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INFLECTRA (infliximab for Injection)

Indications

Indications have been granted on the basis of similarity between INFLECTRA® and the reference biologic drug REMICADE®.

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.
  • the 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.
  • reduction of signs and symptoms and induction and maintenance of clinical remission in pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy (corticosteroid and/or aminosalicylate and/or immunosuppressant). The safety and efficacy of INFLECTRA® is not established in patients less than 9 years of age.
  • 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 and maintenance of clinical remission, and induction of mucosal healing in pediatric 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). The safety and efficacy of INFLECTRA® have not been established in patients less than 6 years of age.
  • 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®.

Pediatrics

INFLECTRA® is indicated for reducing signs and symptoms and for inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. INFLECTRA® is also indicated for reducing signs and symptoms, inducing and maintaining clinical remission and inducing mucosal healing in pediatric 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). In general, the adverse events in pediatric patients with Crohn’s disease or ulcerative colitis who received infliximab for injection were similar to those seen in adult patients with Crohn’s disease or ulcerative colitis respectively. It should be noted that in the Phase 3 trial (REACH) of pediatric patients with Crohn’s disease, all patients were required to be on a stable dose of either 6-mercaptopurine (6-MP), azathioprine (AZA), or methotrexate (MTX). (See INDICATIONS; WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics; ADVERSE REACTIONS, Adverse Reactions in Pediatric Patients, Crohn’s Disease, Adverse Reactions in Pediatric Patients, Ulcerative Colitis; DOSAGE AND ADMINISTRATION; and CLINICAL TRIALS - REFERENCE BIOLOGIC DRUG).

The safety and efficacy of infliximab for injection has not been established in pediatric patients with Crohn’s disease <9 years of age or with ulcerative colitis <6 years of age. The safety and efficacy of infliximab for injection in pediatric patients with plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and in juvenile rheumatoid arthritis have not been established.

Geriatrics (≥ 65years 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).

Contraindications

INFLECTRA® is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging.

  • 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, Cardiovascularand ADVERSE REACTIONS, Congestive Heart Failure).
  • Patients with history of hypersensitivity to infliximab for injection, to other murine proteins, or to any excipients. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section of the product monograph.

Serious Warnings And Precautions Box

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. 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
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).

Dosage And Administration

Recommended Dose and Dosage Adjustment

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

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. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10 mg/kg and/or treating as often as every 4 weeks. Duration of treatment needed to achieve a response after dose escalation is not known. However, higher doses of INFLECTRA® were associated with a slightly higher proportion of patients experiencing adverse events (97% for the 3 mg/kg dose given every 8 weeks vs. 100% for the 10 mg/kg dose given every 4 weeks), including infections (84% for the 3 mg/kg dose given every 8 weeks vs. 91% for the 10 mg/kg dose given every 4 weeks).

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
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 and pediatric patients (≥ 6 years of age) 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 trough levels and titers of antibodies to infliximab should be taken into account before considering dose adjustment.

Crohn’s Disease
Adults
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 trough levels and titers of antibodies to infliximab 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 iInjection 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.

Pediatric
The recommended dose of INFLECTRA® for pediatric patients (≥ 9 years of age) with moderately to severely active Crohn’s disease 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. 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.

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.

Special Populations

Renal Impairment

Infliximab for injection has not been studied in patients with renal impairment. No dose recommendations can be made (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations).

Hepatic Impairment

Infliximab for injection has not been studied in patients with hepatic impairment. No dose recommendations can be made (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations).

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.

Administration

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 - REFERENCE BIOLOGIC DRUG, 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). Do not store any unused portion of the infusion solution.

  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 co-administration of INFLECTRA® with other agents. INFLECTRA® should not be infused concomitantly in the same intravenous line with other agents.

Reconstitution

Table - Reconstitution

Vial Size

Volume of Diluent to be Added to Vial

Approximate Available Volume

Nominal Concentration per mL

100 mg as lyophilized powder

10 mL Sterile Water for Injection, USP

250 mL

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

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 unless the INFLECTRA® infusion is prepared under controlled and validated aseptic conditions (see STORAGE, STABILITY and DISPOSAL and SPECIAL HANDLING INSTRUCTIONS).

Missed Dose

It is important to receive each scheduled dose of this medication as directed. If patients who forget or miss an appointment, contact your doctor as soon as possible to establish a new dosing schedule.

Overdosage

Single doses of the infliximab for injection 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.

Dosage Forms, Strengths, Composition And Packaging

To help ensure the traceability of biologic products, including biosimilars, health professionals should recognise the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table – Dosage Forms, Strengths, Composition and Packaging

Route of Administration

Dosage Form / Strength/Composition

Non-medicinal Ingredients

Intravenous Infusion

Powder for Solution / 100 mg/vial

Di-sodium hydrogen phosphate dihydrate, polysorbate 80, sodium dihydrogen phosphate monohydrate, sucrose

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.

Description

INFLECTRA®(infliximab for Injection) is a biosimilar 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.

Warnings And Precautions

Please see the Serious Warnings and Precautions Box at the beginning of Part I: Health Professional Information.

Risk of Infections

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, loss of detectable serum concentrations of infliximab, 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, infliximab for injection 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 infliximabfor 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 (see WARNINGS AND PRECAUTIONS, Hypersensitivity Reactions). 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 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 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 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), although among patients with juvenile rheumatoid arthritis antibody development occurred in a high percentage of patients receiving 3 mg/kg infliximab for injection with concomitant MTX (see Adverse Reactions in Pediatric Patients, Juvenile Rheumatoid Arthritis).

With repeated dosing of infliximab for injection, serum concentrations of infliximab 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 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.

Vaccinations

It is recommended that all patients, if possible, be brought up to date with all vaccinations in agreement with current vaccination guidelines prior to initiating INFLECTRA® therapy.

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 INFLECTRA® 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 INFLECTRA®.

