Cyclosporine Products: A Potential for Inappropriate Substitution

Reprinted with permission from Novartis Pharmaceuticals.

As health care professionals who play an important role in the treatment of transplant recipients, pharmacists need to be aware of potential risks for patients. With the constant appearance of new drugs and new formulary restrictions, as well as state requirements concerning generic substitution, pharmacists are under constant pressure to make substitutions when filling prescriptions. Yet, incorrect substitutions may present a potential threat to patients. An incorrect substitution problem that has recently emerged is that of nonbioequivalent cyclosporine formulations.

Since the mid-1980s, cyclosporine has been a cornerstone of transplant immunosuppression. The 2 primary marketed formulations of cyclosporine are Neoral (cyclosporine USP [MODIFIED]) and Sandimmune (cyclosporine USP), both manufactured by Novartis. Additionally, generic versions of these 2 products have become available (Figure). Recently there have been concerns that patients prescribed Neoral or a generic equivalent of Neoral could have their prescriptions inappropriately switched to a nonbioequivalent product, or specifically to a newly available generic version of Sandimmune, manufactured by Apotex Corp. The intent of this article is to show why this particular substitution may place the transplant recipient at risk.

The new cyclosporine USP product is AB-rated and is considered therapeutically equivalent to Sandimmune.¹ Because the FDA has determined that products classified as therapeutically equivalent can be substituted for one another (note that bioequivalence is one of the criteria for therapeutic equivalence), the pharmacist reasonably may substitute the new Apotex product for Sandimmune as long as the prescribing physician has not specified to dispense as written. The Apotex product, however, is not bioequivalent to Neoral and cannot be substituted for either Neoral or generic equivalents of Neoral (eg, Gengraf [Abbott Laboratories Inc) or cyclosporine USP (MODIFIED; Eon Labs Manufacturing Inc).

After the Neoral formulation became available, the potential for confusion regarding its use versus Sandimmune became apparent. A national survey of retail pharmacies and analysis of 2830 cyclosporine prescriptions indicated nearly a 1-in-5 chance that a new patient could receive an unintended formulation.² With the subsequent appearance of at least 3 generic cyclosporine USP (MODIFIED) products in addition to 1 cyclosporine USP product, it has become increasingly important to be vigilant when dispensing them, as is illustrated by a recent experience of the author. During a pharmacy inspection, the author found that the new cyclosporine USP product (Apotex) had been placed in the cyclosporine USP (MODIFIED) section. Furthermore, "Sandimmune" had been written on the bottle containing the Apotex product, but it had been crossed out, and "Neoral" had been written on the bottle in its place. Diligence on the part of pharmacists will be needed to prevent inappropriate substitution at the pharmacy level.

Potential Consequences of Inappropriate Switching

Inappropriate substitutions can place a patient at risk. In the case of cyclosporine USP (MODIFIED), inappropriate substitution of Neoral or a generic equivalent (eg, Gengraf) with Sandimmune or a generic equivalent (eg, the new Apotex product) places the patient at risk for cyclosporine underexposure.

Sandimmune, the original formulation of cyclosporine, mixes poorly with gastrointestinal fluids, resulting in low and inconsistent absorption. The Neoral formulation was developed to allow higher and more consistent absorption. In a study of the Neoral formulation, both the absorption rate and the systemic availability were faster, compared with the Sandimmune formulation, for all dose levels studied (200 to 800 mg), and the relative bioavailability of Neoral ranged from 174% to 239%, compared with Sandimmune, depending on the dose.³

Clinically, this means that patients taking Sandimmune (or a Sandimmune generic) could be exposed to considerably more drug if switched to Neoral (or a Neoral generic), with the potential for toxicity. Of particular concern, and the subject of this article, is that persons taking Neoral (or a Neoral generic) could be exposed to considerably less drug if switched to Sandimmune (or a Sandimmune generic). This switch could have serious consequences because decreased bioavailability of cyclosporine is associated with an increased risk for acute rejection? ie, decreased function/failure of the transplanted organ or "graft."⁴ Acute rejection is a condition detected clinically and confirmed by biopsy of the transplanted organ. It is important to note that, although usually treatable, episodes of acute rejection are associated with an increased risk for chronic graft dysfunction and failure.⁵

It is also important to note that there are differences in the level of drug exposure achieved with each dose in the same individual. In studies comparing Neoral and Sandimmune, intrapatient variability in cyclosporine exposure was greater with Sandimmune.^6-8 Increasing intrapatient variability raises the risk for chronic rejection,⁹ a process involving a gradual decline in graft function and eventual graft failure.

From a societal perspective, graft loss is devastating, not only for the transplant recipient, but also for the community. According to the United Network for Organ Sharing (available at www.unos.org), >80,000 people in the United States are currently on the transplant waiting list. Clearly, donated organs are precious, and great care must be taken to ensure their survival after transplantation.

Actions for Pharmacists

Regarding immunosuppressive drugs and the use of generic immunosuppressants, experts convened by the American Society of Transplantation recently recommended that patient welfare be the foremost concern in prescribing or dispensing decisions.¹⁰ The pharmacist needs to be aware of the potential for incorrect substitution and to be vigilant in guarding against it. The pharmacist should check for specific instructions from the prescribing physician regarding substitution so that the intended product is dispensed. Products that are not AB-rated should not be substituted for one another.

If a pharmacist receives a prescription for what appears to be an inappropriate formulation switch, he or she should contact the prescribing physician to verify what is intended. If a pharmacist discovers that an inappropriate substitution already has occurred, he or she must contact the prescribing physician so that appropriate measures, such as timely therapeutic drug monitoring, can be taken to avert untoward effects. Finally, within the pharmacy itself, the pharmacist also may be instrumental in averting problems by ensuring that nonbioequivalent formulations are shelved separately and are clearly differentiated by identifying labels.

Conclusion

As immunosuppressive therapy is a lifelong undertaking, generic medications can offer considerable economic benefit to the transplant recipient. Inappropriate substitution, however, of nonbioequivalent drugs at the pharmacy level?such as that of either the new generic cyclosporine USP (or its innovator drug Sandimmune) for cyclosporine USP (MODIFIED; Neoral or its generic equivalents)?can place the transplant recipient at risk. As a health care professional involved in the care of these patients, the pharmacist can play a key role in helping to ensure the proper maintenance of their immunosuppressive treatment.

Dr. Haug is a transplant and pharmacokinetics clinical specialist in the Pharmacy Department and the Transplant Center, Cleveland Clinic Foundation.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@mwc.com.