Data from FDA - Curated by EPG Health - Last updated 13 July 2018

Indication(s)

1 INDICATIONS AND USAGE INFLECTRA is a tumor necrosis factor (TNF) blocker indicated for: Crohn's Disease (1.1): reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy. reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease. Pediatric Crohn's Disease (1.2): reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy. Ulcerative Colitis (1.3): reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy. Rheumatoid Arthritis (1.4) in combination with methotrexate: reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active disease. Ankylosing Spondylitis (1.5): reducing signs and symptoms in patients with active disease. Psoriatic Arthritis (1.6): reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function. Plaque Psoriasis (1.7): treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. 1.1 Crohn's Disease INFLECTRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy. INFLECTRA is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn's disease. 1.2 Pediatric Crohn's Disease INFLECTRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy. 1.3 Ulcerative Colitis INFLECTRA is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy. 1.4 Rheumatoid Arthritis INFLECTRA, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. 1.5 Ankylosing Spondylitis INFLECTRA is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis. 1.6 Psoriatic Arthritis INFLECTRA is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis. 1.7 Plaque Psoriasis INFLECTRA is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. INFLECTRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warning, Warnings and Precautions (5) ].

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contraindications
4 CONTRAINDICATIONS INFLECTRA at doses >5 mg/kg should not be administered to patients with moderate to severe heart failure. In a randomized study evaluating infliximab in patients with moderate to severe heart failure (New York Heart Association [NYHA] Functional Class III/IV), infliximab treatment at 10 mg/kg was associated with an increased incidence of death and hospitalization due to worsening heart failure [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ]. INFLECTRA should not be readministered to patients who have experienced a severe hypersensitivity reaction to infliximab products. Additionally, INFLECTRA should not be administered to patients with known hypersensitivity to inactive components of the product or to any murine proteins. INFLECTRA doses >5 mg/kg in moderate to severe heart failure. (4) Previous severe hypersensitivity reaction to infliximab products, or known hypersensitivity to inactive components of INFLECTRA or to any murine proteins. (4)
Adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions (>10%) – infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact CELLTRION, Inc. at 1-800-383-7504 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not predict the rates observed in broader patient populations in clinical practice. Adverse Reactions in Adults The data described herein reflect exposure to infliximab in 4779 adult patients (1304 patients with rheumatoid arthritis, 1106 patients with Crohn's disease, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 484 with ulcerative colitis, 1373 with plaque psoriasis, and 17 patients with other conditions), including 2625 patients exposed beyond 30 weeks and 374 exposed beyond 1 year. [For information on adverse reactions in pediatric patients see Adverse Reactions (6.1) ]. One of the most common reasons for discontinuation of treatment was infusion-related reactions (e.g., dyspnea, flushing, headache and rash). Infusion-related 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 patients treated with infliximab experienced an infusion reaction compared to 5% of placebo-treated patients. Of these infliximab-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period. Among all infusions with infliximab, 3% were accompanied by nonspecific symptoms such as fever or chills, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension or dyspnea), and <1% were accompanied by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions occurred in <1% of patients and included anaphylaxis, convulsions, erythematous rash and hypotension. Approximately 3% of patients discontinued treatment with infliximab because of infusion reactions, and all patients recovered with treatment and/or discontinuation of the infusion. Infliximab infusions beyond the initial infusion were not associated with a higher incidence of reactions. The infusion reaction rates remained stable in psoriasis through 1 year in psoriasis Study I. In psoriasis Study II, the rates were variable over time and somewhat higher following the final infusion than after the initial infusion. Across the 3 psoriasis studies, the percent of total infusions resulting in infusion reactions (i.e., an adverse event occurring within 1 hour) was 7% in the 3 mg/kg group, 4% in the 5 mg/kg group, and 1% in the placebo group. Patients who became positive for antibodies to infliximab were more likely (approximately two to three-fold) to have an infusion reaction than were those who were negative. Use of concomitant immunosuppressant agents appeared to reduce the frequency of both antibodies to infliximab and infusion reactions [see Adverse Reactions (6.1) and Drug Interactions (7.4) ]. Infusion reactions following re-administration 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 regimen of infliximab following disease flare, 4% (8/219) of patients in the re-treatment 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. 