evaluated in patients with plaque psoriasis.

Ulcerative Colitis

The safety and efficacy of Remicade were assessed in two randomized, double-blind, placebo-controlled clinical studies in 728 patients with moderately to severely active ulcerative colitis (UC) (Mayo score13 6 to 12 [of possible range 0-12], Endoscopy subscore ≥ 2) with an inadequate response toconventional oral therapies (Studies UC I and UC II). Concomitant treatment with stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents was permitted. Corticosteroi taper was permitted after week 8. Patients were randomized at week 0 to receive either placebo, 5 mg/kg Remicade or 10 mg/kg Remicade at weeks 0, 2, 6, and every 8 weeks thereafter through week 46 in Study UC I, and at weeks 0, 2, 6, and every 8 weeks thereafter through week 22 in Study UC II. In Study UC II, patients were allowed to continue blinded therapy to week 46 at the investigator's discretion.

Patients in Study UC I had failed to respond or were intolerant to oral corticosteroids, 6-mercaptopurine (6-MP), or azathioprine (AZA). Patients in Study UC II had failed to respond or were intolerant to the above treatments and/or aminosalicylates. Similar proportions of patients in Studies UC I and UC II were receiving corticosteroids (61% and 51%, respectively), 6-MP/azathioprine (49% and 43%) and aminosalicylates (70% and 75%) at baseline. More patients in Study UC II than UC I were taking solely aminosalicylates for UC (26% vs. 11%, respectively). Clinical response was defined as a decrease from baseline in the Mayo score by ≥ 30% and ≥ 3 points, accompanied by a decrease in the rectal bleeding subscore of ≥ 1 or a rectal bleeding subscore of 0 or 1.

Clinical Response, Clinical Remission, and Mucosal Healing

In both Study UC I and Study UC II, greater percentages of patients in both Remicade groups achieved clinical response, clinical remission and mucosal healing than in the placebo group. Each of these effects was maintained through the end of each trial (week 54 in Study UC I, and week 30 in Study UC II). In addition, a greater proportion of patients in Remicade groups demonstrated sustained response and sustained remission than in the placebo groups (Table 9).

Of patients on corticosteroids at baseline, greater proportions of patients in the Remicade treatment groups were in clinical remission and able to discontinue corticosteroids at week 30 compared with the patients in the placebo treatment groups (22% in Remicade treatment groups vs. 10% in placebo group in Study UC I; 23% in Remicade treatment groups vs. 3% in placebo group in Study UC II). In Study UC I, this effect was maintained through week 54 (21% in Remicade treatment groups vs. 9% in placebo group). The Remicade-associated response was generally similar in the 5 mg/kg and 10 mg/kg dose groups.

Table 9 Response, Remission and Mucosal Healing in Ulcerative Colitis Studies

* P < 0.001, ** P < 0.01
1 Defined as a decrease from baseline in the Mayo score by ≥ 30% and ≥ 3 points, accompanied by a decrease in the rectal bleeding subscore of ≥ 1 or a rectal bleeding subscore of 0 or 1. (The Mayo score consists of the sum of four subscores: stool frequency, rectal bleeding, physician's global assessment and endoscopy findings.)
2 Defined as a Mayo score ≤2 points, no individual subscore >1.
3 Defined as a 0 or 1 on the endoscopy subscore of the Mayo score.
4 Patients who had a prohibited change in medication, had an ostomy or colectomy, or discontinued study infusions
due to lack of efficacy are considered to not be in clinical response, clinical remission or mucosal healing from the time of the event onward.
	Study UC I			Study UC II
	Placebo	5 mg/kg Remicade	10 mg/kg Remicade	Placebo	5 mg/kg Remicade	10 mg/kg Remicade
Patients randomized	121	121	122	123	121	120
Clinical Response1, 4
Week 8	37%	69%*	62%*	29%	65%*	69%*
Week 30	30%	52%*	51%**	26%	47%*	60%*
Week 54	20%	45%*	44%*	NA	NA	NA
Sustained Response4
(Clinical response at both Week 8 and 30)	23%	49%*	46%*	15%	41%*	53%*
(Clinical response at Weeks 8, 30, and 54)	14%	39%*	37%*	NA	NA	NA
Clinical Remission2, 4
Week 8	15%	39%*	32%**	6%	34%*	28%*
Week 30	16%	34%**	37%*	11%	26%**	36%*
Week 54	17%	35%**	34%**	NA	NA	NA
Sustained Remission4
(Clinical remission at both Week 8 and 30)	8%	23%**	26%*	2%	15%*	23%*
(Clinical remission at Weeks 8, 30 and 54)	7%	20%**	20%**	NA	NA	NA
Mucosal Healing3, 4
Week 8	34%	62%*	59%*	31%	60%*	62%*
Week 30	25%	50%*	49%*	30%	46%**	57%*
Week 54	18%	45%*	47%*	NA	NA	NA

The improvement with Remicade was consistent across all Mayo subscores through week 54 (Study UC I shown in Table 10; Study UC II through week 30 was similar).

