RENFLEXIS®

(infliximab-abda) for injection,
for intravenous use 100 mg

Clinical Data

Approval pathway

RENFLEXIS. FDA-approved as a biosimilar based on structural, functional, and clinical similarity to Remicade® (infliximab)1

The FDA evaluates the "totality-of-the-evidence" submitted to support biosimilarity.

Review the Biosimilar Approval Pathway
Structural Assessments Conducted to Demonstrate Biosimilarity for RENFLEXIS® (infliximab-abda) vs Remicade® (infliximab)

Similar structure

Analytical attributes demonstrate that the protein structures are highly similar to the originator biologic.1,5

Structural attributes assessed for RENFLEXIS vs Remicade included6:

  • Amino acid sequence
  • Higher-order structure
  • Aggregates
  • Purity and impurities
  • Charge variants
  • Posttranslational modifications
  • Glycosylation
Functional Assessments Conducted to Demonstrate Biosimilarity for RENFLEXIS® (infliximab-abda) vs Remicade® (infliximab)

Similar function

Functional attributes support results from structural analyses, demonstrating that the MOA is highly similar to the originator biologic.1,5

Functional attributes assessed for RENFLEXIS vs Remicade included6:

  • TNF-α binding
  • TNF-α neutralization
  • ADCC activity
  • CDC activity
  • Apoptosis
  • Relative activity for Fc receptors and C1q binding
View Data From a Comparative Clinical Trial

Clinical trials

A Pharmacokinetic Similarity Study and a Comparative Clinical Trial in one indication were conducted to confirm there were no clinically meaningful differences between RENFLEXIS and Remicade.7,8

Brands mentioned are the trademark of their respective owners.

Definitions

ADCC = antibody-dependent cell-mediated cytotoxicity

CDC = complement-dependent cytotoxicity

Fc = fragment, crystallizable

MOA = mechanism of action

TNF-α = tumor necrosis factor alpha

Extrapolation through scientific justification1

Based upon studies conducted in a single indication, a biosimilar may be approved for other available indications of the originator product—a concept called “extrapolation.”1

Following demonstration of biosimilarity, it is possible to extrapolate from one indication to other indications of the originator biologic based upon additional scientific justification addressing potential differences in1:

  • Mechanism of action
  • Immunogenicity
  • Pharmacokinetic profile
  • Safety and tolerability

Indications

RHEUMATOID ARTHRITIS

  • RENFLEXIS is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate (MTX)

CROHN'S DISEASE

  • RENFLEXIS is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease (CD) who have had an inadequate response to conventional therapy
  • RENFLEXIS is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn's disease

PEDIATRIC CROHN'S DISEASE

  • RENFLEXIS is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age or older with moderately to severely active Crohn's disease (CD) who have had an inadequate response to conventional therapy

ULCERATIVE COLITIS

  • RENFLEXIS is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy

PSORIATIC ARTHRITIS

  • RENFLEXIS is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis (PsA)

ANKYLOSING SPONDYLITIS

  • RENFLEXIS is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (AS)

PLAQUE PSORIASIS

  • RENFLEXIS is indicated for the treatment of adult patients with chronic severe (ie, extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. RENFLEXIS should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician

Selected Safety Information

SERIOUS INFECTIONS

Patients treated with infliximab products are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue RENFLEXIS if a patient develops a serious infection or sepsis.

Reported infections include:

  • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before RENFLEXIS use and during therapy.a,b Treatment for latent infection should be initiated prior to RENFLEXIS use.
  • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
  • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

The risks and benefits of treatment with RENFLEXIS should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with RENFLEXIS, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy, who are on treatment for latent TB, or who were previously treated for TB infection.

Risk of infection may be higher in patients greater than 65 years of age, pediatric patients, patients with comorbid conditions and/or patients taking concomitant immunosuppressant therapy. In clinical trials, other serious infections observed in patients treated with infliximab products included pneumonia, cellulitis, abscess, and skin ulceration.

MALIGNANCIES

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including infliximab products. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

Postmarketing cases of hepatosplenic T-cell lymphoma, 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. The majority of reported cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. Carefully assess the risks and benefits of treatment with RENFLEXIS, especially in these patient types.

