Renflexis

Crohn's Disease

RENFLEXIS is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy.

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

Pediatric Crohn's Disease

RENFLEXIS is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy.

Ulcerative Colitis

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

Pediatric Ulcerative Colitis

RENFLEXIS is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.

Rheumatoid Arthritis

RENFLEXIS, 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.

Ankylosing Spondylitis

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

Psoriatic Arthritis

RENFLEXIS 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

RENFLEXIS 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. RENFLEXIS 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 (5)].

Crohn's Disease

The recommended dose of RENFLEXIS is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adults with moderately to severely active Crohn's disease or fistulizing Crohn's disease. For adult patients who respond and then lose their response, consideration may be given to treatment with 10 mg/kg. Patients who do not respond by Week 14 are unlikely to respond with continued dosing and consideration should be given to discontinue RENFLEXIS in these patients.

Pediatric Crohn's Disease

The recommended dose of RENFLEXIS for pediatric patients 6 years and older with moderately to severely active Crohn's disease is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks.

Ulcerative Colitis

The recommended dose of RENFLEXIS is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adult patients with moderately to severely active ulcerative colitis.

Pediatric Ulcerative Colitis

The recommended dose of RENFLEXIS for pediatric patients 6 years and older with moderately to severely active ulcerative colitis is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks.

Rheumatoid Arthritis

The recommended dose of RENFLEXIS is 3 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 3 mg/kg every 8 weeks thereafter for the treatment of moderately to severely active rheumatoid arthritis. RENFLEXIS should be given in combination with methotrexate. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks bearing in mind that risk of serious infections is increased at higher doses [see Adverse Reactions (6.1)].

Ankylosing Spondylitis

The recommended dose of RENFLEXIS is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 6 weeks thereafter for the treatment of active ankylosing spondylitis.

Psoriatic Arthritis

The recommended dose of RENFLEXIS is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of psoriatic arthritis. RENFLEXIS can be used with or without methotrexate.

Plaque Psoriasis

The recommended dose of RENFLEXIS is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of chronic severe (i.e., extensive and/or disabling) plaque psoriasis.

Monitoring to Assess Safety

Prior to initiating RENFLEXIS and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection [see Warnings and Precautions (5.1)].

Administration Instructions Regarding Infusion Reactions

Adverse effects during administration of infliximab products have included flu-like symptoms, headache, dyspnea, hypotension, transient fever, chills, gastrointestinal symptoms, and skin rashes. Anaphylaxis might occur at any time during RENFLEXIS infusion. Approximately 20% of patients in all clinical trials of infliximab experienced an infusion reaction compared with 10% of placebo-treated patients [see Adverse Reactions (6.1)]. Prior to infusion with RENFLEXIS, premedication may be administered at the physician's discretion. Premedication could include antihistamines (anti-H1 +/- anti-H2), acetaminophen and/or corticosteroids.

During infusion, mild to moderate infusion reactions may improve following slowing or suspension of the infusion, and upon resolution of the reaction, reinitiation at a lower infusion rate and/or therapeutic administration of antihistamines, acetaminophen, and/or corticosteroids. For patients that do not tolerate the infusion following these interventions, RENFLEXIS should be discontinued.

During or following infusion, patients who have severe infusion-related hypersensitivity reactions should be discontinued from further RENFLEXIS treatment. The management of severe infusion reactions should be dictated by the signs and symptoms of the reaction. Appropriate personnel and medication should be available to treat anaphylaxis if it occurs.

General Considerations and Instructions for Preparation and Administration

RENFLEXIS is intended for use under the guidance and supervision of a physician. The reconstituted infusion solution should be prepared by a trained medical professional using aseptic technique by the following procedure:

1.

Calculate the dose, total volume of reconstituted RENFLEXIS solution required and the number of RENFLEXIS vials needed. Each RENFLEXIS vial contains 100 mg of the infliximab-abda antibody.

2.

Reconstitute each RENFLEXIS vial with 10 mL of Sterile Water for Injection, USP, using a syringe equipped with a 21-gauge or smaller needle as follows: Remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Gently swirl the solution by rotating the vial to dissolve the lyophilized powder. Avoid prolonged or vigorous agitation. DO NOT SHAKE. Foaming of the solution on reconstitution is not unusual. Allow the reconstituted solution to stand for 5 minutes. The reconstituted solution concentration is 10 mg/mL. The solution should be colorless to light yellow and opalescent, and the solution may develop a few translucent particles as infliximab-abda is a protein. Do not use if the lyophilized cake has not fully dissolved or if opaque particles, discoloration, or other foreign particles are present.