Non-Live Vaccines

In a subset of patients from the ASPIRE study, a similar proportion of patients in each treatment group mounted an effective two-fold increase in titers to a polyvalent pneumococcal vaccine indicating that infliximab for injection did not interfere with T-cell independent humoral immune responses.

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 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.

Driving and Operating Machinery

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

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 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 Infectious Agents and Non-Live Vaccines).

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.

Breast-feeding

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.

Pediatrics (6-17 years of age)

INFLECTRA® is indicated for reducing signs and symptoms and for inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. INFLECTRA® is also indicated for reducing signs and symptoms, inducing and maintaining clinical remission and inducing mucosal healing in pediatric 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). In general, the adverse events in pediatric patients with Crohn’s disease or ulcerative colitis who received infliximab for injection were similar to those seen in adult patients with Crohn’s disease or ulcerative colitis respectively. It should be noted that in REACH, all patients were required to be on a stable dose of either 6-MP, AZA, or MTX (See INDICATIONS, Pediatrics; ADVERSE REACTIONS, Adverse Reactions in Pediatric Patients, Crohn’s Disease; Adverse Reactions in Pediatric Patients, Ulcerative Colitis, DOSAGE AND ADMINISTRATION, and CLINICAL TRIALS - REFERENCE BIOLOGIC DRUG. For additional pediatric information, also see WARNINGS AND PRECAUTIONS, Immunogenicity, Live Vaccines/Therapeutic Infectious Agents and Non-Live Vaccines, and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations).

The safety and efficacy of infliximab for injection has not been established in pediatric patients with Crohn’s disease <9 years of age or with ulcerative colitis <6 years of age. The safety and efficacy of infliximab for injection in pediatric patients with plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis have not been established.

Geriatrics (65 years of age or older)

In rheumatoid arthritis clinical trials (ATTRACT) and in plaque psoriasis studies, 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).

Adverse Reactions

The adverse drug reaction profiles reported in clinical studies that compared INFLECTRA® to the reference biologic drug were comparable. The description of adverse reactions in this section is based on clinical experience with the reference biologic drug.

Adverse Reaction Overview

The most common adverse drug reactions reported from both clinical trials and post-marketing reports are 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, Neurological Events), and lymphoma (see WARNINGS AND PRECAUTIONS, Carcinogenesis and Mutagenesis). One of the most common reasons for discontinuation of treatment in clinical trials was infusion-related reactions (dyspnea, flushing, headache and rash) (see WARNINGS AND PRECAUTIONS, Hypersensitivity Reactions). 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 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 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 infliximab for injection in 5561 patients in adequate and well-controlled studies. Infliximab for injection was studied in patients with rheumatoid arthritis (1304 patients exposed), juvenile rheumatoid arthritis (117 patients exposed), Crohn’s disease (1566 patients exposed, including 1427 adult and 139 pediatric patients), ulcerative colitis (544 patients exposed, including 484 adults and 60 children), plaque psoriasis (1373 patients exposed), psoriatic arthritis (293 patients exposed), ankylosing spondylitis (347 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. See PART II, CLINICAL TRIALS - REFERENCE BIOLOGIC DRUG for a description of the individual studies conducted in each indication.

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 at least 5% in infliximab for injection-treated pediatric patients with Crohn’s disease or ulcerative colitis are shown in Table 2. Adverse events occurring at a frequency of ≥1% to <5% in infliximab for injection-treated adult patients are shown in Table 3. Adverse events occurring at a frequency of ≥1% to <5% in infliximab for injection-treated pediatric patients with Crohn’s disease or ulcerative colitis are shown in Table 4. Adverse events in a juvenile rheumatoid arthritis (JRA) trial are set forth in the section entitled Adverse Reactions in Pediatric Patients, Juvenile Rheumatoid Arthritis. In general, the adverse events in pediatric patients with Crohn’s disease or ulcerative colitis who received Infliximab for injection were similar in frequency and type to those seen in adult patients with Crohn’s disease or ulcerative colitis respectively. Differences from adults and other special considerations are discussed in the section, Adverse Reactions in Pediatric Patients, Crohn’s Disease and Adverse Reactions in Pediatric Patients, Ulcerative Colitis.

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
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
 

RA Studies

CD studies

AS studies

UC studies

Pso Studies

PsA studies

 

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Treated patients ≥ 18 years of agea,b

427

1304

217

1427

76

275

248

493

334

1373

98

191

Avg duration of follow-up (weeks)