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, treatment with infliximab was discontinued and/or other treatment instituted with complete resolution of signs and symptoms. Delayed Reactions/Reactions Following Readministration In psoriasis studies, approximately 1% of patients treated with infliximab experienced a possible delayed hypersensitivity reaction, generally reported as serum sickness or a combination of arthralgia and/or myalgia with fever and/or rash. These reactions generally occurred within 2 weeks after repeat infusion. Infections In infliximab clinical studies, treated infections were reported in 36% of patients treated with infliximab (average of 51 weeks of follow-up) and in 25% of placebo-treated patients (average of 37 weeks of follow-up). The infections most frequently reported were respiratory tract infections (including sinusitis, pharyngitis, and bronchitis) and urinary tract infections. Among patients treated with infliximab, serious infections included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial infection. In clinical trials, 7 opportunistic infections were reported; 2 cases each of coccidioidomycosis (1 case was fatal) and histoplasmosis (1 case was fatal), and 1 case each of pneumocystosis, nocardiosis and cytomegalovirus. Tuberculosis was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of tuberculosis, including disseminated tuberculosis, also have been reported postmarketing. Most of these cases of tuberculosis occurred within the first 2 months after initiation of therapy with infliximab and may reflect recrudescence of latent disease [see Warnings and Precautions (5.1) ]. In the 1-year placebo-controlled studies RA I and RA II, 5.3% of patients receiving infliximab every 8 weeks with methotrexate (MTX) developed serious infections as compared to 3.4% of placebo patients receiving MTX. Of 924 patients receiving infliximab, 1.7% developed pneumonia and 0.4% developed tuberculosis, when compared to 0.3% and 0.0% in the placebo arm respectively. In a shorter (22-week) placebo-controlled study of 1082 RA patients randomized to receive placebo, 3 mg/kg or 10 mg/kg infusions with infliximab at 0, 2, and 6 weeks, followed by every 8 weeks with MTX, serious infections were more frequent in the 10 mg/kg infliximab group (5.3%) than the 3 mg/kg or placebo groups (1.7% in both). During the 54-week Crohn's II Study, 15% of patients with fistulizing Crohn's disease developed a new fistula-related abscess. In clinical studies with infliximab in patients with ulcerative colitis, infections treated with antimicrobials were reported in 27% of patients treated with infliximab (average of 41 weeks of follow-up) and in 18% of placebo-treated patients (average 32 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. The onset of serious infections may be preceded by constitutional symptoms such as fever, chills, weight loss, and fatigue. The majority of serious infections, however, may also be preceded by signs or symptoms localized to the site of the infection. Autoantibodies/Lupus-like Syndrome Approximately half of patients treated with infliximab in clinical trials who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately one-fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately one-fifth of patients treated with infliximab compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon. Malignancies In controlled trials, more patients treated with infliximab developed malignancies than placebo-treated patients [see Warnings and Precautions (5.2) ]. In a randomized controlled clinical trial exploring the use of infliximab in patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 patients were treated with infliximab at doses similar to those used in rheumatoid arthritis and Crohn's disease. Of these patients treated with infliximab, 9 developed a malignancy, including 1 lymphoma, for a rate of 7.67 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% confidence interval [CI] 3.51 – 14.56). There was 1 reported malignancy among 77 control patients for a rate of 1.63 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 0.04 – 9.10). The majority of the malignancies developed in the lung or head and neck. Patients with Heart Failure In a randomized study evaluating infliximab in moderate to severe heart failure (NYHA Class III/IV; left ventricular ejection fraction ≤35%), 150 patients were randomized to receive treatment with 3 infusions of infliximab at 10 mg/kg, 5 mg/kg, or placebo, at 0, 2, and 6 weeks. Higher incidences of mortality and hospitalization due to worsening heart failure were observed in patients receiving the 10 mg/kg infliximab dose. At 1 year, 8 patients in the 10 mg/kg infliximab group had died compared with 4 deaths each in the 5 mg/kg infliximab and the placebo groups. There were trends toward increased dyspnea, hypotension, angina, and dizziness in both the 10 mg/kg and 5 mg/kg infliximab treatment groups, versus placebo. Infliximab has not been studied in patients with mild heart failure (NYHA Class I/II) [see Contraindications (4) and Warnings and Precautions (5.5) ]. Immunogenicity Treatment with infliximab products can be associated with the development of antibodies to