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Drug Information on REMICADE - Janssen Biotech, Inc. | Pharmaguru.com
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REMICADE (Janssen Biotech, Inc.)
INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION 10 VIAL, SINGLE-USE in 1 BOX (57894-030-01) > 10 mL in 1 VIAL, SINGLE-USE Label Information
Complete REMICADE Information
These highlights do not include all the information needed to use REMICADE ® safely and effectively. See full prescribing information for REMICADE.
Serious infections â€“ do not give REMICADE during an active infection. If an infection develops, monitor carefully and stop REMICADE if infection becomes serious. (5.1)
Invasive fungal infections â€“ for patients who develop a systemic illness on REMICADE, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic (5.1)
Malignancies â€“ the incidence of malignancies, including invasive cervical cancer and lymphoma, was greater in REMICADE treated patients than in controls. Due to the risk of HSTCL carefully assess the risk/benefit especially if the patient has Crohn's disease or ulcerative colitis, is male, and is receiving azathioprine or 6-mercaptopurine treatment. (5.2)
Hepatitis B virus reactivation â€“ test for HBV infection before starting REMICADE. Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop REMICADE and begin anti-viral therapy. (5.3)
Hepatotoxicity â€“ severe hepatic reactions, some fatal or necessitating liver transplantation. Stop REMICADE in cases of jaundice and/or marked liver enzyme elevations. (5.4)
Heart failure â€“ new onset or worsening symptoms may occur. (4, 5.5)
Cytopenias â€“ advise patients to seek immediate medical attention if signs and symptoms develop, and consider stopping REMICADE. (5.6)
Hypersensitivity â€“ serious infusion reactions including anaphylaxis or serum sickness-like reactions may occur. (5.7)
Cardiovascular and Cerebrovascular Reactions â€“ Cerebrovascular accidents, myocardial infarctions (some fatal), and arrhythmias have been reported during and within 24 hours of initiation of REMICADE infusion. Monitor patients during REMICADE infusion and if serious reaction occurs, discontinue infusion. (5.8)
Demyelinating disease â€“ exacerbation or new onset may occur. (5.9)
Lupus-like syndrome â€“ stop REMICADE if syndrome develops. (5.14)
Live vaccines or therapeutic infectious agents â€“ should not be given with REMICADE. Bring pediatric patients up to date with all vaccinations prior to initiating REMICADE. At least a six month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab (5.15)
Most common adverse reactions (>10%) â€“ infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain. (6.1)
Use with anakinra or abataceptâ€“ increased risk of serious infections (7.1)
Pediatric Use â€“REMICADE has not been studied in children with Crohn's disease or ulcerative colitis <6 years of age. (8.4)
1.1 Crohn's Disease 1.2 Pediatric Crohn's Disease 1.3 Ulcerative Colitis 1.4 Pediatric Ulcerative Colitis 1.5 Rheumatoid Arthritis 1.6 Ankylosing Spondylitis 1.7 Psoriatic Arthritis 1.8 Plaque Psoriasis
2.1 Crohn's Disease 2.2 Pediatric Crohn's Disease 2.3 Ulcerative Colitis 2.4 Pediatric Ulcerative Colitis 2.5 Rheumatoid Arthritis 2.6 Ankylosing Spondylitis 2.7 Psoriatic Arthritis 2.8 Plaque Psoriasis 2.9 Monitoring to Assess Safety 2.10 Administration Instructions Regarding Infusion Reactions 2.11 General Considerations and Instructions for Preparation and Administration
5.1 Serious Infections 5.2 Malignancies 5.3 Hepatitis B Virus Reactivation 5.4 Hepatotoxicity 5.5 Patients with Heart Failure 5.6 Hematologic Reactions 5.7 Hypersensitivity 5.8 Cardiovascular and Cerebrovascular Reactions During and After Infusion 5.9 Neurologic Reactions 5.10 Use with Anakinra 5.11 Use with Abatacept 5.12 Concurrent Administration with Other Biological Therapeutics 5.13 Switching Between Biological Disease-Modifying Antirheumatic Drugs (DMARDs) 5.14 Autoimmunity 5.15 Live Vaccines/Therapeutic Infectious Agents
