RENFLEXIS®

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

Clinical Data

Rigorous development and analysis

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Rigorous development overview

A biosimilar is a biological medicinal product, the active substance of which is similar to that of an already approved reference product. In this case, RENFLEXIS was FDA approved as a biosimilar to Remicade (infliximab) based on data derived from rigorous testing, which demonstrated that it is similar to Remicade and that there are no clinically meaningful differences in safety, purity, and potency.1,2

Biosimilar Analysis

Analysis1

Developed in reference to Remicade

More than 80 batches were analyzed.

Biosimilar Development

Development2,3

  • Optimal Cell Line: Selected for biosimilar production and testing
  • Structural Testing: Biochemistry, purity, and structure were tested for similarity
  • Functional Testing: Potency and binding attributes were tested
  • Clinical Testing: Pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in human subjects
Biosimilar Approval

Approval4,5

RENFLEXIS has THE SAME:

Indications and Usage, mechanism of action (MOA), and dosing and administration as Remicade

Analysis and development

Begin with the reference product

Analyzing Remicade to help support the development of RENFLEXIS1,2

Define critical quality attributes (CQAs)

More than 80 lots of the reference product were analyzed to define over 60 CQAs.1

Select the optimal cell line

Approximately 100 cell lines were chosen from a pool of 20,000 for further analysis. The cell line that most closely matched the established CQAs of the reference biologic was then selected for production.1,3

Analyzing and Developing a Biosimilar

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Structural testing

Multiple assays

Multiple assays confirmed highly similar molecular structure with an identical amino acid sequence.1

Importance of structural data

Highly similar molecular structures are critical to biosimilarity.1

ASSESSMENT Structural similarity to Remicade successfully confirmed5

Structural Testing for RENFLEXIS® (infliximab-abda)

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Functional testing

Testing binding attributes for similarity

RENFLEXIS was developed through the multifactorial analysis of Remicade.1

Importance of functional data

These data relate to the mechanism of action, which has a bearing on how the product works in the body.1

ASSESSMENT

Functional similarity to Remicade successfully confirmed1

Functional Testing for RENFLEXIS® (infliximab-abda)

Functional Testing

TNF-α binding activity

Similarity established

RENFLEXIS. Similar TNF-ɑ binding activity as Remicade.1

Importance of TNF-α activity1
  • Inhibition of TNF activity is the main MOA of Remicade
  • Similar TNF properties equate to similar MOAs

TNA-a Binding Activity Full Analysis Set

  • TNF-ɑ binding, central to infliximab function, showed similar activity between RENFLEXIS and Remicade
  • TNF-ɑ binding activity of RENFLEXIS was measured by a competitive inhibition binding assay using time-resolved fluorescence energy transfer

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Clinical testing

RENFLEXIS was developed through the multifactorial analysis of Remicade.1

Clinical profile demonstrated in:
  • A PK study
  • A large, comparative clinical trial of efficacy and safety in patients with rheumatoid arthritis (N=584)6
Importance of clinical testing

Clinical studies help confirm that any structural or functional differences between the proposed biologic and the reference product are not clinically meaningful in terms of safety, purity, and potency.2

Clinical Testing of RENFLEXIS® (infliximab-abda)

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Consider RENFLEXIS in your appropriate patients

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Brands mentioned are the trademark of their respective owners.

Definitions

FDA = U.S. Food and Drug Administration

IV = intravenous

MOA = mechanism of action

TNF = tumor necrosis factor

TNF-α = tumor necrosis factor alpha

RIGOROUS DEVELOPMENT AND APPROVAL REFERENCES

1. Hong J, Lee Y, Lee C, et al. Physicochemical and biological characterization of SB2, a biosimilar of Remicade® (infliximab). MAbs. 2017;9(2):365–383.

2. US Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. https://www.fda.gov/media/82647/download. Published April 2015. Accessed June 5, 2020.

3. Data on file. Samsung Bioepis. RENFLEXIS: number of cell lines during development process. 2020.

4. Remicade [package insert]. Horsham, PA: Janssen Biotech, Inc; 2018.

5. Samsung Bioepis. 351(k) BLA 761054: Clinical Review of SB2, a Proposed Biosimilar to US-licensed Remicade; 2017.

6. Smolen JS, Choe J-Y, Prodanovic N, et al. Comparing biosimilar SB2 with reference infliximab after 54 weeks of a double-blind trial: clinical, structural and safety results. Rheumatology (Oxford). 2017;56(10):1771–1779.

Indications and Usage

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

PEDIATRIC ULCERATIVE COLITIS

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

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)

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.1,2 Treatment for latent infection should be initiated prior to RENFLEXIS use.
  • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, pneumocystosis, and cryptococcosis. 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, Listeria, and Salmonella.

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 co-morbid 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.

A population-based retrospective cohort study 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.

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 anaphylaxis, 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.

CARDIOVASCULAR AND CEREBROVASCULAR REACTIONS DURING AND AFTER INFUSION

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 a serious reaction occurs, discontinue infusion. Manage reactions according to signs and symptoms.

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 accompanying Prescribing Information, including the Boxed Warning about serious infections and malignancies. The Medication Guide is also available.

REFERENCES

1. 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.
2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients. Accessed February 19, 2020.

US-SBT-00772 03/20
US-SBT-0125002/21