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INFLECTRA (infliximab for Injection)

Health Professional Information

SUMMARY PRODUCT INFORMATION

Route of AdministrationDosage Form / StrengthClinically Relevant Nonmedicinal Ingredients
Intravenous InfusionPowder for Solution /100 mg/vialFor a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

Description

INFLECTRA® (infliximab for Injection) is a subsequent entry biologic to REMICADE®. It consists of a chimeric immunoglobin G1 (IgG1) monoclonal antibody that binds with high affinity to the human tumour necrosis factor alpha (TNFα).

The INFLECTRA® drug product is formulated as a white lyophilized powder in a type I borosilicate glass vial with a 20 mm, double vent butyl rubber stopper and a 20 mm flip-off seal. The lyophilisate is reconstituted with 10 mL of sterile water for injection to yield a single dose formulation of 10 mg/mL infliximab for Injection, at pH 7.2. Each vial is designed to deliver a single dose of 100 mg infliximab active substance. The components of a single vial of the drug product INFLECTRA® are:  infliximab, sucrose, sodium dihydrogen phosphate monohydrate, di-sodium hydrogen phosphate dihydrate, polysorbate 80.

Similarity between INFLECTRA® and REMICADE® (the reference product) was established in accordance with the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), for the authorized indications.

Indications And Clinical Use

Comparability between INFLECTRA® and the reference product has been established based on comparative chemistry and manufacturing studies, comparative non-clinical studies, comparative PK studies and clinical trials, in patients with rheumatoid arthritis or ankylosing spondylitis. Indications in Crohn’s disease, ulcerative colitis, psoriatic arthritis and plaque psoriasis have been granted on the basis of similarity, between INFLECTRA® and the reference product, in product quality, mechanism of action, disease pathophysiology, safety profile, dosage regimen and on clinical experience with the reference product.

INFLECTRA® (infliximab for Injection) is indicated for:

  • use in combination with methotrexate for the reduction in signs and symptoms, inhibition of the progression of structural damage and improvement in physical function in adult patients with moderately to severely active rheumatoid arthritis.
  • reduction of signs and symptoms and improvement in physical function in patients with active ankylosing spondylitis who have responded inadequately, or are intolerant to, conventional therapies.
  • reduction of signs and symptoms, induction and maintenance of clinical remission and mucosal healing and reduction of corticosteroid use in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to a corticosteroid and/or aminosalicylate. INFLECTRA® can be used alone or in combination with conventional therapy.
  • treatment of fistulising Crohn’s disease, in adult patients who have not responded despite a full and adequate course of therapy with conventional treatment. 
  • reduction of signs and symptoms, induction and maintenance of clinical remission and mucosal healing, and reduction or elimination of corticosteroid use in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy (i.e., aminosalicylate and/or corticosteroid and/or an immunosuppressant).
  • reduction of signs and symptoms, induction of major clinical response, and inhibition of the progression of structural damage of active arthritis, and improvement in physical function in patients with psoriatic arthritis.
  • treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, INFLECTRA® should be used after phototherapy has been shown to be ineffective or inappropriate. When assessing the severity of psoriasis, the physician should consider the extent of involvement, location of lesions, response to previous treatments, and impact of disease on the patient’s quality of life.

INFLECTRA® should be used by physicians who have sufficient knowledge of rheumatoid arthritis and/or ankylosing spondylitis and/or Crohn’s disease and/or ulcerative colitis and/or psoriatic arthritis and/or plaque psoriasis and who have fully familiarized themselves with the efficacy/safety profile of INFLECTRA®.

Geriatrics (≥ 65 years of age):

Evidence from clinical studies suggests that the use in geriatric population is associated with no overall differences in safety and efficacy.

In rheumatoid arthritis clinical trials (ATTRACT) and plaque psoriasis trials, no overall differences were observed in the effectiveness or safety in 181 patients with rheumatoid arthritis and 75 patients with plaque psoriasis, aged 65 or older compared to younger patients although the incidence of serious adverse events in patients aged 65 or older was higher in both infliximab for Injection 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 64. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly (see ADVERSE REACTIONS, Infections).

Pediatrics:

The safety and efficacy of INFLECTRA® has not been established in pediatric patients.

Contraindications

  • Patients with severe infections such as sepsis, abscesses, tuberculosis and opportunistic infections (see WARNINGS AND PRECAUTIONS, Risk of Infections).
  • Patients with moderate or severe (NYHA Class III/IV) congestive heart failure (see WARNINGS AND PRECAUTIONS, Cardiovascular and ADVERSE REACTIONS Congestive Heart Failure).
  • Patients with a history of hypersensitivity to infliximab for Injection, to other murine proteins, or to any of the excipients. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

Warnings And Precautions

Serious Warnings and Precautions

RISK OF INFECTIONS

Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation), invasive fungal infections, and other opportunistic infections, have been observed in patients receiving infliximab for Injection. Some of these infections have been fatal.

Patients must be evaluated for the risk of tuberculosis, including latent tuberculosis, prior to initiation of INFLECTRA®. This evaluation should include a detailed medical history of tuberculosis or possible previous contact with tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests, i.e. tuberculin skin test and chest x-ray (if indicated), should be performed in all patients.3 Prescribers are reminded of the risk of false negative tuberculin skin test results especially in patients who are severely ill or immunocompromised. Treatment of latent tuberculosis infection should be initiated prior to therapy with INFLECTRA® (see WARNINGS AND PRECAUTIONS, Risk of Infections).

Hepatosplenic T-cell Lymphoma

Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with TNF-blockers including infliximab for Injection. 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 infliximab for Injection cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were reported in adolescent or young adult males. (see WARNINGS AND PRECAUTIONS, Carcinogenesis and Mutagenesis).

Pediatric Malignancy
INFLECTRA® is not indicated for use in pediatric patients. Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF-blockers, including infliximab for Injection (see WARNINGS AND PRECAUTIONS, Carcinogenesis and Mutagenesis).

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.

Risk of Inflections

Serious infections due to bacterial (including sepsis and pneumonia), invasive fungal, viral, and other opportunistic pathogens, have been reported in patients receiving TNF-blocking agents. Some of these infections have been fatal. Many of the serious infections in patients treated with infliximab for Injection have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease, could predispose them to infections.

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

Cases of histoplasmosis, coccidioidomycosis, blastomycosis, listeriosis, pneumocystosis, and tuberculosis have been observed in patients receiving infliximab for Injection. For patients who have resided in or travelled to regions where histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of INFLECTRA® treatment should be carefully considered before initiation or continuation of INFLECTRA® therapy.

Invasive Fungal Infections

In patients treated with INFLECTRA®, 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 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 antifungal therapy.

Tuberculosis

Cases of active tuberculosis have occurred in patients treated with infliximab for Injection during and after treatment for latent tuberculosis. Patients receiving INFLECTRA® should be monitored closely for signs and symptoms of active tuberculosis during and after treatment, including patients who tested negative for latent tuberculosis infection. The possibility of undetected latent tuberculosis should be considered, especially in patients who have immigrated from or traveled to countries with a high prevalence of tuberculosis or had close contact with a person with active tuberculosis. All patients treated with INFLECTRA® should have a thorough history taken prior to initiating therapy. Some patients who have previously received treatment for latent or active tuberculosis have developed active tuberculosis while being treated with infliximab for Injection. Anti-tuberculosis therapy should be considered prior to initiation of INFLECTRA® 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 INFLECTRA® 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.

Opportunistic Infections

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

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 INFLECTRA® and anakinra is not recommended.

Concurrent Administration of INFLECTRA® with Abatacept

In clinical studies, concurrent administration of TNF-blocking agents and abatacept has been associated with an increased risk of infections including serious infections compared with TNF- blocking agents 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 INFLECTRA® and abatacept is not recommended.

Concurrent Administration with other Biological Therapeutics

There is insufficient information regarding the concomitant use of INFLECTRA® with other biological therapeutics used to treat the same conditions as INFLECTRA®. The concomitant use of INFLECTRA® 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.

Carcinogenesis and Mutagenesis

Pediatric malignancy

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 for Injection. 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 post-marketing reports.

Lymphoma

Lymphomas have been observed in patients treated with TNF-blocking agents, including infliximab for Injection. In clinical trials, patients treated with infliximab for Injection had a higher incidence of lymphoma than the expected rate in the general population. Patients with rheumatoid arthritis and Crohn’s disease, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) for the development of lymphoma than the general population, even in the absence of TNF-blocking therapy. The role of TNF-blockers in the development of malignancy is not known.

Hepatosplenic T-cell lymphoma

Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with TNF-blockers including infliximab for Injection. 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 infliximab for Injection 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 infliximab for Injection. Before initiating or continuing INFLECTRA® 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 infliximab for Injection therapy remains unclear.

Leukemia

Cases of acute and chronic leukemia have been reported with post-marketing 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 clinical trials of some TNF-blocking agents, including infliximab for Injection, more malignancies (excluding lymphoma and non-melanoma skin cancer [NMSC]) have been observed in patients receiving those TNF-blockers compared with control patients (see ADVERSE REACTIONS, Malignancies/Lymphoproliferative Disease). The rate of non-lymphoma malignancies among infliximab for Injection-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 infliximab for Injection in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies were reported in infliximab for Injection-treated patients compared with control patients. All patients had a history of heavy smoking.

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 for Injection compared to biologics-naïve patients or the general population, including those over 60 years of age. A causal relationship between infliximab for Injection and cervical cancer cannot be excluded. Periodic screening should continue in women treated with INFLECTRA®, including those over 60 years of age.