infliximab. An enzyme immunoassay (EIA) method was originally used to measure anti-infliximab antibodies in clinical studies of infliximab. The EIA method is subject to interference by serum infliximab, possibly resulting in an underestimation of the rate of patient antibody formation. A separate, drug-tolerant electrochemiluminescence immunoassay (ECLIA) method for detecting antibodies to infliximab was subsequently developed and validated. This method is 60-fold more sensitive than the original EIA. With the ECLIA method, all clinical samples can be classified as either positive or negative for antibodies to infliximab without the need for the inconclusive category. The incidence of antibodies to infliximab in patients given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through 1 to 2 years of treatment with infliximab. A higher incidence of antibodies to infliximab was observed in Crohn's disease patients receiving infliximab after drug-free intervals >16 weeks. In a study of psoriatic arthritis in which 191 patients received 5 mg/kg with or without MTX, antibodies to infliximab occurred in 15% of patients. The majority of antibody-positive patients had low titers. 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 (6.1) ] than were patients who were antibody negative. Antibody development was lower among rheumatoid arthritis and Crohn's disease patients receiving immunosuppressant therapies such as 6-mercaptopurine /azathioprine (6-MP/AZA) or MTX. In the psoriasis Study II, which included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 36% of patients treated with 5 mg/kg every 8 weeks for 1 year, and in 51% of patients treated with 3 mg/kg every 8 weeks for 1 year. In the psoriasis Study III, which also included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 20% of patients treated with 5 mg/kg induction (weeks 0, 2 and 6), and in 27% of patients treated with 3 mg/kg induction. Despite the increase in antibody formation, the infusion reaction rates in Studies I and II in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year and in Study III in patients treated with 5 mg/kg induction (14.1% – 23.0%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. The clinical significance of apparent increased immunogenicity on efficacy and infusion reactions in psoriasis patients as compared to patients with other diseases treated with infliximab products over the long term is not known. The data reflect the percentage of patients whose test results were positive for antibodies to infliximab in an ELISA assay, and they are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to infliximab products with the incidence of antibodies to other products may be misleading. Hepatotoxicity Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported rarely in patients receiving infliximab products [see Warnings and Precautions (5.4) ]. Reactivation of HBV has occurred in patients receiving TNF blocking agents, including infliximab products, who are chronic carriers of this virus [see Warnings and Precautions (5.3) ]. In clinical trials in rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis, elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving infliximab than in controls (Table 1), both when infliximab was given as monotherapy and when it was used in combination with other immunosuppressive agents. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of infliximab, or modification of concomitant medications. Table 1 Proportion of patients with elevated ALT in clinical trials Proportion of patients with elevated ALT >1 to 3 × ULN ≥3 × ULN ≥5 × ULN Placebo Infliximab Placebo Infliximab Placebo Infliximab Rheumatoid arthritisPlacebo patients received methotrexate while patients treated with infliximab received both infliximab and methotrexate. Median follow-up was 58 weeks. 24% 34% 3% 4% <1% <1% Crohn's diseasePlacebo patients in the 2 Phase 3 trials in Crohn's disease received an initial dose of 5 mg/kg infliximab 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 are included in the infliximab group in ALT analysis. Median follow-up was 54 weeks. 34% 39% 4% 5% 0% 2% Ulcerative colitisMedian follow-up was 30 weeks. Specifically, the median duration of follow-up was 30 weeks for placebo and 31 weeks for infliximab. 12% 17% 1% 2% <1% <1% Ankylosing spondylitisMedian follow-up was 24 weeks for the placebo group and 102 weeks for infliximab group. 15% 51% 0% 10% 0% 4% Psoriatic arthritisMedian follow-up was 39 weeks for infliximab group and 18 weeks for the placebo group. 16% 50% 0% 7% 0% 2% Plaque psoriasisALT values are obtained in 2 Phase 3 psoriasis studies with median follow-up of 50 weeks for infliximab and 16 weeks for placebo. 