The use of generic narrow therapeutic index (NTI) medications remains controversial in certain disease states. This controversy is of particular interest within the field of transplantation, where maintenance immunosuppression is essential for long-term patient and graft survival. Immunosuppressive regimens generally consist of a combination of several agents from different therapeutic classes. For example, a regimen might consist of a calcineurin inhibitor (tacrolimus or cyclosporine), an anti-proliferative agent (mycophenolate mofetil, mycophenolate sodium, or azathioprine), and a corticosteroid. Given the vulnerability of transplant patients, it is essential to be aware that with as little as a two-fold change in blood concentrations with some of these agents, patients can experience toxicity or an episode of acute rejection. For example, if a patient’s tacrolimus target level is 8 to 10 ng/mL, and their level increases two-fold to 20 ng/mL, that patient will likely have manifestations of toxicity, such as hand tremors, acute renal dysfunction, or even seizures. Conversely, if the tacrolimus level abruptly fell below the target, they would be at increased risk for rejection.
The concern over whether conversion to generic immunosuppressants can cause clinically relevant changes in blood concentrations was first brought to light in the late 1990s with the first generic approval of cyclosporine microemulsion oral solution formulation (SangCya; SangStat Medical Corp, Freemont, CA). This product was voluntarily recalled in 2000 after it was discovered that when administered with apple juice, drug delivery was 20% to 30% less than expected. As a result, the controversy over conversion subsided among transplant practitioners for the next decade as tacrolimus (Prograf; Astellas Pharma US, Inc, Northbrook, IL) became the dominant calcineurin inhibitor and mycophenolate mofetil (CellCept; Genentech, Inc, San Francisco, CA) the dominant anti-proliferative agent. In recent years, this controversy reemerged as generic formulations of tacrolimus and mycophenolate mofetil became available within months of each other in 2009.1
Pharmaceutical Equivalence of Products
In order to meet the standards for FDA approval, generic medications must be deemed bioequivalent, in addition to pharmaceutically equivalent (identical ingredients, strength, dosage form, and route of administration), to their brand name counterparts. Generic manufacturers are not required to submit clinical data regarding safety and efficacy. To be considered bioequivalent, the generic product must result in a similar dose vs time relationship (Cmax) and area under curve (AUC) upon analysis. Determining the Cmax and AUC serves to ensure that innovator and generic products have similar pharmacokinetics. The FDA allows the geometric (as opposed to the arithmetic) mean of the Cmax and AUC of generic medications to fall between 80% and 125% when compared to the innovator product. On the surface, this can create a misconception that generic drug concentrations may differ from their respective reference drugs by up to 45%. In reality, studies have found the margin to be closer to ±5% and that mathematically they must lie within ±13% in order to meet FDA standards.2-4 Bioequivalence testing generally involves 24-36 healthy volunteers.
Some clinicians within the transplant community have argued that FDA regulations should be tighter when dealing with NTI drugs in order to avoid acute rejection in the setting of therapy substitutions. These same clinicians often advocate for reference-to-generic bioequivalence testing in transplant recipients, particularly for African Americans and pediatric patients to ensure there are no clinically significant differences in these special populations. Unfortunately, there are very few studies or clinical trials that address these concerns. Regardless, the available data suggests that generic substitution can be implemented safely, in concert with proper therapeutic drug monitoring (TDM), without risk of rejection. This recommendation is echoed in the general position statements of various transplant societies, including the American Society of Transplantation.1
There can be significant cost advantages to using generic immunosuppressive medications for health systems, insurance providers, and patients. However, actual savings for patients may be limited by the fact that Medicare Part A copays are not impacted by generic pricing. Given that Medicare is the largest third-party provider for transplant recipients, a substantial percentage of patients will not experience cost savings. In addition, many innovator immunosuppressant manufacturers offer discount programs that shield qualified patients with private insurance from the higher copay associated with use of a brand name product when a generic alternative is available. However, such copay assistance programs are limited or not allowed in certain states, including New York and Massachusetts.
Health systems and insurance providers, on the other hand, are likely to realize the savings associated with the availability of generic immunosuppressants. In fact, from our experience and review of wholesale prices, a 50% to 90% discount in acquisition cost can be expected. This discount may be realized by using a generic outright, or by negotiating a lower price with a maker of the brand product or branded generic.
An important caveat to factor into any projected savings is that conversion from branded to generic NTI medications may require additional drug level monitoring. Depending on the established drug level monitoring practice at a given center, the additional laboratory work involved in expanded monitoring may impact the savings realized in acquisition cost. At many transplant centers, including Yale-New Haven Transplant Center (YNHTC), drug levels are monitored closely for any admission, so upon conversion to generic products, YNHTC does not require additional TDM beyond our previously established procedure. This practice may vary among transplant centers with some choosing to monitor more sporadically or specifically during switches, but regardless of accepted practice, the policy for TDM should be explored before proceeding with conversion to generic medications.
