Research Article
Is There Evidence to Support Brand to Generic Interchange of the Mycophenolic Acid Products?
Journal of Pharmacy Practice 2017, Vol. 30(1) 9-16 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190015585758 journals.sagepub.com/home/jpp
Karen Phillips, PharmD, BCPS1, Prabashni Reddy, PharmD, MMedSc, RPh1, and Steven Gabardi, PharmD, FAST, FCCP, BCPS2
Abstract The uptake of generic immunosuppressants lags comparatively to other drug classes, despite that the Food and Drug Administration (FDA) uses identical bioequivalence standards for all drugs. Transplant societies acknowledge the cost savings associated with generic immunosuppressants and support their use following heart, lung, kidney, or bone marrow transplantation. Seven studies of the pharmacokinetics or clinical efficacy of generic mycophenolate mofetil compared to the innovator product are published; all studies and products were ex-United States. Three studies did not demonstrate any pharmacokinetic differences between generic and innovator products in healthy subjects, achieving FDA bioequivalence requirements. Two studies in renal allograft recipients demonstrated no difference in area under the curves between generic and innovator products, and in one, the maximum concentration (Cmax) fell outside the FDA regulatory range. Two studies revealed no difference in acute organ rejection or graft function in renal allograft recipients. Patient surveys indicate that cost is a barrier to immunosuppressant adherence. Generics present a viable method to reduce costs to payers, patients, and health care systems. Adherence to immunosuppressants is crucial to prevent graft failure. An affordable regimen potentially confers greater adherence. Concerns regarding the presumed inferiority of generic immunosuppressants should be assuaged by regulatory requirements for bioequivalency testing, transplant society position statements, and pharmacokinetic and clinical studies. Keywords bioequivalence, generic, mycophenolic, pharmacokinetics, transplant
Background Generic dispensing rates are approximately 80% in the United States and present an important means to reduce drug costs and control overall health care expenditures.1 Despite the lower cost of generics, the uptake of generic immunosuppressants has lagged behind other drug classes. For example, based on retail pharmacy claims data, generic mycophenolate mofetil, approved in 2008, comprised 33.5% of the market share for the transplant drug class (as determined by Express Scripts) in 2013.2 The use of generic immunosuppressants in transplant recipients has been debated, as many of the immunosuppressants are considered by the medical community to have a narrow therapeutic index (NTI).3,4 Mycophenolic acid is an inhibitor of inosine monophosphate dehydrogenase, which results in selective inhibition of T- and B-lymphocyte proliferation. There are currently two mycophenolic acid products available, mycophenolate mofetil and entericcoated mycophenolic acid. Despite being the same parent compound, they do not have the exact same indications. Mycophenolate mofetil is approved for the prevention of organ rejection in renal, cardiac, and hepatic transplant, while enteric-coated
mycophenolic acid is approved for prophylaxis of organ rejection only in patients receiving renal transplant.5,6 Despite their different indications, these products are used nearly interchangeably for all solid organ transplant recipients but also in an unlabeled manner for management of several autoimmune disorders, such as system lupus erythematosus. The purpose of this review is to assess the place in therapy of the generic mycophenolic acid products for use in organ transplantation. Generic mycophenolic acid products include mycophenolate mofetil tablets and capsules and mycophenolic acid tablets, and a generic is not available for mycophenolate mofetil intravenous. A generic was recently approved in November 2014 for the oral solution. This article will
1 2
Partners HealthCare, Needham, MA, USA Brigham and Women’s Hospital, Boston, MA, USA
Corresponding Author: Karen Phillips, Partners HealthCare, 115, 4th Avenue, Needham, MA 02494, USA. Email: [email protected]
10 summarize regulatory requirements for generic approvals and position statements regarding generic immunosuppressants from transplant societies. Additionally, a summary of mycophenolic acid pharmacokinetics and clinical and patientreported outcome data comparing generic to branded formulations will be provided. The potential for cost savings, as identified at Partners HealthCare, is also reviewed.