24% 49% <1% 8% 0% 3% Adverse Reactions in Psoriasis Studies During the placebo-controlled portion across the 3 clinical trials up to week 16, the proportion of patients who experienced at least 1 serious adverse reaction (SAE; defined as resulting in death, life threatening, requires hospitalization, or persistent or significant disability/incapacity) was 0.5% in the 3 mg/kg infliximab group, 1.9% in the placebo group, and 1.6% in the 5 mg/kg infliximab group. Among patients in the 2 Phase 3 studies, 12.4% of patients receiving infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 SAE in Study I. In Study II, 4.1% and 4.7% of patients receiving infliximab 3 mg/kg and 5 mg/kg every 8 weeks, respectively, through 1 year of maintenance treatment experienced at least 1 SAE. One death due to bacterial sepsis occurred 25 days after the second infusion of 5 mg/kg of infliximab. Serious infections included sepsis, and abscesses. In Study I, 2.7% of patients receiving infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 serious infection. In Study II, 1.0% and 1.3% of patients receiving infliximab 3 mg/kg and 5 mg/kg, respectively, through 1 year of treatment experienced at least 1 serious infection. The most common serious infection (requiring hospitalization) was abscess (skin, throat, and peri-rectal) reported by 5 (0.7%) patients in the 5 mg/kg infliximab group. Two active cases of tuberculosis were reported: 6 weeks and 34 weeks after starting infliximab. In the placebo-controlled portion of the psoriasis studies, 7 of 1123 patients who received infliximab at any dose were diagnosed with at least one NMSC compared to 0 of 334 patients who received placebo. In the psoriasis studies, 1% (15/1373) of patients experienced serum sickness or a combination of arthralgia and/or myalgia with fever, and/or rash, usually early in the treatment course. Of these patients, 6 required hospitalization due to fever, severe myalgia, arthralgia, swollen joints, and immobility. Other Adverse Reactions Safety data are available from 4779 adult patients treated with infliximab, including 1304 with rheumatoid arthritis, 1106 with Crohn's disease, 484 with ulcerative colitis, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 1373 with plaque psoriasis and 17 with other conditions. [For information on other adverse reactions in pediatric patients, see Adverse Reactions (6.1) ]. Adverse reactions reported in ≥5% of all patients with rheumatoid arthritis receiving 4 or more infusions are in Table 2. The types and frequencies of adverse reactions observed were similar in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis and Crohn's disease patients treated with infliximab except for abdominal pain, which occurred in 26% of patients with Crohn's disease. In the Crohn's disease studies, there were insufficient numbers and duration of follow-up for patients who never received infliximab to provide meaningful comparisons. Table 2 Adverse reactions occurring in 5% or more of patients receiving 4 or more infusions for rheumatoid arthritis Placebo Infliximab (n=350) (n=1129) Average weeks of follow-up 59 66 Gastrointestinal Nausea 20% 21% Abdominal pain 8% 12% Diarrhea 12% 12% Dyspepsia 7% 10% Respiratory Upper respiratory tract infection 25% 32% Sinusitis 8% 14% Pharyngitis 8% 12% Coughing 8% 12% Bronchitis 9% 10% Skin and appendages disorders Rash 5% 10% Pruritus 2% 7% Body as a whole-general disorder Fatigue 7% 9% Pain 7% 8% Resistance mechanism disorders Fever 4% 7% Moniliasis 3% 5% Central and peripheral nervous system disorders Headache 14% 18% Musculoskeletal system disorders Arthralgia 7% 8% Urinary system disorders Urinary tract infection 6% 8% Cardiovascular disorders, general Hypertension 5% 7% The most common serious adverse reactions observed in clinical trials of infliximab were infections [see Adverse Reactions (6.1) ]. Other serious, medically relevant adverse reactions ≥0.2% or clinically significant adverse reactions by body system were as follows: Body as a whole: allergic reaction, edema Blood: pancytopenia Cardiovascular: hypotension Gastrointestinal: constipation, intestinal obstruction Central and Peripheral Nervous: dizziness Heart Rate and Rhythm: bradycardia Liver and Biliary: hepatitis Metabolic and Nutritional: dehydration Platelet, Bleeding and Clotting: thrombocytopenia Neoplasms: lymphoma Red Blood Cell: anemia, hemolytic anemia Resistance Mechanism: cellulitis, sepsis, serum sickness, sarcoidosis Respiratory: lower respiratory tract infection (including pneumonia), pleurisy, pulmonary edema Skin and Appendages: increased sweating Vascular (Extracardiac): thrombophlebitis White Cell and Reticuloendothelial: leukopenia, lymphadenopathy Adverse Reactions in Pediatric Patients Pediatric Crohn's Disease There were some differences in the adverse reactions observed in the pediatric patients receiving infliximab compared to those observed in adults with Crohn's disease. These differences are discussed in the following paragraphs. The following adverse reactions were reported more commonly in 103 randomized pediatric Crohn's disease patients administered 5 mg/kg infliximab through 54 weeks than in 385 adult Crohn's disease patients receiving a similar treatment regimen: anemia (11%), leukopenia (9%), flushing (9%), viral infection (8%), neutropenia (7%), bone fracture (7%), bacterial infection (6%), and respiratory tract allergic reaction (6%). Infections were reported in 56% of randomized pediatric patients in Study Peds Crohn's and in 50% of adult patients in Study Crohn's I. In Study Peds Crohn's, infections were reported more frequently for patients who received every 8-week as opposed to every 12-week infusions (74% and 38%, respectively), while serious infections were reported for 3 patients in the every 8-week and 4 patients in the every 12-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 every 8-week and 1 in the every 12-week maintenance treatment groups). Herpes zoster was reported for 2 patients in the every 8-week maintenance treatment group. In Study Peds Crohn's, 18% of randomized patients experienced 1 or more infusion reactions, with no notable difference between treatment groups. Of the 112 patients in Study Peds Crohn's, there were no serious infusion reactions, and 2 patients had non-serious anaphylactoid reactions. In Study Peds Crohn's, in which all patients received stable doses of 6-MP, AZA, or MTX, excluding inconclusive samples, 3 of 24 patients had antibodies to infliximab. Although 105 patients were tested for antibodies to infliximab, 81 patients were classified as inconclusive because they could not be ruled as negative due to assay interference by the presence of infliximab in the sample. Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in Crohn's disease clinical trials; 4% had ALT elevations ≥3 × ULN, and 1% had elevations ≥5 × ULN. (Median follow-up was 53 weeks.) 6.2 Postmarketing Experience Adverse reactions have been identified during post approval use of infliximab products in adult and pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions, some with fatal outcome, have been reported during postapproval use of infliximab products: neutropenia [see Warnings and Precautions (5.6) ], agranulocytosis (including infants exposed in utero to infliximab), interstitial lung disease (including pulmonary fibrosis/interstitial pneumonitis and very rare rapidly progressive disease), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pericardial effusion, systemic and cutaneous vasculitis, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy), new onset and worsening psoriasis (all subtypes including pustular, primarily palmoplantar), transverse myelitis, and neuropathies (additional neurologic reactions have also been observed) [see Warnings and Precautions (5.9) ], acute liver failure, jaundice, hepatitis, and cholestasis [see Warnings and Precautions (5.4) ], serious infections [see Warnings and Precautions (5.1) ] and malignancies, including melanoma and Merkel cell carcinoma, and cervical cancer [see Warnings and Precautions (5.2) ] and vaccine breakthrough infection including bovine tuberculosis (disseminated BCG infection) following vaccination in an infant exposed in utero to infliximab [see Warnings and Precautions (5.15) ]. Infusion-related Reactions In postmarketing experience, cases of anaphylactic reactions, including laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with administration of infliximab products. Cases of transient visual loss have been reported in association with infliximab products during or within 2 hours of infusion. Cerebrovascular accidents, myocardial ischemia/infarction (some fatal), and arrhythmia occurring within 24 hours of initiation of infusion have also been reported [see Warnings and Precautions (5.8) ]. Adverse Reactions in Pediatric Patients The following serious adverse reactions have been reported in the postmarketing experience in children: infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, and hypersensitivity reactions. Serious adverse reactions in the postmarketing experience with infliximab products in the pediatric population have also included malignancies, including HSTCL [see Boxed Warning and Warnings and Precautions (5.2) ], transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.

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Dosing and administration
2 DOSAGE AND ADMINISTRATION INFLECTRA is administered by intravenous infusion over a period of not less than 2 hours. Crohn's Disease (2.1) 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some adult patients who initially respond to treatment may benefit from increasing the dose to 10 mg/kg if they later lose their response. Pediatric Crohn's Disease (2.2) 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Ulcerative Colitis (2.3) 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Rheumatoid Arthritis (2.4) In conjunction with methotrexate, 3 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some patients may benefit from increasing the dose up to 10 mg/kg or treating as often as every 4 weeks. Ankylosing Spondylitis (2.5) 5 mg/kg at 0, 2 and 6 weeks, then every 6 weeks. Psoriatic Arthritis (2.6) and Plaque Psoriasis (2.7) 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. 2.1 Crohn's Disease The recommended dose of INFLECTRA is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adults with moderately to severely active Crohn's disease or fistulizing Crohn's disease. For adult patients who respond and then lose their response, consideration may be given to treatment with 10 mg/kg. Patients who do not respond by Week 14 are unlikely to respond with continued dosing and consideration should be given to discontinue INFLECTRA in these patients. 2.2 Pediatric Crohn's Disease The recommended dose of INFLECTRA for pediatric patients 6 years and older with moderately to severely active Crohn's disease is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks. 2.3 Ulcerative Colitis The recommended dose of INFLECTRA is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adult patients with moderately to severely active ulcerative colitis. 2.4 Rheumatoid Arthritis The recommended dose of INFLECTRA is 3 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 3 mg/kg every 8 weeks thereafter for the treatment of moderately to severely active rheumatoid arthritis. 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 or treating as often as every 4 weeks bearing in mind that risk of serious infections is increased at higher doses [see Adverse Reactions (6.1) ]. 