INFLECTRA® (infliximab-dyyb) 6 ADVERSE REACTIONS

(infliximab-dyyb)

Prescribing Information

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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

Adverse Reactions in Adults

The data described herein reflect exposure to infliximab in 4779 adult patients (1304 patients with RA, 1106 patients with CD, 202 with AS, 293 with PsA, 484 with UC, 1373 with Ps, 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

Adverse Reactions During or Shortly After Infusion

An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In all the clinical studies, approximately 20% of infliximab-treated patients experienced an infusion reaction compared with 10% of placebo-treated patients. Of infliximab-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period.

Among all infliximab infusions, 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 Ps through 1 year in Ps 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 Ps 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 (6.2) and Drug Interactions (7.3)].

Infusion Reactions Following Re-administration

In a clinical trial of patients with moderate to severe Ps 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 induction 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 Re-administration

In Ps 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 (TB) was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of TB, including disseminated TB, also have been reported postmarketing. Most of these cases of TB 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 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 TB, 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 CD developed a new fistula-related abscess.

In clinical studies with infliximab in patients with UC, 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 UC 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 RA and CD. Of these infliximab-treated patients, 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% 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 [see Warnings and Precautions (5.2)].

Adverse Reactions in Patients with NYHA Class III/IV Heart Failure

In a randomized, double-blind study evaluating infliximab in moderate or 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 products have not been studied in patients with mild heart failure (NYHA Class I/II) [see Contraindications (4) and Warnings and Precautions (5.5)].

Hepatotoxicity

Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported in patients receiving infliximab products [see Warnings and Precautions (5.4)]. Reactivation of hepatitis B virus has occurred in patients receiving TNF blockers, including infliximab products, who are chronic carriers of this virus [see Warnings and Precautions (5.3)].

In clinical trials in RA, CD, UC, AS, Ps, and PsA, 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 in Adults
	Proportion of patients with elevated ALT
	>1 to 3 × ULN		≥3 × ULN		≥5 × ULN
	Placebo	Infliximab	Placebo	Infliximab	Placebo	Infliximab
* Placebo patients received methotrexate while patients treated with infliximab received both infliximab and methotrexate. Median follow-up was 58 weeks. † Placebo patients in the 2 Phase 3 trials in CD 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. ‡ Median follow-up was 30 weeks. Specifically, the median duration of follow-up was 30 weeks for placebo and 31 weeks for infliximab. § Median follow-up was 24 weeks for the placebo group and 102 weeks for infliximab group. ¶ Median follow-up was 39 weeks for infliximab group and 18 weeks for the placebo group. # ALT values are obtained in 2 Phase 3 Ps studies with median follow-up of 50 weeks for infliximab and 16 weeks for placebo.
Rheumatoid arthritis*	24%	34%	3%	4%	<1%	<1%
Crohn's disease†	34%	39%	4%	5%	0%	2%
Ulcerative colitis‡	12%	17%	1%	2%	<1%	<1%
Ankylosing spondylitis§	15%	51%	0%	10%	0%	4%
Psoriatic arthritis¶	16%	50%	0%	7%	0%	2%
Plaque psoriasis#	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 Ps 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 Ps 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 in Adults

Safety data are available from 4779 infliximab-treated adult patients, including 1304 with RA, 1106 with CD, 484 with UC, 202 with AS, 293 with PsA, 1373 with Ps 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 RA receiving 4 or more infusions are in Table 2. The types and frequencies of adverse reactions observed were similar in infliximab-treated RA, AS, PsA, Ps and CD patients except for abdominal pain, which occurred in 26% of infliximab-treated patients with CD. In the CD studies, there were insufficient numbers and duration of follow-up for patients who never received infliximab to provide meaningful comparisons.