52.0

59.9

29.8

44.8

25.3

87.8

31.9

40.5

18.1

41.9

20.2

42.8

Patient with 1 or more adverse events

353 (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 infection

22%

29%

15%

23%

14%

49%

17%

18%

16%

25%

13%

24%

Pharyngitis

7%

12%

6%

13%

5%

20%

6%

10%

4%

9%

4%

10%

Sinusitis

7%

13%

6%

9%

1%

11%

5%

9%

3%

8%

4%

11%

Coughing

7%

12%

6%

7%

3%

13%

4%

6%

1%

5%

1%

7%

Rhinitis

4%

8%

5%

6%

5%

21%

2%

4%

1%

6%

2%

4%

Bronchitis

8%

9%

3%

5%

1%

8%

3%

4%

2%

4%

3%

6%

Gastro-intestinal system disorders

Nausea

19%

19%

25%

21%

9%

11%

9%

11%

4%

8%

6%

5%

Abdominal pain

7%

12%

17%

24%

4%

16%

13%

12%

1%

4%

2%

5%

Diarrhea

11%

11%

7%

9%

5%

20%

5%

5%

2%

5%

3%

2%

Vomiting

6%

7%

13%

12%

4%

6%

7%

6%

1%

3%

2%

1%

Dyspepsia

6%

9%

2%

6%

4%

4%

2%

3%

1%

2%

2%

2%

Skin and appendages disorders

Rash

5%

9%

6%

10%

7%

10%

8%

8%

1%

2%

0%

2%

Pruritus

2%

6%

3%

6%

7%

12%

4%

6%

4%

9%

3%

6%

Body as a whole-general disorders

Pain

7%

7%

6%

13%

5%

29%

12%

11%

5%

10%

1%

4%

Fatigue

6%

8%

13%

14%

4%

15%

8%

10%

2%

7%

3%

4%

Musculo skeletal system disorders

Arthralgia

6%

7%

8%

15%

1%

8%

10%

15%

2%

10%

2%

4%

Back pain

4%

7%

6%

8%

3%

12%

8%

4%

3%

5%

6%

9%

Myalgia

3%

3%

4%

6%

3%

4%

5%

6%

1%

6%

0%

2%

Central & peripheral nervous system

disorders

Headache

12%

17%

15%

23%

11%

20%

18%

19%

8%

17%

5%

10%

Dizziness

6%

7%

6%

10%

4%

10%

5%

6%

2%

4%

4%

4%

Resistance mechanism disorders

                       

Fever

4%

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 ≥ 5%) by WHOART system-organ class and preferred term; treated patients < 18 years of age in ulcerative colitis and Crohn’s disease studies
a
CD Studies include C0168T23, C0168T47 (through Week 54), and C0168T55.
b
UC Study include C0168T72.
c
The adverse events included in this table are determined by the frequency of events in the combined infliximab for injection group. Percentages are rounded to an integer value after the adverse event frequency is determined.
 

CD studiesa

UC studiesb

Placebo

Infliximab for injection

5 mg/kg

Placebo

Infliximab for injection

5 mg/kg

Treated patients < 18 years of age in ulcerative colitis and Crohn’s disease studiesc

0

139

0

60

Avg duration of follow-up (weeks)

N/A

44.1

N/A

38.0

Patients with 1 or more adverse events

0 (N/A)

125 (89.9%)

0 (N/A)

57 (95.0%)

System-organ class/preferred term

Gastro-intestinal system disorders

Colitis ulcerative

NA

0%

NA

47%

Abdominal pain

NA

22%

NA

13%

Vomiting

NA

22%

NA

8%

Nausea

NA

19%

NA

5%

Blood in stool

NA

7%

NA

3%

Diarrhea

NA

13%

NA

3%

Crohn's disease

NA

27%

NA

0%

Respiratory system disorders

Upper respiratory tract infection

N/A

29%

N/A

23%

Pharyngitis

N/A

19%

N/A

18%

Coughing

N/A

11%

N/A

10%

Sinusitis

N/A

8%

N/A

5%

Rhinitis

N/A

8%

N/A

2%

Resistance mechanism disorders

Fever

N/A

17%

N/A

13%

Skin and appendages disorders

Rash

N/A

10%

N/A

5%

Pruritus

N/A

9%

N/A

2%

Body as a whole-general disorders

Pain

N/A

9%

N/A

8%

Central & peripheral nervous system disorders

Headache

N/A

31%

N/A

13%

Musculo-skeletal system disorders

Arthralgia

N/A

9%

N/A

2%

Red blood cell disorders

Anemia

N/A

9%

N/A

10%

White cell and res disorders

Neutropenia

N/A

6%

N/A

3%

Leukopenia

N/A

8%

N/A

2%

Vascular (extracardiac) disorders

Flushing

N/A

8%

N/A

3%

Table 3: 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
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.
 

RA Studies

CD studies

AS studies

UC studies

Pso Studies

PsA studies

 

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Treated patients ≥ 18 years of agea,b

427

1304

217

1427

76

275

248

493

334

1373

98

191

Avg duration of follow-up (weeks)

