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Generic Immunosuppression in Solid Organ Transplantation: A Canadian Perspective

Harrison, Jennifer J.1,13; Schiff, Jeffrey R.2; Coursol, Christian J.3; Daley, Christopher J.A.4; Dipchand, Anne I.5; Heywood, Norine M.6; Keough-Ryan, Tammy M.7; Keown, Paul A.8; Levy, Gary A.9; Lien, Dale C.10; Wichart, Jenny R.11; Cantarovich, Marcelo12

doi: 10.1097/TP.0b013e3182445e9d
Editorials and Perspectives: Overview

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as “critical dose drugs” and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.

1Multi-Organ Transplant Program and the Department of Pharmacy Services, Toronto General Hospital, University Health Network, Toronto, ON, Canada.

2Division of Nephrology and Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada.

3Multi-Organ Transplant Program and the Department of Pharmacy, McGill University Health Center, Montreal, QC, Canada.

4Multi-Organ Transplant Program, Queen Elizabeth II Health Science Centre, Halifax, NS, Canada.

5Department of Pediatrics, University of Toronto; Hospital for Sick Children, Toronto, ON, Canada.

6Multi-Organ Transplant Program and the Department of Nursing, McGill University Health Center, Montreal, QC, Canada.

7Division of Nephrology, Multi Organ Transplant Program, Queen Elizabeth II Health Science Centre; Departments of Medicine and Surgery, Dalhousie University, Halifax, NS, Canada.

8Department of Medicine; Pathology and Laboratory Medicine, University of British Columbia, Diamond Health Care Centre, Vancouver, BC, Canada.

9Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada.

10Lung Transplant Program, University of Alberta, Edmonton, AB, Canada.

11Pediatric Nephrology Program and the Department of Pharmacy, Alberta Children's Hospital, Calgary, AB, Canada.

12Multi-Organ Transplant Program, Department of Medicine, McGill University Health Center, Montreal, QC, Canada.

J.J.H. is a scientific advisory board member for Astellas and has received speaker honoraria and unrestricted educational grants from Astellas, Hoffman LaRoche and Genzyme. J.R.S. has received speaker honoraria from Hoffman LaRoche and Genzyme. C.J.C. is a scientific advisory board member for Astellas and has received speaker honoraria and research grants from Astellas, Hoffman LaRoche, Novartis and Genzyme. C.J.A.D. is a scientific advisory board member for Astellas and has received speaker honoraria from Astellas, Hoffman LaRoche and Genzyme. A.I.D. has received a research grant from Astellas and is a scientific advisory board member for CSL Behring. T.M.K.-R. is a scientific advisory board member for and has received speaker honoraria from Astellas, Hoffman LaRoche and Novartis. P.A.K. has received research support from Novartis, Astellas and Hoffman LaRoche and speaker honoraria from Novartis, Hoffman LaRoche and Bristol Myers Squibb. G.A.L. is a scientific advisory board member and consultant of Novartis, Astellas, Hoffman LaRoche and Abbott. M.C. is a scientific advisory board member for Astellas and has received education grants from Astellas, Genzyme, Hoffman LaRoche, Novartis and Pfizer. The other authors declare no conflict of interest.

Address correspondence to: Jennifer J. Harrison, B.Sc.Hon., B.Sc.Phm., M.Sc., Department of Pharmacy Services, Toronto General Hospital, University Health Network, 585 University Avenue, BCS-076, Toronto, ON, Canada M5G 2N2. E-mail: jennifer.harrison@uhn.ca

J.J.H. led the working group. All authors participated in the critical analysis and review of the data, and in developing and finalizing the recommendations. J.J.H., J.R.S., C.J.C., C.J.A.D., N.M.H., T.M.K.-R., D.C.L., J.R.W., and M.C. participated in the writing of the manuscript. All authors critically reviewed and edited the manuscript.

Received 19 September 2011. Revision requested 27 October 2011.

Accepted 29 November 2011.