Table 2 Adverse Reactions that Occurred in ≥ 5% of Patients who Received ≥ 4 Infliximab Infusions for RA
	Placebo	Infliximab
	(n=350)	(n=1129)
Average weeks of follow-up	59 weeks	66 weeks
Upper respiratory tract infection	25%	32%
Nausea	20%	21%
Headache	14%	18%
Sinusitis	8%	14%
Diarrhea	12%	12%
Abdominal pain	8%	12%
Pharyngitis	8%	12%
Coughing	8%	12%
Bronchitis	9%	10%
Rash	5%	10%
Dyspepsia	7%	10%
Fatigue	7%	9%
Urinary tract infection	6%	8%
Pain	7%	8%
Arthralgia	7%	8%
Pruritus	2%	7%
Fever	4%	7%
Hypertension	5%	7%
Moniliasis	3%	5%

The most common serious adverse reactions observed in clinical trials 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

Adverse Reactions in Pediatric Patients with 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 CD. These differences are discussed in the following paragraphs.

The following adverse reactions were reported more commonly in 103 randomized pediatric CD patients administered 5 mg/kg infliximab through 54 weeks than in 385 adult CD 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.

Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in CD clinical trials; 4% had ALT elevations ≥3 × ULN, and 1% had elevations ≥5 × ULN. (Median follow-up was 53 weeks).

Adverse Reactions in Pediatric Patients with Ulcerative Colitis

Overall, the adverse reactions reported in the pediatric UC trial and adult UC (Study UC I and Study UC II) studies were generally consistent. In a pediatric UC trial, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache.

Infections were reported in 31 (52%) of 60 treated patients in the pediatric UC trial and 22 (37%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in the pediatric UC trial was similar to that in the pediatric CD study (Study Peds Crohn's) but higher than the proportion in the adults' UC studies (Study UC I and Study UC II). The overall incidence of infections in the pediatric UC trial was 13/22 (59%) in the every 8 week maintenance treatment group. Upper respiratory tract infection (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most frequently reported respiratory system infections. Serious infections were reported in 12% (7/60) of all treated patients.

Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 17% (10/60) of pediatric patients in the pediatric UC trial; 7% (4/60) had ALT elevations ≥3 × ULN, and 2% (1/60) had elevations ≥5 × ULN (median follow-up was 49 weeks).

Overall, 8 of 60 (13%) treated patients experienced one or more infusion reactions, including 4 of 22 (18%) patients in the every 8-week treatment maintenance group. No serious infusion reactions were reported.

In the pediatric UC trial, 45 patients were in the 12 to 17 year age group and 15 in the 6 to 11 year age group. 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 (40% vs. 18%) and discontinuation due to adverse events (40% vs. 16%) 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 (60% vs. 49%), for serious infections, the proportions were similar in the two age groups (13% in the 6 to 11 year age group vs. 11% in the 12 to 17 year age group). Overall proportions of adverse reactions, including infusion reactions, were similar between the 6 to 11 and 12 to 17 year age groups (13%).

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other infliximab products may be misleading.

Treatment with infliximab products can be associated with the development of antibodies to infliximab products. 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 was based on the original EIA method in all clinical studies of infliximab except for the Phase 3 study in pediatric patients with UC where the incidence of antibodies to infliximab was detected using both the EIA and ECLIA methods.

Immunogenicity in Adult Patients

The incidence of antibodies to infliximab in patients with RA and CD given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through 1 to 2 years of infliximab treatment. A higher incidence of antibodies to infliximab was observed in CD patients receiving infliximab after drug-free intervals >16 weeks. In a PsA study 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. Antibody development was lower among RA and CD patients receiving immunosuppressant therapies such as 6-MP/AZA or MTX. Patients who were antibody-positive were more likely to have higher rates of clearance, have reduced efficacy, and to experience an infusion reaction than were patients who were antibody negative [see Adverse Reactions (6.1)]. In the Ps 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 Ps 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 Ps patients as compared to patients with other diseases treated with infliximab products over the long term is not known.

Immunogenicity in Pediatric Patients with Crohn's Disease

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.

Immunogenicity in Pediatric Patients with Ulcerative Colitis

In the pediatric UC trial, 58 patients were evaluated for antibodies to infliximab using the EIA as well as the drug-tolerant ECLIA. With the EIA, 4 of 58 (7%) patients had antibodies to infliximab. With the ECLIA, 30 of 58 (52%) patients had antibodies to infliximab. The higher incidence of antibodies to infliximab by the ECLIA method was due to the 60-fold higher sensitivity compared to the EIA method. While EIA-positive patients generally had undetectable trough infliximab concentrations, ECLIA-positive patients could have detectable trough concentrations of infliximab because the ECLIA assay is more sensitive and drug-tolerant.