52.0

59.9

29.8

44.8

25.3

87.8

31.9

40.5

18.1

41.9

20.2

42.8

Patient with 1 or more adverse events

353 (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

Dyspnea

2%

5%

1%

4%

3%

5%

2%

3%

1%

3%

1%

3%

Pneumonia

1%

4%

1%

1%

0%

1%

0%

2%

0%

1%

0%

3%

Respiratory tract allergic reaction

1%

2%

0%

1%

0%

1%

0%

1%

0%

2%

1%

2%

Epistaxis

1%

1%

0%

1%

0%

2%

0%

1%

0%

1%

0%

1%

Gastro-intestinal system disorders

Gastroenteritis

3%

4%

6%

4%

4%

7%

2%

3%

1%

3%

3%

1%

Crohn`s disease

0%

0%

12%

13%

0%

0%

0%

0%

0%

0%

0%

0%

Stomatis ulcerative

5%

6%

1%

3%

1%

1%

1%

1%

0%

1%

1%

1%

Flatulence

1%

2%

3%

6%

0%

1%

2%

4%

0%

0%

0%

0%

Constipation

3%

2%

2%

4%

1%

3%

1%

2%

0%

1%

2%

0%

Gastro-esophageal reflux

1%

2%

0%

2%

0%

3%

2%

1%

0%

1%

1%

2%

Colitis ulcerative

0%

0%

0%

0%

0%

0%

25%

16%

0%

0%

0%

0%

Tooth ache

0%

1%

1%

2%

0%

1%

0%

1%

1%

2%

0%

1%

Anorexia

1%

1%

2%

2%

0%

0%

1%

1%

0%

0%

0%

1%

Blood in stool

1%

1%

1%

2%

0%

1%

1%

1%

0%

0%

0%

0%

Intestinal obstruction

0%

0%

2%

4%

0%

0%

0%

0%

0%

0%

0%

0%

Skin and appendages disorders

Urticaria

1%

4%

0%

2%

0%

2%

0%

1%

1%

4%

0%

4%

Sweating increased

0%

2%

3%

3%

5%

4%

3%

3%

0%

2%

0%

2%

Alopecia

2%

3%

2%

3%

0%

1%

1%

3%

1%

1%

2%

3%

Dermatitis

1%

2%

0%

2%

1%

7%

2%

1%

0%

2%

0%

1%

Dermatitis fungal

1%

3%

1%

1%

0%

5%

3%

1%

0%

2%

1%

2%

Psoriasis

0%

0%

1%

1%

1%

5%

1%

0%

7%

5%

2%

4%

Eczema

1%

2%

0%

3%

0%

3%

3%

1%

1%

1%

0%

1%

Acne

0%

1%

1%

3%

0%

3%

1%

2%

1%

1%

0%

0%

Skin dry

0%

1%

1%

2%

0%

7%

1%

3%

1%

1%

0%

0%

Skin wound

2%

2%

1%

1%

0%

2%

0%

1%

0%

2%

0%

1%

Erythema

0%

2%

1%

1%

0%

3%

1%

1%

0%

1%

1%

0%

Rash erythematous

1%

1%

0%

1%

1%

5%

0%

1%

0%

0%

0%

1%

Folliculitis

0%

1%

1%

1%

0%

1%

0%

1%

1%

1%

0%

0%

Body as a whole-general disorders

Chest pain

3%

4%

4%

5%

1%

6%

2%

3%

0%

4%

2%

4%

Edema peripheral

4%

4%

2%

5%

1%

4%

4%

4%

2%

3%

0%

3%

Chills

2%

3%

1%

2%

3%

3%

2%

4%

1%

3%

0%

1%

Infusion syndrome

0%

2%

0%

2%

1%

3%

0%

2%

0%

3%

0%

2%

Wound

1%

1%

0%

1%

1%

3%

0%

1%

0%

3%

1%

3%

Hot flushes

0%

2%

1%

2%

1%

3%

2%

1%

0%

1%

0%

2%

Allergic reaction

0%

1%

1%

2%

0%

5%

0%

2%

1%

1%

1%

1%

Asthenia

1%

1%

0%

3%

0%

2%

0%

1%

0%

1%

1%

1%

Reaction

unevaluable

0%

1%

2%

2%

0%

2%

1%

1%

1%

1%

0%

0%

Musculo skeletal system disorders

Arthritis

1%

1%

2%

4%

5%

14%

1%

1%

3%

7%

5%

5%

Bone fracture

3%

4%

0%

1%

0%

4%

0%

1%

1%

1%

0%

4%

Skeletal muscle

strain

2%

2%

0%

1%

0%

1%

1%

0%

1%

3%

1%

2%

Tendinitis

2%

0%

0%

1%

1%

5%

1%

1%

0%

1%

2%

1%

Central & peripheral nervous system disorders

Paresthesia

2%

3%

2%

3%

0%

7%

3%

3%

1%

3%

0%

0%

Muscle contractions involuntary

2%

4%

2%

2%

1%

3%

3%

2%

0%

2%

1%

1%

Hypesthesia

1%

2%

1%

2%

4%

3%

1%

1%

0%

2%

1%

1%

Migraine

1%

1%

1%

2%

0%

1%

0%

1%

0%

1%

0%

1%

Vertigo

2%

2%

0%

1%

3%

1%

1%

1%

0%

1%

1%

2%

Resistance mechanism disorders

Abscess

3%

4%

4%

9%

3%

6%

3%

3%

1%

3%

2%

2%

Flu syndrome

3%

4%

1%

6%

1%

8%

2%

4%

1%

3%

0%

3%

Moniliasis

3%

5%

0%

5%

0%

5%

2%

3%

0%

1%

0%

1%

Influenza-like

symptoms

0%

2%

2%

3%

1%

2%

2%

3%

1%

2%

0%

2%

Herpes simplex

1%

2%

2%

2%

0%

9%

2%

1%

1%

2%

1%

4%

Infection

2%

3%

0%

2%

3%

4%

1%

1%

1%

2%

0%

1%

Influenza

1%

2%

2%

3%

1%

1%

2%

2%

1%

2%

0%

1%

Cellulitis

1%

2%

0%

1%

0%

2%

0%

1%

1%

1%

1%

3%

Herpes zoster

1%

1%

0%

1%

0%

0%

0%

1%

1%

1%

0%

2%

Infection bacterial

1%

1%

2%

1%

0%

1%

0%

0%

0%

1%

0%

2%

Psychiatric disorders

Insomnia

4%

4%

3%

6%

1%

4%

2%

4%

1%

2%

1%

0%

Depression

5%

5%

2%

4%

0%

4%

2%

3%

1%

3%

2%

3%

Anxiety

1%

3%

1%

3%

1%

2%

3%

2%

0%

2%

1%

0%

Liver and biliary system disorders

Sgpt increased

4%

5%

1%

3%

5%

12%

1%

1%

1%

4%

1%

8%

Sgot increased

2%

3%

1%

2%

3%

9%

0%

1%

1%

3%

2%

5%

Hepatic enzymes

increased

3%

4%

1%

1%

0%

2%

0%

1%

0%

4%

0%

2%

Hepatic function

abnormal

1%

2%

2%

1%

0%

2%

0%

0%

0%

1%

1%

2%

Vascular (extracardiac) disorders

Flushing

0%

3%

1%

2%

3%

4%

1%

2%

0%

5%

0%

3%

Ecchymosis

2%

4%

0%

2%

0%

2%

1%

1%

0%

2%

0%

1%

Hemorrhoids

1%

1%

0%

2%

1%

3%

3%

1%

0%

0%

0%

1%

Urinary system disorders

Urinary tract

infection

5%

7%

3%

4%

0%

2%

2%

2%

1%

2%

4%

3%

Metabolic and nutritional disorders

Hypokalemia

0%

2%

1%

4%

0%

0%

0%

1%

0%

0%

0%

1%

Weight increase

2%

2%

0%

0%

1%

3%

0%

0%

0%

1%

0%

0%

Cardiovascular disorders, general

Hypertension

5%

6%

2%

3%

5%

8%

2%

2%

3%

4%

2%

3%

Hypotension

1%

2%

0%

2%

1%

3%

0%

2%

0%

1%

0%

2%

Eye and vision disorders

Conjunctivitis

2%

4%

2%

4%

1%

4%

3%

1%

0%

1%

1%

1%

Vision abnormal

1%

2%

1%

2%

0%

4%

2%

1%

0%

1%

0%

2%

Ear and hearing disorders

Otitis

0%

2%

1%

1%

0%

2%

1%

1%

0%

1%

0%

0%

White cell and res disorders

Leukopenia

1%

2%

3%

2%

0%

2%

0%

2%

0%

1%

0%

1%

Lympha-denopathy

0%

1%

1%

2%

0%

2%

1%

1%

0%

1%

0%

1%

Neutropenia

0%

1%

0%

1%

0%

3%

0%

0%

0%

1%

0%

3%

Red blood cell disorders

                       