Skin cancers

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocker therapy, including infliximab for Injection (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

Psoriasis patients should be monitored for nonmelanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for infliximab for Injection, NMSCs were more common in patients with previous phototherapy (see ADVERSE REACTIONS, Malignancies/Lymphoproliferative Disease).

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 (see ADVERSE REACTIONS, Malignancies/Lymphoproliferative Disease).

Long-term studies in animals have not been performed to evaluate the carcinogenic potential. No clastogenic or mutagenic effects of infliximab for Injection 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. Tumourigenicity studies in mice deficient in TNFα demonstrated no increase in tumours when challenged with known tumour initiators and/or promoters.

Cardiovascular

Doses greater than 5 mg/kg should not be administered to patients with congestive heart failure (CHF). INFLECTRA® should be used with caution in patients with mild heart failure (NYHA Class I/II). Patients should be closely monitored, and INFLECTRA® must not be continued in patients who develop new or worsening symptoms of heart failure (see CONTRAINDICATIONS and ADVERSE REACTIONS, Congestive Heart Failure).

The results of a randomized study evaluating the use of infliximab for Injection in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg infliximab for Injection, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg.

Hematologic

There have been reports of pancytopenia, leukopenia, neutropenia, and thrombocytopenia in patients receiving TNF-blockers, including infliximab for Injection. Caution should be exercised in patients treated with INFLECTRA® who have a current or past history of significant cytopenias. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g., persistent fever, bruising, bleeding, pallor). Discontinuation of INFLECTRA® therapy should be considered in patients with confirmed significant hematologic abnormalities.

Hepatic/Biliary/Pancreatic

Cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, have been observed in the post-marketing experience with infliximab for Injection. Isolated cases of liver failure resulting in liver transplantation or death have occurred. A causal relationship between infliximab for Injection 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 develop, INFLECTRA® should be discontinued immediately, and a thorough investigation of the abnormality should be undertaken. As also observed with the use of other immunosuppressive drugs, reactivation of hepatitis B has occurred very rarely in patients receiving infliximab for Injection 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 INFLECTRA®. 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 prior to the initiation of INFLECTRA® therapy and monitored closely during treatment and for several months following discontinuation of therapy.

Immune

To minimize the incidence of hypersensitivity reactions, including infusion reactions and serum sickness-like reactions, INFLECTRA® should be administered as regular maintenance therapy after an induction regimen at weeks 0, 2 and 6 (see DOSAGE AND ADMINISTRATION).

Hypersensitivity Reactions

Infliximab for Injection has been associated with hypersensitivity reactions that vary in their time of onset. Hypersensitivity reactions, which include urticaria, dyspnea, and/or bronchospasm, laryngeal edema and hypotension, have occurred during or within 2 hours of infliximab for Injection infusion. However, in some cases, serum sickness-like reactions have been observed in Crohn’s disease and rheumatoid arthritis patients 3 to 12 days after infliximab for Injection therapy was reinstituted following an extended period without infliximab for Injection treatment. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema and/or dysphagia. These reactions were associated with marked increase in antibodies to infliximab for Injection, loss of detectable serum concentrations of infliximab for Injection, and possible loss of drug efficacy. INFLECTRA® should be discontinued for severe 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, Infusion-related Reactions).

During clinical trials, the reference product was sometimes readministered within 14 weeks following the last infusion. After a drug free interval of 15 weeks to 2 years, the risk of delayed hypersensitivity following readministration has not been accurately determined (see ADVERSE REACTIONS, Infusion-related Reactions, Delayed Hypersensitivity/Reactions following readministration of infliximab for Injection).

Infusion reactions following readministration of infliximab for Injection

In a rheumatoid arthritis clinical trial where subjects were receiving low dose methotrexate and in a psoriasis clinical trial, a 3-dose induction of infliximab for Injection after a period of no treatment resulted in a higher incidence of serious and severe infusion reactions during the reinduction regimen 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 reinduction. Most of these reactions occurred during the second reinduction infusion at Week 2. The serious infusion reactions included anaphylaxis, urticaria, facial edema, chills and itching. Retreatment with a reinduction regimen after a period of no treatment is not recommended (see ADVERSE REACTIONS, Infusion-related Reactions, Infusion Reactions following readministration of infliximab for Injection).

The INFLECTRA Patient Assistance Program facilitates the administration of INFLECTRA®. The INFLECTRA Patient Assistance Program clinics are staffed by qualified healthcare professionals specially trained in the administration of INFLECTRA® infusions and are available across Canada. Information about the INFLECTRA Patient Assistance Program can be obtained by calling 1-844-466-6627.

Autoimmunity

Treatment with infliximab for Injection 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 infliximab for Injection, treatment should be discontinued (see ADVERSE REACTIONS, Autoantibodies/Lupus-like Syndrome).

Immunogenicity

Treatment with infliximab for Injection can be associated with the development of antibodies to infliximab for Injection (see WARNINGS AND PRECAUTIONS, Hypersensitivity). Approximately 10% of patients were antibody positive. The majority of antibody positive patients had low titers.

In a Phase III study of Crohn’s disease (SONIC) in patients who were immunomodulator-naïve, antibodies occurred at Week 30 in 14% of patients receiving infliximab for Injection monotherapy and in 1% of patients receiving infliximab for Injection in combination with azathioprine (AZA). Through Week 50, anti-infliximab for Injection antibodies occurred in 19% and 2.5% of patients, respectively. In the 20 patients on infliximab for Injection monotherapy who were positive for anti-infliximab for Injection antibodies at some point during the study through Week 50, 10 patients had an infusion reaction, one of which was serious. None of the 3 patients on infliximab for Injection in combination with AZA who were positive for anti-infliximab for Injection antibodies had an infusion reaction.

Patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and to experience an infusion reaction (see ADVERSE REACTIONS, Infusion-related Reactions) than were patients who were antibody negative. Antibody development was lower among adult rheumatoid arthritis, Crohn’s disease, and psoriatic arthritis patients receiving immunosuppressant therapies such as 6-mercaptopurine (6-MP), azathioprine (AZA), or methotrexate (MTX).

With repeated dosing of infliximab for Injection, serum concentrations of infliximab for Injection were higher in rheumatoid arthritis patients who received concomitant MTX. In the 2 Phase 3 studies of psoriasis (EXPRESS and EXPRESS II), infliximab for Injection was administered as induction followed by maintenance and without concomitant immunosuppressive therapy. In these studies, antibodies occurred in approximately 26.5% to 35.8% of patients who received 5 mg/kg every 8 week maintenance for 1 year and at higher rates (up to 1.4-fold) with other dose regimens (3 mg/kg q8 week, 3 mg/kg dosed as needed, and 5 mg/kg dosed as needed). Despite the increase in the rate of antibody formation, the infusion reaction rates in the 2 psoriasis Phase 3 studies (EXPRESS and EXPRESS II) in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year (14.1% and 23.0%, respectively) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. In the Phase 3 study of psoriatic arthritis (IMPACT 2), where patients received 5 mg/kg with and without MTX, antibodies to infliximab for Injection occurred in 15.4% of patients.

Immunogenicity tests are generally product-specific. Comparison of antibody rates to those from other products, or comparison of the incidence of antibodies between different tests without cross-validation is not appropriate.

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 infliximab for Injection 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 for Injection. At least a six month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab for Injection (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).

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 infliximab for Injection.

Non-Live Vaccines

It is recommended that the vaccinations of patients be brought up to date with all vaccination guidelines prior to initiating INFLECTRA® therapy.

Neurological Events

Infliximab for Injection and other agents that inhibit TNF 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 INFLECTRA® in patients with these neurological disorders, and should consider discontinuation of INFLECTRA® if these disorders develop.

Physicians should alert patients to the presence of the Patient Package Insert, provide this information to them, and ensure full understanding of the content.

Peri-Operative Considerations

There is limited safety experience of infliximab for Injection in patients who have undergone surgical procedures, including arthroplasty. The long half-life of infliximab for Injection should be taken in to consideration if a surgical procedure is planned. A patient who requires surgery while on INFLECTRA® should be closely monitored for infections, and appropriate actions should be taken.

Sexual Function/Reproduction

It is not known whether infliximab for Injection can impair fertility in humans. No impairment of fertility was observed in a fertility and general reproduction toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα.

Special Populations

Pregnant Women

Since infliximab for Injection does not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab for Injection. 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 INFLECTRA® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. INFLECTRA® should be given to a pregnant woman only if clearly needed.

As with other IgG antibodies, infliximab for Injection crosses the placenta. Infliximab for Injection has been detected in the serum of infants up to 6 months following birth. After in utero exposure to infliximab for Injection, infants may be at increased risk of infection, including disseminated infection that can become fatal (see WARNINGS AND PRECAUTIONS, Live Vaccines/Therapeutic Agents and Non-Live Vaccines).

Nursing Women

It is not known whether infliximab for Injection is excreted in human milk or absorbed systemically after ingestion. Because immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from infliximab for Injection, breast feeding is not recommended during treatment and for 6 months after the last dose of INFLECTRA®. 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.

Women of Childbearing Potential

Women of childbearing potential must use adequate contraception to prevent pregnancy and continue to do so for at least 6 months after the last INFLECTRA® treatment.

Pediatrics (6-17 years of age)

The safety and efficacy of INFLECTRA® has not been established in pediatric patients.

Geriatrics (65 years of age or older)

In rheumatoid arthritis clinical trials (ATTRACT) and in plaque psoriasis studies with infliximab for Injection, no overall differences were observed in the effectiveness or safety in 181 patients with rheumatoid arthritis and 75 patients with plaque psoriasis, aged 65 or older compared to younger patients although the incidence of serious adverse events in patients aged 65 or older was higher in both infliximab for Injection and control groups compared to younger patients. Mean duration of infliximab for Injection treatment in this population (154) was approximately 50 weeks. 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 responded differently from patients aged 18 to 64. There is a greater incidence of infections in the elderly population in general. The incidence of serious infections in infliximab for Injection-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, Infections).