3.

Dilute the total volume of the reconstituted RENFLEXIS solution dose to 250 mL with sterile 0.9% Sodium Chloride Injection, USP, by withdrawing a volume equal to the volume of reconstituted RENFLEXIS from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or bag. Do not dilute the reconstituted RENFLEXIS solution with any other diluent. Slowly add the total volume of reconstituted RENFLEXIS solution to the 250 mL infusion bottle or bag. Gently mix. The resulting infusion concentration should range between 0.4 mg/mL and 4 mg/mL.

4.

The RENFLEXIS infusion should begin within 3 hours of reconstitution and dilution. The infusion must be administered over a period of not less than 2 hours and must use an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 μm or less). The vials do not contain antibacterial preservatives. Therefore, any unused portion of the infusion solution should not be stored for reuse.

5.

No physical biochemical compatibility studies have been conducted to evaluate the coadministration of RENFLEXIS with other agents. RENFLEXIS should not be infused concomitantly in the same intravenous line with other agents.

6.

Parenteral drug products should be inspected visually before and after reconstitution for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulates are observed, the solution should not be used.

Pregnancy

Lactation

Pediatric Use

The safety and effectiveness of infliximab products have been established in pediatric patients 6 to 17 years of age for induction and maintenance treatment of Crohn's disease or ulcerative colitis. However, infliximab products have not been studied in children with Crohn's disease or ulcerative colitis <6 years of age.

Geriatric Use

In rheumatoid arthritis and plaque psoriasis clinical trials, no overall differences were observed in effectiveness or safety in 181 patients with rheumatoid arthritis and 75 patients with plaque psoriasis, aged 65 or older who received infliximab, compared to younger patients -although the incidence of serious adverse reactions in patients aged 65 or older was higher in both infliximab and control groups compared to younger patients. In Crohn's disease, ulcerative colitis, ankylosing spondylitis and psoriatic arthritis studies, there were insufficient numbers of patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. There is a greater incidence of infections in the elderly population in general. The incidence of serious infections in infliximab-treated patients 65 years and older was greater than in those under 65 years of age; therefore caution should be used in treating the elderly [see Adverse Reactions (6.1)].

Serious Infections

Patients treated with infliximab products are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.

Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, salmonellosis and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease.

Treatment with RENFLEXIS should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:

•

with chronic or recurrent infection;

•

who have been exposed to tuberculosis;

•

with a history of an opportunistic infection;

•

who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or

•

with underlying conditions that may predispose them to infection.

Malignancies

Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤ 18 years of age), including infliximab products. 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.

Hepatitis B Virus Reactivation

Use of TNF blockers, including infliximab products, 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 should be tested for HBV infection before initiating TNF blocker therapy, including RENFLEXIS. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with antiviral 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 in postmarketing data in patients receiving infliximab products. 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 infliximab; 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) develop, RENFLEXIS 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 infliximab products without progression to severe hepatic injury [see Adverse Reactions (6.1)].

Patients with Heart Failure

Infliximab products have 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 infliximab in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg infliximab, 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 infliximab. 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 RENFLEXIS to patients with heart failure, they should be closely monitored during therapy, and RENFLEXIS should be discontinued if new or worsening symptoms of heart failure appear [see Contraindications (4) and Adverse Reactions (6.1)].

Hematologic Reactions

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

Hypersensitivity

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

However, in some cases, serum sickness-like reactions have been observed in patients after initial therapy with infliximab products (i.e., as early as after the second dose), and when therapy with infliximab products was reinstituted following an extended period without 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 a marked increase in antibodies to infliximab products, loss of detectable serum concentrations of infliximab products and possible loss of drug efficacy.

RENFLEXIS should be discontinued for severe hypersensitivity reactions. 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 (6.1)].

In rheumatoid arthritis, Crohn's disease and psoriasis clinical trials, re-administration of infliximab after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment [see Adverse Reactions (6.1)]. In general, the benefit-risk of re-administration of RENFLEXIS after a period of no-treatment, especially as a re-induction regimen given at weeks 0, 2 and 6, should be carefully considered. In the case where RENFLEXIS maintenance therapy for psoriasis is interrupted, RENFLEXIS should be reinitiated as a single dose followed by maintenance therapy.

