Remicade

Infliximab.

Each vial of REMICADE contains 100 mg of infliximab, a chimeric IgG1 monoclonal antibody manufactured from a recombinant cell line cultured by continuous perfusion. Upon reconstitution each mL contains 10 mg of infliximab.
Excipients/Inactive Ingredients: Sucrose, polysorbate 80, monobasic sodium phosphate (or monobasic sodium phosphate, monohydrate), dibasic sodium phosphate (or dibasic sodium phosphate, dihydrate).

Pharmacology: Pharmacodynamics: Histologic evaluation of colonic biopsies, obtained before and 4 weeks after administration of the Remicade product, revealed a substantial reduction of detectable TNFα. Remicade treatment of Crohn's disease patients was also associated with a substantial reduction of the commonly elevated serum inflammatory marker C-reactive protein (CRP). Total peripheral white blood cell counts were minimally affected in Remicade-treated patients, although changes in lymphocytes, monocytes and neutrophils reflected shifts toward normal ranges. Peripheral blood mononuclear cells (PBMC) from Remicade-treated patients showed undiminished proliferative responsiveness to stimuli compared to untreated patients and no substantial changes in cytokine production by stimulated PBMC were observed following treatment with Remicade. Analysis of lamina propria mononuclear cells obtained by biopsy of the intestinal mucosa showed that Remicade treatment caused a reduction in the number of cells capable of expressing TNFα and interferonγ. Additional histologic studies provided evidence that treatment with Remicade reduces the infiltration of inflammatory cells into affected areas of the intestine and the presence of inflammation markers at these sites.
Elevated concentrations of TNFα have been found in the joints of rheumatoid arthritis patients and correlate with elevated disease activity. Increased concentrations of TNFα have also been found in joint fluid/tissue and in psoriatic skin lesions in patients with psoriatic arthritis. 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, chemoattraction and tissue degradation. After Remicade treatment, patients exhibited decreased levels of serum interleukin 6 (IL-6) and CRP compared to baseline. Peripheral blood lymphocytes showed no further significant decrease in number or in proliferative responses to in vitro mitogenic stimulation when compared to untreated patients' cells. In psoriasis patients, treatment with infliximab resulted in decreases in epidermal inflammation and normalization of keratinocyte differentiation in psoriatic plaques.
Pharmacokinetics: Single intravenous infusions of 1, 3, 5, 10 or 20 mg/kg of Remicade yielded dose proportional increases in the maximum serum concentration (C_max) and area under the concentration-time curve (AUC). The volume of distribution at steady state (median V_d of 3 to 4.1 liters) was not dependent on the administered dose and indicated that Remicade is predominantly distributed within the vascular compartment. No time-dependency of the pharmacokinetics was observed. The elimination pathways for Remicade have not been characterized. No major differences in clearance or volume of distribution were observed in patient subgroups defined by age, weight, or hepatic or renal function. No notable differences in single dose pharmacokinetic parameters were observed between pediatric and adult Crohn's disease patients.
At single doses of 3, 5 and 10 mg/kg, the median pharmacokinetic values for C_max were 77, 118 and 277 micrograms/mL, respectively. The median terminal half-life at these doses ranged from 8 to 9.5 days. In most patients, infliximab could be detected in the serum for at least 8 weeks after a single infusion.
Following the 3-dose regimen, a slight accumulation of infliximab was observed in the serum after the second dose and no further clinically relevant accumulation thereafter. In most fistulising Crohn's disease patients, infliximab was detected in serum for 12 weeks (range 4-28 weeks) after administration of the regimen.
Non-Clinical Information: 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 REMICADE were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. Chromosomal aberrations were not observed in an assay performed using human lymphocytes. The significance of these findings for human risk is unknown. It is not known whether REMICADE 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.

Adult and Pediatric Crohn's Disease: REMICADE is indicated for: Reducing signs and symptoms; inducing and maintaining clinical remission; inducing and maintaining mucosal healing in adults; reducing or eliminating corticosteroid use in adults; improving quality of life in patients with moderately to severely active Crohn's disease. REMICADE can be used alone or with conventional therapy.
Fistulizing Crohn's Disease: REMICADE is indicated for: Reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure; reducing signs and symptoms; improving quality of life in patients with fistulizing Crohn's disease.
Adult and Pediatric Ulcerative Colitis: REMICADE is indicated for: Reducing signs and symptoms; inducing and maintaining clinical remission; inducing and maintaining mucosal healing; reducing or discontinuing administration of corticosteroids; improving quality of life in adults; reducing ulcerative colitis-related hospitalizations in adults; reducing the incidence of colectomy in adults in patients with active ulcerative colitis who have had an inadequate response to conventional therapy.
REMICADE is also indicated for reducing the incidence of colectomy in adult patients with moderately to severely active ulcerative colitis refractory to IV corticosteroids.
Rheumatoid Arthritis: REMICADE is a Disease-Controlling Anti-Rheumatic Therapy (DCART); in combination with methotrexate, REMICADE is indicated for: Reducing signs and symptoms; preventing structural joint damage; improving physical function and preventing disability in patients with moderately to severely active rheumatoid arthritis.
Ankylosing Spondylitis: REMICADE is indicated for: Improving signs and symptoms, including range of motion; improving physical function; improving quality of life in patients with active ankylosing spondylitis.
Psoriatic Arthritis: REMICADE is indicated for: Reducing signs and symptoms of active arthritis; inducing major clinical response in active arthritis; inhibiting progression of structural damage of active arthritis; improving dactylitis and enthesopathy; improving psoriasis; improving physical function; improving quality of life in patients with psoriatic arthritis when the response to non-steroidal anti-inflammatory or disease modifying drugs has been inadequate. REMICADE can be used with or without methotrexate.
Plaque Psoriasis: REMICADE is indicated for: Improving psoriasis; improving quality of life in patients with moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with moderate plaque psoriasis, REMICADE should be used after phototherapy has been shown to be ineffective or inappropriate.