Methods The English-language literature in the Ovid (Medline), Cochrane Databases of Systematic Reviews, and Health Technology Assessment was searched using the search terms mycophenolate, mycophenolic acid, mycophenolate mofetil, CellCept1, Myfortic1, heart or cardiac, lung, liver or hepatic, renal or kidney, bone marrow transplant, hematopoietic stem cell transplant, stem cell transplant, and generic. Web sites for the Food and Drug Administration (FDA), European Medical Association (EMA), and Health Canada were searched to obtain regulations regarding bioequivalency testing requirements and generic substitution. Articles were considered for inclusion if these were randomized controlled trials, clinical practice guidelines, observation studies, or pharmacokinetic analyses relevant to mycophenolic acid and applicable to transplant recipients. Additional relevant articles were also identified via manual review of the bibliographies of the articles that were reviewed. A total of 23 abstracts were identified and, following review, 9 relevant studies were selected for inclusion. Abstracts were excluded if they were protocols included in the Cochrane Database of Systematic Reviews or were irrelevant to transplant recipients.
Regulatory Criteria For Generic Drug Approval Food and Drug Administration Generic drug manufacturers must submit an Abbreviated New Drug Application to the FDA to gain approval of a generic medication. In order for a generic product to be deemed a therapeutic equivalent to the innovator product, it must be pharmaceutically equivalent and demonstrate bioequivalence in healthy subjects based on a single-dose, nonreplicate crossover study conducted under fasting conditions which is effective to assess the release of the drug from its formulation and subsequent systemic effects. Bioequivalency testing in healthy individuals is more likely to expose potential differences between formulations compared to a more variable end user population. It is generally accepted that when bioequivalence criteria are achieved in healthy subjects, the relative exposure in end users will be the same for both the brand and the generic. Conducting additional tests in end user populations will not necessarily confer additional knowledge or risks. Clinical trials demonstrating safety and efficacy are not required.7,8
Journal of Pharmacy Practice 30(1) Bioequivalence. Bioequivalence is demonstrated by equivalent systemic levels of the rate and extent of absorption of the generic product compared to the innovator product. The core assumption in bioequivalence testing is that the two products will have comparable pharmacokinetic profiles, thereby conferring similar therapeutic profiles. The FDA bioequivalence criteria require that the 90% confidence intervals (CIs) for the geometric, not arithmetic, mean rate, and extent of absorption (maximum concentration [Cmax] and area under the curve [AUC]) of the generic product must lie between 80% and 125% of the innovator product.9,10 Despite the FDA requirements for bioequivalence studies to be conducted by generic manufacturers, the results are not generally published. If a generic drug meets the strict FDA standards for bioequivalence, it can substituted for the innovator product with the full expectation that safety and efficacy are the same as the innovator product.4 Misinterpretation of bioequivalency CIs has contributed to misconceptions of generic equivalency. The range of bioequivalency CIs incorporates both inter- and intrapatient variability and is interpreted to mean that there may be a difference of 20% to þ25% in the rate and extent of absorption. These limits are not considered to be clinically significant. If a generic drug varied by 20% below or 25% above the innovator drug, then the CIs would fall outside the acceptable range of 80% to 125%.4,10,11 Pharmaceutical equivalence. The FDA considers a generic as a pharmaceutical equivalent if the formulation has the same route of administration (eg, oral and injectable), dosage form (eg, tablet and capsule), strength, and active ingredients. Inactive ingredients (eg, dyes and binding agents), dosage form shapes, and tablet scoring do not have to be identical to the brand product. Generic manufacturing processes must be congruent with the FDA’s good manufacturing regulations as required for the innovator product and must attain batch requirements for identity, strength, purity, and quality. If a generic product can demonstrate the above-mentioned criteria, then it is considered pharmaceutically equivalent to the innovator product.9 Immunosuppressant approval criteria. The FDA does not designate drugs as NTI during the approval process nor has a consensus definition for NTI been established in the United States or globally.4 The FDA defines narrow therapeutic range as ‘‘drug products containing certain drug substances subject to therapeutic drug concentration or pharmacodynamic monitoring, and/or where product labeling indicates a narrow therapeutic range designation.’’ The agency has not established a list of medications that are considered to be narrow therapeutic range drugs.8 Whole blood therapeutic drug monitoring (TDM) is used as a surrogate marker of immunosuppression with cyclosporine, tacrolimus, sirolimus, and everolimus. In the case of the mycophenolic acid products, TDM is not the standard of care in the United States and is therefore not used regardless of brand or generic medication choice. The FDA refutes the notion that because a drug is commonly referred to as an NTI by the medical community, it should therefore require different bioequivalency or generic substitution
