Interchangeability: When Biosimilars Can Be Substituted Automatically in the U.S.

When you pick up a prescription for insulin or a biologic drug like Humira, you might not realize the pharmacy could swap it out for a different version without your doctor’s approval. That’s not a mistake-it’s called interchangeability, and it’s a unique feature of how the U.S. handles biosimilars. Unlike generic pills, which are chemically identical to their brand-name counterparts, biosimilars are made from living cells. They’re incredibly complex, and getting them approved as interchangeable isn’t just about matching the original drug-it’s about proving you can switch back and forth between them without risking your health.

What Makes a Biosimilar Interchangeable?

Not all biosimilars are created equal. The FDA approves two types: biosimilars and interchangeable biosimilars. A regular biosimilar must show it’s highly similar to the reference biologic in structure, function, safety, and effectiveness. But to be labeled interchangeable, a drug has to go further. It must prove that switching between the reference product and the biosimilar-multiple times-won’t increase risks or reduce effectiveness.

That means clinical studies where patients are switched from the original drug to the biosimilar, then back again, and sometimes even a third time. These aren’t short-term tests. They’re designed to catch subtle changes in immune response or side effects that might show up after repeated switches. The FDA requires this because biologics are made in living systems-like yeast or hamster cells-and tiny differences in manufacturing can change how the body reacts.

The first interchangeable biosimilar approved was Semglee, an insulin glargine product, in July 2021. Before that, patients had to get a new prescription every time they switched. Now, in many places, a pharmacist can swap it out automatically. Then in August 2023, Cyltezo became the first interchangeable biosimilar for adalimumab (Humira), a drug used for rheumatoid arthritis, psoriasis, and Crohn’s disease. That opened the door for millions of patients.

How Is This Different from Generic Drugs?

Think of generic drugs like aspirin or metformin. They’re small molecules, made in labs with exact chemical formulas. If you make them under the same conditions, they’re virtually identical. That’s why pharmacists can swap them without hesitation.

Biosimilars? They’re more like a handmade quilt than a factory-printed T-shirt. Even if two companies use the same blueprint, the living cells they grow them in might produce slightly different proteins. That’s why the FDA treats them differently. A generic drug just needs to prove it’s bioequivalent-same absorption, same blood levels. An interchangeable biosimilar has to prove you can switch back and forth safely, like swapping out two different brands of car battery and never noticing a difference in how the engine runs.

As of November 2023, the FDA has approved 41 biosimilars, but only 10 have the interchangeable label. That gap shows how tough the bar is.

State Laws Make It a Patchwork

Even if the FDA says a biosimilar is interchangeable, that doesn’t mean every pharmacy can swap it automatically. Each state has its own rules. Forty states, including Arizona and California, let pharmacists substitute without asking the doctor-so long as the product is designated interchangeable. But six states, like Arkansas and Mississippi, only allow substitution if it saves the patient money. Four states-Alabama, Indiana, South Carolina, and Washington-require the prescriber’s permission every time.

This creates real headaches for pharmacists. One community pharmacist in Texas told a 2023 survey they spent nearly nine hours a year just keeping up with state rules. National chains have to program their systems to check the patient’s address before deciding whether substitution is allowed. Independent pharmacies often don’t have the staff or software to handle it smoothly.

And it’s not just about legality. Insurance plans also play a role. About 78% of commercial health plans require automatic substitution for interchangeable biosimilars when state law allows it. So even if your doctor writes "dispense as written," your insurer might override it unless you specifically opt out.

What Patients Are Saying

For many, interchangeability means savings. One patient on the Psoriasis Foundation forum said switching from Humira to Hyrimoz saved them $800 a month-with no change in how they felt. That’s huge for people on expensive biologics that can cost over $20,000 a year.

But not everyone has smooth transitions. Another patient reported an allergic reaction after their pharmacy automatically switched them from Humira to Hadlima. Turns out, they were sensitive to a stabilizer in the new formulation. The reaction wasn’t caused by the active ingredient-it was an excipient, something added to keep the drug stable. That’s why the FDA says all biosimilars, even interchangeable ones, must list every ingredient. But many patients don’t know to check.

A 2022 survey by the National Psoriasis Foundation found 63% of patients were happy with their biosimilar, but nearly 30% were upset they weren’t told about the switch. Transparency matters. In Arizona, pharmacists must notify patients in writing and send a record to the doctor within five days. In other states, no such rule exists.

Why Experts Are Divided

Supporters say interchangeability is the key to cutting costs in the $300 billion biologics market. A 2022 RAND Corporation study found biosimilars typically cost 15-30% less than the original. With insulin alone, the first interchangeable version, Semglee, grabbed 17.3% of the market within six months-much faster than non-interchangeable versions.

But critics worry about unintended consequences. Dr. Kevin Winthrop, a professor at Oregon Health & Science University, pointed to a study showing psoriasis patients switched to biosimilars were 20% more likely to stop treatment entirely. Was it because the drug didn’t work? Or because they didn’t trust the switch? No one knows for sure.

There’s also a push in Congress to eliminate the switching studies entirely. The Biosimilar Red Tape Elimination Act, introduced in 2022, would make every FDA-approved biosimilar automatically interchangeable. Supporters say it’s unnecessary bureaucracy. Opponents, including PhRMA, argue it could put patients at risk by skipping critical safety data.

The FDA’s position is clear: all approved biosimilars are safe and effective. Interchangeability doesn’t mean "better"-it just means "switchable without a doctor’s note." But the public doesn’t always hear that distinction.

What Pharmacists Need to Know

If you’re a pharmacist, you’re on the front lines. You need to know:

• Is the biosimilar FDA-designated as interchangeable?
• What does your state law say about substitution?
• Does the patient’s insurance require substitution?
• Did the prescriber write "dispense as written" or use a DAW code?
• Are you required to notify the patient and the doctor?

The American Pharmacists Association has trained over 12,000 pharmacists through its Biosimilars Certificate Program. But training isn’t enough-systems need to update, records need to be kept, and patients need to be informed.

The Future of Interchangeability

By 2025, 70% of the top 20 biologic drugs in the U.S. will have biosimilar competitors. That’s a massive shift. Insulin, Humira, Enbrel, Remicade-these are all in play. Interchangeable versions will likely become the norm, not the exception.

But the path forward isn’t smooth. State laws are inconsistent. Patient education is lacking. Pharmacists are overwhelmed. And Congress is debating whether to simplify the rules-or make them even more complex.

One thing is certain: if you’re on a biologic, you need to know your options. Ask your doctor: "Is there a biosimilar available?" Ask your pharmacist: "Was this switched?" And always check the label. Your health depends on knowing what’s in the bottle.