Drug Safety-related Labeling Changes (SrLC)

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INFLECTRA (BLA-125544)

(INFLIXIMAB-DYYB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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09/03/2025 (SUPPL-55)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Neurologic Reactions

Additions and/or revisions underlined:

Infliximab products and agents that inhibit TNF have been associated with CNS manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of INFLECTRA in patients with these neurologic disorders and should consider discontinuation of INFLECTRA if these disorders develop.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

• New onset immune disorders (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

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.

06/17/2021 (SUPPL-18)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

The use of INFLECTRA at doses >5 mg/kg is contraindicated in patients with moderate or severe heart failure [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

INFLECTRA is contraindicated in patients with a previous severe hypersensitivity reaction to infliximab products or any of the inactive ingredients of INFLECTRA or any murine proteins [severe hypersensitivity reactions have included anaphylaxis, hypotension, and serum sickness] [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].

5 Warnings and Precautions

5.5 Heart Failure

Additions and/or revisions underlined:

The use of INFLECTRA at doses > 5 mg/kg is contraindicated in patients with moderate or severe heart failure. A randomized, double-blind, placebo-controlled study evaluated the use of infliximab (5 mg/kg or 10 mg/kg at Weeks 0, 2 and 6) in patients with moderate or severe heart failure [New York Heart Association (NYHA) Functional Class III/IV]. Compared to patients who received placebo, there was a higher rate of mortality and a higher risk of hospitalization at Week 28 due to heart failure in patients who received the 10 mg/kg infliximab dose, and higher rates of cardiovascular adverse events in patients who received infliximab doses of 5 mg/kg and 10 mg/kg.

There have been postmarketing reports of new onset and worsening heart failure, with and without identifiable precipitating factors (e.g., pre-existing cardiovascular disease), in patients treated with infliximab products. Some of these patients have been under 50 years of age.

If a decision is made to administer INFLECTRA (less than or equal to  5 mg/kg) to patients with moderate or severe heart failure or to administer INFLECTRA (any approved dose) to patients with mild heart failure, they should be closely monitored during therapy, and INFLECTRA should be discontinued if new or worsening symptoms of heart failure appear [see Contraindications (4) and Adverse Reactions (6.1)].

5.7 Hypersensitivity

Additions and/or revisions underlined:

Infliximab products have been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions (including anaphylaxis, urticaria, dyspnea, and/or hypotension), have occurred during or within 2 hours of infliximab product infusion …

Additions and/or revisions underlined:

5.10 Concurrent Administration with Other Biological Products

… Because of the nature of the adverse reactions seen with the concurrent use of etanercept and anakinra therapy, similar toxicities may also result from the concurrent use of anakinra and other TNF blockers. Therefore, the concurrent use of INFLECTRA and anakinra is not recommended.

In clinical studies, concurrent administration of TNF blockers and abatacept have been associated with an increased risk of infections including serious infections compared with TNF blockers alone, without increased clinical benefit. Therefore, the concurrent use of INFLECTRA and abatacept is not recommended [see Drug Interactions (7.1)].

There is insufficient information regarding the concurrent use of infliximab products with other biological products used to treat the same conditions as INFLECTRA. The concurrent use of INFLECTRA with these biological products is not recommended because of the possibility of an increased risk of infection [see Drug Interactions (7.1)].

Additions and/or revisions underlined:

5.13 Vaccinations and Use of Live Vaccines/Therapeutic Infectious Agents

Vaccinations

Prior to initiating INFLECTRA in pediatric and adult patients, update vaccinations in accordance with current vaccination guidelines.

Live Vaccines and Therapeutic Infectious Agents

In patients receiving TNF blockers, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines …

6 Adverse Reactions

6.1 Clinical Trials Experience

Infusion-Related Reactions

Additions and/or revisions underlined:

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 …

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 …

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 less than or equal to 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.

6.2 Immunogenicity

Additions and/or revisions underlined:

Table 1 Proportion of Patients with Elevated ALT in Clinical Trials in Adults

Table 2 Adverse Reactions that Occurred in greater than or equal to 5% of Patients who Received greater than or equal to 4 Infliximab Infusions for RA

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 … 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 … 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 …

Immunogenicity in Pediatric Patients with Ulcerative Colitis

… 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

Additions and/or revisions underlined:

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.

• Erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, linear IgA bullous dermatosis (LABD), acute generalized exanthematous pustulosis (AGEP), new onset and worsening psoriasis (all subtypes including pustular, primarily palmoplantar), lichenoid reactions.

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, and hypersensitivity reactions.

