RENFLEXIS®

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

Clinical Data

Comparative Clinical Study efficacy data

Comparative Clinical Study in patients with moderate-to-severe rheumatoid arthritis despite MTX treatment

RENFLEXIS. Similar efficacy to Remicade® (infliximab)1

Primary end point: ACR20 response at Week 301

ACR20, ACR50, ACR70 response at Week 30 (per-protocol set)

ACR20, ACR50, and ACR70 Response at Week 30

The 95% CI for all treatment differences (TD) fell within the predefined equivalence margins of ±15%.1

Rapid and sustained reduction in RA symptoms1

Comparable ACR20 response rate through Week 30 (per-protocol set)

ACR20 Response Rate Through Week 30

Back to top

RENFLEXIS. Similar efficacy sustained in patients transitioning from Remicade® (infliximab)2

Comparable ACR20, ACR50, and ACR70 response rate from Week 54 to Week 78 (extended full-analysis set)2

Remained on RENFLEXIS 3 mg/kg IV + MTX % (n/n’) Transitioned from EU-sourced Remicade to RENFLEXIS 3 mg/kg IV + MTX % (n/n’) Remained on EU-sourced Remicade 3 mg/kg IV + MTX % (n/n’)
ACR20 response rate
Week 54 65.7
(132/201)
71.3
(67/94)
69.3
(70/101)
Week 78 68.3
(123/180)
63.5
(54/85)
68.8
(64/93)
ACR50 response rate
Week 54 43.3
(87/201)
41.5
(39/94)
39.6
(40/101)
Week 78 40.6
(73/180)
37.6
(32/85)
47.3
(44/93)
ACR70 response rate
Week 54 24.4
(49/201)
26.6
(25/94)
22.8
(23/101)
Week 78 25.6
(46/180)
22.4
(19/85)
31.2
(29/93)

n = number of responders
n’ = number of patients with an available assessment

Back to top

Comparable DAS28 response rate from Week 0 through Week 783

Mean change in DAS28 score from Week 0 (extended full-analysis set)

Remained on RENFLEXIS 3 mg/kg IV + MTX (n=201) Transitioned from EU-sourced Remicade to RENFLEXIS 3 mg/kg IV + MTX (n=94) Remained on EU-sourced Remicade 3 mg/kg IV + MTX (n=101)
DAS28 score 2.6 2.5 2.6

Back to top

Comparative Clinical Study design

Study design: a randomized, double-blind, parallel-group, multicenter, Comparative Clinical Study enrolling patients with moderate-to-severe RA despite MTX treatment.1,4,5

Comparative Clinical Study Design in Patients With Moderate-to-Severe RA Despite MTX Treatment

Key inclusion criteria6

  • Patients diagnosed with RA according to the revised 1987 ACR criteria for ≥6 months
  • Patients had active disease defined as ≥6 swollen and ≥6 tender joints, and either ESR ≥28 mm/h or serum CRP ≥1.0 mg/dL despite MTX treatment for ≥6 months prior to randomization (stable dose of 10–25 mg/week for ≥4 weeks prior to screening)

Key exclusion criteria6

  • Prior treatment with any biologic agents 
  • Abnormal renal/hepatic function at screening 
  • Positive for hepatitis B/C or known history of HIV infection, active TB; serious infection
  • History of any malignancy within 5 years of screening; history of lymphoproliferative disease
  • Congestive heart failure (NYHA III/IV); unstable angina 
  • Any DMARDs other than MTX or injectable corticosteroids

End points1,4,5

Primary end point: Demonstrate equivalent efficacy of ACR20 response rate at Week 30

  • Inclusion of the 95% CI of the ACR20 response difference within a ±15% margin was required for equivalence

Secondary end points included:

  • ACR20 at Week 54, ACR50 and ACR70 at Week 30 and Week 54, DAS28 at Week 30 and Week 54, mTSS at Week 54
  • Safety and immunogenicity

Transition (Week 54 to Week 78)5

  • This randomized, double-blind, transition period investigated the efficacy, safety, and immunogenicity of RENFLEXIS in subjects with RA who transitioned from EU-sourced Remicade to RENFLEXIS vs subjects who remained on EU-sourced Remicade vs subjects who remained on RENFLEXIS
  • After 54 weeks of treatment, patients in the EU-sourced Remicade group were re-randomized (1:1) either to receive RENFLEXIS or to continue EU-sourced Remicade up to Week 70
  • Patients who received RENFLEXIS from the randomized, double-blind period continued to receive extended treatment of RENFLEXIS up to Week 70
  • Secondary end points for the transition period included5: ACR20, ACR50, and ACR70 response, the change in DAS28 from Week 0, incidence of adverse events, serious adverse events, and antidrug antibodies

Back to top

Brands mentioned are the trademark of their respective owners.

Definitions

ACR = American College of Rheumatology

ACR20/50/70 = American College of Rheumatology 20%/50%/70% criteria response rate

CI = confidence interval

CRP = C-reactive protein

DAS28 = disease activity score measured by 28 joints

ESR = erythrocyte sedimentation rate

IV = intravenous

mTSS = modified Total Sharp Score

MTX = methotrexate

RA = rheumatoid arthritis

TD = treatment difference

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.

BIOS-1261047-0000 07/18

1. 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.

2. Smolen JS, Choe JY, Prodanovic N, et al. Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: results of a randomised, double-blind, phase III transition study. Supplementary data. http://ard.bmj.com/content/annrheumdis/77/2/234/DC1/embed/inline-supplementary-material-1.pdf?download=true. Accessed January 4, 2018.

3. Data available on request from Merck Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package BIOS-1208724-0000.

4. Smolen JS, Choe JY, Prodanovic N, et al. Comparing biosimilar SB2 with reference infliximab after 54 weeks of a double-blind trial: clinical, structural and safety results. Rheumatology. doi:10.1093/rheumatology/kex254.

5. Smolen JS, Choe JY, Prodanovic N, et al. Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: results of a randomised, double-blind, phase III transition study. Ann Rheum Dis. 2018;77(2):234-240. doi:10.1136/annrheumdis-2017-211741.

6. 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. Supplementary data. http://ard.bmj.com/content/suppl/2015/08/27/annrheumdis-2015-207764.DC1/annrheumdis-2015-207764supp.pdf. Accessed January 4, 2018.

BIOS-1202522-000104/18