Phillips et al criteria. The agency affirms that the statistical parameters for bioequivalency testing exclude the potential for therapeutic nonequivalence. The FDA issued the following position statement regarding evaluations of therapeutic equivalences which are: ‘‘prepared to serve as public information and advice to state and health agencies, prescribers, and pharmacists, to promote public education in the areas of drug product selection and to foster containment of health costs.’’ The current acceptable bioequivalence limits have proven to be satisfactory for drugs that are commonly considered NTI.4
Health Canada Health Canada regulations are consistent with the FDA in regard to study design and enrolled population of healthy subjects for bioequivalency testing. It is expected that conclusions will be consistent in the end user population; furthermore, it may be difficult to conduct the studies in end users secondary to disease progression. Bioequivalency criteria are nearly identical to the FDA’s range for the 90% CIs for both Cmax and AUC, with the exception of critical dose drugs (eg, cyclosporine, sirolimus, and tacrolimus) where the 90% CIs must lie between 90% and 112%. No modifications to the CI criteria for the mycophenolic acid products have been established.11,12
European Medical Association Similarly, the EMA relies on pharmacokinetic data in lieu of therapeutic outcomes when assessing the equivalence between a generic and a innovator product. This agency’s regulations are consistent with FDA in regard to study design and population enrollment for bioequivalency studies. Their requirements for pharmaceutical equivalence and bioequivalence are identical to the FDA’s criteria. One exception is that the agency designates the acceptable bioequivalence range of the CIs for immunosuppressants on an individual basis. However, no modifications to the CI criteria for the mycophenolic acid have been mandated. Despite the EMA’s requirements of a narrower 90% CI of 90% to 111.11% for cyclosporine and tacrolimus, generic manufacturers have attained these goals.13-15
Position Statements From Transplantation Societies Six transplantation societies have issued position statements regarding the use of generic immunosuppressants, three from general transplantation organizations and three from diseasespecific groups. Five support the use of generic immunosuppressants, provided adequate monitoring is available. The Canadian Society of Transplantation recommends that generic immunosuppressants should be used with caution until further data are available. However, the panel recommends that if generic substitution occurs, the patient must be educated about the generic alternative and that pharmacists should be involved in the direct care of the patient to provide education, drug monitoring, and assess medication adherence. While TDM is recommended
11 by some societies for NTI immunosuppressant drugs, none of the mycophenolic acid products are classified as NTI drugs, and TDM is not recommended for these agents (Table 1).
Pharmacokinetic Studies Five pharmacokinetic studies utilizing generic mycophenolate mofetil were identified, of which three studies enrolled healthy subjects in concordance with regulatory standards for bioequivalency studies.16-18 The remaining two studies were conducted in stable renal allograft recipients.19,20 All studies were conducted outside the United States using generic products manufactured outside the United States; however, some of the manufacturers produce generics for use in the United States. There have not been any published studies with enteric-coated mycophenolic acid compared to the innovator product.
Healthy Subjects Pharmacokinetic parameters of a generic formulation were compared to CellCept in 103 healthy volunteers. These patients were randomized to receive 500 mg of generic mycophenolate mofetil (note 1) or CellCept (note 2) in a 4-way crossover study. A single 500 mg dose of the randomized treatment was administered followed by a 14-day washout, and the alternate treatment was provided and the cycle was repeated.16 Blood samples were obtained during each testing period and were analyzed in accordance with the FDA’s guidelines for bioanalysis. Pharmacokinetic analysis was congruent with guidelines promulgated from the FDA, Health Canada, and the EMA. The 90% CIs for the Cmax (85.94%-106.63%) and AUC (97.42%100.59%) for the generic product were within the range of 80% to 125% which meets the criteria for bioequivalence from the 3 regulatory agencies.9-11,13 Two additional pharmacokinetic studies in healthy adults (n ¼ not reported [NR]) also demonstrated a similar AUC and Cmax of mycophenolate mofetil (note 3) to CellCept. The least squares mean values, following a single 1-g dose, for the AUC0-t (mg h/mL) were 23.68 versus 24.35 and Cmax (mg/mL) 19.83 versus 18.91 for mycophenolate (note 4) and CellCept (note 5), respectively (P ¼ NR).17 The second study reported the least squares mean values, following a single 500-mg dose, for the AUC0-t (mg h/mL) as 11.65 versus 11.06 and Cmax (mg/mL) 12.20 versus 11.68 for mycophenolate mofetil (note 6) compared to CellCept (note 7), respectively (P ¼ NR). The authors report that the products achieved the FDA standards for bioequivalence, however, the 90% CI were not included in the publications.18 These additional studies provide supporting evidence that generic formulations of mycophenolate mofetil are bioequivalent to CellCept.