2.5 Ankylosing Spondylitis The recommended dose of INFLECTRA is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 6 weeks thereafter for the treatment of active ankylosing spondylitis. 2.6 Psoriatic Arthritis The recommended dose of INFLECTRA is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of psoriatic arthritis. INFLECTRA can be used with or without methotrexate. 2.7 Plaque Psoriasis The recommended dose of INFLECTRA is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of chronic severe (i.e., extensive and/or disabling) plaque psoriasis. 2.8 Monitoring to Assess Safety Prior to initiating INFLECTRA and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection [see Warnings and Precautions (5.1) ]. 2.9 Administration Instructions Regarding Infusion Reactions Adverse effects during administration of infliximab products have included flu-like symptoms, headache, dyspnea, hypotension, transient fever, chills, gastrointestinal symptoms, and skin rashes. Anaphylaxis might occur at any time during INFLECTRA infusion. Approximately 20% of patients in all clinical trials of infliximab experienced an infusion reaction compared with 10% of placebo-treated patients [see Adverse Reactions (6.1) ]. Prior to infusion with INFLECTRA, premedication may be administered at the physician's discretion. Premedication could include antihistamines (anti-H1 +/- anti-H2), acetaminophen and/or corticosteroids. During infusion, mild to moderate infusion reactions may improve following slowing or suspension of the infusion, and upon resolution of the reaction, reinitiation at a lower infusion rate and/or therapeutic administration of antihistamines, acetaminophen, and/or corticosteroids. For patients that do not tolerate the infusion following these interventions, INFLECTRA should be discontinued. During or following infusion, patients who have severe infusion-related hypersensitivity reactions should be discontinued from further INFLECTRA treatment. The management of severe infusion reactions should be dictated by the signs and symptoms of the reaction. Appropriate personnel and medication should be available to treat anaphylaxis if it occurs. 2.10 General Considerations and Instructions for Preparation and Administration INFLECTRA is intended for use under the guidance and supervision of a physician. The reconstituted infusion solution should be prepared by a trained medical professional using aseptic technique by the following procedure: Calculate the dose, total volume of reconstituted INFLECTRA solution required and the number of INFLECTRA vials needed. Each INFLECTRA vial contains 100 mg of the infliximab-dyyb antibody. Reconstitute each INFLECTRA vial with 10 mL of Sterile Water for Injection, USP, using a syringe equipped with a 21-gauge or smaller needle as follows: Remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Gently swirl the solution by rotating the vial to dissolve the lyophilized powder. Avoid prolonged or vigorous agitation. DO NOT SHAKE. Foaming of the solution on reconstitution is not unusual. Allow the reconstituted solution to stand for 5 minutes. The reconstituted solution concentration is 10 mg/mL. The solution should be colorless to light yellow and opalescent, and the solution may develop a few translucent particles as infliximab is a protein. Do not use if the lyophilized cake has not fully dissolved or if opaque particles, discoloration, or other foreign particles are present. Dilute the total volume of the reconstituted INFLECTRA solution dose to 250 mL with sterile 0.9% Sodium Chloride Injection, USP, by withdrawing a volume equal to the volume of reconstituted INFLECTRA from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or bag. Do not dilute the reconstituted INFLECTRA solution with any other diluent. Slowly add the total volume of reconstituted INFLECTRA solution to the 250 mL infusion bottle or bag. Gently mix. The resulting infusion concentration should range between 0.4 mg/mL and 4 mg/mL. The INFLECTRA infusion should begin within 3 hours of reconstitution and dilution. The infusion must be administered over a period of not less than 2 hours and must use an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 µm or less). The vials do not contain antibacterial preservatives. Therefore, any unused portion of the infusion solution should not be stored for reuse. No physical biochemical compatibility studies have been conducted to evaluate the coadministration of INFLECTRA with other agents. INFLECTRA should not be infused concomitantly in the same intravenous line with other agents. Parenteral drug products should be inspected visually before and after reconstitution for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulates are observed, the solution should not be used.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pediatric Use –INFLECTRA has not been studied in children with Crohn's disease or ulcerative colitis <6 years of age. (8.4) 8.1 Pregnancy Pregnancy Category B. It is not known whether infliximab products 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. Because infliximab products do not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab products. 