 Cardiovascular and Cerebrovascular Reactions During and After Infusion

Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of infliximab product infusion. Cases of transient visual loss have been reported during or within 2 hours of infusion of infliximab product. Monitor patients during infusion and if serious reaction occurs, discontinue infusion. Further management of reactions should be dictated by signs and symptoms [See Adverse Reactions (6)].

Neurologic Reactions

Agents that inhibit TNF have been associated with CNS manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of RENFLEXIS in patients with these neurologic disorders and should consider discontinuation of RENFLEXIS if these disorders develop.

Use with Anakinra

Serious infections and neutropenia 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 reactions seen with the 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 RENFLEXIS and anakinra is not recommended.

Use with Abatacept

In clinical studies, concurrent administration of TNF-blocking agents and abatacept have been associated with an increased risk of infections including serious infections compared with TNF-blocking agents alone, without increased clinical benefit. Therefore, the combination of RENFLEXIS and abatacept is not recommended [see Drug Interactions (7.1)].

Concurrent Administration with other Biological Therapeutics

There is insufficient information regarding the concomitant use of infliximab products with other biological therapeutics used to treat the same conditions as RENFLEXIS. The concomitant use of RENFLEXIS with these biologics is not recommended because of the possibility of an increased risk of infection [see Drug Interactions (7.3)].

Switching between Biological Disease-Modifying Antirheumatic Drugs (DMARDs)

Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

Autoimmunity

Treatment with infliximab products may result in the formation of autoantibodies and in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with RENFLEXIS, treatment should be discontinued [see Adverse Reactions (6.1)].

Live Vaccines/Therapeutic Infectious Agents

In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines can result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with RENFLEXIS is not recommended.

Fatal outcome due to disseminated BCG infection has been reported in an infant who received a BCG vaccine after in utero exposure to infliximab products. Infliximab products are known to cross the placenta and have been detected up to 6 months following birth. At least a six month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to infliximab products.

Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with RENFLEXIS.

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

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Postmarketing Experience

Adverse reactions have been identified during post approval use of infliximab products in adult and pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions, some with fatal outcome, have been reported during post-approval use of infliximab products: neutropenia [see Warnings and Precautions (5.6)], agranulocytosis (including infants exposed in utero to infliximab products), 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 leukemia, 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 products [see Warnings and Precautions (5.15)].

Use with Anakinra or Abatacept

An increased risk of serious infections was seen in clinical studies of other TNFα-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 TNFα-blocking agents. Therefore, the combination of RENFLEXIS and anakinra or abatacept is not recommended [see Warnings and Precautions (5.10 and 5.11)].

Use with Tocilizumab

The use of tocilizumab in combination with biological DMARDs such as TNF antagonists, including RENFLEXIS, should be avoided because of the possibility of increased immunosuppression and increased risk of infection.

Use with Other Biological Therapeutics

The combination of RENFLEXIS with other biological therapeutics used to treat the same conditions as RENFLEXIS is not recommended [see Warnings and Precautions (5.12)].

Methotrexate (MTX) and Other Concomitant Medications

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 (NSAIDs), 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 NSAIDs, folic acid and corticosteroids. Concomitant MTX use may decrease the incidence of anti-drug antibody production and increase infliximab product concentrations.

Immunosuppressants

Patients with Crohn's disease who received immunosuppressants tended to experience fewer infusion reactions compared to patients on no immunosuppressants [see Adverse Reactions (6.1)]. 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.

Cytochrome P450 Substrates

The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, 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 products, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of RENFLEXIS 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.

Live Vaccines/Therapeutic Infectious Agents

It is recommended that live vaccines not be given concurrently with RENFLEXIS. It is also recommended that live vaccines not be given to infants after in utero exposure to infliximab products for at least 6 months following birth [see Warnings and Precautions (5.15)].

It is recommended that therapeutic infectious agents not be given concurrently with RENFLEXIS [see Warnings and Precautions (5.15)].

Mechanism of Action

Infliximab products neutralize the biological activity of TNFα by binding with high affinity to the soluble and transmembrane forms of TNFα and inhibit binding of TNFα with its receptors. Infliximab products do 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 products can be lysed in vitro or in vivo. Infliximab products inhibit 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 infliximab products exert their 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 products prevent disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFα, and when administered after disease onset, allow 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 infliximab products 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 infliximab products 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 infliximab products, 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 infliximab product-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 infliximab products 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, treatment with infliximab products may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which infliximab products exert their clinical effects is unknown.