6.3 Postmarketing Experience

Adverse reactions, some with fatal outcomes, 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.

Postmarketing Adverse Reactions in Adults and Pediatric Patients

•: Neutropenia [see Warnings and Precautions (5.6)], agranulocytosis (including infants exposed in utero to infliximab products), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura.
•: Interstitial lung disease (including pulmonary fibrosis/interstitial pneumonitis and rapidly progressive disease).
•: Pericardial effusion, systemic and cutaneous vasculitis.
•: Erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, linear IgA bullous dermatosis (LABD), acute generalized exanthematous pustulosis (AGEP), worsening psoriasis (all subtypes including pustular, primarily palmoplantar), lichenoid reactions.
•: Peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy) 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 vaccine breakthrough infection including bovine tuberculosis (disseminated BCG infection) following vaccination in an infant exposed in utero to infliximab products [see Warnings and Precautions (5.13)].
•: Malignancies, including leukemia, melanoma, Merkel cell carcinoma, and cervical cancer [see Warnings and Precautions (5.2)]
•: Anaphylactic reactions, including anaphylactic shock, laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with administration of infliximab products.
•: 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)].
•: New onset immune disorders (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease).

Postmarketing Serious Adverse Reactions in Pediatric Patients

The following serious adverse reactions have been reported in the postmarketing experience in pediatric patients: infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, hypersensitivity reactions, malignancies, including hepatosplenic T-cell lymphomas [see Boxed Warning and Warnings and Precautions (5.2)], transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.