For recommended infusion duration for patients with each of the indications described as follows, see Instructions for Use and Handling and Disposal under Cautions for Usage.
Adult or Pediatric Crohn's Disease or Adult Fistulizing Crohn's Disease: 5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10 mg/kg. Pediatric Crohn's disease patients who have had the dose adjusted to greater than 5 mg/kg every 8 weeks, may be at greater risk for adverse reactions. Continued therapy with the adjusted dose should be carefully considered in patients who show no evidence of additional therapeutic benefit after dose adjustment.
Adult or Pediatric Ulcerative Colitis: 5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. For adult patients who have an incomplete response or lose their response, consideration may be given to treatment with 10 mg/kg.
Rheumatoid Arthritis: 3 mg/kg given as an intravenous infusion followed with additional similar doses at 2 and 6 weeks after the first infusion then every 8 weeks thereafter. REMICADE 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 and/or treating as often as every 4 weeks.
Ankylosing Spondylitis: 5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 6 weeks thereafter.
Psoriatic Arthritis: 5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.
Plaque Psoriasis: 5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.

Single doses up to 20 mg/kg have been administered to patients without toxic effects.

REMICADE should not be administered to patients with known hypersensitivity to any murine proteins or other component of the product.
In patients with moderate to severe heart failure (NYHA Class III/IV), REMICADE treatment at 10 mg/kg has been associated with an increased incidence of death and hospitalization due to worsening heart failure (see Adverse Reactions).
Therefore, REMICADE at doses >5 mg/kg is contraindicated in patients with moderate to severe heart failure (see Precautions).