7 Drug Interactions

Additions and/or revisions underlined:

7.1 Other Biological Products

The combination of INFLECTRA with other biological products used to treat the same conditions as INFLECTRA is not recommended [see Warnings and Precautions (5.10)].

An increased risk of serious infections … Therefore, the combination of INFLECTRA and anakinra or abatacept is not recommended [see Warnings and Precautions (5.10)].

The concomitant use of tocilizumab with biological DMARDs such as TNF antagonists, including INFLECTRA, should be avoided because of the possibility of increased immunosuppression and increased risk of infection.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Available observational studies in pregnant women exposed to infliximab products showed no increased risk of major malformations among live births as compared to those exposed to non- biologics. However, findings on other birth and maternal outcomes were not consistent across studies of different study design and conduct (see Data).

Monoclonal antibodies such as infliximab products are transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant (see Clinical Considerations). Because infliximab products do not cross-react with TNF? in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab products. In a developmental study conducted in mice using an analogous antibody, no evidence of maternal toxicity or fetal harm was observed (see Data) …

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data suggest that there is an increased risk of adverse pregnancy outcomes in women with inflammatory bowel disease or rheumatoid arthritis associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2.5 kg) and small for gestational age at birth.

Fetal/Neonatal Adverse Reactions

As with other IgG antibodies, infliximab products cross the placenta. Infliximab products have been detected in the serum of infants up to 6 months following birth …

Data

Human Data

Two prospective cohort studies were conducted assessing birth outcomes as well as the health status of infants up to the age of one year in women exposed to infliximab compared to non- biologic comparators including methotrexate, azathioprine, 6-mercaptopurine and systemic corticosteroids used for the treatment of similar diseases. The first study was conducted in an IBD pregnancy registry in the United States and assessed pregnancy outcomes in 294 women with inflammatory bowel disease exposed to infliximab during pregnancy compared with 515 women on a non-biologic treatment. Infliximab exposure was not associated with increased rates of major congenital malformations, miscarriage/stillbirth, infants of low birth weight, small for gestational age, or infection in the first year of life. The second study among IBD and non-IBD patients in Sweden, Finland, and Denmark compared 97, 7, and 166 women exposed to infliximab to 2,693, 2,499 and 1,268 women on non-biologic systemic therapy, respectively. In this study, comparing pooled data across the three countries, exposure to infliximab was not associated with increased rates of congenital anomalies or infant death. Infliximab in combination with immunosuppressants (mainly systemic corticosteroids and azathioprine) was associated with increased rates of preterm birth, small for gestational age, low birth weight, and infant hospitalization for infection compared with non-biologic systemic treatment. Although the study did not show any associations with infliximab monotherapy, the analyses could have been underpowered to detect an association. There were additional methodological limitations with these studies that may account for the study findings in both studies: the concomitant use of other medications or treatments was not controlled and disease severity was not assessed; in the U.S. study, patient reported outcomes were collected without clinical validation. These methodological limitations hinder interpretation of the study results.

Animal Data

Because infliximab products do not cross-react with TNF? in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab products. An embryofetal development study was conducted in pregnant mice using cV1q anti-mouse TNF?, an analogous antibody that selectively inhibits the functional activity of mouse TNF?. This antibody administered in mice, during the period of organogenesis on gestation days (GDs) 6 and 12, at IV doses up to 40 mg/kg produced no evidence of maternal toxicity, fetal mortality, or structural abnormalities. Doses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness. Analyses of fetal samples on GD 14 indicated placental transfer of the antibody and exposure of the fetuses during organogenesis. In a peri-and post-natal development study in mice, no maternal toxicity or adverse developmental effects in offspring were observed when dams were administered IV doses of 10 or 40 mg/kg of the analogous antibody on GDs 6, 12 and 18 and lactation days 3, 9 and 15.

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Published literature show that infliximab is present at low levels in human milk. Systemic exposure in a breastfed infant is expected to be low because infliximab products are largely degraded in the gastrointestinal tract. A U.S. multi-center study of 168 women treated with infliximab for inflammatory bowel disease (breast milk samples obtained, n=29) showed that infants exposed to infliximab through breast milk had no increase in rates of infections and developed normally. There are no data on the effects of infliximab products on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INFLECTRA and any potential adverse effects on the breastfed child from INFLECTRA or from the underlying maternal condition.

8.4 Pediatric Use

Additions and/or revisions underlined:

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 CD and UC. [see Dosage and Administration (2.2, 2.4) and Adverse Reactions (6.1)]. However, the safety and effectiveness of infliximab products in pediatric patients <6 years of age with CD or UC have not been established. The safety and effectiveness of infliximab products in the treatment of pediatric patients with Ps and juvenile rheumatoid arthritis (JRA) have not been established.