Anemia

4%

4%

4%

4%

1%

4%

10%

5%

0%

1%

0%

0%

Heart rate and rhythm disorders

Tachycardia

2%

2%

0%

1%

1%

1%

2%

1%

1%

1%

1%

1%

Palpitation

1%

2%

0%

1%

0%

3%

1%

1%

0%

1%

0%

1%

Administration / application site disorders

Injection site infiltration

3%

2%

0%

1%

0%

0%

1%

0%

0%

2%

0%

0%

Collagen disorders

Arthritis rheumatoid

6%

7%

0%

0%

0%

0%

0%

0%

0%

0%

0%

0%

Table 4: 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 in ulcerative colitis and Crohn’s disease studies
a
CD Studies include C0168T23, C0168T47 (through Week 54), and C0168T55.
b
UC Study include C0168T72.
c
The adverse events included in this table are determined by the frequency of events in the combined infliximab for injection group. Percentages are rounded to an integer value after the adverse event frequency is determined.
 

CD studiesa

UC studiesb

Placebo

Infliximab for injection

5 mg/kg

Placebo

Infliximab for injection

5 mg/kg

Treated patients < 18 years of age in ulcerative colitis and Crohn’s disease studiesc

0

139

0

60

Avg duration of follow-up (weeks)

N/A

44.1

N/A

38.0

Patients with 1 or more adverse events

0 (N/A)

125 (89.9%)

0 (N/A)

57 (95.0%)

System-organ class/preferred term

Gastro-intestinal system disorders

Stomatitis ulcerative

NA

2%

NA

5%

Diarrhea bloody

NA

1%

NA

2%

Pancreatitis

NA

2%

NA

2%

Anal fistula

NA

3%

NA

0%

Anorexia

NA

3%

NA

0%

Constipation

NA

6%

NA

0%

Dyspepsia

NA

6%

NA

0%

Dysphagia

NA

1%

NA

0%

Enterocolitis

NA

3%

NA

0%

Flatulence

NA

4%

NA

0%

Gastroenteritis

NA

5%

NA

0%

Hemorrhage rectum

NA

1%

NA

0%

Intestinal obstruction

NA

1%

NA

0%

Intestinal stenosis

NA

2%

NA

0%

Oral pain

NA

1%

NA

0%

Proctalgia

NA

2%

NA

0%

Tooth ache

NA

2%

NA

0%

Respiratory system disorders

Dyspnea

NA

4%

NA

5%

Bronchitis

NA

5%

NA

3%

Asthma

NA

1%

NA

2%

Respiratory tract allergic reaction

NA

4%

NA

2%

Bronchospasm

NA

1%

NA

0%

Epistaxis

NA

3%

NA

0%

Pneumonia

NA

2%

NA

0%

Resistance mechanism disorders

Influenza

NA

3%

NA

5%

Cellulitis

NA

1%

NA

3%

Infection

NA

3%

NA

3%

Influenza-like symptoms

NA

1%

NA

3%

Moniliasis

NA

4%

NA

3%

Herpes simplex

NA

1%

NA

2%

Herpes zoster

NA

1%

NA

2%

Infection bacterial

NA

5%

NA

2%

Infection viral

NA

6%

NA

2%

Abscess

NA

4%

NA

0%

Flu syndrome

NA

5%

NA

0%

Infectious mononucleosis

NA

1%

NA

0%

Skin and appendages disorders

Alopecia

NA

1%

NA

3%

Eczema

NA

4%

NA

3%

Acne

NA

2%

NA

2%

Dermatitis

NA

1%

NA

2%

Onychocryptosis

NA

1%

NA

2%

Skin lesion

NA

3%

NA

2%

Sweating increased

NA

1%

NA

2%

Urticaria

NA

1%

NA

2%

Verruca

NA

2%

NA

2%

Cracking of skin

NA

4%

NA

0%

Dermatitis contact

NA

2%

NA

0%

Dermatitis fungal

NA

2%

NA

0%

Rash erythematous

NA

2%

NA

0%

Skin dry

NA

2%

NA

0%

Skin hypertrophy

NA

1%

NA

0%

Body as a whole-general disorders

Chest pain

NA

3%

NA

3%

Fatigue

NA

5%

NA

3%

Chills

NA

1%

NA

2%

Cyst (type unknown)