7.1 Use with Anakinra or Abatacept 7.2 Use with Tocilizumab 7.3 Use with Other Biological Therapeutics 7.4 Methotrexate (MTX) and Other Concomitant Medications 7.5 Immunosuppressants 7.6 Cytochrome P450 Substrates 7.7 Live Vaccines/Therapeutic Infectious Agents
14.1 Crohn's Disease 14.2 Pediatric Crohn's Disease 14.3 Ulcerative Colitis 14.4 Pediatric Ulcerative Colitis 14.5 Rheumatoid Arthritis 14.6 Ankylosing Spondylitis 14.7 Psoriatic Arthritis 14.8 Plaque Psoriasis
Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (initiation of therapy â‰¤18 years of age), including REMICADE. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported in postmarketing data in patients receiving REMICADE. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between 2 weeks to more than 1 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., â‰¥5 times the upper limit of normal) develop, 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 (6.1)].
Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFÎ±-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse reactions seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFÎ±-blocking agents. Therefore, the combination of REMICADE and anakinra is not recommended.
In a randomized controlled clinical trial exploring the use of REMICADE in patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 patients were treated with REMICADE at doses similar to those used in rheumatoid arthritis and Crohn's disease. Of these REMICADE-treated patients, 9 developed a malignancy, including 1 lymphoma, for a rate of 7.67 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 3.51 â€“ 14.56). There was 1 reported malignancy among 77 control patients for a rate of 1.63 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 0.04 â€“ 9.10). The majority of the malignancies developed in the lung or head and neck.
In a randomized study evaluating REMICADE in moderate to severe heart failure (NYHA Class III/IV; left ventricular ejection fraction â‰¤35%), 150 patients were randomized to receive treatment with 3 infusions of REMICADE 10 mg/kg, 5 mg/kg, or placebo, at 0, 2, and 6 weeks. Higher incidences of mortality and hospitalization due to worsening heart failure were observed in patients receiving the 10 mg/kg REMICADE dose. At 1 year, 8 patients in the 10 mg/kg REMICADE group had died compared with 4 deaths each in the 5 mg/kg REMICADE and the placebo groups. There were trends toward increased dyspnea, hypotension, angina, and dizziness in both the 10 mg/kg and 5 mg/kg REMICADE treatment groups, versus placebo. REMICADE has not been studied in patients with mild heart failure (NYHA Class I/II) [see Contraindications (4) and Warnings and Precautions (5.5)].
In the psoriasis Study II, which included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 36% of patients treated with 5 mg/kg every 8 weeks for 1 year, and in 51% of patients treated with 3 mg/kg every 8 weeks for 1 year. In the psoriasis Study III, which also included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 20% of patients treated with 5 mg/kg induction (weeks 0, 2 and 6), and in 27% of patients treated with 3 mg/kg induction. Despite the increase in antibody formation, the infusion reaction rates in Studies I and II in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year and in Study III in patients treated with 5 mg/kg induction (14.1%â€“23.0%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. The clinical significance of apparent increased immunogenicity on efficacy and infusion reactions in psoriasis patients as compared to patients with other diseases treated with REMICADE over the long term is not known.
â‰¥3 × ULN
â‰¥5 × ULN
• Placebo patients received methotrexate while REMICADE patients received both REMICADE and methotrexate. Median follow-up was 58 weeks.
• Placebo patients in the 2 Phase 3 trials in Crohn's disease received an initial dose of 5 mg/kg REMICADE at study start and were on placebo in the maintenance phase. Patients who were randomized to the placebo maintenance group and then later crossed over to REMICADE are included in the REMICADE group in ALT analysis. Median follow-up was 54 weeks.
