Insulin Substitution Review: Understanding Purple Book Terminology

Pharmacy level substitution of a reference product is only allowed if biologic drugs are either identified as (i) an interchangeable biosimilar OR (ii) an unbranded biologic with the same BLA number of a reference product. Importantly, unbranded biologics are NOT separately listed in the Purple Book as explained by FDA here (see FAQ #11). For biologic drugs that don’t fall into these two categories, you must obtain prescriber approval prior to substituting.

Additionally, pharmacy level substitution is regulated at the state level. If you’re unsure of your requirements, Cardinal Health has a great website to find biosimilar interchangeability laws for each state.

It is also important to understand the terminology used in the Purple Book as biologic products are not described in familiar terms like “brand”, “generic” or “AB-rated” that most pharmacy staff have been trained on. Here is a short summary of the different terms:

1. Reference product is a single biological product approved under a 351(a) BLA.

Think of these products like brand drugs in the FDA Orange Book – they cannot be substituted for other brand drugs without prescriber approval.

2. Biosimilar products are approved through an abbreviated BLA pathway under a 351(k) biosimilar

Think of these products like B-rated generic drugs in the FDA Orange Book – they cannot be substituted for brand drugs without prescriber approval.

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 

Think of these products like A-rated generic drugs in the FDA Orange Book – they CAN be substituted for brand drugs without prescriber approval (where allowed by state law).

4. Unbranded biologic products are NOT listed in the Purple Book but are approved under the reference product’s 351(a)

Think of these products like authorized generic drugs in the FDA Orange Book – they CAN be substituted for brand drugs without prescriber approval.

Here are some insulin examples to help understand the relationship between various products that have a similar proper name and when pharmacies can (or cannot) substitute without prescriber approval (where allowed by state law).

Insulin Glargine

*Where allowed by state law

Insulin Lispro

*Where allowed by state law

Insulin Aspart

*Where allowed by state law

PAAS Tips:

• Be cautious when interpreting wholesaler ordering websites or pharmacy management software that may “link” products together based on Medi-Span® GPI as this may lead to incorrect conclusions about which products may (or may not) be substituted for one another
  • See May 2022 Newsline article Medi-Span® Generic Product Identifier for further discussion
• Other PAAS resources include:
  • April 2023 Newsline article Biologic Drug Substitution Best Practices (Update)
  • On-demand webinar Understanding Interchangeability with Prescription Biologics August 17, 2022
  • PAAS’ Insulin Medication Chart is a nice summary tool, located on the PAAS Member Portal under Days’ Supply Charts
• Please contact PAAS at (608) 873-1342 or info@paasnational.com if your team has a question about a specific product