Biologic Drug Substitution Best Practices (Update)

**Article update from initial publication in January 2021 due to entry of unbranded biologics in the marketplace and change to BLA approval type for SemgleeTM and RezvoglarTM**

PAAS National® frequently gets questions about whether pharmacies may substitute various medications and if such substitutions require the approval of the prescriber. Pharmacies must refer to the FDA Purple Book to identify if biologic products may be substituted. Additionally, “pharmacy level substitution” is regulated at the state level and you must refer to your individual state pharmacy practice laws. Cardinal Health has a great website to find biosimilar interchangeability laws for each state.

In a June 2020 Newsline article, PAAS discussed the new definition of a biologic product, which now includes commonly dispensed products like insulin, human growth hormone, and pancreatic enzymes. Now licensed as “biologic drugs,” these medications are approved by the FDA under a Biologic Licensing Application (BLA), and listed in FDA’s Purple Book instead of the Orange Book that many pharmacy staff are familiar with.

When reviewing the Purple Book, you will find that pharmacy level substitution of a reference product is only allowed if biologic drugs are either (i) identified as interchangeable OR (ii) an unbranded biologic with the same BLA number of a reference product. For biologic drugs that don’t fall into these two categories, you must obtain prescriber approval prior to substituting.

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  • If a prescription is written for the “proper name” (e.g., insulin lispro), the FDA does not provide interpretative guidance on whether the biologic product can be openly substituted. Some Boards of Pharmacy may require further clarification from the prescriber under these circumstances. PAAS recommends proceeding with caution until further industry guidance is established.

Let’s look at a few types of insulins as examples.

Insulin lispro U-100

Product Name Proper Name BLA Number Labeler BLA Type Substitute without prescriber approval?
Admelog® Insulin lispro 209196 Sanofi 351(a) reference product No
Humalog® Insulin lispro 020563 Eli Lilly 351(a) reference product Yes
Insulin lispro Insulin lispro 020563 Eli Lilly Unbranded biologic Yes
LyumjevTM Insulin lispro-aabc 761109 Eli Lilly 351(a) reference product No

Insulin glargine U-100

Product Name Proper Name BLA Number Labeler BLA Type Substitute without prescriber approval?
Lantus® Insulin glargine 021081 Sanofi 351(a) reference product Yes
Insulin glargine Insulin glargine 021081 Winthrop Unbranded biologic Yes
SemgleeTM Insulin glargine-yfgn 761201 Mylan 351(k) interchangeable Yes
Insulin glargine-yfgn Insulin glargine-yfgn 761201 Mylan Unbranded biologic Yes
Basaglar® Insulin glargine 205692 Eli Lilly 351(a) reference product No
RezvoglarTM Insulin glargine-aglr 761215 Eli Lilly 351(k) interchangeable Yes

FDA approved interchangeable status to Semglee in July 2021 and Rezvoglar in November 2022

Biologic products are not described in familiar terms like “brand”, “generic” or “AB-rated” and the Purple Book uses new terms that are not found in the Orange Book. Here is a short summary of the different terms:

  1. “Reference product” is a single biological product approved under a 351(a) BLA.
  2. “Biosimilar” products are approved through an abbreviated BLA pathway under a 351(k) biosimilar BLA.
  3. “Interchangeable” biological products are biosimilar products that have been deemed interchangeable with a reference product after going through additional switching studies and are approved under a 351(k) interchangeable BLA.
  4.  “Unbranded biologic” products are NOT listed in the Purple Book but are approved under the reference product’s 351(a) BLA.

FDA has more detailed definitions on the Purple Book website here. Additionally, there is a frequently asked question section that discusses unbranded biologics (FAQ #11).

PAAS Tips:

  • Pharmacy level substitution of biologic products is only allowed if products are either (i) identified as interchangeable AND your state pharmacy practice law allows OR (ii) an unbranded biologic with the same BLA number.
  • See FDA Purple Book to determine interchangeability status of a particular biologic drug
  • State pharmacy laws may limit biosimilar interchangeability, but this does not apply to unbranded biologics. For information about your state laws:
  • If you are ever in doubt about whether products may be substituted it is best to call the prescriber to obtain approval – don’t forget to document with a clinical note.
  • PAAS has created the following resources
  • FDA has a website with educational materials for both patients and healthcare professionals including frequently asked questions, handouts and videos here.

Eric Hartkopf, PharmD
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