• Median follow-up was 30 weeks. Specifically, the median duration of follow-up was 30 weeks for placebo and 31 weeks for REMICADE.
• Median follow-up was 24 weeks for the placebo group and 102 weeks for the REMICADE group.
• Median follow-up was 39 weeks for the REMICADE group and 18 weeks for the placebo group.
• ALT values are obtained in 2 Phase 3 psoriasis studies with median follow-up of 50 weeks for REMICADE and 16 weeks for placebo.
Crohn's diseaseâ€ 34% 39% 4% 5% 0% 2%
Ulcerative colitisâ€¡ 12% 17% 1% 2% <1% <1%
Safety data are available from 4779 REMICADE-treated adult patients, including 1304 with rheumatoid arthritis, 1106 with Crohn's disease, 484 with ulcerative colitis, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 1373 with plaque psoriasis and 17 with other conditions. [For information on other adverse reactions in pediatric patients, see Adverse Reactions (6.1)]. Adverse reactions reported in â‰¥5% of all patients with rheumatoid arthritis receiving 4 or more infusions are in Table 2. The types and frequencies of adverse reactions observed were similar in REMICADE-treated rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis and Crohn's disease patients except for abdominal pain, which occurred in 26% of REMICADE-treated patients with Crohn's disease. In the Crohn's disease studies, there were insufficient numbers and duration of follow-up for patients who never received REMICADE to provide meaningful comparisons.
The most common serious adverse reactions observed in clinical trials were infections [see Adverse Reactions (6.1)]. Other serious, medically relevant adverse reactions â‰¥0.2% or clinically significant adverse reactions by body system were as follows:
Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in Crohn's disease clinical trials; 4% had ALT elevations â‰¥3 × ULN, and 1% had elevations â‰¥5 × ULN. (Median follow-up was 53 weeks.)
Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 17% (10/60) of pediatric patients in the pediatric UC trial; 7% (4/60) had ALT elevations â‰¥3 × ULN, and 2% (1/60) had elevations â‰¥5 × ULN (median follow-up was 49 weeks).
The following adverse reactions, some with fatal outcome, have been reported during post-approval use of REMICADE: neutropenia [see Warnings and Precautions (5.6)], agranulocytosis (including infants exposed in utero to infliximab), interstitial lung disease (including pulmonary fibrosis/interstitial pneumonitis and rapidly progressive disease), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pericardial effusion, systemic and cutaneous vasculitis, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy), new onset and worsening psoriasis (all subtypes including pustular, primarily palmoplantar), transverse myelitis, and neuropathies (additional neurologic reactions have also been observed) [see Warnings and Precautions (5.9)], acute liver failure, jaundice, hepatitis, and cholestasis [see Warnings and Precautions (5.4)], serious infections [see Warnings and Precautions (5.1)], malignancies, including melanoma, Merkel cell carcinoma, and cervical cancer [see Warnings and Precautions (5.2)] and vaccine breakthrough infection including bovine tuberculosis (disseminated BCG infection) following vaccination in an infant exposed in utero to infliximab [see Warnings and Precautions (5.15)].
An increased risk of serious infections was seen in clinical studies of other TNFÎ±-blocking agents used in combination with anakinra or abatacept, with no added clinical benefit. Because of the nature of the adverse reactions seen with these combinations with TNF-blocker therapy, similar toxicities may also result from the combination of anakinra or abatacept with other TNFÎ±-blocking agents. Therefore, the combination of REMICADE and anakinra or abatacept is not recommended [see Warnings and Precautions (5.10 and 5.11)].
The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFÎ±, IL-1, IL-6, IL-10, IFN) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as infliximab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of REMICADE in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.
Pregnancy Category B. It is not known whether REMICADE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. REMICADE should be given to a pregnant woman only if clearly needed. Because infliximab does not cross-react with TNFÎ± 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 analogous antibody that selectively inhibits the functional activity of mouse TNFÎ±. Doses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness. Doses up to 40 mg/kg were shown to produce no adverse effects in animal reproduction studies.