In order to improve the traceability of biological medicinal products, the trademark and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Infections: Bacterial (including sepsis and pneumonia), mycobacterial [including tuberculosis (frequently disseminated or extrapulmonary at clinical presentation)], invasive fungal, viral, and other opportunistic infections have been observed in patients receiving REMICADE. Some of these infections have been fatal.
Patients should be evaluated for tuberculosis risk factors (including close contact with a person with active tuberculosis) and tested for latent tuberculosis infection prior to treatment with REMICADE. Tuberculin tests may yield false negative results, especially in patients who are severely ill or immunocompromised.
Treatment of latent tuberculosis infection should be initiated prior to therapy with REMICADE.
Anti-tuberculosis therapy should be considered prior to initiation of REMICADE in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.
Anti-tuberculosis therapy prior to initiating REMICADE should also be considered in patients who have several or highly significant risk factors for tuberculosis infection and have a negative test for latent tuberculosis.
The decision to initiate anti-tuberculosis therapy in these patients should only be made following consultation with a physician with expertise in the treatment of tuberculosis and taking into account both the risk for latent tuberculosis infection and the risks of anti-tuberculosis therapy.
Cases of active tuberculosis have occurred in patients treated with REMICADE during and after treatment for latent tuberculosis. Patients receiving REMICADE should be monitored closely for signs and symptoms of active tuberculosis during and after treatment, including patients who tested negative for latent tuberculosis infection.
For patients who have resided in or traveled to regions where invasive fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of REMICADE treatment should be carefully considered before initiation of REMICADE therapy.
In patients treated with REMICADE, an invasive fungal infection such as aspergillosis, candidiasis, pneumocystosis, histoplasmosis, coccidioidomycosis or blastomycosis should be suspected if they develop a serious systemic illness. Invasive fungal infections may present as disseminated rather than localized disease, and antigen and antibody testing may be negative in some patients with active infection. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. The decision to administer empiric antifungal therapy should be made in consultation if feasible with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of anti-fungal therapy.
REMICADE should not be given to patients with a clinically important, active infection. Caution should be exercised when considering the use of REMICADE in patients with a chronic infection or a history of recurrent infection. Patients should be advised of and avoid exposure to potential risk factors for infection as appropriate.
Congestive Heart Failure: In patients with moderate to severe heart failure (NYHA Class III/IV), an increased incidence of death and hospitalization due to worsening heart failure has not been observed with the 5 mg/kg dose (see Adverse Reactions). However, an adverse effect at this or lower doses, or in mild heart failure (NYHA Class I/II), particularly during long term treatment, cannot be excluded. Therefore, REMICADE should only be used with extreme caution in patients with heart failure and after consideration of other treatment options for the indicated conditions; the dose of REMICADE should not exceed 5 mg/kg.
If a decision is made to administer REMICADE to patients with heart failure, they should be closely monitored during therapy, and REMICADE must not be continued if new or worsening symptoms of heart failure appear (see Adverse Reaction).
Infusion-Related Reactions and Hypersensitivity Reactions: To minimize the incidence of hypersensitivity reactions, including infusion reactions and serum sickness-like reactions, REMICADE should be administered as regular maintenance therapy after an induction regimen at weeks 0, 2 and 6 (see Dosage & Administration).
REMICADE has been associated with hypersensitivity reactions that vary in their time of onset. Hypersensitivity reactions, which include urticaria, dyspnea and/or rarely bronchospasm, laryngeal edema, pharyngeal edema, and hypotension, have occurred during or within 2 hours of REMICADE infusion. However, in some cases, serum sickness-like reactions have been observed in Crohn's disease patients 1 to 14 days after REMICADE therapy. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema, and/or dysphagia. REMICADE should be discontinued for severe reactions. Medications for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction.
Data from the ATTRACT trial indicates that prophylactic pretreatment (acetaminophen and/or antihistamines) of patients for infusion reactions reduced the occurrence of subsequent infusion reactions. The infusion rate may be slowed in order to decrease infusion reactions especially if infusion reactions have occurred previously.
Infusion Reactions Following Re-administration of REMICADE: In a psoriasis clinical trial, a 3-dose induction of REMICADE after a period of no treatment resulted in a higher incidence of serious infusion reactions during the re-induction regimen (see Adverse Reactions) than had been observed in rheumatoid arthritis, psoriasis and Crohn's disease trials in which a period of no drug treatment was followed by regular maintenance therapy without re-induction.
In the case where REMICADE maintenance therapy for psoriasis is interrupted, REMICADE should be reinitiated as a single dose followed by maintenance therapy.
In general, the benefit-risk of re-administration of REMICADE after a period of no-treatment, especially as a re-induction regimen given at weeks 0, 2 and 6, should be carefully considered.
Autoimmune Processes: Treatment with REMICADE 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 REMICADE, treatment should be discontinued.
Neurological Events: REMICADE and other agents that inhibit TNFα have been associated with 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 REMICADE in patients with these neurologic disorders and should consider discontinuation of REMICADE if these disorders develop.
Hepatobiliary Events: Cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, have been observed in the post-marketing experience of REMICADE. Isolated cases of liver failure resulting in liver transplantation or death have occurred. A causal relationship between REMICADE and these events has not been established. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or ALT elevations ≥5 times the upper limit of normal develops, REMICADE should be discontinued, and a thorough investigation of the abnormality should be undertaken. As also observed with the use of other immunosuppressive drugs, use of TNF blockers, including REMICADE, has been associated with reactivation of hepatitis B virus in patients who are chronic carriers of this virus (i.e., surface antigen positive). Patients should be tested for Hepatitis B Virus (HBV) infection before initiating treatment with immunosuppressants, including REMICADE. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Chronic carriers of hepatitis B should be appropriately evaluated and monitored prior to the initiation of, during treatment with, and for several months following discontinuation of REMICADE.