In 2009, generic medications saved Canadians an estimated 6.5 billion dollars in direct drug costs (1). As new federal pricing regulations are introduced, these savings will become even more impressive (2). For solid organ transplant recipients (SOTR), the yearly cost of immunosuppressive drugs may be as high as $15,000 Canadian per patient. With the pending Canadian patent expiry on several branded immunosuppressive agents (Table 1), there may be an opportunity for substantial cost containment, provided generic formulations can offer equivalent efficacy and safety to their branded counterparts. The purpose of this report is to review the available data and provide recommendations on the use of generic immunosuppressive medications in SOTR.

TABLE 1

TABLE 1

An interprofessional working group of the Canadian Society of Transplantation was established to identify and discuss data on generic immunosuppressive medications and their use in SOTR. Participation in the working group was solicited by invitation to promote broad geographical representation and diversity of expertise across solid organ transplant settings. The final working group was composed of seven physicians, four pharmacists, and one nurse who are the authors of this report. Published literature was reviewed and recommendations were made by the working group. The Grading of Recommendations Assessment, Development, and Evaluations system of recommendations was used to classify the quality of evidence and strength of recommendations (3). The report and recommendations were finalized and the article was approved for submission for publication after an internal peer-review process conducted by the Canadian Society of Transplantation independent from the working group to minimize possible bias resulting from conflicts of interest of the authors.

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APPROVAL PROCESS FOR GENERIC DRUGS IN CANADA

Licensing of a generic formulation by Health Canada requires a demonstration of pharmaceutical equivalence and bioequivalence (BE) with the branded product. For pharmaceutical equivalence, the generic preparation must be identical in active ingredient(s), strength and dosage form, intended route of administration, and therapeutic indication. Differences in excipients (i.e., inactive ingredients) and product characteristics such as shape, color, scoring, release mechanism, packaging, labeling, and expiration time are allowable (5, 6). To be deemed bioequivalent, the generic product must show that the rate and extent to which the active ingredient becomes available at the site of drug action in the body is comparable with the branded formulation under similar conditions (5, 6). A typical BE study involves 18 to 36 healthy adults, administered a single dose of both the generic and branded products in a two-way crossover study design with blood sampling throughout the dosing interval. The mean maximal plasma concentration (Cmax) and the mean area under the curve (AUC) are calculated. Products are considered bioequivalent if the 90% confidence intervals for both Cmax and AUC mean ratio fall entirely within the acceptance limits of 0.8 to 1.25 (57).

Certain medications designated as “critical dose drugs” are required to meet a stricter acceptance margin of 0.9 to 1.12 for the AUC component of the BE test. Nine critical dose drugs are identified by Health Canada, which include the immunosuppressants cyclosporine A (CsA), tacrolimus, and sirolimus. At this time, mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium have not received this designation (8).

Under current regulations, there is no requirement for generic products to demonstrate BE in the target population or to confirm that BE is maintained in the setting of multiple comedications or with chronic use. More importantly, although generic formulations must demonstrate BE with the branded product, they are not required to show BE with each other. Once BE with the branded product is established, study findings are used to bridge clinical data such that therapeutic equivalence of generic formulations is assumed and clinical outcome studies are not required (6, 7).

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SPECIAL CONSIDERATIONS IN SOLID ORGAN TRANSPLANTATION

A central controversy surrounding generic immunosuppressant drugs is whether a demonstration of BE by single-dose studies in healthy adults offers sufficient guarantee of therapeutic equivalence in an individual of the intended population. Table 2 outlines key factors affecting medication pharmacokinetics in SOTR that are not addressed under current licensing requirements.

TABLE 2

TABLE 2

In the absence of adequate supporting evidence (reviewed below), uncertainty regarding efficacy of generic immunosuppression is of principal concern. For most other generic therapeutic agents there is a measurable clinical endpoint (e.g., blood pressure control with antihypertensives, cholesterol levels with statins) that allows for titration to equivalent biologic effect and detection of efficacy failure. In SOTR, there is no accurate test to determine whether the level of immunosuppression is adequate, suboptimal, or excessive. Failure to maintain an appropriate balance can lead to potentially catastrophic consequences. In the setting of under-immunosuppression this can include acute rejection and graft failure causing death (in heart, lung, or liver transplant recipients) and infection, and malignancy with excessive drug exposure. Over-immunosuppression may also lead to complications such as nephrotoxicity, neurotoxicity, hypertension, diabetes, and dyslipidemia.