The safety and efficacy of REMICADE in patients with juvenile rheumatoid arthritis (JRA) were evaluated in a multicenter, randomized, placebo-controlled, double-blind study for 14 weeks, followed by a double-blind, all-active treatment extension, for a maximum of 44 weeks. Patients with active JRA between the ages of 4 and 17 years who had been treated with MTX for at least 3 months were enrolled. Concurrent use of folic acid, oral corticosteroids (â‰¤0.2 mg/kg/day of prednisone or equivalent), NSAIDs, and/or disease modifying antirheumatic drugs (DMARDs) was permitted.
Infliximab, the active ingredient in REMICADE, is a chimeric IgG1Îº monoclonal antibody (composed of human constant and murine variable regions) specific for human tumor necrosis factor-alpha (TNFÎ±). It has a molecular weight of approximately 149.1 kilodaltons. 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.
Infliximab neutralizes the biological activity of TNFÎ± by binding with high affinity to the soluble and transmembrane forms of TNFÎ± and inhibits binding of TNFÎ± with its receptors. Infliximab does not neutralize TNFÎ² (lymphotoxin-Î±), a related cytokine that utilizes the same receptors as TNFÎ±. Biological activities attributed to TNFÎ± 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 TNFÎ± bound by infliximab can be lysed in vitro or in vivo. Infliximab inhibits the functional activity of TNFÎ± 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-TNFÎ± 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 TNFÎ±, and when administered after disease onset, allows eroded joints to heal.
Elevated concentrations of TNFÎ± 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 TNFÎ± production in inflamed areas of the intestine, and reduced the proportion of mononuclear cells from the lamina propria able to express TNFÎ± 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.
The significance of the results of nonclinical studies for human risk is unknown. A repeat dose toxicity study was conducted with mice given cV1q anti-mouse TNFÎ± to evaluate tumorigenicity. CV1q is an analogous antibody that inhibits the function of TNFÎ± 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. 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.
The safety and efficacy of single and multiple doses of REMICADE were assessed in 2 randomized, double-blind, placebo-controlled clinical studies in 653 patients with moderate to severely active Crohn's disease [Crohn's Disease Activity Index (CDAI) â‰¥220 and â‰¤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 trial of 108 patients, 16% (4/25) of placebo patients achieved a clinical response (decrease in CDAI â‰¥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.
Three-Dose Inductionâ€
• REMICADE at Week 0
• REMICADE 5 mg/kg administered at Weeks 0, 2 and 6
• P-values represent pairwise comparisons to placebo
• Of those receiving corticosteroids at baseline
P-valueâ€¡ 0.022 0.001
P-valueâ€¡ 0.059 0.005
In the first trial, 94 patients received 3 doses of either placebo or REMICADE at Weeks 0, 2 and 6. Fistula response (â‰¥50% reduction in number of enterocutaneous fistulas draining upon gentle compression on at least 2 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 fistulas was achieved in 52% of REMICADE-treated patients compared with 13% of placebo-treated patients (P<0.001).
At Week 10, 88% of patients were in clinical response (defined as a decrease from baseline in the PCDAI score of â‰¥15 points and total PCDAI score of â‰¤30 points), and 59% were in clinical remission (defined as PCDAI score of â‰¤10 points).
• Defined as a decrease from baseline in the PCDAI score of â‰¥15 points and total score of â‰¤30 points.
• P-value <0.01
• Defined as a PCDAI score of â‰¤10 points.