Table 10 Proportion of patients in Study UC I with Mayo subscores indicating inactive or mild disease through week 54

	Study UC I
		Remicade
	Placebo	5 mg/kg	10 mg/kg
	(n=121)	(n=121)	(n=122)
Stool frequency
Baseline	17%	17%	10%
Week 8	35%	60%	58%
Week 30	35%	51%	53%
Week 54	31%	52%	51%
Rectal bleeding
Baseline	54%	40%	48%
Week 8	74%	86%	80%
Week 30	65%	74%	71%
Week 54	62%	69%	67%
Physician's global assessment
Baseline	4%	6%	3%
Week 8	44%	74%	64%
Week 30	36%	57%	55%
Week 54	26%	53%	53%
Endoscopy findings
Baseline	0%	0%	0%
Week 8	34%	62%	59%
Week 30	26%	51%	52%
Week 54	21%	50%	51%

Indications and Usage for Remicade

Rheumatoid Arthritis

Remicade, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.

Crohn's Disease

Remicade is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy(see Boxed WARNINGS, WARNINGS, and PRECAUTIONS-Pediatric Use).

Remicade is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn's disease.

Ankylosing Spondylitis

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

Psoriatic Arthritis

Remicade is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.

Plaque Psoriasis

Remicade is indicated for the treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. Remicade should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician (See Boxed WARNINGS, WARNINGS, and PRECAUTIONS).

Ulcerative Colitis

Remicade is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.

Contraindications

Remicade at doses >5 mg/kg should not be administered to patients with moderate to severe heart failure. In a randomized study evaluating Remicade in patients with moderate to severe heart failure (New York Heart Association [NYHA] Functional Class III/IV), Remicade treatment at 10 mg/kg was associated with an increased incidence of death and hospitalization due to worsening heart failure (see WARNINGS and ADVERSE REACTIONS, Patients with Heart Failure).

Remicade should not be re-administered to patients who have experienced a severe hypersensitivity reaction to Remicade. Additionally, Remicade should not be administered to patients with known hypersensitivity to inactive components of the product or to any murine proteins.

Warnings

RISK OF INFECTIONS

(See Boxed WARNINGS)

Serious infections, including sepsis and pneumonia, have been reported in patients receiving TNF-blocking agents. Some of these infections have been fatal. Although some of the serious infections in patients treated with Remicade have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infections, some patients who were hospitalized or had a fatal outcome from infection were treated with Remicade alone.

Remicade should not be given to patients with a clinically important, active infection. Caution should be exercised when considering the use of Remicade in patients with a chronic infection or a history of recurrent infection. Patients should be monitored for signs and symptoms of infection while on or after treatment with Remicade. New infections should be closely monitored. If a patient develops a serious infection, Remicade therapy should be discontinued (see ADVERSE REACTIONS: Infections).

Cases of tuberculosis, histoplasmosis, coccidioidomycosis, listeriosis, pneumocystosis, other bacterial, mycobacterial and fungal infections have been observed in patients receiving Remicade. Patients should be evaluated for tuberculosis risk factors and be tested for latent tuberculosis infection. Treatment of latent tuberculosis infections should be initiated prior to therapy with Remicade. When tuberculin skin testing is performed for latent tuberculosis infection an induration size of 5 mm or greater should be considered positive, even if vaccinated previously with Bacille Calmette-Guerin (BCG).

Patients receiving Remicade should be monitored closely for signs and symptoms of active tuberculosis, particularly since tests for latent tuberculosis infection may be falsely negative. The possibility of undetected latent tuberculosis should be considered, especially in patients who have immigrated from or traveled to countries with a high prevalence of tuberculosis or had close contact with a person with active tuberculosis. All patients treated with Remicade should have a thorough history taken prior to initiating therapy. Some patients who have previously received treatment for latent or active tuberculosis have developed active tuberculosis while being treated with Remicade. Anti-tuberculosis therapy should be considered prior to initiation of Remicade in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Anti-tuberculosis therapy prior to initiating Remicade should also be considered in patients who have several or highly significant risk factors for tuberculosis infection14 and have a negative test for latent tuberculosis. The decision to initiate anti-tuberculosis therapy in these patients should only be made following consultation with a physician with expertise in the treatment of tuberculosis and taking into account both the risk for latent tuberculosis infection and the risks of anti-tuberculosis therapy.