Effects on Ability to Drive and Use Machines

INFLECTRA® may have a minor influence on the ability to drive and use machines. Dizziness may occur following administration of INFLECTRA®.

Adverse Reactions

The adverse drug reaction profiles reported in the clinical trials that compared INFLECTRA® to REMICADE® were comparable. No new adverse reactions were reported. The description of adverse reactions in this section is based on clinical experience with the reference product REMICADE®.

Adverse Drug Reaction Overview

In studies with infliximab for Injection, the most common adverse drug reactions reported from both clinical trials and post-marketing reports were infections, allergic reactions and infusion-related reactions. Less common adverse drug reactions from these sources, which may be serious and clinically relevant include hepatobiliary events (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic), demyelinating disorders (see WARNINGS AND PRECAUTIONS, Neurologic Events), and lymphoma (see WARNINGS AND PRECAUTIONS, Carcinogenesis and Mutagenesis). One of the most common reasons for discontinuing treatment in clinical trials was infusion-related reactions (dyspnea, flushing, headache and rash). (See WARNINGS AND PRECAUTIONS, Hypersensitivity). Adverse events have been reported in a higher proportion of rheumatoid arthritis patients receiving the 10 mg/kg dose than the 3 mg/kg dose, however, no differences were observed in the frequency of adverse events between the 5 mg/kg dose and the 10 mg/kg dose in patients with Crohn’s disease or ulcerative colitis and between the 3 mg/kg and 5 mg/kg dose in patients with plaque psoriasis.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Description of Data Sources

The data described herein reflect the exposure to infliximab for Injection in 5243 patients in adequate and well-controlled studies. Infliximab for Injection was studied in patients with rheumatoid arthritis (1304 patients exposed), Crohn’s disease 1427 adult patients exposed), ulcerative colitis (484 adult patients exposed), plaque psoriasis (1373 patients exposed), psoriatic arthritis (293 patients exposed), ankylosing spondylitis (345 patients exposed) and other conditions (17 patients exposed), primarily in double-blind, placebo-controlled trials. In general, integration of data in the following sections is based on clinical trials in rheumatoid arthritis and adult Crohn’s disease.

Relative Frequency of Adverse Drug Reactions

Adverse events occurring at a frequency of at least 5% in infliximab for Injection-treated adult patients with rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, and ulcerative colitis are shown in Table 1. Adverse events occurring at a frequency of ≥1% to <5% in infliximab for Injection-treated adult patients are shown in Table 2.

Table 1: Number of patients with 1 or more adverse events (with frequency of ≥ 5%) by WHOART system-organ class and preferred term; treated patients ≥ 18 years of age
 RA StudiesCD studiesAS studiesUC studiesPso StudiesPsA studies
 PlaceboInfliximab for InjectionPlaceboInfliximab for InjectionPlaceboInfliximab for InjectionPlaceboInfliximab for InjectionPlaceboInfliximab for InjectionPlaceboInfliximab for Injection
a
Rheumatoid Arthritis Studies include C0168T07, C0168T09, C0168T14, C0168T15, C0168T18, C0168T22, and C0168T29. Crohn's Disease Studies include C0168T08, C0168T11, C0168T16, C0168T20, C0168T21, C0168T26, and C0168T67. Ankylosing Spondylitis Studies include C0168T51. Ulcerative Colitis Studies include C0168T12, C0168T37 (through Week 54), and C0168T46 (through Week 54 including 24-week study extension). Psoriasis Studies include C0168T31, C0168T38, and C0168T44. Psoriatic Arthritis Studies include C0168T50.
b
The adverse events included in this table are determined by the frequency of events in the combined infliximab for Injection group over all indications in this table. Percentages are rounded to an integer value after the adverse event frequency is determined.
Treated patients ≥ 18 years of agea,b4271304217142776275248493334137398191
Avg duration of follow-up (weeks)52.059.929.844.825.387.831.940.518.141.920.242.8
Patient with 1 or more adverse events353 (82.7%)1198 (91.9%)179 (82.5%)1297 (90.9%)57 (75.0%)268 (97.5%)199 (80.2%)425 (86.2%)210 (62.9%)1209 (88.1%)66 (67.3%)162 (84.8%)
System-organ class/preferred term            
Respiratory system disorders            
Upper respiratory tract infection22%29%15%23%14%49%17%18%16%25%13%24%
Pharyngitis7%12%6%13%5%20%6%10%4%9%4%10%
Sinusitis7%13%6%9%1%11%5%9%3%8%4%11%
Coughing7%12%6%7%3%13%4%6%1%5%1%7%
Rhinitis4%8%5%6%5%21%2%4%1%6%2%4%
Bronchitis8%9%3%5%1%8%3%4%2%4%3%6%
Gastro-intestinal system disorders            
Nausea19%19%25%21%9%11%9%11%4%8%6%5%
Abdominal pain7%12%17%24%4%16%13%12%1%4%2%5%
Diarrhea11%11%7%9%5%20%5%5%2%5%3%2%
Vomiting6%7%13%12%4%6%7%6%1%3%2%1%
Dyspepsia6%9%2%6%4%4%2%3%1%2%2%2%
Skin and appendages disorders            
Rash5%9%6%10%7%10%8%8%1%2%0%2%
Pruritus2%6%3%6%7%12%4%6%4%9%3%6%
Body as a whole general disorders            
Pain7%7%6%13%5%29%12%11%5%10%1%4%
Fatigue6%8%13%14%4%15%8%10%2%7%3%4%
Musculo skeletal system disorders            
Arthralgia6%7%8%15%1%8%10%15%2%10%2%4%
Back pain4%7%6%8%3%12%8%4%3%5%6%9%
Myalgia3%3%4%6%3%4%5%6%1%6%0%2%
Central & peripheral nervous system disorders            
Headache12%17%15%23%11%20%18%19%8%17%5%10%
Dizziness6%7%6%10%4%10%5%6%2%4%4%4%
Resistance mechanism disorders            
Fever4%7%11%11%0%8%9%10%1%4%1%2%
Table 2: Number of patients with 1 or more adverse events (with frequency of ≥ 1% to < 5%) by WHOART system-organ class and preferred term; treated patients ≥ 18 years of age
 RA StudiesCD studiesAS studiesUC studiesPso StudiesPsA studies
 PlaceboInfliximab for InjectionPlaceboInfliximab for InjectionPlaceboInfliximab for InjectionPlaceboInfliximab for InjectionPlaceboInfliximab for InjectionPlaceboInfliximab for Injection
a
Rheumatoid Arthritis Studies include C0168T07, C0168T09, C0168T14, C0168T15, C0168T18, C0168T22, and C0168T29. Crohn's Disease Studies include C0168T08, C0168T11, C0168T16, C0168T20, C0168T21, C0168T26, and C0168T67. Ankylosing Spondylitis Studies include C0168T51. Ulcerative Colitis Studies include C0168T12, C0168T37 (through Week 54), and C0168T46 (through Week 54 including 24-week study extension). Psoriasis Studies include C0168T31, C0168T38, and C0168T44. Psoriatic Arthritis Studies include C0168T50.
b
The adverse events included in this table are determined by the frequency of events in the combined infliximab for Injection group over all indications in this table. Percentages are rounded to an integer value after the adverse event frequency is determined.
Treated patients ≥ 18 years of agea,b4271304217142776275248493334137398191
Avg duration of follow-up (weeks)52.059.929.844.825.387.831.940.518.141.920.242.8
Patient with 1 or more adverse events353 (82.7%)1198 (91.9%)179 (82.5%)1297 (90.9%)57 (75.0%)268 (97.5%)199 (80.2%)425 (86.2%)210 (62.9%)1209 (88.1%)66 (67.3%)162 (84.8%)
System-organ class/preferred term            
Respiratory system disorders            
Dyspnea2%5%1%4%3%5%2%3%1%3%1%3%
Pneumonia1%4%1%1%0%1%0%2%0%1%0%3%
Respiratory tract allergic reaction1%2%0%1%0%1%0%1%0%2%1%2%
Epistaxis1%1%0%1%0%2%0%1%0%1%0%1%
Gastro-intestinal system disorders            
Gastroenteritis3%4%6%4%4%7%2%3%1%3%3%1%
Crohn`s disease0%0%12%13%0%0%0%0%0%0%0%0%
Stomatis ulcerative5%6%1%3%1%1%1%1%0%1%1%1%
Flatulence1%2%3%6%0%1%2%4%0%0%0%0%
Constipation3%2%2%4%1%3%1%2%0%1%2%0%
Gastro-esophageal reflux1%2%0%2%0%3%2%1%0%1%1%2%
Colitis ulcerative0%0%0%0%0%0%25%16%0%0%0%0%
Tooth ache0%1%1%2%0%1%0%1%1%2%0%1%
Anorexia1%1%2%2%0%0%1%1%0%0%0%1%
Blood in stool1%1%1%2%0%1%1%1%0%0%0%0%
Intestinal obstruction0%0%2%4%0%0%0%0%0%0%0%0%
Skin and appendages disorders            
Urticaria1%4%0%2%0%2%0%1%1%4%0%4%
Sweating increased0%2%3%3%5%4%3%3%0%2%0%2%
Alopecia2%3%2%3%0%1%1%3%1%1%2%3%
Dermatitis1%2%0%2%1%7%2%1%0%2%0%1%
Dermatitis fungal1%3%1%1%0%5%3%1%0%2%1%2%
Psoriasis0%0%1%1%1%5%1%0%7%5%2%4%
Eczema1%2%0%3%0%3%3%1%1%1%0%1%
Acne0%1%1%3%0%3%1%2%1%1%0%0%
Skin dry0%1%1%2%0%7%1%3%1%1%0%0%
Skin wound2%2%1%1%0%2%0%1%0%2%0%1%
Erythema0%2%1%1%0%3%1%1%0%1%1%0%
Rash erythematous1%1%0%1%1%5%0%1%0%0%0%1%
Folliculitis0%1%1%1%0%1%0%1%1%1%0%0%
Body as a whole general disorders            
Chest pain3%4%4%5%1%6%2%3%0%4%2%4%
Edema peripheral4%4%2%5%1%4%4%4%2%3%0%3%
Chills2%3%1%2%3%3%2%4%1%3%0%1%
Infusion syndrome0%2%0%2%1%3%0%2%0%3%0%2%
Wound1%1%0%1%1%3%0%1%0%3%1%3%
Hot flushes0%2%1%2%1%3%2%1%0%1%0%2%
Allergic reaction0%1%1%2%0%5%0%2%1%1%1%1%
Asthenia1%1%0%3%0%2%0%1%0%1%1%1%
Reaction unevaluable0%1%2%2%0%2%1%1%1%1%0%0%
Musculo skeletal system disorders            
Arthritis1%1%2%4%5%14%1%1%3%7%5%5%
Bone fracture3%4%0%1%0%4%0%1%1%1%0%4%
Skeletal muscle strain2%2%0%1%0%1%1%0%1%3%1%2%
Tendinitis2%0%0%1%1%5%1%1%0%1%2%1%
Central & peripheral nervous system disorders            
Paresthesia2%3%2%3%0%7%3%3%1%3%0%0%
Muscle contractions involuntary2%4%2%2%1%3%3%2%0%2%1%1%
Hypesthesia1%2%1%2%4%3%1%1%0%2%1%1%
Migraine1%1%1%2%0%1%0%1%0%1%0%1%
Vertigo2%2%0%1%3%1%1%1%0%1%1%2%
Resistance mechanism disorders            
Abscess3%4%4%9%3%6%3%3%1%3%2%2%
Flu syndrome3%4%1%6%1%8%2%4%1%3%0%3%
Moniliasis3%5%0%5%0%5%2%3%0%1%0%1%
Influenza-like symptoms0%2%2%3%1%2%2%3%1%2%0%2%
Herpes simplex1%2%2%2%0%9%2%1%1%2%1%4%
Infection2%3%0%2%3%4%1%1%1%2%0%1%
Influenza1%2%2%3%1%1%2%2%1%2%0%1%
Cellulitis1%2%0%1%0%2%0%1%1%1%1%3%
Herpes zoster1%1%0%1%0%0%0%1%1%1%0%2%
Infection bacterial1%1%2%1%0%1%0%0%0%1%0%2%
Psychiatric disorders            
Insomnia4%4%3%6%1%4%2%4%1%2%1%0%
Depression5%5%2%4%0%4%2%3%1%3%2%3%
Anxiety1%3%1%3%1%2%3%2%0%2%1%0%
Liver and biliary system disorders            
Sgpt increased4%5%1%3%5%12%1%1%1%4%1%8%
Sgot increased2%3%1%2%3%9%0%1%1%3%2%5%
Hepatic enzymes increased3%4%1%1%0%2%0%1%0%4%0%2%
Hepatic function abnormal1%2%2%1%0%2%0%0%0%1%1%2%
Vascular (extracardiac) disorders            
Flushing0%3%1%2%3%4%1%2%0%5%0%3%
Ecchymosis2%4%0%2%0%2%1%1%0%2%0%1%
Hemorrhoids1%1%0%2%1%3%3%1%0%0%0%1%
Urinary system disorders            
Urinary tract infection5%7%3%4%0%2%2%2%1%2%4%3%
Metabolic and nutritional disorders            
Hypokalemia0%2%1%4%0%0%0%1%0%0%0%1%
Weight increase2%2%0%0%1%3%0%0%0%1%0%0%
Cardiovascular disorders, general            
Hypertension5%6%2%3%5%8%2%2%3%4%2%3%
Hypotension1%2%0%2%1%3%0%2%0%1%0%2%
Eye and vision disorders            
Conjunctivitis2%4%2%4%1%4%3%1%0%1%1%1%
Vision abnormal1%2%1%2%0%4%2%1%0%1%0%2%
Ear and hearing disorders            
Otitis0%2%1%1%0%2%1%1%0%1%0%0%
White cell and res disorders            
Leukopenia1%2%3%2%0%2%0%2%0%1%0%1%
Lympha-denopathy0%1%1%2%0%2%1%1%0%1%0%1%
Neutropenia0%1%0%1%0%3%0%0%0%1%0%3%
Red blood cell disorders            
Anemia4%4%4%4%1%4%10%5%0%1%0%0%
Heart rate and rhythm disorders            
Tachycardia2%2%0%1%1%1%2%1%1%1%1%1%
Palpitation1%2%0%1%0%3%1%1%0%1%0%1%
Administration / application site disorders            
Injection site infiltration3%2%0%1%0%0%1%0%0%2%0%0%
Collagen disorders            
Arthritis rheumatoid6%7%0%0%0%0%0%0%0%0%0%0%