Therapeutic drug monitoring (TDM) provides a useful surrogate marker of exposure for some immunosuppressive drugs (Table 1). However, there is no requirement for generic manufacturers to validate the branded drug's TDM strategy and an equivalent relationship between drug levels and exposure cannot be assumed. Virtually all clinical trials assessing immunosuppressive drugs, doses, and combinations have been conducted using branded products, and this experience forms the basis of dosing and target drug levels used by transplant programs worldwide.

The utility of TDM for dosing MMF and enteric-coated mycophenolate sodium remains controversial. Although there is significant between- and within-subject pharmacokinetic variability with these products, how exposure is best measured in clinical practice is unclear and TDM strategies are formulation specific. Data in kidney transplantation support a relationship between mycophenolate AUC and clinical efficacy (and to a lesser extent, toxicity); however, there are few studies in nonrenal transplant populations. Also, because the optimal means of performing mycophenolate TDM requires an abbreviated AUC measurement, it has not be implemented as part of routine care by many centers at this time (20, 21).

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EVIDENCE FOR USE OF GENERIC IMMUNOSUPPRESSION IN SOLID ORGAN TRANSPLANTATION

The use of generic medications is widespread in many areas of medicine with few reported safety issues. For example, a recent meta-analysis of trials comparing different formulations of drugs used in cardiovascular disease concluded that generic preparations offer similar clinical outcomes to their branded counterparts (22). Given media controversy regarding generic drugs in general and the interests of innovator companies to delay their introduction, it behooves transplant clinicians to understand the scientific evidence for the use of generic immunosuppression in SOTR to dispassionately evaluate the issue. We performed a search of Medline and EMBASE from 1985 to June 2011 for articles pertaining to generic immunosuppressant use in SOTR. Appendix 1 outlines the search strategy and study selection criteria. The following is an overview of the published experience.

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Adult Kidney Transplant Recipients

Cyclosporine A

Most of the available evidence comes from generic CsA conversion trials in stable kidney transplant recipients (KTR), comparing the pharmacokinetic profiles of the generic product and branded microemulsion formulation (Neoral) (2336). Although most of these studies found the tested products to be similar (2334), the only two trials with a prospective, randomized controlled design both found significant differences between generic and branded compounds (35, 36).

Equivalent graft function with no apparent adverse outcomes on short-term follow-up has been shown in nonrandomized conversion trials (2325, 27, 33, 35, 3739). In de novo KTR, acceptable outcomes have been demonstrated with generic preparations (27, 4042), but there have been reports of higher rates of acute rejection (43, 44). None of these studies used a prospective, randomized controlled design. In the largest retrospective analysis of 188 de novo KTR, patients receiving generic CsA had a higher rate of biopsy-proven acute rejection (BPAR), despite achieving comparable levels with those on branded product (44).

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Tacrolimus

There are few clinical studies comparing generic tacrolimus formulations to the branded product (Prograf). Three single-arm, non-randomized studies in de novo KTR have shown acceptable short-term outcomes with generic preparations (4547), as has one conversion trial (48). In a 3-year, open-label, randomized controlled study of 222 adult and pediatric de novo KTR in Mexico, patients receiving a generic formulation had lower tacrolimus levels at 6 months and twice the rate of acute rejection compared with those receiving branded tacrolimus, although this difference was not statistically significant. This work has not come to peer-reviewed publication (49).

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Mycophenolate

At the time of writing, three studies evaluating generic formulations of the branded MMF product (Cellcept) were identified. Two were open-label, nonrandomized, single-arm, observational studies. In the first, 24 stable KTR were converted from branded MMF to a generic formulation. Mycophenolic acid exposure was similar and renal function remained stable 1 year after conversion (50). In the second, 17 de novo KTR were administered generic formulations of both tacrolimus and MMF. No episodes of BPAR, graft loss, or death were observed after a mean follow-up of 7.6 months (47). The third was a prospective, open-label study of 18 de novo KTR randomized to branded MMF or generic formulation. At 2 years follow-up, serum creatinine, acute rejection rates, and patient and graft survival were similar (51).

