Generic Tacrolimus: Lack of Bioequivalence Data in Transplant Recipients Raises Concerns

Hogan, Michelle

doi: 10.1097/01.NEP.0000361308.74364.5d

Amidst the approval of the first generic version of the immunosuppressant tacrolimus, transplant professionals are prescribing caution.

The generic agent—launched by Sandoz, a division of the Novartis group—was approved in August by the Food and Drug Administration (FDA).

“It's causing some concern in the transplant community,” said Barbara Murphy, MD, Past President of the American Society of Transplantation (AST) and Chief of the Division of Nephrology at Mount Sinai Medical Center, in a phone interview.

“It's specific to drugs like tacrolimus that have narrow therapeutic windows and are monitored by drug levels, so the fact that the generics haven't actually been tested for bioequivalence in transplant patients who are on other medications that interact with them is of concern.”

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Studied in Healthy Subjects

For FDA approval, bioequivalence of a generic version of tacrolimus must be demonstrated in single-dose, two-treatment, two-period crossover studies in healthy individuals in the fed and fasting states, but similar studies in transplant recipients are not required.

In a Citizen Petition filed in September 2007, Astellas, the holder of the New Drug Application for the brand version of tacrolimus, asked the FDA to make bioequivalence studies in transplant patients a necessity for approval of oral immunosuppressants with a narrow therapeutic index.

The American Society of Transplant Surgeons (ASTS) and the American Society of Transplantation (AST) also made this recommendation in comments submitted to the FDA the same month. The request in the Citizen Petition was denied.

“[W]ith regard to tacrolimus, there is insufficient scientific evidence to suggest that the use of specific patient population(s) in bioequivalence studies would detect differences in formulation that might have clinical significance and that would not be detected by bioequivalence in healthy subjects,” the Agency noted in its response to the petition.

But patients with kidney disease have different absorption, distribution, metabolic, and excretion characteristics, said Steven Gabardi, PharmD, BCPS, Abdominal Organ Transplant Specialist at Brigham and Women's Hospital and Instructor in Medicine at Harvard Medical School, in a phone interview.

“I think that the FDA has to understand that different patient populations—and not just ethnic or racial lines but different patient populations with different disease states—have different pharmacokinetics.…

“I understand that their take is hey listen, the brand name manufacturer already did all that. They already evaluated this in the kidney transplant population.

“But even a small change in a patient's dose or a change in their level that goes unnoticed, that we're not aware of because we weren't aware of a conversion in the outpatient setting, can have catastrophic consequences.

“It's not like the blood pressure is elevated for a couple days or a couple weeks until we can get the patient in. It could obviously cause issues with severe toxicities or immunologic consequences.”

Astellas filed a request for emergency relief and preliminary injunction from the FDA decision on its Citizen Petition, but the request was denied by the US District Court in Washington, DC.

“We maintain that it really is essential to demonstrate bioequivalence in the transplant population,” said William E. Fitzsimmons, PharmD, MS, Senior Vice President of Research and Development for Astellas, in a phone interview.

“We are disappointed in the decision by the FDA, and that's why we were continuing to pursue what we think is the best way of ensuring that any generic product on the market is both safe and effective.”

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Lessons from Cyclosporine

Of course, tacrolimus is not the first calcineurin inhibitor for which a generic agent was launched: In 1998, a generic version of cyclosporine, SangStat's SangCya, was approved, but it was voluntarily withdrawn from the market in 2000.

Subsequently, though, several other generic formulations of cyclosporine were authorized that remain on the market.

As is the case with generic tacrolimus, there was some anxiety surrounding the approvals of generic versions of cyclosporine, noted Alan Wilkinson, MD, Director of the Kidney Transplant Program at UCLA, in a phone interview.

The main concern was that although a group of subjects taking a generic formulation might fall within the required 80%–125% range for bioequivalence, each individual patient might of course be very different, Dr. Wilkinson noted.

“You might have one patient with a very good value on one drug and a very low value on the other, and the opposite in the second patient, and they sort of neutralize each other out if you just take the average of the group, but even with that concern we really had no problems.”

He added, “Although you can look at the FDA approval process for generics compared with brands as being a little sketchy in some ways, there's no evidence that I know of that there's been any major failure.”

The approval of generic versions of cyclosporine gave transplant professionals some experience in managing patients switched among the brand and generic formulations of a narrow-therapeutic-index immunosuppressant.

“We've dealt with this in the past, and you can manage it,” Dr. Murphy said. “You make sure that you bring your patient in; you check their lab values, make sure that they're within the therapeutic range that you want them in; etcetera.”

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Notifying Physicians

However, in order to respond accordingly, a physician must be notified that the pharmacist has made a swap. The Astellas Citizen Petition requested that such notification be mandated—a measure that's also supported in the AST comments—but the request was denied.

“The current review process for ANDAs [Abbreviated New Drug Applications] is adequate to assure the interchangeability of generic versions of immunosuppressant drugs such as tacrolimus with their branded counterparts,” the Agency noted.

The absence of a requirement for such notification is something that's missing from the rules and regulations, Dr. Wilkinson said.