Stable Renal Allograft Recipients The pharmacokinetics of mycophenolate mofetil (note 8) were compared to CellCept (note 9) in stable renal allograft patients
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Table 1. Transplant Societies’ Recommendations for Generic Immunosuppressants. Transplant society
Recommendations for generic immunosuppressants
General transplant societies American Society of Transplantation28 The majority of the committee agreed with adequate monitoring the use of FDAapproved generic immunosuppressants conferred adequate immunosuppression in low-risk patients and strongly supported the availability of cost-effective generic alternatives Canadian Society of Transplantation29 The panel concluded the following: Routine monitoring of mycophenolic acid serum levels is unnecessary regardless of brand or generic drug choice. There is insufficient literature regarding the safety and efficacy of generic immunosuppressants based on the lack of data from randomized controlled trials and the belief that regulatory standards need to be more stringent. Generic immunosuppressants should be used with caution in the setting of solid organ transplant recipients and should not be routinely used, given the pharmacokinetic differences. If generic substitution occurs, a consistent formulation should be used, and patients should be educated about the generic alternative. Pharmacists should be involved in the direct care of the patient to provide education, drug monitoring, and assess medication adherence European Society for Organ The committee recognizes the cost savings associated with the use of generic Transplantation30 immunosuppressants and is not opposed to the use, provided the following parameters are implemented to control generic substitution: Only the transplant physician should initiate the change between a brand and generic formulation. Anytime a formulation is switched close monitoring should occur to ensure attainment of appropriate therapeutic parameters. Avoid repetitive consecutive generic substitutions; product specification is recommended when prescribing. Uncontrolled switching among generics may expose the patient to cycles of overor underexposure secondary to intrapatient variability, which may affect long-term clinical outcomes. Educate patients regarding generic substitution including how to identify when they have received a different generic. The patient should contact the prescriber if a different generic is received. De novo generic use would permit for dose individualization and monitoring during the hospital stay. Switching among generics should be avoided early after transplant when the risk of rejection is highest. The panel does not recommend routine TDM for mycophenolate Organ-specific transplant societies American Society for Blood and Comparative outcome studies of generic immunosuppressants following hematopoietic Marrow Transplantation31 stem cell transplant are not available; therefore, the committee relied on the experience of the American Society of Transplantation, Kidney Disease Improving Global Outcomes, and the International Society for Heart and Lung Transplantation. Although not proven among hematopoietic stem cell transplant recipients, the committee suggested that lower patient copayments associated with generics may promote adherence International Society for Heart and The Society recommends that the following parameters be followed regarding generic Lung Transplantation32 substitution: Additional monitoring may be required. Patients should be educated about the receipt of a generic medication and the potential for a change to the appearance of their immunosuppressant. Transplant centers should develop protocols for education regarding the use of generic immunosuppressants. There were no specific recommendations regarding mycophenolate mofetil or mycophenolic acid Kidney Disease Improving Global In an effort to reduce cost, the committee recommends the use of bioequivalent generic Outcomes33 drugs. It is essential that patients and health care providers be notified of generic substitution Abbreviations: FDA, Food and Drug Administration; TDM, therapeutic drug monitoring.
