Not long after the U.S. Food and Drug Administration approved its first biosimilar agent for use in patients with rheumatoid arthritis (RA), our office undertook its initial journey to become better educated about what this meant for ourselves and our patients.
We started with infliximab-dyyb (Inflectra), a biosimilar to infliximab (Remicade), as that was the first biosimilar available in California.1 Our first step was to review the product insert. What are the differences between the biosimilar and the reference product? What do our patients need to be made aware of?
The FDA defines a biosimilar as follows:
“A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an already-approved biological product, known as a reference product. The biosimilar also must show it 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.”1
As our team started doing its research, our first concern involved patient safety. What constitutes a “minor difference”? In the case of Inflectra, the difference is in the fragment crystallizable (FC) region of the antibody, which is why it is not considered to be bioidentical to Remicade. According to a report from the European Medicines Agency, there is a “small difference in the amount of affucosylated infliximab, which translates to lower binding affinity towards the FC receptors.”2 Remember that communication to the immune system is mediated through the Y portion of the antibody. The top portion of the Y (the antigen-binding site) serves as “the lock” that traps the harmful antibody while the bottom portion communicates the message to the B and T cells for further immune mediation.
While Inflectra is approved as a biosimilar to Remicade, it is not an interchangeable product as defined by the FDA. An interchangeable biological product, in addition to meeting the standard for biosimilarity, is expected to produce the same clinical result as the reference product in any given patient.1 This is an important distinction, and one that has been emphasized by patient advocacy groups such as the Patients for Biological Safety & Access, which says on its website that “the choice of products should not be determined by pharmacist, regulator, or insurer, but by the prescriber in consultation with their patient.”3
Inflectra first became available in our practice this spring. Its wholesale acquisition cost is approximately 15% less than Remicade. So if you do the math (understanding that each pharmacy has a different actual sale price), this is what the cost savings might look like: Remicade is approximately $1,113 per 100 mg vial and Inflectra $946 per 100 mg vial. That is a savings of $167 per vial, which can be pretty significant over the course of a patient’s full year of therapy.4
In June 2013, the European Medicines Agency published a 105-page Assessment Report on Inflectra that thoroughly reviewed the clinical trials and studies completed before Inflectra was approved by the FDA. While there was a numerically higher number of serious infections, including active tuberculosis, in the patients treated with Inflectra compared to Remicade, the report authors concluded that “the observed difference was most likely a chance finding” due to the low numbers of patients with serious infections. There were no new safety signals that were identified.2
When we were initially compelled to use Inflectra earlier this year, we proceeded with caution. One of our initial experiences was with JT, an RA patient who had done well with 5 previous Remicade treatments. She had no previous tolerance issues and demonstrated notable improvements in swollen and tender joints, as well as Health Assessment Questionnaire scores, with Remicade. When the switch was made to Inflectra, we had JT come in during her usual appointment slot. She was given 3 mg/kg of Inflectra at her first infusion.
About 20 minutes into the infusion, JT developed chest pain, shortness of breath, and erythema, which is not uncommon in patients receiving an initial infusion of a new biologic. We stopped the infusion, immediately began a normal saline flush, and pushed an additional 25 mg of diphenhydramine. JT’s reaction abated to a degree with these interventions, but she still reported some chest tightness. We gave her an additional 6 mg of intravenous dexamethasone, which mitigated her symptoms, but JT refused to have us restart the infusion.
So now we were faced with a dilemma. JT had been stable and was doing well on Remicade. Is she now considered a TNF non-responder after her reaction to Inflectra? Should we (and could we) go back to Remicade? Typically, if a patient develops antibodies to Remicade, we try another TNF inhibitor, but would JT’s failure on Inflectra mean that she had failed two TNF inhibitors and would benefit more from a biologic with a different mechanism of action?
For safety reasons, we decided to transition JT to a non-TNF biologic—abatacept. Early results are mixed —her tender and swollen joint counts have increased, but she has not any tolerance issues.
Since our experience with JT, we have changed our protocol for infusion of Inflectra. Patients now receive pre-infusion hydration, dexathamethsone 6 mg IV (unless they are diabetic), and diphenhydramine 50 mg. We have also lengthened the infusion time from 2 to 3 hours. There have been no further serious adverse events (SAEs) since JT.
It is important to note that, after our report of JT’s SAE to the Inflectra manufacturer, I received a phone call and met with a representative to complete a full report within 24 hours. There have been two follow-up calls to check on JT’s condition. Clearly, this is not something being taken lightly, which is comforting.
Our office is admittedly a bit perplexed by the changes being forced upon us in regard to biosimilars. For some patients currently taking Remicade, we have written “Please use brand name” or “Dispense as written” on the prescription, but it seems to make little difference at the pharmacy.
If you haven’t yet had to navigate patients onto biosimilars, I am confident that you soon will. Our office is currently involved in phase III clinical trials for 7 different biosimilars, and none of our patients in the trials have suffered an SAE. Nonetheless, we remain on high alert, knowing that severe reactions, including anaphylaxis, can occur in patients receiving any infusible biologic or biosimilar.
Undoubtedly, biologics are both life-altering and expensive. Making any sort of change in a patient who is doing well on any therapy is nerve wracking, and perhaps with time, we’ll learn that the switch from a biologic reference product to a biosimilar will be “no big deal.” For now, I will remain hopeful yet vigilant, doing what I believe is best for my patients and helping them navigate through the many hurdles put in front of them by their disease as they seek to return to work, regain their self-esteem, and recapture their quality of life.
AUTHOR PROFILE:
Jacqueline Fritz, RN, MSN, CNS, RN-BC, is Owner and Coordinator of Education at the Medical Advancement Center in Cypress, CA. Her primary responsibility is working as an advanced practice nurse for a large rheumatology practice where she is involved in patient visits, research programs, and infusion center coordination. In addition, she enjoys speaking, teaching, and learning about immunology.
References
1. U.S. Food and Drug Administration. FDA approves Inflectra, a biosimilar to Remicade. Available at https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm494227.htm. Accessed May 24, 2017.
2. European Medicines Agency. Assessment report: Inflectra. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002778/WC500151490.pdf. Accessed May 24, 2017.
3. Patients for Biological Safety & Access. PBSA Principles. Available at http://www.biosimsafety.org/pbsa-principles/. Accessed May 24, 2017.
4. National Public Radio. Small savings for drugs made to mimic biotech blockbusters. Available at http://www.npr.org/sections/health-shots/2016/10/19/498559386/small-savings-for-drugs-made-to-mimic-biotech-blockbusters. Accessed May 24, 2017.