Malignancies: Lymphoma: In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF-blocker compared with control patients. During clinical trials of REMICADE in patients with rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis, the incidence of lymphoma in REMICADE-treated patients was higher than expected in the general population, but the occurrence of lymphoma was rare. Patients with Crohn's disease or rheumatoid arthritis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy.
Pediatric Malignancy: Post-marketing cases of malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) who received TNF-blocking agents (initiation of therapy ≤18 years of age), including REMICADE, to treat Juvenile Idiopathic Arthritis (JIA), Crohn's disease or other conditions. Approximately half the reports were lymphomas. The other cases represented a variety of different malignancies and included malignancies that are not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants such as methotrexate, azathioprine or 6-mercaptopurine. The role of TNF blockers in the development of malignancies in children and adolescents remains unclear.
Hepatosplenic T-Cell Lymphoma: Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with TNF-blockers including REMICADE. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Almost all patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with or immediately prior to a TNF-blocker. The vast majority of REMICADE cases have occurred in patients with Crohn's disease or ulcerative colitis and most were reported in adolescent or young adult males. Cases of hepatosplenic T-cell lymphoma have also occurred in Crohn's disease and ulcerative colitis patients receiving azathioprine or 6-mercaptopurine who were not treated with REMICADE. Before initiating or continuing REMICADE therapy in a patient who is receiving an immunosuppressant such as azathioprine or 6-mercaptopurine, carefully assess the need for continuing the immunosuppressant therapy in light of the potential risks of concomitant treatment. The causal relationship of hepatosplenic T-cell lymphoma to REMICADE therapy remains unclear.
Leukemia: Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF-blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.
Non-Lymphoma Malignancy: In the controlled portions of some clinical trials of the TNF-blocking agents, more cases of non-lymphoma malignancy have been observed among patients receiving a TNF blocker compared with control patients. The rate of non-lymphoma malignancies among REMICADE-treated patients was similar to that expected in the general population whereas the rate among control patients was lower than expected.
In an exploratory clinical trial evaluating the use of REMICADE in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies were reported in REMICADE-treated patients compared with control patients. All patients had a history of heavy smoking.
Skin Cancers: Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including REMICADE (see Adverse Reaction). Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Cervical Cancer: A population based retrospective cohort study using data from Swedish national health registries found an increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics naïve patients or the general population, including those over 60 years of age. A causal relationship between infliximab and cervical cancer cannot be excluded. Periodic screening should continue in women treated with REMICADE, including those over 60 years of age.
The potential role of TNF-blocking therapy in the development of malignancies is not known. Caution should be exercised when considering TNF-blocking therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy.
Concurrent Administration of TNF-Alpha Inhibitor and 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 events seen with combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, the combination of REMICADE and anakinra is not recommended.
Concurrent Administration of REMICADE 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 agent alone, without increased clinical benefit. Because of the nature of the adverse events seen with the combination of TNF-blocking agents and abatacept therapy, the combination of REMICADE and abatacept is not recommended.
Concurrent Administration with Other Biological Therapeutics: There is insufficient information regarding the concomitant use of REMICADE with other biological therapeutics used to treat the same conditions as REMICADE. The concomitant use of REMICADE with these biologics is not recommended because of the possibility of an increased risk of infection.
Switching Between Biological Therapeutics: When switching from one biologic to another, patients should continue to be monitored, since overlapping biological activity may further increase the risk of infection.
Hematologic Reactions: There have been reports of pancytopenia, leukopenia, neutropenia and thrombocytopenia in patients receiving TNF-blockers, including REMICADE. Caution should be exercised in patients treated with REMICADE who have a current or past history of significant cytopenias.
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 REMICADE is not recommended.
Fatal outcome due to disseminated Bacille Calmette-Guérin (BCG) infection has been reported in an infant who received BCG vaccine after in utero exposure to infliximab. At least a six month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab (see Use in Pregnancy & Lactation).
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 REMICADE.
Non-Live Vaccines: In a subset of patients from the ASPIRE study, a similar proportion of patients in each treatment group mounted an effective two-fold increase in titers to a polyvalent pneumococcal vaccine, indicating that REMICADE did not interfere with T-cell independent humoral immune responses.
It is recommended that pediatric patients, if possible, be brought up to date with all vaccinations in agreement with current vaccination guidelines prior to initiating REMICADE therapy.
Effects on Ability to Drive and Use Machines: Not applicable.
Use in Children: REMICADE is indicated for reducing signs and symptoms and for inducing and maintaining clinical remission in pediatric patients who have moderately to severely active Crohn's disease. It should be noted that all pediatric patients in the Phase 3 trial (REACH) were required to be on a stable dose of either 6-mercaptopurine, azathioprine, or methotrexate (see previously mentioned texts and Adverse Reactions in Pediatric Crohn's disease).
REMICADE is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and reducing or discontinuing corticosteroid use in pediatric patients with ulcerative colitis who have had an inadequate response to conventional therapy (see previously mentioned texts and Adverse Reactions in Pediatric Ulcerative Colitis).
REMICADE has not been studied in children with JRA <4 years of age or in children with Crohn's disease or ulcerative colitis <6 years of age.
Safety and effectiveness of REMICADE in pediatric patients with juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis have not been established.
The pharmacokinetics of REMICADE has been evaluated in pediatric patients with Crohn's disease and ulcerative colitis (see Pharmacology: Pharmacokinetics under Actions).
Use in Elderly: Specific studies of REMICADE in elderly patients have not been conducted. No major age-related differences in clearance or volume of distribution were observed in clinical studies. The incidence of serious infections in REMICADE-treated patients 65 years and older was greater than in those under 65 years of age. In addition, there is a greater incidence of infections in the elderly population in general, therefore, caution should be used in treating the elderly.