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Phillips et al (n ¼ 13) with a mean posttransplant time of 32 months. Five patients were switched from CellCept to mycophenolate mofetil for 60 days and then resumed CellCept for 45 days, at which time all patients changed back to mycophenolate mofetil. Pharmacokinetic parameters were assessed at 15 days and 6 months. There was no difference in exposure to mycophenolic acid (AUC0-6 [mg h/mL] 22.69 vs 24.81 [Pearson ¼ 0.882; P < .25]) in those who received both the generic and the innovator product. There were no dose adjustments or changes in renal function reported.19 The pharmacokinetic parameters (AUC and Cmax) of Myfenax (note 10; generic mycophenolate mofetil) were compared to CellCept (note 11) in 43 stable renal transplant recipients (serum creatinine < 2.3 mg/dL for at least 3 months; population was not further defined). Patients were followed for 112 days with pharmacokinetic assessments occurring over the study period, and all patients were exposed to both the generic and the brand product. On days 1 to 14, patients received either the generic or the brand product. On days 15 to 28, the other respective product was administered and continued until day 112. After day 112, all patients received branded product. The 90% CI for the AUC was found to be within the EMA parameters of 80% to 125%, however, the Cmax was slightly outside the regulatory range (78%-96%). Rates of adverse events were similar between the groups.20 Despite the Cmax falling outside the specified range, most transplant practitioners would argue that this would have limited clinical value as long as the AUCs of the products were similar. The pharmacokinetics of mycophenolate are complex and complicated by betweensubject (eg, comorbidities and concomitant medications) and within-subject variability (eg, renal function and time since transplant). Various methods are available to monitor pharmacokinetics including trough, single, or multiple concentrations and full AUC. Monitoring full AUC provides the best correlation with clinical outcomes.21 Pharmacokinetic studies in healthy patients are required by regulatory agencies for generic drug approval but are generally not published; however, in the case of mycophenolate mofetil three have been published and no differences between generic mycophenolate mofetil and CellCept have been revealed. Despite the lack of regulatory requirements, pharmacokinetic assessments of two different mycophenolate mofetil formulations compared to CellCept in stable renal transplant recipients have been conducted and did not reveal any differences in AUCs; however, the Cmax was slightly outside the EMA regulatory range for one product.19,20
Clinical Trials Although clinical trials are not required for the approval of generic medications by regulatory agencies, two nonUS, single-center studies were identified that compared organ rejection rates between generic mycophenolate mofetil and CellCept in renal transplant recipients.22,23 Clinical trials of mycophenolic acid compared to Myfortic1 have not been published.
13 A total of 18 patients received either mycophenolate mofetil (note 12) or CellCept (note 13). Graft survival at 2 years was 100% in both treatment arms (P¼NR), and there were no differences in the rates of acute rejection or adverse events. There were no significant differences in any of the study parameters between the treatment groups.22 Given the small sample size and selected population, additional long-term studies in the United States with a product available in the United States could be beneficial to substantiate these findings. A preliminary report of clinical outcomes in 34 patients from a transplant center in Poland assessed patients who received generic mycophenolate mofetil (note 14) compared to the pooled group (n ¼ 127) who received CellCept (note 15), Myfortic (note 16), or mycophenolate mofetil (note 17) for 6 months was also published. There was no statistical difference in acute rejection, delayed graft failure, graft loss, or death between treatment groups after six months.23 Outcomes of this study are limited by the small sample size and the short study duration. Additional outcomes were assessed in this trial, however, the methodology and outcomes are not clearly depicted. Further well-controlled, long-term studies would be beneficial to replicate these findings. Equivalent graft function with no apparent difference in adverse events was demonstrated in two randomized trials of patients who received a generic mycophenolate mofetil formulation compared to innovator products or other generic formulations. The generic formulations used in both studies are manufactured outside the United States, however, Teva and Apotex pharmaceuticals produce generic mycophenolate mofetil formulations for use in the United States. Both studies were small scale and of short duration but provide additional support of the efficacy of generic mycophenolate mofetil use in stable renal transplant patients. Outcomes of both studies did not demonstrate a difference in the incidence of acute rejection, graft survival, or adverse events.