Medication Guide

MEDICATION GUIDE

This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: September 2025
MEDICATION GUIDE INFLECTRA® (In-flec-tra) (infliximab-dyyb) for injection, for intravenous use
Read the Medication Guide that comes with INFLECTRA before you receive the first treatment, and before each time you get a treatment of INFLECTRA. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. What is the most important information I should know about INFLECTRA? INFLECTRA may cause serious side effects, including: 1. Risk of infection INFLECTRA is a medicine that affects your immune system. INFLECTRA can lower the ability of your immune system to fight infections. Serious infections have happened in patients receiving INFLECTRA. These infections include tuberculosis (TB) and infections caused by viruses, fungi, or bacteria that have spread throughout the body. Some patients have died from these infections. • Your doctor should test you for TB before starting INFLECTRA. • Your doctor should monitor you closely for signs and symptoms of TB during treatment with INFLECTRA. Before starting INFLECTRA, tell your doctor if you: • think you have an infection. You should not start receiving INFLECTRA if you have any kind of infection. • are being treated for an infection. • have signs of an infection, such as a fever, cough, flu-like symptoms. • have any open cuts or sores on your body. • get a lot of infections or have infections that keep coming back. • have diabetes or an immune system problem. People with these conditions have a higher chance for infections. • have TB, or have been in close contact with someone with TB. • live or have lived in certain parts of the country (such as the Ohio and Mississippi River valleys) where there is an increased risk for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, or blastomycosis). These infections may develop or become more severe if you receive INFLECTRA. If you do not know if you have lived in an area where histoplasmosis, coccidioidomycosis, or blastomycosis is common, ask your doctor. • have or have had hepatitis B. • use the medicines KINERET (anakinra), ORENCIA (abatacept), ACTEMRA (tocilizumab), or other medicines called biologics used to treat the same conditions as INFLECTRA. After starting INFLECTRA, if you have an infection, any sign of an infection including a fever, cough, flu-like symptoms, or have open cuts or sores on your body, call your doctor right away. INFLECTRA can make you more likely to get infections or make any infection that you have worse. 2. Risk of Cancer • There have been cases of unusual cancers in children and teenage patients using tumor necrosis factor (TNF) blocker medicines, such as INFLECTRA. • For children and adults receiving TNF blocker medicines, including INFLECTRA, the chances of getting lymphoma or other cancers may increase. • Some people receiving TNF blockers, including INFLECTRA, developed a rare type of cancer called hepatosplenic T-cell lymphoma. This type of cancer often results in death. Most of these people were male teenagers or young men. Also, most people were being treated for Crohn's disease or ulcerative colitis with a TNF blocker and another medicine called azathioprine or 6-mercaptopurine. • People who have been treated for rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis for a long time may be more likely to develop lymphoma. This is especially true for people with very active disease. • Some people treated with infliximab products, such as INFLECTRA, have developed certain kinds of skin cancer. If any changes in the appearance of your skin or growths on your skin occur during or after your treatment with INFLECTRA, tell your doctor. • Patients with Chronic Obstructive Pulmonary Disease (COPD), a specific type of lung disease, may have an increased risk for getting cancer while being treated with INFLECTRA. • Some women being treated for rheumatoid arthritis with infliximab products have developed cervical cancer. For women receiving INFLECTRA, including those over 60 years of age, your doctor may recommend that you continue to be regularly screened for cervical cancer. • Tell your doctor if you have ever had any type of cancer. Discuss with your doctor any need to adjust medicines you may be taking. See the section "What are the possible side effects of INFLECTRA?" below for more information.
What is INFLECTRA? INFLECTRA is a prescription medicine that is approved for patients with: • Rheumatoid Arthritis - adults with moderately to severely active rheumatoid arthritis, along with the medicine methotrexate. • Crohn's Disease - children 6 years and older and adults with Crohn's disease who have not responded well to other medicines. • Ankylosing Spondylitis in adults • Psoriatic Arthritis in adults • Plaque Psoriasis - adult patients with plaque psoriasis that is chronic (does not go away) severe, extensive, and/or disabling. • Ulcerative Colitis – children 6 years and older and adults with moderately to severely active ulcerative colitis who have not responded well to other medicines. INFLECTRA blocks the action of a protein in your body called tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is made by your body's immune system. People with certain diseases have too much TNF-alpha that can cause the immune system to attack normal healthy parts of the body. INFLECTRA can block the damage caused by too much TNF-alpha. It is not known if INFLECTRA is safe and effective in children under 6 years of age.
Who should not receive INFLECTRA? You should not receive INFLECTRA if you have: • heart failure, unless your doctor has examined you and decided that you are able to receive INFLECTRA. Talk to your doctor about your heart failure. • had an allergic reaction to infliximab products or any of the ingredients in INFLECTRA. See the end of this Medication Guide for a complete list of ingredients in INFLECTRA.