Since REMICADE does not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with REMICADE. No evidence of maternal toxicity, embryotoxicity or teratogenicity was observed in a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα. 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. 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.
As with other IgG antibodies, infliximab crosses the placenta. Infliximab has been detected in the serum of infants up to 6 months following birth.
After in utero exposure to infliximab, infants may be at increased risk of infection, including disseminated infection that can become fatal (see Precautions).
It is not known whether REMICADE is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from REMICADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety data from clinical trials are available from 5561 REMICADE-treated patients including 1304 with rheumatoid arthritis, 117 with juvenile rheumatoid arthritis, 1566 with Crohn's disease (1427 adults and 139 children), 347 with ankylosing spondylitis, 293 with psoriatic arthritis, 1373 with plaque psoriasis, 544 with ulcerative colitis (484 adults and 60 children) and 17 with other conditions. Adverse reactions in clinical trials are summarized in Table 1. Infusion-related reactions (e.g., dyspnea, flushing, headache and rash) were among the most common causes for discontinuation, except in ulcerative colitis, pediatric Crohn's disease and psoriatic arthritis. (See Table 1).


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Infusion-Related Reactions: In Phase 3 clinical studies, 18% of REMICADE-treated patients compared with 5% of placebo-treated patients experienced an infusion-related reaction during infusion or within 1 hour post infusion. Of infliximab-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period.
Approximately 3% of REMICADE infusions were accompanied by nonspecific symptoms such as fever or chills, <1% were accompanied by pruritus or urticaria, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension, or dyspnea), or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions occurred in <1% of patients, and included anaphylaxis, convulsions, erythematous rash, and hypotension. Approximately 3% of patients discontinued treatment due to infusion reactions and all patients recovered with or without medical therapy.
In a clinical study of patients with rheumatoid arthritis (ASPIRE), sixty six percent of the patients (686 out of 1040) received at least one shortened infusion of 90 minutes or less and 44% of the patients (454 out of 1040) received at least one shortened infusion of 60 minutes or less. Of the REMICADE-treated patients who received at least one shortened infusion, infusion-related reactions occurred in 15% (74/494) of patients and serious infusion reactions occurred in 0.4% (2/494) of patients. Shortened infusions at doses >6 mg/kg have not been studied (see Pharmacology under Actions).
In Phase 3 clinical studies, in patients receiving infliximab with or without concomitant immunomodulator therapy, 13-19% of patients receiving infliximab at a low infusion rate (≤6 mg/kg/2-hr) experienced an infusion-related reaction, compared to 15-16% of patients receiving infliximab at a high infusion rate (>6 mg/kg/2-hr or equivalent to >3 mg/kg/1-hr). Of patients receiving infliximab at a low infusion rate, 0.4%-0.7% experienced a serious infusion-related reaction, compared to 0.4%-0.5% of patients receiving infliximab at a high infusion rate.
In a clinical study of patients with Crohn's disease (SONIC), infusion-related reactions occurred in 16.6% (27/163) of patients receiving REMICADE monotherapy, 5.0% (9/179) of patients receiving REMICADE in combination with azathioprine, and 5.6% (9/161) of patients receiving azathioprine monotherapy. One patient experienced a serious infusion reaction with REMICADE monotherapy.
In post-marketing surveillance, reports of anaphylactic-like reactions including laryngeal edema, pharyngeal edema, severe bronchospasm, and seizure have been associated with REMICADE administration. Cases of transient visual loss occurring during or within 2 hours of REMICADE infusion have been reported. Cerebrovascular accidents, myocardial ischemia/infarction (some fatal), and arrhythmia occurring within 24 hours of initiation of infusion have also been reported.
Infusion Reactions Following Re-Administration of REMICADE: In rheumatoid arthritis, Crohn's disease and psoriasis clinical trials, re-administration of REMICADE after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment.
In a clinical trial of patients with moderate to severe psoriasis designed to assess the efficacy of long-term maintenance therapy versus re-treatment with an induction cycle of REMICADE, 4% (8/219) of patients in the intermittent therapy arm experienced serious infusion reactions versus <1% (1/222) in the maintenance therapy arm. Patients enrolled in this trial did not receive any concomitant immunosuppressant therapy. Intermittent therapy in this trial was defined as the re-administration of an induction cycle (maximum of 4 infusions at 0, 2, 6 and 14 weeks) of REMICADE upon disease flare after a period of no treatment. In this study, the majority of serious infusion reactions occurred during the second infusion at Week 2. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension. In all cases, REMICADE treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.
Delayed Hypersensitivity/Reactions Following Re-Administration: In a study where 37 of 41 patients with Crohn's disease were retreated with REMICADE following a 2 to 4 year period without REMICADE treatment, 10 patients experienced adverse events manifesting 3 to 12 days following infusion of which 6 were considered serious. Signs and symptoms included myalgia and/or arthralgia with fever and/or rash, with some patients also experiencing pruritus, facial, hand or lip edema, dysphagia, urticaria, sore throat, and headache. Patients experiencing these adverse events had not experienced infusion-related adverse events associated with their initial REMICADE therapy. These adverse events occurred in 39% (9/23) of patients who had received liquid formulation which is no longer in use and 7% (1/14) of patients who received lyophilized formulation. The clinical data are not adequate to determine if occurrence of these reactions is due to differences in formulation. Patients' signs and symptoms improved substantially or resolved with treatment in all cases. There are insufficient data on the incidence of these events after drug-free intervals of 1 to 2 years. These events have been observed only infrequently in clinical studies and post-marketing surveillance with re-treatment intervals up to 1 year. In the 3 psoriasis studies, 1% (15/1373) of patients experienced symptoms of arthralgia, serum sickness, myalgia, fever and rash. When these occurred, they were often early in the treatment course following REMICADE infusions.
REMICADE treatment was discontinued and/or other treatment instituted in most cases with improvement or resolution of signs and symptoms.
Immunogenicity: Patients who developed antibodies to REMICADE were more likely (approximately 2- to 3-fold) to develop infusion-related reactions. Antibodies to REMICADE occurred in approximately 10% of patients given a 3-dose induction regimen followed by maintenance dosing. Use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to REMICADE and infusion reactions. In a Phase III study of Crohn's disease in patients who were immunomodulator-naive, antibodies occurred at Week 30 in 14% of patients receiving REMICADE monotherapy and 1% of patients receiving REMICADE in combination with azathioprine. A higher incidence of antibodies to REMICADE was observed in Crohn’s disease patients receiving REMICADE after drug free intervals >16 weeks. In the Phase III study of psoriatic arthritis, where patients received 5 mg/kg with and without concomitant methotrexate, antibodies occurred in 15% of patients. In the 2 Phase III studies of psoriasis, REMICADE was administered with induction followed by maintenance therapy without concomitant immunosuppressants. In these studies, antibodies occurred in approximately 25%-30% of patients, who received 5 mg/kg every 8 week maintenance for 1 year, and at higher rates (up to 1.6-fold) with other dosage regimens (3 mg/kg every 8 weeks, 3 mg/kg dosed as needed and 5 mg/kg dosed as needed). Despite the increase in antibody formation, the infusion reaction rates in the two psoriasis phase III studies in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year (14.1%-23%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations.
Infections: In clinical studies, 36% of REMICADE-treated patients were treated for infections compared with 28% of placebo-treated patients. No increased risk of serious infections was observed with REMICADE compared with placebo in Crohn's disease studies and the phase III study of psoriatic arthritis. In RA trials, the incidence of serious infections, including pneumonia, was higher in REMICADE plus MTX treated patients compared with methotrexate alone, especially at doses of 6 mg/kg or greater. In the psoriasis studies, 1.5% of patients (average of 41.9 weeks of follow-up) receiving REMICADE and 0.6% of patients (average of 18.1 weeks of follow-up) receiving placebo developed serious infections.
In post-marketing experience, infections have been observed with various pathogens including viral, bacterial, fungal, and protozoal organisms. Infections have been noted in all organ systems and have been reported in patients receiving REMICADE alone or in combination with immunosuppressive agents.
Hepatobiliary Events: In post-marketing surveillance, very rare cases of jaundice and hepatitis, some with features of autoimmune hepatitis, have been reported in patients receiving REMICADE (see Precautions).
In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving REMICADE without progression to severe hepatic injury. Elevations of ALT >5 x ULN have been observed (see Table 2). Elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving REMICADE than in controls, both when REMICADE was given as monotherapy and when it was used in combination with other immunosuppressive agents (see Table 2).
Most aminotransferase abnormalities were transient; however, a small number of patients experienced more prolonged elevations. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of REMICADE, or modification of concomitant medications.