Pediatric Crohn’s Disease

The safety and effectiveness of infliximab products have been established 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 CD who have had an inadequate response to conventional therapy. The use of infliximab for this indication is supported by evidence from a randomized, open-label pediatric CD study in 112 pediatric patients aged 6 years and older [see Clinical Studies (14.2)].

Due to the risk of HSTCL, a careful risk-benefit assessment should be made when INFLECTRA is used in combination with other immunosuppressants in pediatric UC patients [see Boxed Warning and Warnings and Precautions (5.2)].

The longer term (greater than 1 year) safety and effectiveness of infliximab products in pediatric UC patients have not been established in clinical trials.

Juvenile Rheumatoid Arthritis (JRA)

The safety and effectiveness of infliximab products in the treatment of pediatric patients with juvenile rheumatoid arthritis (JRA) have not been established.

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.

Population pharmacokinetic analysis showed that in pediatric patients with JRA with a body weight of up to 35 kg receiving 6 mg/kg infliximab and pediatric patients with JRA with body weight greater than 35 kg up to adult body weight receiving 3 mg/kg infliximab, the steady state area under the concentration curve (AUCss) was similar to that observed in adults receiving 3 mg/kg of infliximab.

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.

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the total number of infliximab-treated patients in RA and Ps clinical studies, 256 (9.6%) were 65 years old and over, while 17 (0.6%) were 75 years old and over. In these trials, no overall differences in safety or effectiveness were observed between geriatric patients (patients greater than or equal to 65 years old) and younger adult patients (patients 18 to 65 years old). However, the incidence of serious adverse reactions in geriatric patients was higher in both infliximab and control groups compared to younger adult patients.

Of the total number of infliximab-treated patients in CD, UC, AS, and PsA clinical studies, 76 (3.2%) were 65 years old and over, while 9 (0.4%) were 75 years old and over. In the CD, UC, AS, and PsA studies, there were insufficient numbers of geriatric patients to determine whether they respond differently from younger adults.

The incidence of serious infections in  infliximab-treated geriatric patients was greater than in infliximab-treated younger adult patients; therefore close monitoring of geriatric patients for the development of serious infections is recommended [see Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

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 INFLECTRA?

INFLECTRA is a prescription medicine that is approved for patients with:

• Ankylosing Spondylitis in adults

• Psoriatic Arthritis in adults

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient or their caregiver to read the FDA-Approved Patient Labeling (Medication Guide).

Patients or their caregivers should be advised of the potential benefits and risks of INFLECTRA. Healthcare providers should instruct their patients or their caregivers to read the Medication Guide before starting INFLECTRA therapy and to reread it each time they receive an infusion.

Infections

Inform patients that INFLECTRA increases the risk for developing serious infections. Instruct patients of the importance of contacting their healthcare provider if they develop any symptoms of an infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections [see Warnings and Precautions (5.1, 5.3)].

Malignancies

Malignancies have been reported among children, adolescents and young adults who received treatment with TNF blockers. Patients should be counseled about the risk of lymphoma and other malignancies while receiving INFLECTRA [see Warnings and Precautions (5.2)].

Hepatotoxicity

Instruct patients to seek medical attention if they develop signs or symptoms of hepatotoxicity (e.g., jaundice) [see Warnings and Precautions (5.4)].

Heart Failure

Instruct patients to seek medical attention and consult their prescriber if they develop signs or symptoms of heart failure [see Contraindications (4) and Warnings and Precautions (5.5)].

Hematologic Reactions

Instruct patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever) while on INFLECTRA [see Warnings and Precautions (5.6)].

Hypersensitivity

Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.7)].

Cardiovascular and Cerebrovascular Reactions During and After Infusion

Advise patients to seek immediate medical attention if they develop any new or worsening symptoms of cardiovascular and cerebrovascular reactions which have been reported during and within 24 hours of initiation of INFLECTRA infusion [see Warnings and Precautions (5.8)].

Neurologic Reactions

Advise patients to seek medical attention if they develop signs or symptoms of neurologic reactions [see Warnings and Precautions (5.9)].

Live Vaccines/Therapeutic Infectious Agents

Instruct INFLECTRA-treated patients to avoid receiving live vaccines or therapeutic infectious agents [see Warnings and Precautions (5.13)].

06/18/2019 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Infections

(Additions and/or revisions underlined)

Patients treated with infliximab products are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, salmonellosis and tuberculosis have been reported with TNF blockers.  Patients have frequently presented with disseminated rather than localized disease.