What should I tell my doctor before starting treatment with INFLECTRA? Your doctor will assess your health before each treatment. Tell your doctor about all of your medical conditions, including if you: • have an infection (see "What is the most important information I should know about INFLECTRA?"). • have other liver problems including liver failure. • have heart failure or other heart conditions. If you have heart failure, it may get worse while you receive INFLECTRA. • have or have had any type of cancer. • have had phototherapy (treatment with ultraviolet light or sunlight along with a medicine to make your skin sensitive to light) for psoriasis. You may have a higher chance of getting skin cancer while receiving INFLECTRA. • have COPD (Chronic Obstructive Pulmonary Disease), a specific type of lung disease. Patients with COPD may have an increased risk of getting cancer while receiving INFLECTRA. • have or have had a condition that affects your nervous system such as: o multiple sclerosis, or Guillain-Barré syndrome, or o if you experience any numbness or tingling, or o if you have had a seizure. • have recently received or are scheduled to receive a vaccine. Adults and children receiving INFLECTRA should not receive live vaccines (for example, the Bacille Calmette-Guérin [BCG] vaccine) or treatment with a weakened bacteria (such as BCG for bladder cancer). Adults and children should have all of their vaccines brought up to date before starting treatment with INFLECTRA. • are pregnant or plan to become pregnant, are breastfeeding or plan to breastfeed. You and your doctor should decide if you should receive INFLECTRA while you are pregnant or breastfeeding. If you have a baby and you were receiving INFLECTRA during your pregnancy, it is important to tell your baby's doctor and other healthcare professionals about your INFLECTRA use so they can decide when your baby should receive any vaccine. Certain vaccinations can cause infections. If you received INFLECTRA while you were pregnant, your baby may be at higher risk for getting an infection. If your baby receives a live vaccine within 6 months after birth, your baby may develop infections with serious complications that can lead to death. This includes live vaccines such as the BCG, rotavirus, or any other live vaccines. For other types of vaccines, talk with your doctor.
How should I receive INFLECTRA? • You will be given INFLECTRA through a needle placed in a vein (IV or intravenous infusion) in your arm. • Your doctor may decide to give you medicine before starting the INFLECTRA infusion to prevent or lessen side effects. • Only a healthcare professional should prepare the medicine and administer it to you. • INFLECTRA will be given to you over a period of about 2 hours. • If you have side effects from INFLECTRA, the infusion may need to be adjusted or stopped. In addition, your healthcare professional may decide to treat your symptoms. • A healthcare professional will monitor you during the INFLECTRA infusion and for a period of time afterward for side effects. Your doctor may do certain tests while you are receiving INFLECTRA to monitor you for side effects and to see how well you respond to the treatment. • Your doctor will determine the right dose of INFLECTRA for you and how often you should receive it. Make sure to discuss with your doctor when you will receive infusions and to come in for all your infusions and follow-up appointments.
What should I avoid while receiving INFLECTRA? Do not take INFLECTRA together with medicines such as KINERET (anakinra), ORENCIA (abatacept), ACTEMRA (tocilizumab), or other medicines called biologics that are used to treat the same conditions as INFLECTRA. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. These include any other medicines to treat Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or psoriasis. Know the medicines you take. Keep a list of your medicines and show them to your doctor and pharmacist when you get a new medicine.
What are the possible side effects of INFLECTRA? INFLECTRA can cause serious side effects, including: See "What is the most important information I should know about INFLECTRA?". Serious Infections • Some patients, especially those 65 years and older have had serious infections while receiving infliximab products, such as INFLECTRA. These serious infections include TB and infections caused by viruses, fungi, or bacteria that have spread throughout the body or cause infections in certain areas (such as skin). Some patients die from these infections. If you get an infection while receiving treatment with INFLECTRA your doctor will treat your infection and may need to stop your INFLECTRA treatment. • Tell your doctor right away if you have any of the following signs of an infection while receiving or after receiving INFLECTRA:
	o a fever o feel very tired o have a cough o have flu-like symptoms o warm, red, or painful skin
• Your doctor will examine you for TB and perform a test to see if you have TB. If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with INFLECTRA and during treatment with INFLECTRA. • Even if your TB test is negative, your doctor should carefully monitor you for TB infections while you are receiving INFLECTRA. Patients who had a negative TB skin test before receiving infliximab products have developed active TB. • If you are a chronic carrier of the hepatitis B virus, the virus can become active while you are being treated with INFLECTRA. In some cases, patients have died as a result of hepatitis B virus being reactivated. Your doctor should do a blood test for hepatitis B virus before you start treatment with INFLECTRA and occasionally while you are being treated. Tell your doctor if you have any of the following symptoms:
	o feel unwell o poor appetite o tiredness (fatigue) o fever, skin rash, or joint pain