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Malignancies: During clinical trials of REMICADE, new or recurrent malignancies have been reported in REMICADE-treated patients. The incidence of lymphoma in REMICADE-treated patients was higher than expected in the general populations. The observed incidences of non-lymphoma malignancies were similar to what would be expected in the general population whereas the rate among control patients was lower than expected. In an exploratory clinical trial involving patients with moderate to severe COPD who were either current smokers or ex-smokers, more malignancies were reported in REMICADE-treated patients compared with control patients (see Precautions). A population-based retrospective cohort study found an increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the general population, including those over 60 years of age (see Precautions).
The potential role of TNF-blocking therapy in the development of malignancies is not known.
Antinuclear Antibodies (ANA)/Double-Stranded DNA (dsDNA) Antibodies: Approximately half of REMICADE-treated patients in clinical trials who were ANA negative at baseline developed a positive ANA during the trial compared with approximately one-fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately 17% of REMICADE-treated patients compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndrome remain uncommon.
Congestive Heart Failure: In a phase II study evaluating REMICADE in moderate to severe heart failure (NYHA Class III/IV with a left ventricular ejection fraction ≤35%), 150 patients were randomized to receive treatment with 3 infusions of REMICADE 10 mg/kg, 5 mg/kg or placebo.
Higher incidences of mortality and hospitalization due to worsening heart failure were seen in patients receiving the 10 mg/kg REMICADE dose. At 28 weeks, 3 patients in the 10 mg/kg REMICADE group died compared with 1 death in the 5 mg/kg REMICADE group, and no deaths in the placebo group. At the same time point, 11 of 51 patients in the 10 mg/kg REMICADE group were hospitalized for worsening heart failure compared with 3 of 50 patients in the 5 mg/kg Remicade group and 5 of 49 in the placebo group. In follow-up, at 1 year, 8 patients in the 10 mg/kg REMICADE group died compared with 4 deaths each in the 5 mg/kg REMICADE and the placebo groups. REMICADE has not been studied in patients with mild heart failure (NYHA Class I/II) (see Contraindications and Precautions). There have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking REMICADE.
There have also been rare post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age.
Adverse Reactions in JRA: The safety and efficacy of REMICADE were assessed 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. A total of 122 patients with active JRA between the ages of 4 and 17 years who had been treated with methotrexate for at least 3 months were enrolled; 120 subjects received study drug. Concurrent use of folic acid, oral corticosteroids (≤10 mg/day), non-steroidal anti-inflammatory drugs and/or MTX was permitted.
Doses of 3 mg/kg REMICADE or placebo were administered intravenously at weeks 0, 2, 6, 14, 20 and then every 8 weeks through week 44. To maintain the treatment blind, the 3 mg/kg treatment group also received a single placebo infusion at week 16 while subjects randomized to placebo crossed-over to receive 6 mg/kg REMICADE at weeks 14, 16, and 20, and then every 8 weeks through week 44.
The safety and efficacy of REMICADE in the treatment of children with JRA have not been established. Forty-one of 60 children (68.3%) with JRA receiving REMICADE 3 mg/kg in combination with methotrexate experienced an infection over 52 weeks of observation compared with 37 of 57 (64.9%) children with JRA receiving REMICADE 6 mg/kg in combination with methotrexate over 38 weeks of observation and 28 of 60 (46.7%) receiving placebo in combination with methotrexate over 14 weeks of observation. The most commonly reported infections were upper respiratory tract infection and pharyngitis and the most commonly reported serious infection was pneumonia. Other notable infections included primary varicella infection in 1 patient and herpes zoster in 1 patient.
The incidence of infusion reactions in pediatric patients with JRA receiving 3 mg/kg REMICADE was 35% compared with 17.5% in patients receiving 6 mg/kg. The most common infusion reactions reported were vomiting, fever, headache, and hypotension. In the 3 mg/kg REMICADE group, 4 patients had a serious infusion reaction and three patients reported a possible anaphylactic reaction (2 of which were among the serious infusion reactions). In the 6 mg/kg REMICADE group, 2 patients had a serious infusion reaction, one of whom had a possible anaphylactic reaction. Two of the 6 patients who experienced serious infusion reactions received REMICADE by rapid infusion (duration time less than 2 hours).
Antibodies to REMICADE developed in 37.7% of patients with JRA receiving 3 mg/kg of REMICADE compared with 12.2% of patients receiving 6 mg/kg. The antibody titers were notably higher for the 3 mg/kg compared to the 6 mg/kg group.
Adverse Reactions in Pediatric Crohn's Disease: In general, the adverse events in pediatric patients who received REMICADE were similar in frequency and type to those seen in adult Crohn's disease patients. Differences from adults and other special consideration are discussed as follows.