Pharmacokinetics

In adults, single intravenous (IV) infusions of 3 mg/kg to 20 mg/kg of infliximab 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 infliximab, 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 8week intervals. Development of antibodies to infliximab increased infliximab clearance. At 8 weeks after a maintenance dose of 3 to 10 mg/kg of infliximab, 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 pharmacokinetic characteristics (including peak and trough concentrations and terminal half-life) were similar in pediatric (aged 6 to 17 years) and adult patients with Crohn's disease or ulcerative colitis following the administration of 5 mg/kg infliximab.

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 infliximab and children with JRA with body weight greater than 35 kg up to adult body weight receiving 3 mg/kg infliximab, the steady state area under the concentration curve (AUCss) was similar to that observed in adults receiving 3 mg/kg of infliximab.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 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. It is not known whether infliximab products 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.

Crohn's Disease

Active Crohn's Disease

The safety and efficacy of single and multiple doses of infliximab 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) ≥ 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 trial 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 infliximab (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 infliximab achieved clinical remission (CDAI < 150) at Week 4.

In a multidose trial (ACCENT I [Study Crohn's I]), 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 3). Additionally, a significantly greater proportion of patients in the 5 mg/kg and 10 mg/kg infliximab 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 3).

Table 3 Clinical remission and steroid withdrawal

	Single 5-mg/kg Dose *	Three-Dose Induction †
	Placebo Maintenance	Infliximab Maintenance q 8 wks
		5 mg/kg	10 mg/kg
* Infliximab at Week 0 † Infliximab 5 mg/kg administered at Weeks 0, 2 and 6 ‡ P-values represent pairwise comparisons to placebo § Of those receiving corticosteroids at baseline
Week 30	25/102	41/104	48/105
Clinical remission	25%	39%	46%
P-value ‡		0.022	0.001
Week 54	6/54	14/56	18/53
Patients in remission able to discontinue corticosteroid use §	11%	25%	34%
P-value ‡		0.059	0.005

Patients in the infliximab 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 infliximab-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.

Figure 1 Kaplan-Meier estimate of the proportion of patients who had not lost response through Week 54

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 infliximab maintenance group had endoscopic evidence of mucosal healing compared to 1 of 28 patients in the placebo group at Week 10. Of the infliximab-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 infliximab 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 infliximab 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 (2)].

Fistulizing Crohn's Disease

The safety and efficacy of infliximab 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, 94 patients received 3 doses of either placebo or infliximab at Weeks 0, 2 and 6. Fistula response (≥ 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 infliximab group (P = 0.002) and 56% (18/32) of patients in the 10 mg/kg infliximab 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 infliximab-treated patients was 2 and 12 weeks, respectively. Closure of all fistulas was achieved in 52% of infliximab-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 1 draining enterocutaneous (perianal, abdominal) fistula. All patients received 5 mg/kg infliximab at Weeks 0, 2 and 6. Patients were randomized to placebo or 5 mg/kg infliximab maintenance at Week 14. Patients received maintenance doses at Week 14 and then every 8 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 infliximab 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 infliximab-treated patients had no draining fistulas compared with 22% (20/90) of placebo-treated patients (P=0.02). Compared to placebo maintenance, patients on infliximab maintenance had a trend toward fewer hospitalizations.

Figure 2 Life table estimates of the proportion of patients who had not lost fistula response through Week 54

Patients who achieved a fistula response and subsequently lost response were eligible to receive infliximab 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 infliximab, and 57% (12/21) of infliximab 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 infliximab.

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

Pediatric Crohn's Disease

The safety and efficacy of infliximab were assessed in a randomized, open-label study (Study Peds Crohn's) in 112 pediatric patients aged 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-MP, AZA, or MTX; 35% were also receiving corticosteroids at baseline.

All patients received induction dosing of 5 mg/kg infliximab at Weeks 0, 2, and 6. At Week 10, 103 patients were randomized to a maintenance regimen of 5 mg/kg infliximab 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 12week treatment group (60% vs. 35% at Week 30, and 56% vs. 24% at Week 54), (Table 4).

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.

Ulcerative Colitis

The safety and efficacy of infliximab 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 ≥ 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 infliximab or 10 mg/kg infliximab 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 ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1.

Pediatric Ulcerative Colitis

The safety and effectiveness of infliximab products 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 infliximab 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 ≥ 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.