Infusion-related Reactions

Acute infusion reactions

An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In Phase 3 clinical studies, 18% of infliximab for Injection-treated patients experienced an infusion reaction compared with 5% of placebo-treated patients. Of infliximab for Injection-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 patients discontinued infliximab for Injection because of infusion reactions, and all patients recovered with treatment and/or discontinuation of infusion.

In clinical trials, approximately 3% of infliximab for Injection infusions were accompanied by nonspecific symptoms such as fever or chills, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension or dyspnea), <1% were accompanied by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions occurred in less than 1% of patients and included anaphylaxis, convulsions, erythematous rash and hypotension.

Infliximab for Injection infusions beyond the initial infusion were not associated with a higher incidence of reactions. In psoriatic arthritis (IMPACT 2), infusion reactions were reported in 12% of infliximab for Injection-treated patients compared with 7% of placebo-treated patients. Among the 1376 infliximab for Injection infusions, 2% of these led to an infusion reaction. In plaque psoriasis, infusion reactions were reported in 22% of infliximab for Injection-treated patients compared with 5% of placebo-treated patients. Among the 8366 infliximab for Injection infusions, 5% of these led to an infusion reaction. In the ankylosing spondylitis study ASSERT, infusion reactions were reported in 19% of infliximab for Injection-treated patients compared with 9% of placebo-treated patients. Among the 4257 infliximab for Injection infusions, 2% of these led to an infusion reaction.

In a clinical study of patients with early rheumatoid arthritis (ASPIRE), 66% of all treated 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 infliximab for Injection-treated patients who received at least one shortened infusion of 90 minutes or less at the dose of 3 mg/kg, infusion-related reactions occurred in 19% (48/248) of patients and serious infusion reactions occurred in 0.4% (1/248) of patients. Of the infliximab for Injection-treated patients who received at least one shortened infusion of 90 minutes or less at the dose of 6 mg/kg, infusion-related reactions occurred in 11% (26/246) of patients and serious infusion reactions occurred in 0.4% (1/246) of patients. Shortened infusions at doses >6 mg/kg have not been studied.

In the UC studies ACT 1 and ACT 2 through Week 30, the proportion of subjects with infusion reactions was comparable in the placebo and combined infliximab for Injection treatment groups. Through Week 54, the proportion of subjects with infusion reactions rose and was greater in the combined infliximab for Injection treatment group than in the placebo treatment group (13.4% versus 9.4%, respectively). A greater proportion of subjects in the 10 mg/kg than in the 5 mg/kg infliximab for Injection treatment group (16.1% versus 10.7%) experienced an infusion reaction.

In a clinical study of patients with Crohn’s disease (SONIC), infusion-related reactions occurred in 17% of patients receiving infliximab for Injection monotherapy, 5% of patients receiving infliximab for Injection in combination with azathioprine (AZA) and 6% of patients receiving AZA monotherapy. One patient experienced a serious infusion reaction with infliximab for Injection monotherapy.

Patients who became positive for antibodies to infliximab for Injection were more likely to develop infusion reactions than were those who were negative (approximately 3-fold). Use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab for Injection and infusion reactions (see WARNINGS AND PRECAUTIONS, Immunogenicity and DRUG INTERACTIONS).

In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngeal edema, severe bronchospasm, and seizure have been associated with infliximab for Injection administration (see WARNINGS AND PRECAUTIONS, Neurological Events). Cases of transient visual loss occurring during or within 2 hours of infliximab for Injection infusion have been reported. Cerebrovascular accidents, myocardial ischmemia/infarction (some fatal), and arrhythmia occurring within approximately 24 hours of initiation of infusion have also been reported.

Infusion reactions following readministration of infliximab for Injection

In rheumatoid arthritis, Crohn’s disease and psoriasis clinical trials, readministration of infliximab for Injection 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 infliximab for Injection, 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 readministration of an induction cycle (maximum of four infusions at 0, 2, 6, and 14 weeks) of infliximab for Injection 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, infliximab for Injection treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms (see WARNINGS AND PRECAUTIONS, Immune, Infusion reactions following readministration of infliximab for Injection).

Delayed hypersensitivity/Reactions following readministration of infliximab for Injection

In a clinical study where 37 of 41 patients with Crohn’s disease were retreated with infliximab for Injection following a 2 to 4 year period without infliximab for Injection 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 infliximab for Injection therapy. Of these patients, adverse events occurred in 9 of 23 (39%) who had received liquid formulation which is no longer in use and 1 of 14 (7%) 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 retreatment intervals up to 1 year.