• P-value <0.05
Week 30 73%â€ 47%
Week 54 64%â€ 33%
Clinical Remissionâ€¡
Week 54 56%â€ 24%
The safety and efficacy of REMICADE were assessed in 2 randomized, double-blind, placebo-controlled clinical studies in 728 patients with moderately to severely active ulcerative colitis (UC) (Mayo score5 6 to 12 [of possible range 0 to 12], Endoscopy subscore â‰¥2) with an inadequate response to conventional oral therapies (Studies UC I and UC II). Concomitant treatment with stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents was permitted. Corticosteroid 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-MP, or 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/AZA (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 â‰¥30% and â‰¥3 points, accompanied by a decrease in the rectal bleeding subscore of â‰¥1 or a rectal bleeding subscore of 0 or 1.
• Defined as a decrease from baseline in the Mayo score by â‰¥30% and â‰¥3 points, accompanied by a decrease in the rectal bleeding subscore of â‰¥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.)
• 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.
• P<0.001,
• Defined as a Mayo score â‰¤2 points, no individual subscore >1.
• Defined as a 0 or 1 on the endoscopy subscore of the Mayo score.
Clinical Response*, â€
Week 8 37% 69%â€¡ 62%â€¡ 29% 65%â€¡ 69%â€¡
Week 30 30% 52%â€¡ 51%§ 26% 47%â€¡ 60%â€¡
Week 54 20% 45%â€¡ 44%â€¡ NA NA NA
Sustained Responseâ€
(Clinical response at both Weeks 8 and 30) 23% 49%â€¡ 46%â€¡ 15% 41%â€¡ 53%â€¡
(Clinical response at Weeks 8, 30, and 54) 14% 39%â€¡ 37%â€¡ NA NA NA
Clinical Remission¶, â€
Week 8 15% 39%â€¡ 32%§ 6% 34%â€¡ 28%â€¡
Week 30 16% 34%§ 37%â€¡ 11% 26%§ 36%â€¡
Sustained Remissionâ€
(Clinical remission at both Weeks 8 and 30) 8% 23%§ 26%â€¡ 2% 15%â€¡ 23%â€¡
Mucosal Healing#, â€
Week 8 34% 62%â€¡ 59%â€¡ 31% 60%â€¡ 62%â€¡
Week 30 25% 50%â€¡ 49%â€¡ 30% 46%§ 57%â€¡
Week 54 18% 45%â€¡ 47%â€¡ NA NA NA
The safety and effectiveness of REMICADE for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy are supported by evidence from adequate and well-controlled studies of REMICADE in adults. Additional safety and pharmacokinetic data were collected in an open-label pediatric UC trial in 60 pediatric patients aged 6 through 17 years (median age 14.5 years) with moderately to severely active ulcerative colitis (Mayo score of 6 to 12; Endoscopic subscore â‰¥2) and an inadequate response to conventional therapies. At baseline, the median Mayo score was 8, 53% of patients were receiving immunomodulator therapy (6-MP/AZA/MTX), and 62% of patients were receiving corticosteroids (median dose 0.5 mg/kg/day in prednisone equivalents). Discontinuation of immunomodulators and corticosteroid taper were permitted after Week 0.
Clinical response at Week 8 was defined as a decrease from baseline in the Mayo score by â‰¥30% and â‰¥3 points, including a decrease in the rectal bleeding subscore by â‰¥1 points or achievement of a rectal bleeding subscore of 0 or 1.
Clinical remission at Week 8 was measured by the Mayo score, defined as a Mayo score of â‰¤2 points with no individual subscore >1. Clinical remission was also assessed at Week 8 and Week 54 using the Pediatric Ulcerative Colitis Activity Index (PUCAI)6 score and was defined by a PUCAI score of <10 points.
The safety and efficacy of REMICADE were assessed in 2 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 (â‰¤10 mg/day) and/or non-steroidal anti-inflammatory drugs (NSAIDs) was permitted.
• Pâ‰¤0.001
• 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.