An important consideration when purchasing products—in addition to price at the hospital or health-system level—is how they are supplied. Some generic medications are supplied in unit dose packaging, which is more cost-effective and practical from a purchasing and dispensing perspective (see Table 1). Furthermore, pre-packaged unit dose medications offer enhanced patient safety by reducing dispensing errors with bar code technology. Alternately, purchasing generic products in bulk and re-packaging them also can contribute to overall cost; unfortunately, among generic immunosuppressive medications, certain manufacturers only supply products in bulk packaging. Thus, packaging options should be considered when choosing immunosuppressive medications as workhorse formulary agents.
A Practical Approach to Managing Generic Immunosuppressants
Given the cost-saving advantages associated with generic products, most hospitals or health-systems are likely to pursue the use of generic immunosuppressants. Since it is impractical to keep an inventory of brand and several generics for every immunosuppressant, one cost-effective approach would be to utilize a single product and apply TDM for NTI drugs when patients are switched between products. In this scenario, providers carefully monitor drug concentrations and adjust doses accordingly for each patient based on laboratory results. Non-NTI drugs can be switched without application of TDM.
Role of the Transplant Pharmacist
In addition to applying TDM when patients are switched between products, prescribers and patients should be educated on the importance of therapy changes, TDM, and the risks and benefits of using generic immunosuppressants. This is a role optimally filled by the transplant pharmacist. Most transplant centers employ at least one transplant pharmacist, and these pharmacotherapy experts are well equipped and positioned to ensure transitions between products are handled in a way that minimizes the risk for adverse events. The transplant pharmacist and pharmacy purchasers should collaborate to ensure the best product is selected based on all of the above considerations. Likewise, changes in formulary always should be communicated to prescribers and patients to minimize confusion and ensure a smooth transition.5
There is a substantial opportunity for hospitals and health systems to gain cost savings with the use of generic immunosuppressants. However, there are several clinical, operational, and purchasing considerations that must be evaluated before committing to a formulary conversion to a generic product, and many of these considerations are institution- and manufacturer-specific. The ultimate choice of a formulary agent will vary among facilities following a thorough analysis of these options. Given that the availability of generic immunosuppressive products will continue to rise in the coming years, thoughtful contemplation of these critical dose medications is an advisable course of action.
- Ensor CR, Trofe-Clark J, Gabardi S, et al. Generic Maintenance Immunosuppression in Solid Organ Transplant Recipients. Pharmacotherapy 2011 Nov;31(11): 1111-29.
- Trofe-Clark J, Gabardi S, McDevitt-Potter L, Alloway RR. Immunosuppression, Generic Drugs, and the FDA. Am J Transplant 2012 Mar;12(3): 792-3.
- Davit BM, Nwakama PE, Buehler GJ, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the US Food and Drug Administration. Ann Pharmacother 2009 Oct;43(10):1583–97.
- Malinowski HJ, Johnson SB. Bioavailability and Bioequivalency Testing. In: Troy DB, ed. Remington: The Science and Practice of Pharmacy, 21st ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005:1037–46.
- Alloway RR, Dupuis R, Gabardi S, et al. Evolution of the Role of the Transplant Pharmacist on the Multidisciplinary Transplant Team. Am J Transplant 2011 Aug;11(8): 1576–83.
- US Food and Drug Administration. Approved Drug Products with Therapeutic Equivalence Evaluations, 30th ed. Washington, DC: US Department of Health and Human Services, Public Health Service, FDA Center for Drug Evaluation and Research; Office of Pharmaceutical Sciences, Office of Generic Drugs, April 2010. Available at: http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm
- Cardinal Health. Pharmaceutical Ordering. Accessed August 20, 2012.Available at: http://www.cardinal.com
Eric Tichy, PharmD, BCPS, is a clinical pharmacy specialist in solid organ transplant at Yale-New Haven Hospital in New Haven, Connecticut. He is a graduate of the University of Connecticut School of Pharmacy and trained in pharmacy practice at Yale-New Haven Hospital. Eric also is board-certified in pharmacotherapy and holds adjunct faculty appointments at the University of Connecticut School of Pharmacy and Duquesne University Mylan School of Pharmacy. A member of the heart, kidney, and liver transplant teams at Yale-New Haven Transplantation Center, Eric serves as director of the YNHTC transplant pharmacy residency.
Ginger Morris, PharmD, is a PGY-2 solid organ transplant pharmacy resident at Yale-New Haven Hospital. She is a graduate of Duquesne University Mylan School of Pharmacy and holds an adjunct faculty appointment at the University of Connecticut School of Pharmacy. Ginger is currently training in solid organ transplantation with the liver, kidney, and heart teams at the YNHTC.
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