In 3 psoriasis studies, 1% (15/1373) of patients experienced a possible delayed hypersensitivity reaction with symptoms of arthralgia, myalgia, fever, and rash, often early in the treatment course following infliximab for Injection infusions. There were no possible delayed hypersensitivity reactions identified in the psoriatic arthritis study (IMPACT 2) (see WARNINGS AND PRECAUTIONS, Immune, Hypersensitivity Reactions).

Infections

In infliximab for Injection clinical studies, primarily of RA and CD, treated infections were reported in 36% of infliximab for Injection-treated patients (average of 53 weeks of follow-up) and in 28% of placebo treated patients (average of 47 weeks of follow-up). In the ATTRACT I1, study, 60% of Infliximab for Injection-treated RA patients (average of 97 weeks of follow-up) had treated infections reported vs. 43% of placebo-treated patients (average of 75 weeks of follow-up); treated infections were more common with higher doses of infliximab for Injection. In the ASPIRE2 study, 37% of infliximab for Injection-treated RA patients (average of 54 weeks of follow-up) had treated infections reported vs. 30% of placebo-treated patients (average of 52 weeks of follow-up). The infections most frequently reported in the RA studies were respiratory tract infections (including URI, sinusitis, pharyngitis, and bronchitis) and urinary tract infections. No increased risk of serious infections or sepsis was observed with infliximab for Injection compared with placebo in the ATTRACT or ACCENT I3 and II4 studies. However, in the ATTRACT study, the incidence of serious events of pneumonia and lobar pneumonia combined was higher in patients receiving infliximab for Injection plus MTX vs. MTX alone (2.6% vs. 1.2%, respectively). In the ASPIRE study, the incidence of serious pneumonia was also higher in patients receiving infliximab for Injection plus MTX vs. MTX alone (2.5% vs. 0%, respectively). In other RA trials, the incidence of serious infections including pneumonia was higher in infliximab for Injection plus MTX treated patients compared with methotrexate alone, especially at higher than recommended induction regimen of infliximab for Injection 6 mg/kg or greater. Among infliximab for Injection-treated patients, serious infections included pneumonia, cellulitis, abscess and sepsis. In ATTRACT, one patient died with miliary tuberculosis, one died with disseminated coccidioidomycosis and one died due to sepsis. In the ASPIRE study, four patients were diagnosed with tuberculosis. In the ACCENT I study, one patient was diagnosed with tuberculosis. In EXPRESS II5, two patients with psoriasis were diagnosed with tuberculosis. Other cases of tuberculosis, including disseminated tuberculosis, also have been reported post-marketing. Most of the cases of tuberculosis occurred within the first two months after initiation of therapy with infliximab for Injection and may reflect recrudescence of latent disease (see WARNINGS AND PRECAUTIONS, Risk of Infections). In the ACCENT II study, serious infections of nocardiosis (one patient) and cytomegalovirus (one patient) were reported. Twelve percent of patients with fistulising Crohn’s disease developed a new abscess 8 to 16 weeks after the last infusion of infliximab for Injection in the T20 study. In the ACCENT II study, there was no difference between the infliximab for Injection and placebo maintenance arms for proportions of patients with newly diagnosed fistula-related abscesses. In the psoriasis studies, 1.5% of patients (average of 41.9 weeks of follow up) receiving infliximab for Injection and 0.6% of patients (average of 18.1 weeks of follow up) receiving placebo developed serious infections. In EXPRESS6, one patient died due to sepsis. In the IMPACT 27 study of psoriatic arthritis, 1.6% of patients (average 42.8 weeks of follow-up) receiving infliximab for Injection and 2.0% of patients (average 20.2 weeks of follow-up) receiving placebo developed serious infections.

In the infliximab for Injection clinical studies in patients with ulcerative colitis (ACT 1 and ACT 28), the most frequently reported infections were upper respiratory infection (URI), sinusitis, pharyngitis, bronchitis and moniliasis. In the UC studies, infections were reported in 30.6% and 40.1% of infliximab for Injection-treated patients at Week 30 (average 26.9 weeks of follow-up) and at Week 54 (average 41.1 weeks of follow-up) and in 29.5% and 32.8% of placebo-treated patients at Week 30 (average 22.2 weeks of follow up) and at Week 54 (average 32.2 weeks of follow-up). The types of infections, including serious infections, reported in patients with ulcerative colitis were similar to those reported in other clinical studies, and included one case of tuberculosis and a fatal case of histoplasmosis.


1
ATTRACT (the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy)16
2
ASPIRE (the Active-controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset
3
ACCENT I (the Anti-TNF Trial in Long-term Treatment of Moderately to Severely Active Crohn’s Disease)19,20
4
ACCENT II (the Anti-TNF Trial in Long-term Treatment of Fistulising Crohn’s Disease)23
5
EXPRESS II Evaluation of Infliximab for Psoriasis in a REMICADE Efficacy and Safety Study
6
EXPRESS European infliximab for Psoriasis (infliximab) Efficacy and Safety32
7
IMPACT 2 Induction and Maintenance Psoriatic Arthritis Clinical Trial33
8
ACT 1 and ACT 2 (the Anti-TNF Trials in moderately to severely active ulcerative colitis)

 

In post-marketing experience with infliximab for Injection, 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 infliximab for Injection alone or in combination with immunosuppressive agents.

Autoantibodies/Lupus-like Syndrome

Approximately 55% of 1598 infliximab for Injection-treated patients in clinical trials (primarily RA and CD) who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately 20% of 265 placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately 19% of 2116 infliximab for Injection-treated patients compared with 0% of 422 placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.

In the ATTRACT rheumatoid arthritis study through Week 102, 62% of infliximab for Injection-treated patients developed antinuclear antibodies (ANA) between screening and last evaluation, compared with 27% of placebo-treated patients. In the ASPIRE study through Week 58, 66% of
Infliximab for Injection-treated patients developed antinuclear antibodies (ANA) between screening and last evaluation, compared with 21% of placebo-treated patients. In both RA studies, anti-dsDNA antibodies developed in approximately 15% of infliximab for Injection-treated patients, compared to none of the placebo-treated patients. No association was seen between infliximab for Injection dose/schedule and development of ANA or anti-dsDNA antibodies.

Of Crohn’s disease patients treated with infliximab for Injection who were evaluated for antinuclear antibodies (ANA), 40% developed ANA between screening and last evaluation. Anti-dsDNA antibodies developed in approximately 20% of Crohn’s disease patients treated with infliximab for Injection.  The development of anti-dsDNA antibodies was not related to either the dose or duration of infliximab for Injection treatment. However, baseline therapy with an immunosuppressant in Crohn’s disease patients was associated with reduced development of anti-dsDNA antibodies (3% compared to 21% in patients not receiving any immunosuppressant). Crohn’s disease patients were approximately 2 times more likely to develop anti-dsDNA antibodies if they were ANA-positive at study entry.

In the EXPRESS plaque psoriasis study through Week 50, 59% of infliximab for Injection-treated patients developed antinuclear antibodies following infliximab for Injection treatment compared to 2% of placebo-treated patients. Anti-dsDNA antibodies developed in 16% of infliximab for Injection-treated patients, compared to none of the placebo-treated patients. In the EXPRESS II plaque psoriasis study through Week 50, 65% of infliximab for Injection-treated patients developed antinuclear antibodies following infliximab for Injection treatment compared to 8% of placebo-treated patients. Anti-dsDNA antibodies developed in 27% of infliximab for Injection-treated patients, compared to none of the placebo-treated patients. No association was seen between infliximab for Injection dose/schedule and development of ANA or anti-dsDNA antibodies.

In the IMPACT 2 psoriatic arthritis study through Week 66, 59% of infliximab for Injection-treated patients developed antinuclear antibodies following infliximab for Injection treatment compared to 11% of placebo-treated patients. Anti-dsDNA antibodies developed in 12% of infliximab for Injection-treated patients, compared to none of the placebo-treated patients.

In the ASSERT ankylosing spondylitis study through week 102, 35% of infliximab for Injection-treated patients developed antinuclear antibodies following infliximab for Injection treatment compared to 1% of placebo-treated patients. Anti-dsDNA antibodies developed in 30% of infliximab for Injection-treated patients, compared to none of the placebo-treated patients.

In clinical studies, 22 patients were diagnosed with a possible lupus-like syndrome, four with Crohn’s disease, eight patients with plaque psoriasis [seven (0.5%) patients treated with infliximab for Injection and one (0.3%) patient treated with placebo], 8 patients with ankylosing spondylitis, and two with rheumatoid arthritis. Twenty-one patients improved following discontinuation of therapy and/or appropriate medical treatment. One psoriasis patient on concomitant hydralazine had central nervous system involvement. No patients had renal involvement. No cases of lupus-like syndromes were reported in the psoriatic arthritis studies. The lupus-like syndrome in one patient with rheumatoid arthritis and one patient with ankylosing spondylitis remained ongoing at the end of the study. One case of a lupus-like reaction has been observed in a Crohn’s disease patient in up to three years of long-term follow-up (see WARNINGS AND PRECAUTIONS, Autoimmunity).

Hepatobiliary Events

In post-marketing surveillance, cases of jaundice and hepatitis, some with features of autoimmune hepatitis, have been reported in patients receiving infliximab for Injection (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving infliximab for Injection without progression to severe hepatic injury. Elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving infliximab for Injection than in controls, both when infliximab for Injection was given as monotherapy and when it was used in combination with other immunosuppressive agents. 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 infliximab for Injection, or modification of concomitant medications.