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Pediatric Kidney Transplant Recipients

Pediatrics are a potentially at-risk population with known differences in pharmacokinetics of immunosuppressive drugs (17). In a 2003 report, the American Society of Transplantation concluded that there were insufficient data to recommend the use of generic immunosuppression in pediatrics (52). Since then, little additional research has been published. In an open-label, single-arm, prospective study of 155 de novo adult and pediatric living donor KTR receiving generic tacrolimus, a 4% rate of BPAR over a follow-up period of 3 to 33 months was reported. There were nine cases of death with a functioning graft, of which eight were due to infectious complications (46). A recent retrospective case series involving four pediatric KTR inadvertently converted from branded to generic tacrolimus reported one episode of acute rejection and one case of lower drug levels after the switch (53).

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Non-Kidney Transplant Recipients

In a double-blind, randomized, two-period, crossover study in 26 stable liver transplant recipients, the pharmacokinetic profile of one generic CsA product was found to be similar to the branded compound (54). This particular formulation was later withdrawn from the market after it was found not to be bioequivalent when taken with apple juice (16).

In a recent retrospective analysis, tacrolimus levels were evaluated in 48 liver and 55 kidney recipients after conversion to a generic formulation. Overall, 42% of patients required a dose adjustment, of which approximately one half were increases and the other half were reductions. The mean tacrolimus concentration/dose ratio differed significantly between the two products. There were no changes in liver or kidney function and no rejection episodes during the short follow-up period (48). Another recent study in liver and kidney recipients reported that dose titration was necessary more often after conversion to generic tacrolimus compared with patients remaining on branded product. No difference in rejection rates was observed postconversion after a follow-up period of 2 weeks (55).

In a randomized, crossover pharmacokinetic study in 16 stable heart transplant recipients, a lower Cmax and AUC were observed with generic versus branded CsA, and Cmax of the generic formulation did not meet formal BE criteria (56). The authors concluded that this generic CsA formulation may not be clinically bioequivalent in heart transplantation.

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Evidence Summary and Practice Implications

Overall, the quality of available evidence is poor. Most trials are unblinded, non-randomized, retrospective or observational, single-center, and statistically underpowered. Results obtained with one generic product cannot be generalized to another. Although some studies suggest comparable clinical outcomes, long-term follow-up data are lacking, and there are no prospective, randomized controlled trials. This is not surprising, given the practical challenges and lack of incentives for executing such studies. Generic companies should be encouraged to support further research on their products, including pharmacokinetic studies in SOTR and investigator-driven trials. Transplant centers converting patients to generic formulations should study and publish their experience, and any adverse drug events should be reported. Registries and enhanced postmarketing surveillance protocols for immunosuppressive drugs could also serve to generate additional safety data.

The role of generic medications in the immunosuppressive management of SOTR continues to be debated. Some have suggested that prescribing of generic formulations may be reasonable in the de novo setting (52); however, this recommendation is based on BE studies, not clinical data. Others have suggested that generic formulations are more appropriately reserved for conversion in stable patients with a lower risk of acute rejection (23, 24). However, it is difficult to rationalize a switch in a stable patient since BE margins are arbitrary and do not guarantee the absence of relevant clinical differences for an individual patient upon product substitution. The paucity of literature on the use of generic immunosuppressant drugs in heart, lung, or liver transplantation is also concerning as these are life-saving procedures and differences in efficacy or safety could lead to graft loss and death.

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PRACTICAL CONSIDERATIONS

Drug Prescribability vs. Switchability

“Prescribability” is the willingness to prescribe a drug to a naive patient because confidence in safety and efficacy of the product has been addressed by BE studies (57). Drug “switchability” is the ability to appropriately transfer a given patient from a branded to bioequivalent generic formulation of the same drug (or vice versa), or from one generic product to another. The relevant metric for switchability is individual BE, which compares individual responses to two formulations within a subject. Many factors contribute to kinetic variability in an individual (Table 2), and although individual BE metrics have been proposed they have never been adopted into regulatory criteria (57). Drug switchability has been identified as a critical issue in the management of conditions such as epilepsy, where multiple-generic substitution has been associated with increased costs and negative outcomes (5860).