In clinical trials of all TNF inhibitors, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF inhibitors, including infliximab products, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with infliximab products was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. As the potential role of TNF inhibitors in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocker therapy, including infliximab products. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

CONTRAINDICATIONS

RENFLEXIS is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have been observed in these patients. RENFLEXIS should be used with caution and only after consideration of other treatment options. Patients should be monitored closely. Discontinue RENFLEXIS if new or worsening CHF symptoms appear. RENFLEXIS should not be (re)administered to patients who have experienced a severe hypersensitivity reaction or to patients with hypersensitivity to murine proteins or other components of the product.

HEPATITIS B REACTIVATION

TNF inhibitors, including infliximab products, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients should be tested for HBV infection before initiating RENFLEXIS. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. Exercise caution when prescribing RENFLEXIS for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with RENFLEXIS. Discontinue RENFLEXIS in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of RENFLEXIS and monitor patients closely.

HEPATOTOXICITY

Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported rarely in patients receiving infliximab products postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of normal) develop, RENFLEXIS should be discontinued, and a thorough investigation of the abnormality should be undertaken.

HEMATOLOGIC EVENTS

Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported in patients using infliximab products. The causal relationship to infliximab therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of RENFLEXIS in patients who develop significant hematologic abnormalities.

HYPERSENSITIVITY

Infliximab products have been associated with hypersensitivity reactions that differ in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions, which include urticaria, dyspnea, and hypotension, have occurred during or within 2 hours of infusion. Serious infusion reactions including anaphylaxis were infrequent. RENFLEXIS should be discontinued for severe hypersensitivity reactions. Medications for the treatment of hypersensitivity reactions should be available.

NEUROLOGIC EVENTS

TNF inhibitors, including infliximab products, have been associated in rare cases with CNS manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering RENFLEXIS in patients with these disorders and consider discontinuation if these disorders develop.

AUTOIMMUNITY

Treatment with infliximab products may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

USE WITH OTHER DRUGS

Concomitant use of RENFLEXIS with anakinra, abatacept, tocilizumab, or other biologics used to treat the same conditions as RENFLEXIS is not recommended because of the possibility of an increased risk of infection. Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS

Live vaccines or therapeutic infectious agents should not be given with RENFLEXIS due to the possibility of clinical infections, including disseminated infections.

Bring pediatric patients up to date with all vaccinations prior to initiating RENFLEXIS. At least a 6-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to infliximab products.

ADVERSE REACTIONS

In clinical trials with infliximab products, the most common adverse reactions occurring in >10% of patients treated with infliximab products included infections (eg, upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.

Before prescribing RENFLEXIS, please read the Prescribing Information, including the Boxed Warning about serious infections and malignancies. The Medication Guide also is available.

References

a. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221-S247.
b. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients. http://www.cdc.gov/tb/publications/ltbi/diagnosis.htm. Accessed January 19, 2018.

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1. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Published April 2015. Accessed January 4, 2018.

2. US FDA. Guidance for Industry. Providing clinical evidence of effectiveness for human drug and biological products. https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4227B1-02-02-FDA-Appendix1.pdf. Published May 1998. Accessed January 4, 2018.

3. Kingham R, Klasa G, Hessler K. Key regulatory guidelines for the development of biologics in the United States and Europe. Pharmaceutical Sciences Encyclopedia. 2013. http://dx.doi.org/10.1002/9780470571224.pse503.

4. US FDA. Overview of the regulatory pathway and FDA’s guidance for the development and approval of biosimilar products in the US. 2016. http://www.fda.gov/downloads/advisorcommittees/committeesmeetingmaterials/drugs/arthritisadvisorycommittee/ucm486171.pdf. Accessed January 4, 2018.

5. US FDA. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291134.pdf. Published April 2015. Accessed January 4, 2018.

6. Hong J, Lee Y, Lee C, et al. Physicochemical and biological characterization of SB2, a biosimilar of Remicade® (infliximab). mAbs. 2016;9(2):365-383. http://dx.doi.org/10.1080/19420862.2016.1264550.

7. Choe JY, Prodanovic N, Niebrzydowski J, et al. A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis. 2015. doi:10.1136/annrheumdis-2015-207764.

8. Shin D, Kim Y, Kim YS, et al. A randomized, Phase I pharmacokinetic study comparing SB2 and infliximab reference product (Remicade®) in healthy subjects. BioDrugs. 2015;29(6):381-388.

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