Malignancies/Lymphoproliferative Disease

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

In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF-blocker compared with control patients. In the controlled and open-label portions of infliximab for Injection clinical trials, 5 patients developed lymphomas among 5780 patients treated with infliximab for Injection (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In rheumatoid arthritis patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately 3-fold higher than expected in the general population. In the combined clinical trial population for rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, psoriasis, ankylosing spondylitis, and ulcerative colitis, 5 lymphomas were observed for a rate of 0.09 cases per 100 patient-years of follow-up, which is approximately 4-fold higher than expected in the general population. Patients with Crohn’s disease 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.

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

Among the 345 patients who received infliximab for Injection in ankylosing spondylitis trials, 3 patients developed malignancies (1 patient had a squamous cell and a basal cell carcinoma, 1 patient had a pulmonary carcinoma, and 1 patient had breast cancer). Additionally, 1 patient in ASSERT developed a nonseminoma testicular carcinoma after leaving the trial, approximately 1 year after his last dose of infliximab for Injection.

In the IMPACT 2 study of psoriatic arthritis, 2 malignancies were reported through Week 54 (Stage I Hodgkin’s lymphoma in an infliximab for Injection-treated patient and basal cell carcinoma in a placebo-treated patient). No malignancies were reported through Week 50 of IMPACT. An adenocarcinoma of the pancreas was reported 2 months after completing the year 2 extension of IMPACT.

During the infliximab for Injection plaque psoriasis trials, no patients developed lymphoma. In the placebo-controlled portions of the psoriasis studies, 7 of 1123 patients who received infliximab for Injection at any dose (443 patient-years) were diagnosed with a nonmelanoma skin cancer (NMSC) compared to 0 of 334 patients who received placebo (113 patient-years). Among the 1373 patients with psoriasis who received infliximab for Injection at any dose in the controlled and uncontrolled portions of the psoriasis studies (1101 patient-years), a total of 17 were diagnosed with NMSC (12 basal cell cancers, 5 squamous cell cancers). The size of the placebo group and limited duration of the controlled portions of studies precludes the ability to draw firm conclusions. Patients on infliximab for Injection should be monitored for the development of NMSC. Two noncutaneous malignancies (breast cancer and adenocarcinoma) were reported during the psoriasis clinical trials.

A population-based retrospective cohort study found an increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab for Injection compared to biologics-naïve patients or the general population, including those over 60 years of age.

Congestive Heart Failure

In a phase II study evaluating infliximab for Injection in NYHA Class III/IV CHF patients (left ventricular ejection fraction ≤35%), higher incidences of mortality and hospitalization due to worsening heart failure were seen in infliximab for Injection-treated patients, especially those treated with 10 mg/kg. One hundred and fifty patients were treated with 3 infusions of infliximab for Injection 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At 28 weeks, 4 of 101 patients treated with infliximab for Injection (1 at 5 mg/kg and 3 at 10 mg/kg) died compared with no deaths among the 49 placebo-treated patients. In follow-up, at 38 weeks, 9 patients treated with infliximab for Injection (2 at 5 mg/kg and 7 at 10 mg/kg) died compared with one death among the placebo-treated patients. At 28 weeks, 14 of 101 patients treated with infliximab for Injection (3 at 5 mg/kg and 11 at 10 mg/kg) were hospitalized for worsening CHF compared with 5 of the 49 placebo-treated patients (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Cardiovascular).

There have also been 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.

Less Common Clinical Trial Adverse Drug Reactions

Other medically relevant adverse events occurring at a frequency <1% were as follows, presented by body system:

Administration / application site: injection site inflammation, injection site ecchymosis, injection site swelling, injection site infection
Autonomic Nervous System: fecal incontinence
Body as a whole: anaphylactoid reaction, diaphragmatic hernia, generalized edema, surgical/procedural sequela, substernal chest pain, rigors
Blood: pancytopenia, splenomegaly
Cardiovascular: circulatory failure, hypotension postural, pallor
Collagen: LE syndrome, anti-DNA antibodies, positive antinuclear factor test
Ear and Hearing: otitis externa
Endocrine: adrenal insufficiency, hypothyroidism
Eye and Vision: lacrimation abnormal, iritis, scleritis, eye pain, glaucoma
Gastrointestinal: ileus, intestinal stenosis, pancreatitis, peritonitis, rectal hemorrhage, appetite increased, anal fistula, diarrhea bloody, gastritis, intestinal obstruction, intestinal perforation
Central & Peripheral Nervous: meningitis, neuritis, optic neuritis, peripheral neuropathy, neuralgia, ataxia, dysesthesia, tremor, hyperkinesia
Heart Rate and Rhythm: arrhythmia, bradycardia, cardiac arrest, palpitations
Liver and Biliary: cholelithiasis, hepatitis, bilirubinemia, cholecystitis, hepatocellular damage, elevated GGT, fatty liver, hepatomegaly
Metabolic and Nutritional: hypercholesterolemia
Musculoskeletal: intervertebral disk herniation, tendon disorder, joint stiffness
Myo-, Endo-, Pericardial and Coronary Valve: myocardial infarction, mitral insufficiency, heart murmur, cardiac failure
Platelet, Bleeding and Clotting: thrombocytopenia
Neoplasms: adenocarcinoma, basal cell carcinoma, breast cancer, lymphoma, malignant melanoma, squamous cell carcinoma, bladder carcinoma, rectal carcinoma, uterine cancer, pulmonary carcinoma
Psychiatric: confusion, suicide attempt, irritability, nervousness, amnesia
Red Blood Cell: iron deficiency anemia, hemolytic anemia
Reproductive: menstrual irregularity, dysmenorrhea, menorrhagia, breast fibroadenosis, amenorrhea, female breast pain
Resistance Mechanism: sepsis, serum sickness, tuberculosis, fungal infection, viral infection, sarcoid-like reaction
Respiratory: Adult respiratory distress syndrome, respiratory tract infection, pleural effusion, lobar pneumonia, pulmonary edema, respiratory insufficiency, bronchospasm, asthma, hemoptysis, epistaxis, laryngitis
Skin and Appendages: erythema nodosum, rash maculopapular, rash pustular, photosensitivity reaction, edema periorbital, fascitis
Special Senses, Other: taste perversion, taste loss
Urinary: renal failure, dysuria, renal calculus, pyelonephritis
Vascular (Extracardiac): brain infarction, thrombophlebitis, vasculitis, brain ischemia, pulmonary embolism
White Cell and Reticuloendothelial: neutropenia, neutrophilia, lymphocytosis

Abnormal Hematologic and Clinical Chemistry Findings

Serious, medically relevant hematologic adverse events ≥0.2%, or clinically relevant hematologic adverse reactions observed in clinical trials include: pancytopenia, thrombocytopenia, anemia, hemolytic anemia, neutropenia and leukopenia.

The proportion of patients with abnormal ALT levels in response to infliximab for Injection is presented in Table 3.

Table 3: Proportion of patients with elevated ALT in infliximab for Injection Clinical Trials
1
Note that placebo patients received methotrexate while infliximab for Injection patients received both infliximab for Injection and methotrexate. Median follow-up was 58 weeks for placebo patients and infliximab for Injection-treated patients. RA trials include ATTRACT (T22) and ASPIRE (T29).
2
Note that placebo patients in 2 of the 3 Phase III trials in Crohn’s disease, ACCENT I and ACCENT II, received an initial dose of 5 mg/kg infliximab for Injection at study start and were on placebo in the maintenance phase. Patients who were randomized to the placebo maintenance group and then later crossed over to infliximab for Injection are included in the infliximab for Injection group in this table. Median follow-up time was 54 weeks. In SONIC, placebo patients received AZA 2.5 mg/kg/day.
3
Ulcerative colitis trials include ACT I (C0168T37) through Week 54 and ACT II (C0168T46) through Week 30; median duration of follow up was 30.8 weeks for the infliximab for Injection group and 30.1 weeks for placebo group.
4
IMPACT 2 median duration of follow up was 39.1 weeks for the infliximab for Injection group and 18.1 weeks for placebo group.
5
EXPRESS and EXPRESS II median duration of follow up was 16.1 weeks for placebo and 50.1 weeks for infliximab for Injection groups.
6
Patients from the ASSERT trial (T51); median duration of follow-up was 24.1 weeks for placebo and 101.9 weeks for the infliximab for Injection group.
 Proportion of patients with elevated ALT
 >1 to <3 X ULN3 X ULN5 X ULN
 Placeboinfliximab for InjectionPlaceboinfliximab for InjectionPlaceboinfliximab for Injection
Rheumatoid arthritis124.0%34.4%3.2%3.9%0.8%0.9%
Crohn’s disease224.1%34.9%2.2%4.9%0.0%1.5%
Ulcerative colitis312.4%17.4%1.2%2.5%0.4%0.6%
Psoriatic arthritis416.3%49.5%0.0%6.8%0.0%2.1%
Plaque psoriasis523.8%49.4%0.4%7.7%0.0%3.4%
Ankylosing spondylitis614.5%51.1%0.0%9.5%0.0%3.6%

The difference in rates of ALT elevations ≥3 X ULN between infliximab for Injection and placebo treatment groups tended to be greater in ankylosing spondylitis, psoriasis and psoriatic arthritis clinical trials than in rheumatoid arthritis, Crohn’s disease and ulcerative colitis clinical trials. See Hepatobiliary Events.

Post-Market Adverse Drug Reactions

Additional adverse events, some with fatal outcome, reported from worldwide post-marketing experience with infliximab for Injection are included in Table 4 (see ADVERSE REACTIONS, Infections and Infusion-related Reactions). 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 infliximab for Injection exposure.

Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with infliximab for Injection with the vast majority of cases occurring in Crohn’s disease and ulcerative colitis, most of whom were adolescent or young adult males (see WARNINGS AND PRECAUTIONS, Carcinogenesis and Mutagenesis, Hepatosplenic T-cell Lymphoma).

Hemophagocytic lymphohistiocytosis (HLH) has been very rarely reported in patients treated with infliximab for Injection.

Table 4: POST-MARKETING REPORTS
*
including bovine tuberculosis (disseminated BCG inflection), see WARNINGS AND PRECAUTIONS, Live Vaccines/Therapeutic Infectious Agents
Blood and Lymphatic System Disordersagranulocytosis (including infants exposed in utero to infliximab for Injection), idiopathic thrombocytopenic purpura, hemolytic anemia, pancytopenia, thrombotic thrombocytopenic purpura
General Disorders and Administration Site Conditionsanaphylactic reactions, anaphylactic shock, infusion-related reactions, serum sickness
Cardiac Disorderspericardial effusion, myocardial ischemia/myocardial infarction (within 24 hours of initiation of infusion), arrhythmia (within 24 hours of initiation of infusion)
Eye DisordersTransient visual loss occurring during or within 2 hours of infusion
Immune System Disordersvasculitis, sarcoidosis
Neoplasm Benign and Malignanthepatosplenic T-cell lymphoma (the vast majority in Crohn’s disease and ulcerative colitis: primarily adolescents and young adults), pediatric malignancy, leukemia, melanoma, Merkel cell carcinoma, cervical cancer
Hepatobiliary System Disordershepatocellular damage, hepatitis, jaundice, autoimmune hepatitis, liver failure
Nervous System Disorderscentral nervous system demyelinating disorders (such as multiple sclerosis and optic neuritis), peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy), neuropathies, numbness, seizure, tingling, transverse myelitis, cerebrovascular accidents occurring within approximately 24 hours of initiation of infusion
Infections and Infestationsopportunistic infections (such as aspergillosis, atypical mycobacteria, coccidioidomycosis, cryptococcosis, candidiasis, histoplasmosis, legionellosis, listeriosis, pneumocystosis), salmonellosis, sepsis tuberculosis, protozoal infections, hepatitis B reactivation and vaccine breakthrough infection (after in utero exposure to infliximab for Injection)*
Respiratory, Thoracic and Mediastinal Disordersinterstitial lung disease, including pulmonary fibrosis/interstitial pneumonitis, and rapidly progressive disease
Skin and Subcutaneous Tissue Disordersvasculitis (primarily cutaneous) , psoriasis including new onset and pustular (primarily palmar/plantar), erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis

Drug Interactions

Overview

Specific drug interaction studies have not been conducted. The majority of patients in rheumatoid arthritis, Crohn’s disease or ulcerative colitis clinical trials received one or more concomitant medications. In rheumatoid arthritis, concomitant medications besides MTX were nonsteroidal anti-inflammatory agents, folic acid, corticosteroids and/or narcotics. Concomitant Crohn’s disease medications were antibiotics, antivirals, corticosteroids, 6-mercaptopurine/azathioprine (6-MP/AZA), methotrexate (MTX), and aminosalicylates. Patients with Crohn’s disease who received immunosuppressants tended to experience fewer infusion reactions compared to patients using no immunosuppressants (see WARNINGS AND PRECAUTIONS, Immunogenicity and ADVERSE REACTIONS, Infusion-related Reactions).

Drug-Drug Interactions

Concurrent Use of INFLECTRA® with other Biological Therapeutics

The combination of INFLECTRA® with other biological therapeutics used to treat the same conditions as INFLECTRA®, including anakinra or abatacept, is not recommended (see WARNINGS AND PRECAUTIONS, Risk of Infections).

Live Vaccines/Therapeutic Infectious Agents

It is recommended that live vaccines not be given concurrently with INFLECTRA®. It is also recommended that live vaccines not be given to infants after in utero exposure to infliximab for Injection for at least 6 months following birth (see WARNINGS AND PRECAUTIONS).

It is recommended that therapeutic infectious agents not be given concurrently with INFLECTRA® (see WARNINGS AND PRECAUTIONS).

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 for Injection, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of INFLECTRA® 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.

Interactions with other drugs have not been established.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Dosage And Administration

Recommended Dose and Dose Adjustment

For recommended infusion duration for patients with each of the indications described below, see DOSAGE AND ADMINISTRATION, Preparation and Administration Instructions.

Rheumatoid Arthritis
The recommended dose of INFLECTRA® (infliximab for Injection) is 3 mg/kg given as an intravenous infusion followed by additional 3 mg/kg doses at 2 and 6 weeks after the first infusion then every 8 weeks thereafter. INFLECTRA® should be given in combination with methotrexate.

Ankylosing Spondylitis
The recommended dose of INFLECTRA® is 5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg doses at 2 and 6 weeks after the first infusion, then every 6 to 8 weeks thereafter.

Ulcerative Colitis (Adult):
The recommended dose of INFLECTRA® is 5 mg/kg given as an induction regimen at 0, 2 and 6 weeks followed by 5 mg/kg every 8 weeks thereafter, for the treatment of adult patients with moderately to severely active ulcerative colitis. In some adult patients, consideration may be given to adjusting the dose up to 10 mg/kg to sustain clinical response and remission. Some adult patients may not benefit from dose escalation. In addition to the physician’s clinical assessment, measurement of infliximab for Injection trough levels and titers of antibodies to infliximab for Injection should be taken into account before considering dose adjustment.

Crohn’s Disease (Adult):
The recommended dose of INFLECTRA® is 5 mg/kg given as an 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 moderate to severe, active Crohn’s disease. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10 mg/kg. Some adult patients may not benefit from dose escalation. In addition to the physician’s clinical assessment, measurement of infliximab for Injection trough levels and titers of antibodies to infliximab for Injection should be taken into account before considering dose adjustment.

The recommended dose of INFLECTRA® is 5 mg/kg given as an 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 fistulising Crohn’s disease. Patients who do not respond by Week 14 are unlikely to respond with continued dosing and consideration should be given to discontinue INFLECTRA® in these patients. For patients who respond and then lose their response, consideration may be given to treatment with 10 mg/kg. In the ACCENT II clinical study, among patients who lost response at 5 mg/kg infliximab for Injection and re-established response following dose escalation to 10 mg/kg infliximab for Injection, most had done so after 1 dose and all had done so after 2 doses of 10 mg/kg.

Psoriatic Arthritis
The recommended dose of INFLECTRA® is 5 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. INFLECTRA® can be used with or without methotrexate. If a patient shows no response at 24 weeks, no additional treatment with INFLECTRA® should be given.

Plaque Psoriasis
The recommended dose of INFLECTRA® is 5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. If a patient does not show an adequate response at Week 14, after infusions at weeks 0, 2, and 6, no additional treatment with INFLECTRA® should be given.

The infusion solution must be administered over a period of not less than 2 hours. All patients administered INFLECTRA® should be observed for at least 1 to 2 hours post-infusion for side effects. Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be available (see ADVERSE REACTIONS, Infusion-related Reactions).

The INFLECTRA Patient Assistance Program facilitates the administration of INFLECTRA®. The INFLECTRA Patient Assistance Program clinics are staffed by qualified healthcare professionals specially trained in the administration of INFLECTRA® infusions and are available across Canada. Information about the Inflectra Patient Assistance Program can be obtained by calling 1-844-466-6627.

Reconstitution:

Vial SizeVolume of Diluent to be Added to VialApproximate Available VolumeNominal Concentration per mL
100 mg as lyophilized powder

10 mL Sterile Water for Injection, USP
 

The total dose of the reconstituted product must be further diluted to 250 mL with 0.9% Sodium Chloride Injection, USP

250 mLBetween 0.4 mg/mL and 4 mg/mL

Since no preservative is present, it is recommended that the INFLECTRA® infusion be started within 3 hours of reconstitution and dilution.

Preparation and Administration Instructions

Use aseptic technique.

INFLECTRA® vials do not contain antibacterial preservatives. Therefore, after reconstitution, the vials should be used immediately, not re-entered or stored. The diluent to be used for reconstitution is 10 mL of Sterile Water for Injection, USP. The total dose of the reconstituted product must be further diluted to 250 mL with 0.9% Sodium Chloride Injection, USP. The infusion concentration should range between 0.4 mg/mL and 4 mg/mL. Since no preservative is present, it is recommended that the INFLECTRA® infusion be started within 3 hours of reconstitution and dilution.
 

  1. Calculate the dose and the number of INFLECTRA® vials needed. Each INFLECTRA® vial contains 100 mg of infliximab. Calculate the total volume of reconstituted INFLECTRA® solution required.
     
  2. Reconstitute each INFLECTRA® vial with 10 mL of Sterile Water for Injection, USP, using a syringe equipped with a 21-gauge or smaller needle. Remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the centre 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 solution should be colourless to light yellow and opalescent, and the solution may develop a few 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 INFLECTRA® solution dose to 250 mL with 0.9% Sodium Chloride Injection, USP, by withdrawing a volume of 0.9% Sodium Chloride Injection, USP, equal to the volume of reconstituted INFLECTRA® from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or bag. Slowly add the total volume of reconstituted INFLECTRA® solution to the 250 mL infusion bottle or bag. Gently mix.
     
  4. For patients with Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, the infusion solution must be administered 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 INFLECTRA®. At the discretion of the treating physician, some patients with rheumatoid arthritis who have tolerated 3 initial 2-hour infusions of INFLECTRA® may be considered for receiving subsequent infusions at the same dose over a period of not less than 1 hour (see CLINICAL TRIALS, Rheumatoid Arthritis and ADVERSE REACTIONS, Infusion-Related Reactions). The safety of shortened infusions at doses >6 mg/kg has not been studied.