For patients who have resided in regions where histoplasmosis or coccidioidomycosis is endemic, the benefits and risks of Remicade treatment should be carefully considered before initiation of Remicade therapy.

Serious infections were seen in clinical studies with concurrent use of anakinra and another TNFα-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse events seen with combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, the combination of Remicade and anakinra is not recommended.

HEPATOSPLENIC T-CELL LYMPHOMAS

(See Boxed WARNINGS)

Rare postmarketing cases of hepatosplenic T-cell lymphomas have been reported in adolescent and young adult patients with Crohn's disease treated with Remicade. All of these reports have occurred in patients on concomitant treatment with azathioprine or 6-mercaptopurine. The clinical course of this disease is very aggressive with a fatal outcome in most patients within 2 years of diagnosis.15 The causal relationship of hepatosplenic T-cell lymphoma to Remicade therapy remains unclear.

Hepatitis B Virus Reactivation

Use of TNF blockers, including Remicade 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 prior evidence of HBV infection before initiating TNF blocker therapy. Prescribers should exercise caution in prescribing TNF blockers, including Remicade, 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. Patients who are carriers of HBV and require treatment with TNF blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF blocker therapy in this situation and monitor patients closely.

Hepatotoxicity

Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis have been reported rarely in postmarketing data in patients receiving Remicade. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between two weeks to more than a year after initiation of Remicade; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥5 times the upper limit of normal) develops, Remicade should be discontinued, and a thorough investigation of the abnormality should be undertaken. In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving Remicade without progression to severe hepatic injury (see ADVERSE REACTIONS, Hepatotoxicity).

Patients with Heart Failure

Remicade has been associated with adverse outcomes in patients with heart failure, and should be used in patients with heart failure only after consideration of other treatment options. The results of a randomized study evaluating the use of Remicade in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg Remicade, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg. There have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking Remicade. There have also been rare post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. If a decision is made to administer Remicade to patients with heart failure, they should be closely monitored during therapy, and Remicade should be discontinued if new or worsening symptoms of heart failure appear. (See CONTRAINDICATIONS and ADVERSE REACTIONS, Patients with Heart Failure.)

Hematologic Events

Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving Remicade. The causal relationship to Remicade therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with Remicade who have ongoing or a history of significant hematologic abnormalities. 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) while on Remicade. Discontinuation of Remicade therapy should be considered in patients who develop significant hematologic abnormalities.

Hypersensitivity

Remicade has been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions, which include urticaria, dyspnea, and/or hypotension, have occurred during or within 2 hours of Remicade infusion.

However, in some cases, serum sickness-like reactions have been observed in patients after initial Remicade therapy (i.e., as early as after the second dose), and when Remicade therapy was reinstituted following an extended period without Remicade treatment. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema and/or dysphagia. These reactions were associated with marked increase in antibodies to infliximab, loss of detectable serum concentrations of infliximab, and possible loss of drug efficacy.

Remicade should be discontinued for severe hypersensitivity reactions (see also CONTRAINDICATIONS). Medications for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be available for immediate use in the event of a reaction (see ADVERSE REACTIONS: Infusion-related Reactions).

Neurologic Events

Remicade and other agents that inhibit TNF have been associated in rare cases with optic neuritis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis, and CNS manifestation of systemic vasculitis. Prescribers should exercise caution in considering the use of Remicade in patients with pre-existing or recent onset of central nervous system demyelinating or seizure disorders. Discontinuation of Remicade should be considered in patients who develop significant central nervous system adverse reactions.

Malignancies

In the controlled portions of clinical trials of some TNF-blocking agents including Remicade, more malignancies (excluding lymphoma and nonmelanoma skin cancer [NMSC]) have been observed in patients receiving those TNF-blockers compared with control patients. During the controlled portions of Remicade trials in patients with moderately to severely active rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 14 patients were diagnosed with malignancies (excluding lymphoma and NMSC) among 4019 Remicade-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 patient-years among Remicade-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for Remicade-treated patients and 0.4 years for control patients. Of these, the most common malignancies were breast, colorectal, and melanoma. The rate of malignancies among Remicade-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected.