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. As with other IgG antibodies, infliximab products cross the placenta. Infliximab has been detected in the serum of infants at up to 6 months following birth. Consequently, these infants may be at increased risk of infection, including disseminated infection which can become fatal. At least a six month waiting period following birth is recommended before the administration of live vaccines (e.g., BCG vaccine or other live vaccines, such as the rotavirus vaccine) to these infants [see Warnings and Precautions (5.15) ]. Cases of agranulocytosis in infants exposed in utero have also been reported [See Adverse Reactions (6.2) ] 8.3 Nursing Mothers It is not known whether infliximab products are excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from infliximab products, women should not breast-feed their infants while taking 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. 8.4 Pediatric Use The safety and effectiveness of infliximab products have been established in pediatric patients 6 to 17 years of age for induction and maintenance treatment of Crohn's disease. However, infliximab products have not been studied in children with Crohn's disease or ulcerative colitis <6 years of age. Pediatric Crohn's Disease INFLECTRA is indicated for reducing signs and symptoms and 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 [see Boxed Warning, Warnings and Precautions (5), Indications and Usage (1.2), Dosage and Administration (2.2), Clinical Studies (14.2) and Adverse Reactions (6.1) ]. Infliximab has been studied only in combination with conventional immunosuppressive therapy in pediatric Crohn's disease. The longer term (greater than 1 year) safety and effectiveness of infliximab products in pediatric Crohn's disease patients have not been established in clinical trials. A pediatric assessment for INFLECTRA demonstrates that INFLECTRA is safe and effective in another pediatric indication. However, INFLECTRA is not approved for such indication due to marketing exclusivity for REMICADE (infliximab). Juvenile Rheumatoid Arthritis (JRA) The safety and efficacy of infliximab in patients with juvenile rheumatoid arthritis (JRA) were evaluated in a multicenter, randomized, placebo-controlled, double-blind study for 14 weeks, followed by a double-blind, all-active treatment extension, for a maximum of 44 weeks. Patients with active JRA between the ages of 4 and 17 years who had been treated with MTX for at least 3 months were enrolled. Concurrent use of folic acid, oral corticosteroids (≤0.2 mg/kg/day of prednisone or equivalent), NSAIDs, and/or disease modifying antirheumatic drugs (DMARDs) was permitted. Doses of 3 mg/kg of infliximab or placebo were administered intravenously at Weeks 0, 2 and 6. Patients randomized to placebo crossed-over to receive 6 mg/kg of infliximab at Weeks 14, 16, and 20, and then every 8 weeks through Week 44. Patients who completed the study continued to receive open-label treatment with infliximab for up to 2 years in a companion extension study. The study failed to establish the efficacy of infliximab in the treatment of JRA. Key observations in the study included a high placebo response rate and a higher rate of immunogenicity than what has been observed in adults. Additionally, a higher rate of clearance of infliximab was observed than had been observed in adults [see Clinical Pharmacology (12.3) ]. A total of 60 patients with JRA were treated with doses of 3 mg/kg and 57 patients were treated with doses of 6 mg/kg. The proportion of patients with infusion reactions who received 3 mg/kg infliximab was 35% (21/60) over 52 weeks compared with 18% (10/57) in patients who received 6 mg/kg over 38 weeks. The most common infusion reactions reported were vomiting, fever, headache, and hypotension. In the 3 mg/kg infliximab group, 4 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were among the serious infusion reactions). In the 6 mg/kg infliximab group, 2 patients had a serious infusion reaction, 1 of whom had a possible anaphylactic reaction. Two of the 6 patients who experienced serious infusion reactions received infliximab by rapid infusion (duration of less than 2 hours). Antibodies to infliximab developed in 38% (20/53) of patients who received 3 mg/kg infliximab compared with 12% (6/49) of patients who received 6 mg/kg. A total of 68% (41/60) of patients who received 3 mg/kg of infliximab in combination with MTX experienced an infection over 52 weeks compared with 65% (37/57) of patients who received 6 mg/kg of infliximab in combination with MTX over 38 weeks. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was pneumonia. Other notable infections included primary varicella infection in 1 patient and herpes zoster in 1 patient. 8.5 Geriatric Use In rheumatoid arthritis and plaque psoriasis clinical trials, no overall differences were observed in effectiveness or safety in 181 patients with rheumatoid arthritis and 75 patients with plaque psoriasis, aged 65 or older who received infliximab, compared to younger patients – although the incidence of serious adverse reactions in patients aged 65 or older was higher in both infliximab and control groups compared to younger patients. In Crohn's disease, ulcerative colitis, ankylosing spondylitis and psoriatic arthritis studies, there were insufficient numbers of patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. There is a greater incidence of infections in the elderly population in general. The incidence of serious infections in patients 65 years and older treated with infliximab was greater than in those under 65 years of age; therefore caution should be used in treating the elderly [see Adverse Reactions (6.1) ].