    Use only an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 μm or less). Any unused portion of the infusion solution should not be stored for reuse.
     
  5. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. If visibly opaque particles, discolouration or other foreign particulates are observed, the solution should not be used.
     
  6. No physical biochemical compatibility studies have been conducted to evaluate the coadministration of INFLECTRA® with other agents. INFLECTRA® should not be infused concomitantly in the same intravenous line with other agents.

Overdosage

Single doses of the reference product up to 20 mg/kg have been administered without any direct toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects. Appropriate symptomatic treatment should be instituted immediately.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action And Clinical Pharmacology

Mechanism of Action

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

Infliximab for Injection neutralizes the biological activity of TNFα by binding with high affinity to the soluble and transmembrane forms of TNFα and inhibits binding of TNFα with its receptors.7-9 Infliximab for Injection does not neutralize TNFβ (lymphotoxin α), a related cytokine that utilises 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, and induction of acute phase reactants and other liver proteins.10 Cells expressing transmembrane TNFα bound by infliximab for Injection can be lysed in vitro by complement or effector cells.8 Infliximab for Injection inhibits the functional activity of TNFα in a wide variety of in vitro bioassays utilising human fibroblasts, endothelial cells, neutrophils,7 B and T lymphocytes,11,12 and epithelial cells. Anti-TNFα antibodies reduce disease activity in a cotton-top tamarin colitis model13 and decrease synovitis and joint erosions in a murine model of collagen-induced arthritis. Infliximab for Injection prevents disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFα, and, when administered after disease onset, facilitates eroded joints to heal.

Pharmacodynamics

PRECLINICAL

Infliximab for Injection binds to the soluble and transmembrane forms of TNFα with high affinity and blocks the interaction of TNFα with its receptors, thereby neutralising the biological activity of TNFα.7-8 Cells expressing transmembrane TNFα can be lysed in vitro by complement or effector cell-mediated mechanisms after infliximab for Injection binds.8 Infliximab for Injection inhibits the functional activity of TNFα in a wide variety of in vitro bioassays utilising human fibroblasts, endothelial cells, neutrophils,9 B and T lymphocytes,11-12 and epithelial cells.12

Infliximab for Injection specifically neutralises TNFα-induced cell cytotoxicity but not lymphotoxin α.8 Lymphotoxin α is a cytokine that shares 30% homology with TNFα and utilises the same receptors as TNFα. Species cross-reactivity of infliximab for Injection is limited to human and chimpanzee TNFα. In vivo, infliximab for Injection rapidly forms stable complexes with human TNFα, a process that parallels the loss of TNFα bioactivity.

In a transgenic mouse (Tg197) that constitutively expresses human TNFα, infliximab for Injection administered twice weekly at 5 mg/kg or once weekly at 10 mg/kg prevents the development of polyarthritis by Week 10, demonstrating that infliximab for Injection neutralises TNFα in vivo.

CLINICAL

Elevated concentrations of TNFα have been found in the joints of rheumatoid arthritis patients15 in the joints of psoriatic arthritis patients and in the skin lesions of plaque psoriasis patients, and in the stools of Crohn’s disease and ulcerative colitis patients. This correlates with elevated disease activity.15 In rheumatoid arthritis, treatment with infliximab for Injection 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].15 In Crohn’s disease, treatment reduces infiltration of inflammatory cells and TNFα production in inflamed areas of the intestine, and reduces the proportion of mononuclear cells in the lamina propria able to express TNFα and interferon γ ex vivo.15 After treatment with the reference product, patients with rheumatoid arthritis or Crohn’s disease exhibited decreased levels of serum IL-6 and C-reactive protein compared to baseline. Peripheral blood lymphocytes from infliximab for Injection-treated patients showed no decrease in proliferative responses to in vitro mitogenic stimulation when compared to cells from untreated patients. In psoriatic arthritis, treatment with infliximab for Injection 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. Infliximab for Injection treatment alters the histopathological features of plaque psoriasis as demonstrated in lesional skin biopsies collected at baseline, day 3 and Week 10 following initiation of treatment. Infliximab for Injection treatment reduced epidermal thickness and infiltration of inflammatory cells, downregulated the percentage of activated and cutaneous lymphocyte antigen (CLA)-positive inflammatory cells, including CD3-, CD4-, and CD8-positive lymphocytes, and upregulated the percentage of CD1a-positive epidermal Langerhans cells. In ulcerative colitis, treatment with infliximab for Injection showed changes consistent with histological healing and decreased expression of pharmacodynamic markers of tissue injury and inflammation in colonic biopsies. Treatment with infliximab for Injection also decreased serum levels of the proinflammatory molecules with statistically significant and consistent decreases observed for IL-2R, and ICAM-1. In patients with ankylosing spondylitis, infliximab for Injection was more effective at decreasing levels of serum markers of inflammation (IL-6 and VEGF) at both weeks 2 and 24 than placebo. In addition, serum levels of markers of bone formation (bone alkaline phosphatase and osteocalcin) were increased at both weeks 2 and 24 in patients with ankylosing spondylitis treated with infliximab for Injection compared with patients receiving placebo.

Pharmacokinetics

Single intravenous infusions of 1 to 20 mg/kg showed a linear relationship between the dose administered and the maximum serum concentration. The volume of distribution at steady state was independent of dose and indicated that infliximab for Injection was distributed primarily within the vascular compartment. Median pharmacokinetic results for the 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 terminal half-life of infliximab for Injection is approximately 7.7 to 10 days. The terminal half-life in ulcerative colitis trials was 12.3 to 14.7 days.

 Rheumatoid ArthritisCrohn’s Disease
StudyT09
(n=14)
T09
(n=29)
T11
(n=5)
T11
(n=5)
Dose3 mg/kg10 mg/kg5 mg/kg10 mg/kg
Cmax (μg/mL)77.327774.9181.0
AUC (μg/day/mL)46122827882038
CL (mL/day/kg)6.44.46.34.9
Vss (mL/kg)67.557.28065
t1/2(day)89.17.810

Absorption: Infliximab for Injection is administered intravascularly and thus has no absorption profile.

Distribution: Infliximab for Injection is primarily distributed into the blood, its apparent median steady state volume of distribution of 57.2 to 80 mL/kg estimated to 4.0 to 5.60 litres in a 70 kg individual corresponds to the total blood volume.

Metabolism: It is believed that infliximab for Injection is metabolized in a similar manner to other proteins in the body. It is probably hydrolysed into its component amino acids and recycled or catabolized.

Excretion: Infliximab for Injection as a whole molecule was not detected in the urine after its intravenous infusion.

Following an initial dose of infliximab for Injection, repeated infusions at 2 and 6 weeks resulted in predictable concentration-time profiles following each treatment. No systemic accumulation of infliximab for Injection occurred upon continued repeated treatment with 3 mg/kg or 10 mg/kg at 4- or 8-week intervals in rheumatoid arthritis patients or patients with moderate or severe Crohn’s disease retreated with 4 infusions of 10 mg/kg infliximab for Injection at 8-week intervals. No systemic accumulation of infliximab for Injection occurred upon continued repeated treatment with 3 mg/kg or 5 mg/kg at 8-week intervals in patients with psoriatic arthritis or plaque psoriasis. The proportion of patients with rheumatoid arthritis who had undetectable infliximab for Injection concentrations at 8 weeks following an infusion was approximately 25% for those receiving 3 mg/kg every 8 weeks, 15% for patients administered 3 mg/kg every 4 weeks, and 0% for patients receiving 10 mg/kg every 4 or 8 weeks. At steady state, the proportion of patients with plaque psoriasis who had undetectable infliximab for Injection concentrations at 8 weeks following an infusion ranged from 71.4% to 73.1% for patients receiving 3 mg/kg every 8 weeks (EXPRESS II), and from 25.9% to 46.4% for those administered 5 mg/kg every 8 weeks (EXPRESS and EXPRESS II). The proportion of patients with psoriatic arthritis who had undetectable infliximab for Injection concentrations was 15.8% at Week 38 when administered 5 mg/kg every 8 weeks (IMPACT 2). In IMPACT 2, approximately half of the patients received concomitant MTX.

Special populations

No major differences in clearance or volume of distribution were observed in patient subgroups defined by age. It is not known if gender differences, genetic polymorphism, renal insufficiency or hepatic insufficiency have effects on clearance or volume of distribution of infliximab for Injection.

Storage And Stability

Store the lyophilized product under refrigeration between 2 °C and 8 °C (36 °F to 46 °F). Do not use beyond the expiration date. This product contains no preservative. Since no preservative is present, it is recommended that the administration of the infusion solution should begin within 3 hours of reconstitution and dilution.

Special Handling Instructions

Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 24 hours at room temperature (25 °C). Diluted INFLECTRA® infusion solution is stable for 48 hours when stored between 5±3 °C and 30±2 °C/65±5% RH. If the infusion solution is not used immediately (i.e., within 3 hours of preparation), the in-use storage times and conditions prior to its use are the responsibility of the user and would not normally be longer than 24 hours between 2 °C and 8 °C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions.

Dosage Forms, Composition And Packaging

INFLECTRA® (infliximab for Injection) is supplied as a sterile white lyophilized powder for intravenous infusion. Each vial contains 100 mg infliximab, 500 mg sucrose, 0.5 mg polysorbate 80, 2.2 mg sodium dihydrogen phosphate monohydrate and 6.1 mg di-sodium hydrogen phosphate dihydrate. No preservatives are present.

INFLECTRA® (infliximab for Injection) lyophilized concentrate for IV injection is supplied in individually boxed single-use vials in the following strength: 100 mg infliximab for Injection.

 

Control #: 218146
August 24, 2018

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