In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. In the controlled and open-label portions of Remicade clinical trials, 5 patients developed lymphomas among 5707 patients treated with Remicade (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In rheumatoid arthritis patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately 3-fold higher than expected in the general population. In the combined clinical trial population for rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 5 lymphomas were observed for a rate of 0.10 cases per 100 patient-years of follow-up, which is approximately 4-fold higher than expected in the general population. Patients with Crohn's disease, rheumatoid arthritis or plaque psoriasis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy.

In a clinical trial exploring the use of Remicade in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, the majority of lung or head and neck origin, were reported in Remicade-treated patients compared with control patients. All patients had a history of heavy smoking (see ADVERSE REACTIONS, Malignancies). Prescribers should exercise caution when considering the use of Remicade in patients with moderate to severe COPD.

Psoriasis patients should be monitored for nonmelanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for Remicade, NMSCs were more common in patients with previous phototherapy (see ADVERSE REACTIONS: Adverse Reactions in Psoriasis Studies).

The potential role of TNF-blocking therapy in the development of malignancies is not known (see ADVERSE REACTIONS, Malignancies). Rates in clinical trials for Remicade cannot be compared to rates in clinical trials of other TNF-blockers and may not predict rates observed in a broader patient population. Caution should be exercised in considering Remicade treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving Remicade.

Precautions

Autoimmunity

Treatment with Remicade may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Remicade, treatment should be discontinued (see ADVERSE REACTIONS, Autoantibodies/Lupus-like Syndrome).

Vaccinations

No data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines in patients receiving anti-TNF therapy. It is recommended that live vaccines not be given concurrently.

It is recommended that all pediatric Crohn's disease patients be brought up to date with all vaccinations prior to initiating Remicade therapy. The interval between vaccination and initiation of Remicade therapy should be in accordance with current vaccination guidelines.

Information for Patients

Patients developing signs and symptoms of infection should seek medical evaluation immediately.

Patients or their caregivers should be provided the Remicade Medication Guide and provided an opportunity to read it and ask questions prior to each treatment infusion session. Because caution should be exercised in administering Remicade to patients with clinically important active infections, it is important that the patient's overall health be assessed at each treatment visit and any questions resulting from the patient's or caregiver's reading of the Medication Guide be discussed.

Drug Interactions

Concurrent administration of etanercept (another TNFα-blocking agent) and anakinra (an interleukin-1 receptor antagonist) has been associated with an increased risk of serious infections, and increased risk of neutropenia and no additional benefit compared to these medicinal products alone. Other TNFα-blocking agents (including Remicade) used in combination with anakinra may also result in similar toxicities (see WARNINGS, RISK OF INFECTIONS).

Specific drug interaction studies, including interactions with MTX, have not been conducted. The majority of patients in rheumatoid arthritis or Crohn's disease clinical studies received one or more concomitant medications. In rheumatoid arthritis, concomitant medications besides MTX were nonsteroidal anti-inflammatory agents, folic acid, corticosteroids and/or narcotics. Concomitant Crohn's disease medications were antibiotics, antivirals, corticosteroids, 6-MP/AZA and aminosalicylates. In psoriatic arthritis clinical trials, concomitant medications included MTX in approximately half of the patients as well as nonsteroidal anti-inflammatory agents, folic acid and corticosteroids.

Patients with Crohn's disease who received immunosuppressants tended to experience fewer infusion reactions compared to patients on no immunosuppressants (see ADVERSE REACTIONS, Immunogenicity and Infusion-related Reactions). Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of Crohn's disease including corticosteroids, antibiotics (metronidazole or ciprofloxacin) and aminosalicylates.

Carcinogenesis, Mutagenesis and Impairment of Fertility

A repeat dose toxicity study was conducted with mice given cV1q anti-mouse TNFα to evaluate tumorigenicity. CV1q is an analogous antibody that inhibits the function of TNFα in mice. Animals were assigned to 1 of 3 dose groups: control, 10 mg/kg or 40 mg/kg cV1q given weekly for 6 months. The weekly doses of 10 mg/kg and 40 mg/kg are 2 and 8 times, respectively, the human dose of 5 mg/kg for Crohn's disease. Results indicated that cV1q did not cause tumorigenicity in mice. No clastogenic or mutagenic effects of infliximab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. Chromosomal aberrations were not observed in an assay performed using human lymphocytes. The significance of these findings for human risk is unknown. It is not known whether infliximab can impair fertility in humans. No impairment of fertility was observed in a fertility and general reproduction toxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study.

Pregnancy Category B

Since infliximab does not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with Remicade. No evidence of maternal toxicity, embryotoxicity or teratogenicity was observed in a developmental toxicity study conducted in mice using an analogo