5.5 Patients with Heart Failure

(Additions and/or revisions underlined)

… If a decision is made to administer INFLECTRA to patients with heart failure, they should be closely monitored during therapy, and INFLECTRA should be discontinued if new or worsening symptoms of heart failure appear.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Adverse Reactions in Adults

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.

…

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 ulcerative colitis where the incidence of antibodies to infliximab was detected using both the EIA and ECLIA methods.

Hepatotoxicity

… 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.

Adverse Reactions in Pediatric Patients

Pediatric Ulcerative Colitis

Overall, the adverse reactions reported in the pediatric ulcerative colitis trial and adult ulcerative colitis (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 Crohn’s disease study (Study Peds Crohn’s) but higher than the proportion in the adults’ ulcerative colitis 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.

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.

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 greater than or equal to 3 x ULN, and 2% (1/60) had elevations greater than or equal to 5 x 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 Postmarketing Experience

(Additions and/or revisions underlined)

… serious infections and malignancies, including leukemia, melanoma and, Merkel cell carcinoma, and cervical cancer and vaccine breakthrough infection including bovine tuberculosis (disseminated BCG infection) following vaccination in an infant exposed in utero to infliximab products.

Infusion-related Reactions

In postmarketing experience, cases of anaphylactic reactions, including anaphylactic shock, laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with administration of infliximab products.

7 Drug Interactions

7.4 Methotrexate (MTX) and Other Concomitant Medications

(Additions and/or revisions underlined)

… Concomitant MTX use may decrease the incidence of anti-drug antibody production and increase infliximab product concentrations.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR); Additions and/or revisions underlined)

Risk Summary

Available data from published literature on the use of infliximab products can cause fetal harm when during pregnancy have not reported a clear association with infliximab products and adverse pregnancy outcomes. Infliximab products cross the placenta and infants exposed in utero should not be administered to a pregnant womanlive vaccines for at least 6 months after birth. 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 TNF alpha.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Infliximab products cross the placenta, and have been detected in the serum of infants up to 6 months following birth. Consequently, these infants may be at increased risk of infection, including disseminated infection which can become fatal. a pregnant woman only if clearly needed. 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. Cases of agranulocytosis in infants exposed in utero have also been reported.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR); Additions and/or revisions underlined)

Risk Summary

Available information is insufficient to assess the amount of infliximab products present in human milk, and the effects on breastfed infants. There are no data on the effects of infliximab products on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for an infliximab product and any potential adverse effects on the breastfed infant from infliximab products or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions underlined)

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. or ulcerative colitis.

Pediatric Ulcerative Colitis

The safety and effectiveness of infliximab products for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy are supported by evidence from adequate and well-controlled studies of infliximab in adults. Additional safety and pharmacokinetic data were collected in 60 pediatric patients aged 6 years and older. The effectiveness of infliximab in inducing and maintaining mucosal healing could not be established. Although 41 patients had a Mayo endoscopy subscore of 0 or 1 at the Week 8 endoscopy, the induction phase was open-label and lacked a control group. Only 9 patients had an optional endoscopy at Week 54.

In the pediatric UC trial, approximately half of the patients were on concomitant immunomodulators (AZA, 6-MP, MTX) at study start. Due to the risk of HSTCL, a careful risk-benefit assessment should be made when INFLECTRA is used in combination with other immunosuppressants.

The longer term (greater than 1 year) safety and effectiveness of infliximabproducts in pediatric ulcerative colitis patients have not been established in clinical trials.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Newly added information; please refer to label for complete information)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-Approved Patient Labeling (Medication Guide)

…

07/27/2018 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Malignancies

(Additions and/or revisions are underlined)

Cervical Cancer

A population-based retrospective cohort study using data from Swedish national health registries found a 2 to 3 fold increase in the incidence of invasive cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the general population, particularly those over 60 years of age. A causal relationship between infliximab products and cervical cancer cannot be excluded. Periodic screening should continue in women treated with infliximab products.

5.8 Cardiovascular and Cerebrovascular Reactions During and After Infusion

(Newly Added Subsection)

Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of infliximab infusion. Cases of transient visual loss have been reported during or within 2 hours of infusion of infliximab. Monitor patients during infusion and if serious reaction occurs, discontinue infusion. Further management of reactions should be dictated by signs and symptoms.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

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, , 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), acute liver failure, jaundice, hepatitis, and cholestasis, serious infections, and malignancies, including melanoma and Merkel cell carcinoma, and cervical cancer…

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.

8 Use in Specific Populations

8.1 Pregnancy

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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. Cases of agranulocytosis in infants exposed in utero have also been reported.