Heart Failure If you have a heart problem called congestive heart failure, your doctor should check you closely while you are receiving INFLECTRA. Your congestive heart failure may get worse while you are receiving INFLECTRA. Be sure to tell your doctor of any new or worse symptoms including:
	• shortness of breath • swelling of ankles or feet	• sudden weight gain
Treatment with INFLECTRA may need to be stopped if you get new or worse congestive heart failure. Other Heart Problems Some patients have experienced a heart attack (some of which led to death), low blood flow to the heart, or abnormal heart rhythm within 24 hours of beginning their infusion of infliximab products. Symptoms may include chest discomfort or pain, arm pain, stomach pain, shortness of breath, anxiety, lightheadedness, dizziness, fainting, sweating, nausea, vomiting, fluttering or pounding in your chest, and/or a fast or a slow heartbeat. Tell your doctor right away if you have any of these symptoms. Liver Injury Some patients receiving infliximab products have developed serious liver problems. Tell your doctor if you have:
	• jaundice (skin and eyes turning yellow) • dark brown-colored urine • pain on the right side of your stomach area (right-sided abdominal pain)	• fever • extreme tiredness (severe fatigue)
Blood Problems In some patients receiving infliximab products, the body may not make enough of the blood cells that help fight infections or help stop bleeding. Tell your doctor if you:
	• have a fever that does not go away • bruise or bleed very easily	• look very pale
Nervous System Disorders Some patients receiving infliximab products have developed problems with their nervous system. Tell your doctor if you have:
	• changes in your vision • numbness or tingling in any part of your body	• seizures • weakness in your arms or legs
Some patients have experienced a stroke within approximately 24 hours of their infusion with infliximab products. Tell your doctor right away if you have symptoms of a stroke which may include: numbness or weakness of the face, arm or leg, especially on one side of the body; sudden confusion, trouble speaking or understanding; sudden trouble seeing in one or both eyes, sudden trouble walking, dizziness, loss of balance or coordination or a sudden, severe headache. Allergic Reactions Some patients have had allergic reactions to infliximab products. Some of these reactions were severe. These reactions can happen while you are getting your INFLECTRA treatment or shortly afterward. Your doctor may need to stop or pause your treatment with INFLECTRA and may give you medicines to treat the allergic reaction. Signs of an allergic reaction can include:
	• hives (red, raised, itchy patches of skin) • difficulty breathing • chest pain	• high or low blood pressure • fever • chills
Some patients treated with infliximab products have had delayed allergic reactions. The delayed reactions occurred within 3 to 12 days after receiving treatment with infliximab products. Tell your doctor right away if you have any of these signs of delayed allergic reaction to INFLECTRA:
	• fever • rash • headache • sore throat	• muscle or joint pain • swelling of the face and hands • difficulty swallowing
Lupus-like Syndrome Some patients have developed symptoms that are like the symptoms of Lupus. If you develop any of the following symptoms, your doctor may decide to stop your treatment with INFLECTRA.
	• chest discomfort or pain that does not go away • shortness of breath	• joint pain • rash on the cheeks or arms that gets worse in the sun
Psoriasis Some people receiving infliximab products had new psoriasis or worsening of psoriasis they already had. Tell your doctor if you develop red scaly patches or raised bumps on the skin that are filled with pus. Your doctor may decide to stop your treatment with INFLECTRA. The most common side effects of infliximab products include:
	• respiratory infections, such as sinus infections and sore throat • headache	• coughing • stomach pain
Infusion reactions can happen up to 2 hours after your infusion of INFLECTRA. Symptoms of infusion reactions may include:
	• fever • chills • chest pain	• low blood pressure or high blood pressure • shortness of breath	• rash • itching
Children with Crohn's disease who received infliximab showed some differences in side effects of treatment compared with adults with Crohn's disease. The side effects that happened more in children were: anemia (low red blood cells), leukopenia (low white blood cells), flushing (redness or blushing), viral infections, neutropenia (low neutrophils, the white blood cells that fight infection), bone fracture, bacterial infection and allergic reactions of the breathing tract. Among patients who received infliximab for ulcerative colitis in clinical studies, more children had infections as compared with adults. Tell your doctor about any side effect that bothers you or does not go away. These are not all of the side effects with INFLECTRA. Ask your doctor or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about INFLECTRA Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your doctor or pharmacist for information about INFLECTRA that is written for health professionals. For more information go to www.pfizer.com or call 1-800-383-7504.
What are the ingredients in INFLECTRA? The active ingredient is infliximab-dyyb. The inactive ingredients in INFLECTRA include: dibasic sodium phosphate dihydrate, monobasic sodium phosphate monohydrate, polysorbate 80, and sucrose. No preservatives are present. Not made with natural rubber latex.
Manufactured by: CELLTRION, Inc. 23, Academy-ro, Yeonsu-gu, Incheon, 22014, Republic of Korea U.S. License No. 1996 ©CELLTRION, Inc. Distributed by Pfizer Labs, Division of Pfizer Inc., New York, NY 10001 For more information go to www.pfizer.com or call 1-800-383-7504.

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