Interchangeable Biosimilar Meaning
What does interchangeable biosimilar mean?
In the US, an interchangeable biosimilar is a biosimilar that the FDA has also found meets a higher statutory standard, so it may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. In practice that means a pharmacist can swap it in, much as with a generic, where state pharmacy law allows. The term comes from section 351 of the Public Health Service Act, codified at 42 U.S.C. 262.
Two tiers in the statute
| Tier | What has to be shown (42 U.S.C. 262) |
|---|---|
| Biosimilar, s.262(i)(2) | The product is "highly similar to the reference product notwithstanding minor differences in clinically inactive components" and there are "no clinically meaningful differences" in safety, purity and potency. |
| Interchangeable, s.262(k)(4) | The FDA "shall determine" interchangeability if the application shows the product (A)(i) is biosimilar and (A)(ii) "can be expected to produce the same clinical result as the reference product in any given patient". (B) For a product given to a patient more than once, the risk to safety, or of reduced efficacy, from alternating or switching between it and the reference product must be no greater than the risk of staying on the reference product. |
Both are licensed through the same 351(k) pathway. The interchangeability data can be filed in the original application or in a later supplement (s.262(k)(2)(B)).
What it means in practice
- Substitution at the pharmacy: The FDA's patient page says an interchangeable "may be substituted without consulting the prescribing doctor," and that "pharmacy-level substitution" is "subject to state law" (FDA, Biosimilars Basics for Patients). The FDA designation makes a product eligible for substitution; whether it actually happens depends on each state's pharmacy law.
- Switching studies are no longer generally expected: These studies alternate patients between the reference product and the biosimilar. The FDA's June 20, 2024 draft guidance "Considerations for Demonstrating Interchangeability with a Reference Product: Update" says they "will generally not be needed." The FDA also noted that 9 of the 13 interchangeables approved by then had been licensed without switching data (FDA statement). On October 29, 2025 the FDA said it "now generally does not recommend switching studies" (FDA press announcement).
- First-interchangeable exclusivity: The first product found interchangeable with a given reference product gets a period during which later interchangeability approvals cannot take effect. It ends at the earliest of the dates in s.262(k)(6): for example, 1 year after the first one is first marketed, or 18 months after its approval if it has not been sued.
- How to tell in the Purple Book: The FDA's database of licensed biological products lists these products under licence type "351(k) Interchangeable", separate from "351(k) Biosimilar". The August 2026 edition has 146 licensed product entries of this type, covering 46 distinct proper names. They include adalimumab, denosumab, insulin glargine, ranibizumab and ustekinumab products, for example Yusimry (adalimumab-aqvh), BLA 761216 [1].
"Interchangeable" with this legal effect is a US status. I did not check how the EU (EMA) or UK (MHRA) treat interchangeability, so this answer does not cover those regimes.
Approach: I took the definitions from the official US Code text of 42 U.S.C. 262 and the FDA's own biosimilar pages, guidance notice and press announcement. I took the product listings from the FDA Purple Book.
Which biosimilars are interchangeable?
The FDA Purple Book (September 2026 edition) lists 57 branded products licensed as "351(k) Interchangeable". They cover 46 distinct proper names and 16 reference products, built on 13 molecules: adalimumab, aflibercept, denosumab, eculizumab, etanercept, golimumab, insulin aspart, insulin glargine, omalizumab, pertuzumab, ranibizumab, rituximab, tocilizumab and ustekinumab. Interchangeability is a US designation, so this is a US list.
Approach: I took every product listed with licence type "351(k) Interchangeable" in the September 2026 edition of the FDA Purple Book, which is newer than the August edition I cited last time, and grouped them by reference product.
| Reference product | Interchangeable products (date first designated interchangeable) |
|---|---|
| Humira (adalimumab), 9 | Cyltezo, adalimumab-adbm, 2021-10-15 [2]; Abrilada, -afzb, 2023-10-04 [3]; Simlandi, -ryvk, 2024-02-23 [4]; Hyrimoz, -adaz, 2024-04-05 [5]; Hadlima, -bwwd, 2024-06-28 [6]; Amjevita, -atto, 2024-08-20 [7]; Hulio, -fkjp, 2025-02-05 [8]; Yuflyma, -aaty, 2025-04-07 [9]; Yusimry, -aqvh, 2026-08-28 [10] |
| Stelara (ustekinumab), 8 | Wezlana, -auub, 2023-10-31 [11]; Otulfi, -aauz [12], Pyzchiva, -ttwe [13], Selarsdi, -aekn [14], Steqeyma, -stba [15] and Yesintek, -kfce [16], all 2025-04-30; Starjemza, -hmny, 2025-05-22 [17]; Imuldosa, -srlf, 2026-06-05 [18] |
| Prolia (denosumab), 10 | Jubbonti, -bbdz, 2024-03-05 [19]; Bildyos, -nxxp [20], Bosaya, -kyqq [21], Conexxence, -bnht [22], Enoby, -qbde [23], Ospomyv, -dssb [24], Osvyrti, -desu [25] and Stoboclo, -bmwo [26], all 2025-10-29; Boncresa, -mobz, 2025-12-19 [27]; Ponlimsi, -adet, 2026-03-27 [28] |
| Xgeva (denosumab), 10 | Wyost, -bbdz, 2024-03-05 [29]; Aukelso, -kyqq [30], Bilprevda, -nxxp [31], Bomyntra, -bnht [32], Jubereq, -desu [33], Osenvelt, -bmwo [34], Xbryk, -dssb [35] and Xtrenbo, -qbde [36], all 2025-10-29; Oziltus, -mobz, 2025-12-19 [37]; Degevma, -adet, 2026-09-25 [38] |