The following adverse events were reported more commonly in 103 randomized pediatric Crohn's disease patients administered REMICADE 5 mg/kg through 54 weeks than in 385 adult Crohn's disease patients receiving a similar treatment regimen: Anemia (10.7%), blood in stool (9.7%), leukopenia (8.7%), flushing (8.7%), viral infection (7.8%), neutropenia (6.8%), bone fracture (6.8%), bacterial infection (5.8%) and respiratory tract allergic reaction (5.8%).
Infections were reported in 56.3% of randomized subjects in REACH and in 50.3% of subjects receiving REMICADE 5 mg/kg in ACCENT 1. Within REACH, infections were reported more frequently for subjects who received q8 week as opposed to q12 week infusions (73.6% and 38%, respectively) while serious infections were reported for 3 subjects in the q8 week and 4 subjects in the q12 week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Pneumonia was reported in 3 patients, 2 in the q8 week and 1 in the q12 week maintenance treatment groups. Herpes zoster was reported in 2 patients in the q8 week maintenance treatment group.
Overall, in REACH, 17.5% of randomized patients experienced 1 or more infusion reactions, with 17.0% and 18.0% of patients in the q8 week and q12 week maintenance treatment groups, respectively. There were no serious infusion reactions and 2 subjects in REACH had non-serious anaphylactic reactions.
Antibodies to REMICADE developed in 3 (2.9%) pediatric patients.
Adverse Reactions in Pediatric Ulcerative Colitis: Overall proportions of patients with adverse events and serious adverse events were generally consistent in the pediatric ulcerative colitis and adult ulcerative colitis (ACT 1 and ACT 2) studies. In the pediatric ulcerative colitis study (Study Peds UC), the most common adverse event was worsening of ulcerative colitis which was greater in patients on the q12 week vs the q8 week dosing regimen. In the ACT1 and ACT 2 studies, the most common adverse event was headache. The most common serious adverse event across these 3 studies was worsening of the disease under study.
Infections were reported in 31 (51.7%) of 60 treated patients in Study Peds UC and 22 (36.7%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in Study Peds UC was similar to that in the pediatric Crohn's disease study (REACH) but higher than the proportion in the adults ulcerative colitis studies (ACT 1 and ACT 2). Unlike REACH, in which infections were reported more frequently for patients who received q8 week as opposed to q12 week infusions; in Study Peds UC, the overall incidence of infections was similar in the q8 week [13/22 (59.1%)] and q12 week [14/23 (60.9%)] maintenance treatment groups. In Study Peds UC, serious infections were reported for 3 of 22 (13.6%) patients in the q8 week and 3 of 23 (13.0%) patients in the q12 week maintenance treatment group. Upper respiratory tract infection [7/60 (11.7%)] and pharyngitis [5/60 (8.3%)] were the most frequently reported respiratory system infections among all treated patients. The infections occurring in more than one patient in a treatment group that required antimicrobial treatment were pharyngitis [4/60 (6.7%)], urinary tract infection [4/60 (6.7%)], and bronchitis [2/60 (3.3%)].
Overall, 8 (13.3%) of 60 treated patients experienced one or more infusion reactions, with 4 of 22 (18.2%) in the q8 week and 3 of 23 (13.0%) in the q12 week treatment maintenance group. No serious infusion reactions were reported. All infusion reactions were mild or moderate in intensity.
Antibodies to REMICADE were detected in 4 (7.7%) patients through week 54.
In Study Peds UC, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group [45/60 (75.0%)] versus 15/60 (25.0%)]. While the numbers of patients in each subgroup are too small to make any definitive conclusions about the effect of age on safety events, there were higher proportions of patients with serious adverse events and discontinuation due to adverse events in the younger age group than in the older age group.
While the proportion of patients with infections was also higher in the younger age group, for serious infections, the proportions were similar in the two age groups. Overall proportions of adverse events and infusion reactions were similar between the 6 to 11 and 12 to 17 year age groups.
Post-Marketing Experience: Additional adverse events, some with fatal outcome, reported from worldwide post-marketing experience with REMICADE are included in Table 3. Because these events 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 REMICADE exposure. (See Table 3).
The most common serious adverse events reported in the postmarketing experience in children were infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions and hypersensitivity reactions. Spontaneous serious adverse events in the postmarketing experience with REMICADE in the pediatric population have included malignancies, transient hepatic enzyme abnormalities, lupus-like syndromes, and positive autoantibodies.
Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with REMICADE with the vast majority of cases occurring in Crohn's disease and ulcerative colitis and most of whom were adolescent or young adult males (see Precautions).