All patients received induction dosing of 5 mg/kg infliximab at Weeks 0, 2, and 6. Patients who did not respond to infliximab at Week 8 received no further infliximab and returned for safety follow-up. At Week 8, 45 patients were randomized to a maintenance regimen of 5 mg/kg infliximab given either every 8 weeks through Week 46 or every 12 weeks through Week 42. Patients were allowed to change to a higher dose and/or more frequent administration schedule if they experienced loss of response.

Clinical response at Week 8 was defined as a decrease from baseline in the Mayo score by ≥ 30% and ≥ 3 points, including a decrease in the rectal bleeding subscore by ≥ 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 ≤ 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.

Endoscopies were performed at baseline and at Week 8. A Mayo endoscopy subscore of 0 indicated normal or inactive disease and a subscore of 1 indicated mild disease (erythema, decreased vascular pattern, or mild friability).

Of the 60 patients treated, 44 were in clinical response at Week 8. Of 32 patients taking concomitant immunomodulators at baseline, 23 achieved clinical response at Week 8, compared to 21 of 28 of those not taking concomitant immunomodulators at baseline. At Week 8, 24 of 60 patients were in clinical remission as measured by the Mayo score and 17 of 51 patients were in remission as measured by the PUCAI score.

At Week 54, 8 of 21 patients in the every 8-week maintenance group and 4 of 22 patients in the every 12-week maintenance group achieved remission as measured by the PUCAI score.

During maintenance phase, 23 of 45 randomized patients (9 in the every 8-week group and 14 in the every 12-week group) required an increase in their dose and/or increase in frequency of infliximab administration due to loss of response. Nine of the 23 patients who required a change in dose had achieved remission at Week 54. Seven of those patients received the 10 mg/kg every 8-week dosing.

Rheumatoid Arthritis

The safety and efficacy of infliximab were assessed in 2 multicenter, randomized, doubleblind, 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 (NSAIDs) 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 infliximab + MTX: 3 mg/kg or 10 mg/kg of infliximab 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 3 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, 3 mg/kg or 6 mg/kg infliximab at Weeks 0, 2, and 6 and every 8 weeks thereafter.

Data on use of infliximab products without concurrent MTX are limited [see Adverse Reactions (6.1)].

Ankylosing Spondylitis

The safety and efficacy of infliximab 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 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 infliximab 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 infliximab-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 10).

Figure 3 Proportion of patients achieving ASAS 20 response

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 infliximab, compared to 9% and 4%, respectively, for patients receiving placebo (P < 0.001, infliximab vs. placebo). A low level of disease activity (defined as a value < 20 [on a scale of 0-100 mm] in each of the 4 ASAS response parameters) was achieved in 22% of infliximab-treated patients vs. 1% in placebo-treated patients (P < 0.001).

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 infliximab 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 infliximab 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 infliximab 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 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 ≥ 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 infliximab 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 infliximab induction (early escape). At Week 24, all placebo-treated patients crossed over to infliximab induction. Dosing continued for all patients through Week 46.

Plaque Psoriasis

The safety and efficacy of infliximab were assessed in 3 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 infliximab 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 infliximab induction therapy (5 mg/kg), followed by maintenance therapy every 8 weeks. Patients originally randomized to infliximab continued to receive infliximab 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 infliximab at doses of 3 mg/kg or 5 mg/kg at Weeks 0, 2, and 6 (induction therapy). At Week 14, within each infliximab 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 infliximab 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 infliximab 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 12.

In Study I, in the subgroup of patients with more extensive psoriasis who had previously received phototherapy, 85% of patients on 5 mg/kg infliximab 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 infliximab 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 infliximab 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 infliximab-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 infliximab 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 3 mg/kg every 8-week dose group compared to the 5 mg/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 (6.1)]. 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 infliximab 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 5 mg/kg every 8 weeks maintenance dose group were similar to the results from Study II.

Figure 4 Proportion of patients achieving ≥75% improvement in PASI from baseline through Week 50; patients randomized at Week 14

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

Storage and Stability

Store unopened RENFLEXIS vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF).

If needed, unopened RENFLEXIS vials may be stored at room temperatures up to a maximum of 30ºC (86°F) for a single period of up to 6 months but not exceeding the original expiration date. Once removed from the refrigerator, RENFLEXIS cannot be returned to the refrigerator.

[For storage conditions of the reconstituted product, see Dosage and Administration (2.11)].