Week 54 17% 42%* 48%* 59%* 59%* 54% 62%â€ 66%*
Week 54 9% 21%â€ 34%* 40%* 38%* 32% 46%* 50%*
Week 30 0% 8%â€¡ 11%â€¡ 18%* 11%* N/A N/A N/A
Week 54 2% 11%â€ 18%* 26%* 19%* 21% 33%â€¡ 37%*
Major clinical response§ 0% 7%â€ 8%â€¡ 15%* 6%â€ 8% 12% 17%*
• All doses/schedules of REMICADE + MTX
• Visual Analog Scale (0=best, 10=worst)
• Health Assessment Questionnaire, measurement of 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities (0=best, 3=worst)
Painâ€ 6.7 6.1 6.8 3.3
Physician's Global Assessmentâ€ 6.5 5.2 6.2 2.1
Patient's Global Assessmentâ€ 6.2 6.2 6.3 3.2
Disability Index (HAQ-DI)â€¡ 1.8 1.5 1.8 1.3
In Study RA II, >90% of patients had at least 2 evaluable X-rays. Inhibition of progression of structural damage was observed at Weeks 30 and 54 (Table 9) 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 â‰¤0 unit) of structural damage compared to 45% of 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%).
• P<0.001 for each outcome against placebo.
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 (Pâ‰¤0.001). No worsening in the SF-36 mental component summary score was observed.
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.4 Patients were to have had active disease as evidenced by both a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score >4 (possible range 0â€“10) and spinal pain >4 (on a Visual Analog Scale [VAS] of 0â€“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, 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 0â€“100 mm] in each of the 4 ASAS response parameters) was achieved in 22% of REMICADE-treated patients vs. 1% in placebo-treated patients (P<0.001).
• Measured on a VAS with 0="none" and 10="severe"
• Bath Ankylosing Spondylitis Functional Index (BASFI), average of 10 questions
• Inflammation, average of last 2 questions on the 6-question BASDAI
• CRP normal range 0â€“1.0 mg/dL
• Spinal mobility normal values: modified Schober's test: >4 cm; chest expansion:>6 cm; tragus to wall: <15 cm; lateral spinal flexion: >10 cm
BASFIâ€ 5.8 5.6 5.7 3.6 <0.001
Inflammationâ€¡ 6.9 5.8 6.9 3.4 <0.001
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 (â‰¥5 swollen joints and â‰¥5 tender joints) with 1 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 â‰¥2 cm in diameter. Forty-six percent of patients continued on stable doses of methotrexate (â‰¤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.
• 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
• Scale 0â€“68
• Scale 0â€“66
• Normal range 0â€“0.6 mg/dL
No. of Tender Jointsâ€ 24 20 20 6
No. of Swollen Jointsâ€¡ 12 9 12 3
Improvement in Psoriasis Area and Severity Index (PASI) in psoriatic arthritis patients with baseline body surface area (BSA) â‰¥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 Clinical Studies (14.8)].
During the placebo-controlled portion of the trial (24 weeks), 54% of REMICADE-treated patients achieved a clinically meaningful improvement in HAQ-DI (â‰¥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.
The safety and efficacy of REMICADE were assessed in 3 randomized, double-blind, placebo-controlled studies in patients 18 years of age and older with chronic, stable plaque psoriasis involving â‰¥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.
• Patients with missing data at Week 10 were considered as nonresponders.
• P<0.001 compared with placebo
• Patients with missing data at Week 10 were imputed by last observation.
Psoriasis Study I - patients randomized* 77 â€” 301
PASI 75 2 (3%) â€” 242 (80%)â€
sPGA 3 (4%) â€” 242 (80%)â€
PASI 75 4 (2%) 220 (70%)â€ 237 (75%)â€
rPGA 2 (1%) 217 (69%)â€ 234 (75%)â€
Psoriasis Study III - patients randomizedâ€¡ 51 99 99
PASI 75 3 (6%) 71 (72%)â€ 87 (88%)â€
sPGA 5 (10%) 71 (72%)â€ 89 (90%)â€
Figure 4: Proportion of patients achieving â‰¥75% improvement in PASI from baseline through Week 50; patients randomized at Week 14
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