NA

1%

NA

2%

Edema

NA

1%

NA

2%

Edema peripheral

NA

1%

NA

2%

Reaction unevaluable

NA

1%

NA

2%

Allergic reaction

NA

4%

NA

0%

Asthenia

NA

1%

NA

0%

Central &peripheral nervous system disorders

Hyperkinesia

NA

0%

NA

3%

Dizziness

NA

6%

NA

2%

Muscle contractions involuntary

NA

1%

NA

2%

Migraine

NA

1%

NA

0%

Paresthesia

NA

2%

NA

0%

Musculo-skeletal system disorders

Back pain

NA

2%

NA

3%

Bone development abnormal

NA

1%

NA

2%

Joint swelling

NA

1%

NA

2%

Sprain

NA

1%

NA

2%

Bone fracture

NA

6%

NA

0%

Myalgia

NA

4%

NA

0%

Red blood cell disorders

Anemia iron deficiency

NA

1%

NA

2%

Psychiatric disorders

Anxiety

NA

2%

NA

2%

Depression

NA

2%

NA

2%

Insomnia

NA

4%

NA

2%

Thinking abnormal

NA

1%

NA

2%

Irritability

NA

1%

NA

0%

Somnolence

NA

3%

NA

0%

Suicide attempt

NA

1%

NA

0%

Urinary system disorders

Urinary tract infection

NA

1%

NA

8%

Dysuria

NA

1%

NA

0%

Liver and biliary system disorders

Hepatic enzymes increased

NA

2%

NA

3%

Hepatic function abnormal

NA

2%

NA

2%

Sgot increased

NA

1%

NA

2%

Sgpt increased

NA

1%

NA

2%

White cell and res disorders

Neutrophilia

NA

1%

NA

2%

Eosinophilia

NA

3%

NA

0%

Lymphadenopathy

NA

1%

NA

0%

Monocytosis

NA

1%

NA

0%

Eye and vision disorders

       

Conjunctivitis

NA

4%

NA

3%

Eye pain

NA

3%

NA

0%

Metabolic and nutritional disorders

Dehydration

NA

2%

NA

0%

Weight decrease

NA

3%

NA

0%

Vascular (extracardiac) disorders

Ecchymosis

NA

4%

NA

0%

Cardiovascular disorders, general

Hypotension

NA

1%

NA

0%

Syncope

NA

2%

NA

0%

Collagen disorders

Antinuclear factor test positive

NA

3%

NA

2%

Ear and hearing disorders

Otitis

NA

1%

NA

2%

Otitis media

NA

2%

NA

2%

Earache

NA

2%

NA

0%

Platelet, bleeding & clotting disorders

Thrombocythemia

NA

1%

NA

3%

Thrombocytopenia

NA

1%

NA

0%

Heart rate and rhythm disorders

Palpitation

NA

1%

NA

2%

Administration/application site disorders

Injection site infiltration

NA

4%

NA

0%

Reproductive disorders

Dysmenorrhea

NA

2%

NA

0%

Ovarian cyst

NA

1%

NA

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 (see PART II, CLINICAL TRIALS - REFERENCE BIOLOGIC DRUG, Rheumatoid Arthritis).

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 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 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 ischemia/infarction (some fatal), and arrhythmia occurring within 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 other 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 ATTRACT1, 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 (see CLINICAL TRIALS TRIALS - REFERENCE BIOLOGIC DRUG, Fistulising Crohn’s Disease). 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.

In post-marketing experience, infections have been observed with various pathogens including viral, bacterial, fungal, and protozoal organisms. Infections have been noted in all organ systems and have been reported in patients receiving infliximab for injectionalone or in combination with immunosuppressive agents.


1
ATTRACT (the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy)
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)
4
ACCENT II (the Anti-TNF Trial in Long-term Treatment of Fistulising Crohn’s Disease)
5
EXPRESS II Evaluation of Infliximab for Psoriasis in a REMICADE Efficacy and Safety Study
6
EXPRESS European infliximab for Psoriasis (REMICADE) Efficacy and Safety Study
7
IMPACT 2 Induction and Maintenance Psoriatic Arthritis Clinical Trial
8
ACT 1 and ACT 2 (the Anti-TNF Trials in moderately to severely active ulcerative colitis)

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 injectiontreatment 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 patientswith 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 infliximabfor 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 infliximabfor 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 injectionthan in controls, both when infliximab for injectionwas 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 of age.

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, anticardiolipin antibodies
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 Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

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 5.

Table 5: 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 pediatric Crohn’s disease trials T23, T55 and T47 (REACH). Median follow-up was 53.0 weeks.
7
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.
8
Data from the pediatric ulcerative colitis study T72.
 

Proportion of patients with elevated ALT

 

>1 to <3 X ULN

≥3 X ULN

≥5 X ULN

 

Placebo

Infliximab for

injection

Placebo

Infliximab for

injection

Placebo

Infliximab for

injection

Rheumatoid arthritis1

24.0%

34.4%

3.2%

3.9%

0.8%

0.9%

Crohn’s disease2

24.1%

34.9%

2.2%

4.9%

0.0%

1.5%

Ulcerative colitis3

12.4%

17.4%

1.2%

2.5%

0.4%

0.6%

Psoriatic arthritis4

16.3%

49.5%

0.0%

6.8%

0.0%

2.1%

Plaque psoriasis5

23.8%

49.4%

0.4%

7.7%

0.0%

3.4%

Pediatric Crohn’s disease6

N/A

18.2%

N/A

4.4%

N/A

1.5%

Ankylosing spondylitis7

14.5%

51.1%

0.0%

9.5%

0.0%

3.6%

Pediatric ulcerative colitis8

N/A

16.7%

N/A

6.7%

N/A

1.7%

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.

Clinical Trial Adverse Reactions (Pediatrics)

Crohn’s Disease

Adverse events occurring at a frequency of ≥5% or from ≥1% to <5% in infliximab for injection-treated pediatric patients with Crohn’s disease are shown in Tables 2 and 4, respectively. In general, the adverse events in pediatric patients who received infliximab for injection were similar in frequency and type to those seen in adult patients with Crohn’s disease. Differences from adults and other special considerations are discussed in the following paragraphs.

The following adverse events were reported more commonly in the 103 randomised pediatric patients with Crohn’s disease (Phase 3 Trial, REACH) who received 5 mg/kg infliximab for Injection through 54 weeks than in the 385 adult patients with Crohn’s disease (ACCENT I) where 193/385 patients received 5 mg/kg and 192/385 received 10 mg/kg infliximab for injection through 54 weeks: anemia (10.7%), blood in stool (9.7%), leukopenia (8.7%), flushing (8.7%), viral infection (7.8%), neutropenia (6.8%), bone fracture (6.8%), bacterial infection (5.8%), and respiratory tract allergic reaction (5.8%). The Phase 3 study (REACH) enrolled 112 pediatric patients 6 to 17 years old (median age 13.0 years) with moderately to severely active Crohn’s disease and an inadequate response to conventional therapies.