| Lucentis (ranibizumab), 4 | Cimerli, -eqrn, 2022-08-02 [39]; Byooviz, -nuna, 2023-10-03 [40]; Nufymco, -leyk, 2025-12-18 [41]; Ranluspec, -hkdz, 2026-06-02 [42] |
| Lantus (insulin glargine), 3 | Semglee, -yfgn, 2021-07-28 [43]; Rezvoglar, -aglr, 2022-11-16 [44]; Langlara, -aldy, 2026-04-29 [45] |
| Novolog (insulin aspart), 2 | Kirsty, -xjhz, 2025-07-15 [46]; Garzulys, -fsan, 2026-09-15 [47] |
| Eylea (aflibercept), 2 | Opuviz, -yszy [48] and Yesafili, -jbvf [49], both 2024-05-20 |
| Soliris (eculizumab), 2 | Bkemv, -aeeb, 2024-05-28 [50]; Epysqli, -aagh, 2025-11-28 [51] |
| Simponi / Simponi Aria (golimumab), 1 each | Immgolis [52] and Immgolis Intri [53], golimumab-sldi, both 2026-05-15 |
| Xolair (omalizumab) | Omlyclo, -igec, 2025-03-07 [54] |
| Actemra (tocilizumab) | Avtozma, -anoh, 2025-01-24 [55] |
| Perjeta (pertuzumab) | Poherdy, -dpzb, 2025-11-13 [56] |
| Rituxan (rituximab) | Truxima, -abbs, 2026-06-29 [57] |
| Enbrel (etanercept) | Eticovo, -ykro, 2024-06-25; both its presentations are listed as discontinued [58] |
Points worth knowing
- Designation can differ by presentation. It applies to each strength or presentation separately, not to the whole brand at once. For example, Cyltezo 40 mg/0.8 mL has been interchangeable since 2021-10-15 [2], but its 40 mg/0.4 mL presentation only since 2025-05-20 [59]. The dates in the table are the earliest for each brand.
- First-interchangeable exclusivity still running as of today: The Purple Book shows a later expiry date for Omlyclo 300 mg/2 mL, 2027-06-01 [60]. The aflibercept exclusivity for Opuviz and Yesafili ended 2026-10-22 [48].
- Discontinued but still licensed: Abrilada 10 mg/0.2 mL [61], Hyrimoz 10 mg/0.2 mL [62] and both Eticovo presentations are marked discontinued.
The panel document lists all 146 product entries, with BLA and product number, strength, applicant, marketing status, interchangeability date and exclusivity date, each with its citation.
Can pharmacists substitute them automatically?
Often yes, but it isn't automatic everywhere. FDA approval as interchangeable means a product may be substituted for its reference product without the prescriber stepping in. Whether a pharmacist actually can, and on what terms, is set by each state's pharmacy law. Even where substitution is allowed, states usually attach conditions: the prescriber can block it, and the patient must be told.
What the FDA says
- An interchangeable biosimilar "may be substituted for the original product without consulting the prescriber, much like how generic drugs are routinely substituted for brand name drugs." The FDA calls this "pharmacy-level substitution" and says it is "subject to state pharmacy laws" (FDA Consumer Update; same point on Biosimilars Basics for Patients).
- Biosimilars that are not interchangeable are treated differently: "Depending on state pharmacy laws, a biosimilar typically has to be prescribed by name, while an interchangeable biosimilar may be substituted for the reference product at a pharmacy without the intervention of the prescriber" (FDA, 9 Things to Know).
Example of what a state adds: Florida, s. 465.0252, 2026 Florida Statutes
The section says a pharmacist "may only dispense a substitute biological product for the prescribed biological product if" all of these are met (Florida Legislature):
- (2)(a): the FDA has found the substitute "biosimilar to and interchangeable for" the prescribed product. A biosimilar that is not interchangeable cannot be substituted.
- (2)(b): the prescriber "does not express a preference against substitution in writing, verbally, or electronically."
- (2)(c): the pharmacist tells the person presenting the prescription about the substitution, in the manner set by s. 465.025(3)(a).
- (2)(d): the pharmacist keeps a written or electronic record of the substitution "for at least 2 years."
- (3): in Class II, Modified Class II and Class III institutional pharmacies, notice is given by entering the substitution in the institution's medical record.
- (4): the Board of Pharmacy "shall maintain" a public list of FDA-designated interchangeable products.
So even in a state that allows it, substitution is permitted rather than required, and the prescriber can block it.
What to keep in mind for the products I listed earlier
- It applies to the matching reference product only. Interchangeability is set against one reference product. For example, Wyost is listed as interchangeable with Xgeva, not with Prolia [29].
- It can apply to some presentations only. Cyltezo 40 mg/0.8 mL has been interchangeable since 2021-10-15 [2], but its 40 mg/0.4 mL presentation only since 2025-05-20 [59]. Whether a given pack can be substituted depends on that presentation's own status.
- The rules differ by state. Florida is just one example. I tried to open California's Business and Professions Code s. 4073.5 and Texas Occupations Code ch. 562 on the official state sites but could not, so I can't tell you what they require. For any other state I haven't checked, I can't say what conditions apply.
Approach: I checked the FDA Purple Book and found no dataset covering US state pharmacy substitution laws, so I used the FDA's own biosimilar pages and the official Florida Statutes text. I could not open the official California and Texas statute pages.