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether infliximab products are excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from infliximab products, women should not breast-feed their infants while taking 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.

Interactions

7 DRUG INTERACTIONS Use with anakinra or abatacept– increased risk of serious infections (7.1) 7.1 Use with Anakinra or Abatacept An increased risk of serious infections was seen in clinical studies of other TNFα blocking agents used in combination with anakinra or abatacept, with no added clinical benefit. Because of the nature of the adverse reactions seen with these combinations with TNF blocker therapy, similar toxicities may also result from the combination of anakinra or abatacept with other TNFα blocking agents. Therefore, the combination of INFLECTRA and anakinra or abatacept is not recommended [see Warnings and Precautions (5.10 and 5.11) ]. 7.2 Use with Tocilizumab The use of tocilizumab in combination with biological DMARDs such as TNF antagonists, including INFLECTRA, should be avoided because of the possibility of increased immunosuppression and increased risk of infection. 7.3 Use with Other Biological Therapeutics The combination of INFLECTRA with other biological therapeutics used to treat the same conditions as INFLECTRA is not recommended [see Warnings and Precautions (5.12) ]. 7.4 Methotrexate (MTX) and Other Concomitant Medications Specific drug interaction studies, including interactions with MTX, have not been conducted. The majority of patients in rheumatoid arthritis or Crohn's disease clinical studies received one or more concomitant medications. In rheumatoid arthritis, concomitant medications besides MTX were nonsteroidal anti-inflammatory agents (NSAIDs), folic acid, corticosteroids and/or narcotics. Concomitant Crohn's disease medications were antibiotics, anti-virals, corticosteroids, 6-MP/AZA and aminosalicylates. In psoriatic arthritis clinical trials, concomitant medications included MTX in approximately half of the patients as well as NSAIDs, folic acid and corticosteroids. Concomitant MTX use may decrease the incidence of anti-infliximab antibody production and increase infliximab concentrations. 7.5 Immunosuppressants Patients with Crohn's disease who received immunosuppressants tended to experience fewer infusion reactions compared to patients on no immunosuppressants [see Adverse Reactions (6.1) ]. Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of Crohn's disease including corticosteroids, antibiotics (metronidazole or ciprofloxacin) and aminosalicylates. 7.6 Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, interleukin-1 (IL-1), IL-6, IL-10, IFN) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as infliximab products, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of 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. 7.7 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 products for at least 6 months following birth [see Warnings and Precautions (5.15) ]. It is recommended that therapeutic infectious agents not be given concurrently with INFLECTRA [see Warnings and Precautions (5.15) ].

More information

Category Value
Authorisation number BLA125544
Agency product number B72HH48FLU
Orphan designation No
Product NDC 0069-0809
Date Last Revised 21-11-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1790541
Storage and handling Storage and Stability INFLECTRA must be refrigerated at 2°C to 8°C (36°F to 46°F). Do not use INFLECTRA beyond the expiration date (Exp) located on the carton and the vial. This product contains no preservative.
Marketing authorisation holder Pfizer Laboratories Div Pfizer Inc
Warnings WARNING: SERIOUS INFECTIONS and MALIGNANCY WARNING: SERIOUS INFECTIONS and MALIGNANCY See full prescribing information for complete boxed warning Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis) and infections due to other opportunistic pathogens. Discontinue INFLECTRA if a patient develops a serious infection. Perform test for latent TB; if positive, start treatment for TB prior to starting INFLECTRA. Monitor all patients for active TB during treatment, even if initial latent TB test is negative. (5.1) Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including infliximab products. Postmarketing cases of fatal hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF blockers, including infliximab products. Almost all had received azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of cases were reported in patients with Crohn's disease or ulcerative colitis, most of whom were adolescent or young adult males. (5.2) SERIOUS INFECTIONS Patients treated with infliximab products are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. INFLECTRA should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before INFLECTRA use and during therapy.1,2 Treatment for latent infection should be initiated prior to INFLECTRA use. Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria. The risks and benefits of treatment with INFLECTRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with INFLECTRA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including infliximab products [see Warnings and Precautions (5.2) ]. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including infliximab products. These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and most were in adolescent and young adult males.