Drug Safety-related Labeling Changes (SrLC)

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AVSOLA (BLA-761086)

(INFLIXIMAB-AXXQ)

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

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08/25/2025 (SUPPL-13)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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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 RA, AS, PsA, Ps and CD patients treated with infliximab 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.

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6.2 Immunogenicity

Additions and/or revisions underlined:
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of infliximab or of other infliximab products.

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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

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

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8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

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The safety and effectiveness of AVSOLA 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 AVSOLA for this indication is supported by evidence from a randomized, open-label pediatric CD study of infliximab in 112 pediatric patients aged 6 years and older [see Clinical Studies (14.2)].

…

Juvenile Rheumatoid Arthritis (JRA)

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

The safety and efficacy of AVSOLA in patients with JRA is based on the evaluation of infliximab 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 infliximab or placebo were administered intravenously at Weeks 0, 2 and 6. Patients randomized to placebo crossed over to receive 6 mg/kg 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.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

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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.

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09/09/2021 (SUPPL-1)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

The use of AVSOLA 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)].

AVSOLA is contraindicated in patients with a previous severe hypersensitivity reaction to infliximab products or any of the inactive ingredients of AVSOLA 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

5.1 Serious Infections

(Additions and/or revisions are underlined)

Tuberculosis

Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving infliximab products, including patients who have previously received treatment for latent or active tuberculosis. Cases of active tuberculosis have also occurred in patients being treated with infliximab products during treatment for latent tuberculosis.

Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating AVSOLA and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF- blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating AVSOLA, even for patients previously vaccinated with Bacille Calmette-Guérin (BCG).

5.10 Concurrent Administration with Other Biological Products

(Additions and/or revisions are underlined)

Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNF blocker, etanercept, with no added clinical benefit compared to etanercept alone. 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 AVSOLA 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 AVSOLA 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 AVSOLA. The concurrent use of AVSOLA with these biological products is not recommended because of the possibility of an increased risk of infection [see Drug Interactions (7.1)].

5.13 Vaccinations and Use of Live Vaccines/Therapeutic Infectious Agents

(Additions and/or revisions are underlined)

Vaccinations

Prior to initiating AVSOLA 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. Use of live vaccines can result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with AVSOLA is not recommended.

Fatal outcome due to disseminated BCG infection has been reported in an infant who received a BCG vaccine after in utero exposure to infliximab products. Infliximab products are known to cross the placenta and have been detected up to 6 months following birth. At least a six-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to infliximab products.

5.2 Malignancies

(Additions and/or revisions are underlined)

Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF- blockers (initiation of therapy less than or equal to 18 years of age), including infliximab products…

Lymphomas

In the controlled portions of clinical trials of all the TNF blockers, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. In the controlled and open-label portions of infliximab clinical trials, 5 patients developed lymphomas among 5707 patients treated with infliximab (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In RA patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately three-fold higher than expected in the general population. In the combined clinical trial population for RA, CD, PsA, AS, UC,  and Ps, 5 lymphomas were observed for a rate of 0.10 cases per 100 patient-years of follow-up, which is approximately four-fold higher than expected in the general population. Patients with CD, RA or Ps, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Cases of acute and chronic leukemia have been reported with postmarketing TNF blocker use in RA and other diseases. Even in the absence of TNF blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.

Hepatosplenic T-cell Lymphoma (HSTCL)

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 the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF -blocker at or prior to diagnosis. The majority of reported cases have occurred in patients with CD or UC and most were in adolescent and young adult males…

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 RA treated with infliximab compared to biologics-naïve patients or the general population, particularly those over 60 years of age….