Infections were reported in 56.3% of randomised pediatric patients in the REACH trial, and in 50.3% of patients in the ACCENT I Study. In the pediatric Phase 3 trial, infections were reported more frequently for subjects who received q8 week as opposed to q12 week infusions (73.6% and 38.0%, respectively), while serious infections were reported for 3 patients in the q8 week and 4 patients in the q12 week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Pneumonia was reported for 3 patients, 2 in the q8 week and 1 in the q12 week maintenance treatment groups. Herpes zoster was reported for 2 patients in the q8 week maintenance treatment group.

In REACH, 17.5% of randomised patients experienced 1 or more infusion reactions, with no notable difference between treatment groups (17.0% and 18.0% of patients in the q8 week and q12 week maintenance treatment groups, respectively). There were no serious infusion reactions, and 2 patients had non-serious anaphylactic reactions.

Antibodies to infliximab developed in 3 (2.9%) pediatric patients in the REACH trial and in the patients in the Phase 2 trial (T23).

Juvenile Rheumatoid Arthritis

The efficacy of infliximab for injection in the treatment of children with juvenile rheumatoid arthritis, JRA, has not been established. In a clinical trial where children were treated with either 3 mg/kg or 6 mg/kg of infliximab for injection, the proportion of children with infusion reactions, most commonly vomiting, fever, headache and hypotension, was 35% at a dosage of 3 mg/kg. Four of these reactions were serious, and three were considered to be possible anaphylactic reactions. Two of the 4 patients who experienced serious infusion reactions at a dose of 3 mg/kg received infliximab for injection by rapid infusion (duration time less than 2 hours). Antibodies to infliximab developed in 37.7% of children receiving that dosage, but only in 12.2% receiving a higher dosage (6 mg/kg).

Ulcerative Colitis

Overall, the adverse reactions reported in the pediatric ulcerative colitis (Study Peds UC) and adult ulcerative colitis (ACT 1 and ACT 2) studies were generally consistent. In Study Peds UC, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache. In Study Peds UC, there were a total of 20 serious adverse events: 10 were serious adverse events of ulcerative colitis, 7 were infections (which included cellulitis, urinary tract infection, pneumonia, pharyngitis, ulcerative colitis, viral infection, and infection not otherwise specified) and one event each of anemia, neutropenia and pancreatitis. An additional 12 adverse events were considered to be severe (4 events of ulcerative colitis, 3 of abdominal pain and 1 event each of pharyngitis, sinusitis, malnutrition, inflammation and headache). None of these serious or severe adverse events were opportunistic infections.

Infections were reported in 31 (51.7%) of 60 treated patients in Study Peds UC and 22 (36.7%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in Study Peds UC was similar to that in the pediatric Crohn’s disease study (REACH) but higher than the proportion in the adult ulcerative colitis studies (ACT 1 and ACT 2). Unlike REACH, in which infections were reported more frequently for patients who received q8 week as opposed to q12 week infusions; in Study Peds UC, the overall incidence of infections was similar in the q8 week (13/22 [59.1%]) and q12 week (14/23 [60.9%]) maintenance treatment groups. In Study Peds UC, serious infections were reported for 3 of 22 (13.6%) patients in the q8 week and 3 of 23 (13.0%) patients in the q12 week maintenance treatment group. Upper respiratory tract infection (7/60 [11.7%]) and pharyngitis (5/60 [8.3%]) were the most frequently reported respiratory system infections among all treated patients. The infections occurring in more than one patient in a treatment group that required antimicrobial treatment were pharyngitis (4/60 [6.7%]), urinary tract infection (4/60 [6.7%]), and bronchitis (2/60 [3.3%]).

Overall, 8 (13.3%) of 60 treated patients experienced one or more infusion reactions, with 4 of 22 (18.2%) in the q8 week and 3 of 23 (13.0%) in the q12 week treatment maintenance group. No serious infusion reactions were reported. All infusion reactions were mild or moderate in intensity.

Antibodies to infliximab were detected in 4 of 52 (7.7%) patients through week 54.

In Study Peds UC, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group (45/60 [75.0%]) vs.15/60 [25.0%]). While the numbers of patients in each subgroup are too small to make any definitive conclusions about the effect of age on safety events, there were higher proportions of patients with serious adverse events and discontinuation due to adverse events in the younger age group than in the older age group. While the proportion of patients with infections was also higher in the younger age group, the proportions of patients with serious infections were similar in the two age groups. Overall proportions of adverse events and infusion reactions were similar between the 6 to 11 and 12 to 17 year age groups.

Post-Market Adverse Reactions

Additional adverse events, some with fatal outcome, reported from worldwide post-marketing experience with infliximab for injection are included in Table 6 (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.

The most common serious adverse events reported in the post-marketing experience in children were infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, and hypersensitivity reactions. Spontaneous serious adverse events in the postmarketing experience with infliximab for injection in the pediatric population have also included malignancies, transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.

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 6: POST-MARKETING REPORTS
 
* including bovine tuberculosis (disseminated BCG infection), see WARNINGS AND PRECAUTIONS, Live Vaccines/Therapeutic Infectious Agents.