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Inform the physician of all undesirable effects upon drug administration.

Specific drug interaction studies have not been conducted with REMICADE.
Concurrent Use of REMICADE with other Biological Therapeutics: The combination of REMICADE with other biological therapeutics used to treat the same conditions as REMICADE, including anakinra and abatacept is not recommended (see Precautions).
Live Vaccines/Therapeutic Infectious Agents: It is recommended that live vaccines not be given concurrently with REMICADE (see Precautions). It is also recommended that live vaccines not be given to infants after in utero exposure to infliximab for at least 6 months following birth.
It is recommended that therapeutic infectious agents not be given concurrently with REMICADE (see Precautions).

Instructions for Use and Handling and Disposal: Use aseptic technique.
1. Calculate the dose and the number of REMICADE vials needed. Each REMICADE vial contains infliximab 100 mg. Calculate the total volume of reconstituted REMICADE solution required.
2. Reconstitute each REMICADE vial with 10 mL of Sterile Water for Injections, using a syringe equipped with a 21-gauge (0.8 mm) or smaller needle. Remove flip-top from the vial and wipe the top with a 70% alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injections 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. Check that the solution is colorless to light yellow and opalescent. The solution may develop a few fine translucent particles, as infliximab is a protein. Do not use if opaque particles, discoloration or other foreign particles are present.
3. Dilute the total volume of the reconstituted REMICADE solution dose to 250 mL with 0.9% w/v sodium chloride solution for infusion. Do not dilute the reconstituted REMICADE solution with any other diluent. This can be accomplished by withdrawing a volume of the 0.9% sodium chloride solution from the 250-mL glass bottle or infusion bag equal to the volume of reconstituted REMICADE. Slowly add the total volume of reconstituted REMICADE solution to the 250-mL infusion bottle or bag. Gently mix.
4. For adult and pediatric patients with Crohn's disease, adult patients with fistulizing Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis administer the infusion solution over a period of not less than 2 hours. For patients with rheumatoid arthritis, the recommended infusion duration is over a period of not less than 2 hours in patients not previously treated with REMICADE. In carefully selected patients with rheumatoid arthritis who have tolerated 3 initial 2-hour infusions of REMICADE, consideration may be given to administering subsequent infusions over a period of not less than 1 hour. Shortened infusions at doses >6 mg/kg have not been studied.
For adult and pediatric patients, administer the infusion solution over a period of not less than 2 hours.
In carefully selected adult patients who have tolerated at least 3 initial 2-hour infusions of REMICADE (induction phase) and are receiving maintenance therapy, consideration may be given to administering subsequent infusions over a period of not less than 1 hour. Shortened infusions at doses >6 mg/kg have not been studied.
Use only an infusion set with an in-line, sterile, nonpyrogenic, low protein-binding filter (pore size 1.2 micrometer or less). Do not store any unused portion of the infusion solution for reuse.
5. No physical biochemical compatibility studies have been conducted to evaluate the co-administration of REMICADE with other agents. Do not infuse REMICADE concomitantly in the same intravenous line with other agents.
6. Visually inspect parenteral medicinal products for particulate matter or discoloration prior to administration. Do not use if visibly opaque particles, discoloration or foreign particulates are observed.
Incompatibilities: Specific drug interaction studies have not been conducted.

Store at 2°C-8°C.
REMICADE may be stored at temperatures up to a maximum of 30°C for a single period of up to 6 months; but not exceeding the original expiration date. The new expiration date should be written on the carton. Upon removal from refrigerated storage, REMICADE cannot be returned to refrigerated storage.
For storage conditions of the reconstituted medicinal product, see Shelf life as follows.
Shelf-Life: 36 months from the manufacturing date.
Do not use beyond the expiration date.
This product contains no preservative.
It is recommended that when Remicade is prepared for infusion, it is used as soon as possible (within 3 hours). However, if the solution is prepared in germ-free conditions, it can be stored in a refrigerator at 2°C to 8°C for 24 hours.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs) / Immunosuppressants

L04AB02 - infliximab ; Belongs to the class of tumor necrosis factor alpha (TNF-alpha) inhibitors. Used as immunosuppressants.

Infusion conc 100 mg (lyophilized powd for conc for soln for infusion in single use vials) x 1's.