Other Malignancies

In the controlled portions of clinical trials of some TNF blockers including infliximab products, more malignancies (excluding lymphoma and nonmelanoma skin cancer [NMSC]) have been observed in patients receiving those TNF blockers compared with control patients. During the controlled portions of trials with infliximab, in patients with moderately to severely active RA, CD, PsA, AS, UC, and Ps, 14 patients were diagnosed with malignancies (excluding lymphoma and NMSC) among 4019 infliximab-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 patient-years among infliximab-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for infliximab-treated patients and 0.4 years for control patients…

Ps patients should be monitored for nonmelanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment...

The potential role of TNF blockers in the development of malignancies is not known [see Adverse Reactions (6.1)]…

5.5 Heart Failure

(Additions and/or revisions are underlined)

The use of AVSOLA 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 post-marketing 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 AVSOLA (less than or equal to 5 mg/kg) to patients with moderate or severe heart failure or to administer AVSOLA (any approved dose) to patients with mild heart failure, they should be closely monitored during therapy, and AVSOLA 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 are 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.

However, in some cases, serum sickness-like reactions have been observed in patients after initial therapy with infliximab products (i.e., as early as after the second dose), and when therapy with infliximab products was reinstituted following an extended period without treatment. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema and/or dysphagia. These reactions were associated with a marked increase in antibodies to infliximab products, loss of detectable serum concentrations of infliximab products, and possible loss of drug efficacy.

AVSOLA should be discontinued for severe hypersensitivity reactions. Medications for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be available for immediate use in the event of a reaction [see Dosage and Administration (2.10) and Adverse Reactions (6.1)].

In RA, CD and Ps clinical trials, re-administration of infliximab after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment [see Adverse Reactions (6.1)]. In general, the benefit-risk of re-administration of AVSOLA after a period of no-treatment, especially as a re-induction regimen given at Weeks 0, 2 and 6, should be carefully considered. In the case where AVSOLA maintenance therapy for Ps is interrupted, AVSOLA should be reinitiated as a single-dose followed by maintenance therapy.

5.8 Cardiovascular and Cerebrovascular Reactions During and After Infusion

(Additions and/or revisions are underlined

Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of infliximab product infusion. Cases of transient visual loss have been reported during or within 2 hours of infliximab product infusion. Monitor patients during infusion and if serious reaction occurs, discontinue infusion. Further management of reactions should be dictated by signs and symptoms [see Adverse Reactions (6)].

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to labeling)

6.2 Immunogenicity

(Extensive changes; please refer to labeling)

6.3 Postmarketing Experience

(Additions and/or revisions are 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.

• 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), new onset and 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)].

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.

7 Drug Interactions

7.1 Other Biological Products

(Additions and/or revisions are underlined)

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

An increased risk of serious infections was seen in clinical studies of other TNF blockers 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 TNF blockers. Therefore, the combination of AVSOLA 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 AVSOLA, should be avoided because of the possibility of increased immunosuppression and increased risk of infection.

7.2 Methotrexate and Other Concomitant Medications

(Additions and/or revisions are underlined)

Specific drug interaction studies, including interactions with methotrexate (MTX), have not been conducted. The majority of patients in RA or CD clinical studies received one or more concomitant medications. In RA, concomitant medications besides MTX were non-steroidal anti-inflammatory agents (NSAIDs), folic acid, corticosteroids and/or narcotics. Concomitant CD medications were antibiotics, antivirals, corticosteroids, 6-MP/AZA and aminosalicylates. In PsA 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-drug antibody production and increase infliximab product concentrations.

7.3 Immunosuppressants

(Additions and/or revisions are underlined)

Patients with CD 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 CD including corticosteroids, antibiotics (metronidazole or ciprofloxacin) and aminosalicylates.

8 Use in Specific Populations

8.1 Pregnancy

(Extensive changes; please refer to labeling)

8.2 Lactation

(Additions and/or revisions are 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 AVSOLA and any potential adverse effects on the breastfed child from AVSOLA or from the underlying maternal condition.

8.4 Pediatric Use

(Extensive changes; please refer to labeling)

8.5 Geriatric Use

(Additions and/or revisions are 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 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 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)

17 PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to labeling)