Inflectra - Remicade Biosimilar Approved for Rheumatoid Arthritis

Inflectra (infliximab-dyyb), a biosimilar to Remicade (infliximab), was approved by the U.S. Food and Drug Administration (FDA) on April 5, 2016. According to the FDA, "A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products." Remicade, a TNF blocker which is manufactured by Janssen Biotech, Inc., is the reference drug for Inflectra.

Inflectra is manufactured by Celltrion, Inc (based in Yeonsu-gu, Incheon, Republic of Korea) for Hospira of Lake Forest, Illinois. Inflectra is the second biosimilar approved in the United States by the FDA. The first, Zarxio, was approved March 6, 2015 for specific indications related to cancer.

Inflectra is approved and can be prescribed for:

• patients with moderately to severely active rheumatoid arthritis.
• patients with active ankylosing spondylitis.
• patients with active psoriatic arthritis.
• adult patients with chronic severe plaque psoriasis.
• adult patients or children 6 years old and older with moderately to severely active Crohn's disease who had an inadequate response to conventional treatment.
• adults with moderately to severely active ulcerative colitis who had an inadequate response to conventional therapy. 

For rheumatoid arthritis, Inflectra is used to reduce signs and symptoms associated with the disease, inhibit progression of joint damage, and to improve physical function. In patients with ankylosing spondylitis, Inflectra is indicated for reducing signs and symptoms. In psoriatic arthritis, Inflectra may be prescribed to reduce signs and symptoms of active arthritis, inhibit progression of structural damage and improve physical function.

For rheumatoid arthritis, Inflectra is administered as an intravenous infusion (given over a period of at least 2 hours) at a dose of 3mg/kg given at 0, 2, and 6 weeks. Thereafter, a maintenance dose of 3 mg/kg is administered every 8 weeks. Patients treated with Inflectra for rheumatoid arthritis should also take methotrexate. Patients who have an inadequate response at the aforementioned dosage may have the dose adjusted up to 10mg/kg or the interval between doses may be shortened to every 4 weeks. The adjustments may increase the risk of adverse reactions.

For ankylosing spondylitis, the recommended dose is 5mg/kg as an intravenous infusion at 0, 2, and 6 weeks followed by a maintenance dose of 5 mg/kg every 6 weeks. The recommended dose is also 5 mg/kg at 0, 2, and 6 weeks for psoriatic arthritis, but the maintenance dose of 5 mg/kg is given every 8 weeks. For psoriatic arthritis, it can be used with or without methotrexate.

The most common adverse reactions, based on clinical trials of infliximab products, include infections (upper respiratory, sinusitis, and pharyngitis), infusion-related reactions (shortness of breath, flushing, rash), headache, and abdominal pain.

Inflectra, at doses greater than 5 mg/kg, should not be given to patients with moderate to severe heart failure. Also, Inflectra should not be given to patients who have had a severe hypersensitivity reaction to Remicade (infliximab). Inflectra should not be administered to anyone with known hypersensitivity to any inactive ingredients in the drug or to murine (rodent) proteins. 

Certain warnings and precautions have been established to ensure the safe use of Inflectra. Those warnings include:

• Risk of developing serious infections - Inflectra should not be administered during an active infection. Also, if an infection develops while using Inflectra, it should be monitored carefully and if it becomes serious, Inflectra should be stopped. Opportunistic infections (infections that occur more severely or frequently in those with weakened immune systems) have been reported in patients treated with TNF blockers. Also, reactivation of tuberculosis or new tuberculosis infections have occurred with the use of infliximab products.
• Invasive fungal infections - If a patient develops a systemic illness while using Inflectra, anti-fungal therapy should be considered for those living in regions where fungal conditions are endemic.
• Malignancies - The incidence of malignancies, including lymphoma, was found to be greater in patients treated with TNF blockers than in controls. The risk/benefit of using Inflectra should be assessed, especially in patients with certain factors in their medical history. 
• Hepatitis B virus (HBV) reactivation - Patients should be tested for Hepatitis B virus prior to starting Inflectra. Carriers of HBV should be monitored during and for several months after using Inflectra. If reactivation of HBV occurs, Inflectra should be discontinued and anti-viral treatment initiated.
• Hepatotoxicity - Rare severe hepatic reactions can occur. Some may be potentially fatal or require liver transplantation. With the development of jaundice or significantly elevated liver enzymes, Inflectra should be stopped.
• Heart failure - New onset heart failure or worsening symptoms of existing heart failure may occur with use of Inflectra.
• Cytopenias - There may be a reduction in the number of blood cells with use of Inflectra. Patients should seek medical attention if symptoms develop.
• Hypersensitivity - Serious infusion reactions may develop, including anaphylaxis or serum sickness-like reactions.
• Demyelinating disease - New onset or worsening of existing demyelinating disease can occur with use of Inflectra.
• Lupus-like syndrome - A syndrome associated with lupus-like symptoms can develop with use of Inflectra. The drug should be stopped if the syndrome develops.
• Live vaccines or therapeutic infectious agents - Neither should be given with Inflectra. Children should be up to date on all vaccines prior to starting Inflectra. If an infant was exposed in utero to Inflectra or infliximab, there should be at least a 6 month waiting period after birth before any live vaccine is given.

Inflectra carries a black box warning with regard to the increased risk of serious infection and lymphoma, as well as a directive to test for latent tuberculosis prior to starting the drug.

The combination of Inflectra with anakinra or Orencia (abatacept) is not recommended. The use of Actemra (tocilizumab) with Inflectra should be avoided due to the potential of increased immunosuppression and increased risk of infection. Inflectra should not be combined with other biologic drugs as well.

The Bottom Line

Biosimilars have been in development for years for rheumatoid arthritis. To have the first biosimilar finally FDA-approved is a big deal. From the patient perspective, biosimilars provide even more treatment options (that's a good thing!) and the price should be comparatively lower than original biologic drugs (that's another good thing!). Yet, it doesn't come without a bit of controversy. There has been concern expressed by some people regarding whether biosimilars will be truly equivalent. Think generic versus brand name oral medications -- are they equally effective? That has been debated for decades. The FDA states that "patients and health care professionals will be able to rely upon the safety and effectiveness of the biosimilar or interchangeable product, just as they would the reference product." In fact, a biosimlar drug is approved based on evidence it is "highly similar" to the reference drug. Is highly similar synonymous with equivalent?

There is yet another category, which the FDA calls an interchangeable drug. According to the FDA, "An interchangeable biological product is biosimilar to an FDA-approved reference product and meets additional standards for interchangeability. An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product."

Perhaps it is a bit confusing at this stage. As always, our advice is to discuss biosimilars with your own doctor or rheumatologist. It is also important for you to familiarize yourself with the response from the rheumatology community regarding the approval of Inflectra and future biosimiliars. Read this statement from Joan Von Feldt, MD, MSEd, President of the American College of Rheumatology.