“There's a physician-patient relationship that may be interfered with. … The other thing that we've had sometimes is, for example, with nifedipine, where you had Procardia, Adalat, and nifedipine generic, we had patients come in taking all three of those because the labeling on the bottle didn't make it clear they were the same drug. The generic name wasn't always on the bottle, and even if it were the patient might still not have noticed.

“We've had patients in fact come in taking both Neoral [brand cyclosporine] and say Eon [generic cyclosporine] not realizing they were the same thing.

“They don't really know—they have this huge bag of medications, they go to the pharmacist, they go in with 15, they come out with 16—they don't realize that two of them are actually the same thing, and so that's the other danger if pharmacists aren't clear when they switch and don't explain to patients that this drug is being substituted for another.”

Letting the prescriber know of a switch among brand and generic formulations could also facilitate the accumulation of outcomes data, Dr. Gabardi said.

“I think any notification where we could capture the entire group, one, would obviously be safer for the patient but, two, would help give us a better idea of what might go on when RAPA becomes generic.

“I know every single center in Boston that has a PharmD, we're all collecting data on what the outcomes are of conversion to generic tacrolimus because that was something that wasn't done with Neoral.…

“We can potentially make cases that we're worried for nothing or our worry was justified because in ‘x’ number of conversions we had this issue.”

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Multiple Generics

The potential approval of multiple generic formulations of tacrolimus complicates the issue, Dr. Gabardi added.

“With only one generic on the market, it's not such a big deal because once you get a conversion you can bring the patient in, do a level, and then manage the patient pretty simply.

“The big sticking point or the problem that I am most concerned about is when multiple generics hit the market. … With Prograf [tacrolimus], once we get seven, eight, nine, or ten, converting from generic drug ‘A’ to generic drug ‘B’ is what scares me.”

While generic drugs are considered to be bioequivalent to the brand agent, they are not necessarily bioequivalent to each other.

“For example, generic drug ‘A’ may drop your Prograf levels by 15 percent, and the FDA says that's within the acceptable range, and generic drug ‘B’ may increase Prograf levels by 20 percent, which the FDA also says is acceptable, but when you go from A to B you have a 35 percent change in level, which is a humongous change,” Dr. Gabardi said.

“There's no way of stipulating a generic manufacturer on a prescription, so I can't write, “Give tacrolimus: Please dispense manufacturer ‘X's' version of tacrolimus every time.’ That doesn't work.”

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Watching and Waiting

Dr. Gabardi and his colleagues have a couple strategies for dealing with concerns over the potential availability of multiple generic versions of tacrolimus.

“We use a few pharmacies relatively frequently,” Dr. Gabardi said. “When CellCept went generic, we had two of them agree that they would only purchase one version … and that's what we're hoping for a couple of our big-use pharmacies that we use in the outpatient setting. So that's certainly one way that we can mitigate it.

“The other and what our plan is right now is to just ‘Dispense as Written’ Prograf prescriptions until we get patients who have financial hardships who we need to give generics because of the price, until we can figure out if there are any issues with the generic products.

“We did this with Neoral as well in that we waited six to 12 months until we had a pretty good feel of what was going on in the market.”

But it's difficult to draw lessons from the experience with generic cyclosporine, Dr. Gabardi said.

“It's tough because if you look back to when Neoral went generic, nationwide most centers had already converted or were in the process of converting to Prograf as their primary immunosuppressant, so if we ran into problems—real bad problems—then we could always convert a patient over to Prograf.

“The Neoral experience is probably the closest, but it's also one that's flawed because we certainly had a comparable immunosuppressant that we could put the patient on and guarantee that they would be able to get the same formulation.

“Even though RAPA won't be generic for a long time, I know a lot of people don't feel the same way about Rapamune as they did with Prograf because they're completely different molecules.

“Now CellCept going generic I think nationwide most people said hooray. This is not a therapeutic monitored drug; it's not a narrow-therapeutic-window drug. There's a large range in terms of overall exposure to the drug where the drug works well, and so a lot of people said great let's convert to generic—I know we did. Those who were worried, they had Myfortic to fall back on.

“There isn't a whole lot that we've had in the past 10 or 15 years, even though we've had two major drugs go generic, that I think will be comparable to this conversion.”

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Raising Awareness

Amidst the uncertainties over the approval of generic tacrolimus, awareness of the issue is crucial, Dr. Murphy noted.

“Really I think unfortunately it's going to wind up a responsibility of the patients because they're going to be the ones who see that the tablet looks different.

“So I think for transplant nephrologists, for nephrologists in the community, it's going to be important for them to emphasize to their patients to be aware, to be alert; that if they see a difference, ask the pharmacist; if they see a difference and they want to clarify they can always call their doctor, but really to heighten the awareness amongst the patient population and to make sure that they communicate with their doctor when there are changes in their medications so that then they can be informed that they need to come in and have their blood levels checked and make sure that they are still within the therapeutic window.”

Dr. Murphy added, “Obviously rising health care costs and burdens of co-pays for transplant patients are significant, so to have an alternative that makes it more affordable for patients is beneficial, but there has to be a mechanism first off for the medical community to be able to work with it and deal with it and know that their patients are going to be appropriately treated and … that it is actually safe for them to be on those medications.”

© 2009 Lippincott Williams & Wilkins, Inc.