High intrasubject variability in immunosuppressant drug exposure is known to have serious consequences in SOTR, including increased rates of rejection and graft loss (44, 6164). In the setting of multiple generic products, potential variability in drug exposure is further amplified because generic formulations may not be bioequivalent with each other. Despite this, current regulations allow for uncontrolled interchange. A significant proportion of patients require dose adjustment when switching formulations (35, 48, 55) and close monitoring in this setting is strongly recommended (52, 6567). However, in the absence of a mechanism for prescriber notification upon product substitution, instituting the necessary monitoring will present a major challenge (discussed later). Furthermore, any additional therapeutic drug and clinical monitoring that does take place will offset the generic drug cost savings. These issues have been eloquently summarized in a recent editorial by Klintmalm (68).

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Drug Dispensing and Notification of Generic Substitution

Substitution of one generic formulation for another without prescriber or patient knowledge is a major concern. Drug interchangeability is determined by the individual province or territory, and pharmacists may be legally required to dispense an interchangeable generic product where they exist (1). The specific product inventory at the retail pharmacy may change frequently and is determined by pricing, tendering processes, purchasing contracts, and market availability. Pharmacists may perform generic substitution as long as the prescriber has not handwritten “no substitution” on the prescription. If the branded product is specifically requested by the prescriber or patient, in most cases the patient must cover any cost differential out-of-pocket (1). There is no legal requirement that the pharmacist notify the prescriber or patient when performing generic substitution or when switching from one generic product to another, including in the case of critical dose drugs. Furthermore, in the absence of “branded generics,” the power of prescribers to support a particular generic product is limited. A few provinces have instituted centralized dispensing for immunosuppressive drugs through one or more designated pharmacies. This can allow for greater control over drug product dispensing, and the potential feasibility of establishing a mechanism for prescriber notification should a product switch occur.

Hospital formularies often restrict medication selection to one brand that may not reflect the choices available in the community. Drug product switches are therefore likely to occur when patients are admitted or discharged from hospitals or other health care facilities, or when traveling from one province to another. Medication reconciliation and close monitoring at such interfaces of care will be essential.

The Ordre des Pharmaciens du Québec has developed guidelines for generic substitution. For critical dose drugs prescribed for patients in high-risk clinical states, it is recommended that automatic substitution be avoided. If the patient's usual product cannot be dispensed, the pharmacist is directed to notify the prescriber to establish appropriate monitoring (69). This is however only a directive, not a legal requirement, and no data are available on the impact of these guidelines.

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Medication Adherence and Patient Care Issues

Non-adherence in transplantation is prevalent and carries serious consequences (7072). Although high medication costs have been identified as a risk factor for nonadherence in some healthcare settings (7173), this is not likely to be the case in Canada where public payers and private insurers bear the costs of immunosuppression for nearly all patients.

It is more likely that the availability of generic formulations will have a negative impact on medication adherence, as has been reported in other disease states (74). Medication-taking behavior is strongly influenced by beliefs, and the perception that a generic product is less effective may result in intentional nonadherence (72, 7476). Unintentional nonadherence resulting from confusion between generic and trade names has also been identified as one of the most prevalent medication-related risk factors leading to poor health outcomes (74, 77, 78).

Medication regimens for SOTR involve large numbers of drugs and a high dosing frequency, and patients develop routines based on the appearance of medications. In the setting of multiple generic products, a preparation with a different name and appearance could be dispensed on each pharmacy visit (72, 74), which will make a complex therapeutic landscape that much more difficult to navigate (79). If the patient fails to recognize the medication they may not take it, or they may delay dosing until obtaining clarification from the transplant center (74). Patients with lower literacy levels may not question health care providers if confused by a substituted medication (80). Other complications arising from confusion with generic medications include double or triple dosing (as high as 1 in 20 patients in one study), and the mixing of two different brands of medication simultaneously (74).