Blood and Lymphatic System Disorders

agranulocytosis (including infants exposed in utero to infliximab for injection), idiopathic thrombocytopenic purpura, hemolytic anemia, pancytopenia, thrombotic thrombocytopenic purpura

General Disorders and Administration Site Conditions

anaphylactic reactions, anaphylactic shock, infusion-related reactions, serum sickness

Cardiac Disorders

pericardial effusion, myocardial ischemia/myocardial (within 24 hours of initiation of infusion), arrhythmia (within 24 hours of initiation of infusion)

Eye Disorders

Transient visual loss occurring during or within 2 hours of infusion

Immune System Disorders

vasculitis, sarcoidosis

Neoplasm Benign and Malignant

hepatosplenic 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 Disorders

hepatocellular damage, hepatitis, jaundice, autoimmune hepatitis, liver failure

Nervous System Disorders

central 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 Infestations

opportunistic 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 Disorders

interstitial lung disease, including pulmonary fibrosis/interstitial pneumonitis, and rapidly progressive disease

Skin and Subcutaneous Tissue Disorders

vasculitis (primarily cutaneous) , psoriasis including new onset and pustular (primarily palmar/plantar), erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, linear IgA bullous dermatosis (LABD), acute generalized exanthematous pustulosis (AGEP), lichenoid reactions

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 Test Interactions

Interactions with laboratory tests have not been established.

Action And Clinical Pharmacology

Mechanism of Action

Infliximab is a chimeric IgG1κ monoclonal antibody with an approximate molecular weight of 149,100 daltons. It is composed of human constant and murine variable regions. Infliximab binds specifically to human tumour necrosis factor alpha (TNFα) with an association constant of 1010 M-1. Infliximab 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 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 receptors9,10,11. Infliximab 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 proteins12. Cells expressing transmembrane TNFα bound by infliximab can be lysed in vitro by complement or effector cells.11 Infliximab inhibits the functional activity of TNFα in a wide variety of in vitro bioassays utilising human fibroblasts, endothelial cells, neutrophils,10 B and T lymphocytes13,14, and epithelial cells. Anti-TNFα antibodies reduce disease activity in a cotton-top tamarin colitis model15 and decrease synovitis and joint erosions in a murine model of collagen-induced arthritis. Infliximab prevents disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFα, and, when administered after disease onset, facilitates eroded joints to heal.

Pharmacodynamics

Preclinical

Infliximab 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.10,11 Cells expressing transmembrane TNFα can be lysed in vitro by complement or effector cell-mediated mechanisms after infliximab binds.11 Infliximab inhibits the functional activity of TNFα in a wide variety of in vitro bioassays utilising human fibroblasts, endothelial cells, neutrophils,12 B and T lymphocytes,14,15 and epithelial cells.15

Infliximab specifically neutralises TNFα-induced cell cytotoxicity but not lymphotoxin α.11 Lymphotoxin α is a cytokine that shares 30% homology with TNFα and utilises the same receptors as TNFα. Species cross-reactivity of infliximab is limited to human and chimpanzee TNFα. In vivo, infliximab 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 patients16 in the joints of psoriatic arthritis patients, 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.17 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].17 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 y ex vivo.17 After treatment with infliximab for injection, 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.


9
Siegel SA, Shealy DJ, Nakada MT, Le J, Woulfe DS, Probert L, Kollias G, Ghrayeb J, Vilcek J, Daddona PE. The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine 1995;7:15-25.
10
Beutler B. Tumour necrosis factor. The molecules and their emerging roles in medicine. Raven Press, NY, 1992.
11
Boussiotis VA, Nadler LM, Strominger JL, Goldfeld AE. Tumour necrosis factor α is an autocrine growth factor for normal human B cells. Proc Natl Acad Sci USA 1994;91:7007-7011.
12
Cope AP, Londei M, Chu NR, Cohen SBA, Elliott MJ, Brennan FM, Maini RN, Feldmann M. Chronic exposure to tumour necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti- TNF antibodies in patients with rheumatoid arthritis. J Clin Invest 1994;94:749-760.
13
Watkins PE, Warren BF, Stephens S, Ward P, Foulkes R. Treatment of ulcerative colitis in the cottontop tamarin using antibody to tumour necrosis factor alpha. Gut 1997;40:628-633.
14
Jones M, Symmons D, Finn J, Wolfe F. Does exposure to immunosuppressive therapy increase the 10 year malignancy and mortality risks in rheumatoid arthritis? A matched cohort study. Br J Rheum 1996;35:738-45.
15
Chu CQ, Field M, Feldmann M, et al. Localization of tumor necrosis factor α in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis and Rheum 1991;34:1125-1132.
16
Plevy SE, Landers CS, Prehn J, Carramanzana NM, Deem RL, Shealy D, Targan SR. A role for TNFα and mucosal T helper-1 cytokines in the pathogenesis of Crohn’s disease. J Immunol 1997;159:6276-6282.
17
Lipsky PE, van der Heijde D., St. Clair EW et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343:1594-1602.

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.

Study

Rheumatoid Arthritis

Crohn’s Disease

T09

(n=14)

T09

(n=29)

T11

(n=5)

T11

(n=5)

Dose

3 mg/kg

10 mg/kg

5 mg/kg

10 mg/kg

Cmax (μg/mL)

77.3

277

74.9

181.0

AUC (μg • day/mL)

461

2282

788

2038

CL (mL/day/kg)

6.4

4.4

6.3

4.9

Vss (mL/kg)

67.5

57.2

80

65

t1/2(day)

8

9.1

7.8

10

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 and Conditions

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.

Pediatrics: Infliximab pharmacokinetic characteristics (including peak and trough concentrations) were generally similar in pediatric patients (aged 6 to 17 years) with Crohn’s disease or ulcerative colitis following the administration of 5 mg/kg infliximab for injection. Similar terminal half-life values were also observed in pediatric patients with Crohn’s disease, and adult patients with Crohn’s disease or ulcerative colitis. However, for pediatric patients with ulcerative colitis, median serum peak and steady-state trough infliximab concentrations were about 13% and 25% lower than those in adult patients with ulcerative colitis, respectively; the clinical significance of the relatively lower serum infliximab concentrations in pediatric patients is unknown (see INDICATIONS, Pediatrics, and WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics).

Storage, Stability And Disposal

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.

 

Control #: 220321
August 28, 2019

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