Patient education regarding generic medications and generic substitution will be essential (76). Patients must be taught the names and appearance of their prescribed immunosuppression and to question their pharmacist or physician if changes are noted (65, 66). Although medication review commonly occurs during clinic visits, it will now need to include specification of the drug product. This will require patients to bring original medication vials or a pharmacy medication record to the clinic, or a review of electronic dispensing records where available. These measures will aid in monitoring and assessing whether a drug product switch correlates with any change in the patient's clinical status, but is likely to increase transplant center workload substantially (76, 81).

Transplant pharmacists have specialized skills in patient education, adherence, medication reconciliation, pharmacokinetics and TDM, and are uniquely qualified to collaborate within a multidisciplinary team to manage these issues (82). Accreditation standards in the United States require that transplant centers have a clinical pharmacist to provide care for outpatient SOTR (83). At present, there is no similar standard in Canada. The advent of generic immunosuppression presents an opportunity for transplant pharmacists to assume a more active role in this setting provided a funding source can be established.

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PHARMACOECONOMICS OF GENERIC IMMUNOSUPPRESSION IN SOLID ORGAN TRANSPLANTATION

Although the use of generic immunosuppression may reduce drug acquisition costs, pharmacoeconomic analyses must also take into account the added patient care costs for increased monitoring, clinic visits, patient education, medication reconciliation, and communication with pharmacies. Existing pharmacoeconomic data regarding generic immunosuppression in SOTR are limited and inconclusive (84, 85). Moreover, without clinical data from prospective, randomized controlled trials or postmarketing surveillance protocols, the question of a potential pharmacoeconomic benefit cannot be appropriately addressed because downstream costs of managing adverse outcomes could outweigh any initial drug savings. To validate the clinical and pharmacoeconomic impact of generics in everyday practice would require a randomized comparison of the branded product to a strategy where pharmacies could freely dispense an interchangeable preparation, thus allowing patients to be exposed to multiple switches between generic products.

Although generic immunosuppression may reduce healthcare expenditures at the level of provincial drug benefit programs, at this time it is not apparent that any of these cost savings will be re-directed to transplant centers to offset the increased patient care requirements. Without adequate funding, transplant programs will be challenged to provide the necessary additional care, which may ultimately jeopardize patient safety and outcomes.

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RECOMMENDATIONS AND CONCLUSIONS

Recommendations are presented in Table 3. Using the Grading of Recommendations Assessment, Development, and Evaluations classification, all statements received a strong recommendation (i.e., desirable effects clearly outweigh undesirable effects) with a low quality evidence rating (i.e., further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate).

TABLE 3

TABLE 3

Overall there are limited data to support BE and clinical equivalence of generic immunosuppressant formulations in SOTR. This concern, coupled with the potential for indiscriminate product switching without prescriber involvement, poses a significant patient safety risk. Randomized controlled trials to validate that equivalent efficacy and safety are achievable with generic products would be informative; however, results obtained in a controlled trial setting may not reflect the way in which generic preparations will be used in everyday practice. Improved regulatory safeguards including more stringent licensing requirements, mandatory prescriber notification for generic substitution of critical dose drugs, and enhanced postmarketing surveillance protocols would also allow greater confidence in the use of generic formulations. Until such time, caution in the use of generic immunosuppressive drugs in SOTR is warranted.

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Article Selection

From the 85 articles identified in the Medline search, 56 were excluded based on the following criteria: 31 did not involve the use of a generic immunosuppressant formulation; 20 were not a clinical trial; 2 were not conducted in SOTR; 2 presented duplicate data to another study already included in our review; and 1 involved therapeutic interchange between different immunosuppressive agents. The same search strategy performed in EMBASE yielded no additional articles meeting our inclusion criteria. In addition to the 29 articles included from the literature search, four additional citations were identified by hand-searching reference lists of identified studies and through personal communication with leaders in the field.

TABLE A1

TABLE A1

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                      Keywords:

                      Solid organ transplantation; Generic; Immunosuppression; Bioequivalence.

                      © 2012 Lippincott Williams & Wilkins, Inc.