Patient-Reported Outcomes Two single-center observational patient surveys assessed transplantation patients’ perceptions about generic medications.24,25 One study, specific to the use of generic immunosuppressants, was conducted in the United States24 and surveyed 255 patients of whom 75% were renal transplant recipients. In the entire cohort, 81 (~33%) patients had changed to a generic immunosuppressant of which 44 were changed to generic mycophenolate mofetil. Three overall domains were included in the survey: demographics, perception of generic conversion, and experience with generic conversion. Cost, equivalency, and provider recommendations were reported as the most common factor regarding perception of generic products. Cost was identified as a barrier to adherence and a reason supporting conversion to a generic. Those who had switched to a generic or had an annual income of less than US$30,000 perceived generics favorably and had a higher belief of equivalency. Ethnicity, income, and previous experience with generics affected the perception of generic products.24
14 The second survey was conducted in renal transplant patients (n ¼ 163) in the United Kingdom.25 The survey was comprised of 36 questions in 3 domains (knowledge of generic substitution, attitude toward generic substitution, and the professionals’ role in generic substitution) which assessed the perception of all generic medications, not just generic immunosuppressants. The majority of patients were aware that generic medications were available, but three-quarters of them were unaware whether they were taking a generic. Level of education, disease severity, and discussing the patients concerns were most influential on the patients’ perception of generics. Reassurance by health care professionals was influential on their perception of generics.25 Patient reported outcome surveys in transplant recipients have demonstrated that provider recommendations influence their perception and decision to use generic immunosuppressants. Cost was identified as a barrier to adherence and a reason supporting conversion to a generic. There are some limitations to these studies including that neither of surveys have been validated and both were subject to recall bias. The outcomes from the UK study may not be applicable, given the differences in the health care systems between countries. The authors from the US study recommended that patients consistently use the same generic formulation following conversion in order to minimize variation and that transplant centers create a standard position on the use of generic products.
Journal of Pharmacy Practice 30(1) intravenous to oral mycophenolate mofetil, tablets or capsules only, confers a savings of approximately US$368 per patient per day. We estimate the potential cost reduction of approximately US$33,000 at our health system. Reducing duration of intravenous therapy with the substitution of generic oral mycophenolate at a lower cost would increase the margin for the inpatient stay under the diagnosis-related group payment system. Costs are based on average wholesale price for patients receiving 1 g twice daily. Savings would vary depending on organization size, number of patients, duration of treatment, and volume of mycophenolate mofetil use. The FDA, EMA, and Health Canada have established strict criteria for demonstrating bioequivalence between generic and innovator products. The FDA uses the same bioequivalence standards for all drugs including those which are considered by the medical community to be NTI drugs. None of the agencies have established unique bioequivalency criteria for the approval of the mycophenolic acid products. Generics are considered equally as safe and effective as the innovator product and therefore may be substituted. Concerns regarding the presumed inferiority of generics should be assuaged by regulatory requirements for bioequivalency testing, position statements from leading transplant societies, and local expert opinion.
Conclusion Discussion The FDA approved generic mycophenolate mofetil in October 2008, and there are 10 drug manufacturing companies approved to produce interchangeable generics for CellCept oral solid dosage forms. On January 9, 2014, the FDA approved the first generic enteric-coated mycophenolic acid formulation, and there are currently 3 manufacturers of this generic product. Generic immunosuppressant substitution has the potential for cost reduction for payers, patients, and health care systems. The cost of transplantation is not insignificant. Based on 2011 data, total charges for solid organ and tissue transplants ranged from US$262,900 to US$805,400 per transplant for the 30 days pretransplant to 180 days posttransplant. Total medication charges (including transplant and nontransplant drugs) represented US$18,200 to US$23,300 of that transplant charge.26 Similarly, a 2007 retrospective claims analysis of patients with a history of a renal transplant (n ¼ 2157) using a major US health plan database found transplant-related medication costs to be US$9,991 for the 1-year analysis period.27 Partners HealthCare is comprised of 14 hospitals including academic medical centers, community, and specialty hospitals. Our health system has two solid organ transplant centers. We identified an opportunity to reduce drug costs by optimizing generic oral mycophenolate utilization. We estimate a potential savings (cost difference between generic and innovator product) of approximately US$80,000 if mycophenolate mofetil is substituted for brand name tablets and capsules across the health system.34 Additionally, optimizing the conversion of
Given the pharmacokinetic data, rigorous bioequivalency standards enforced by the FDA, EMA, and Health Canada and support from transplant organizations, we advocate for the use of generic mycophenolic acid products. Advantages of generic utilization include a lower cost burden to payers, patients, and health care systems. Adherence to immunosuppressive regimens is crucial for the prevention of graft failure, and theoretically, a more affordable regimen could confer higher rates of adherence. Increasing the utilization of generic immunosuppressants may reduce the overall health care burden associated with life-saving transplants and can be safely implemented with proper clinical monitoring (eg, complete blood counts and patient adherence). As health care costs continue to escalate, it is imperative that providers continue to be stewards of expenditures and optimize available resources. Increasing generic utilization is an essential component of lowering the overall burden on the health care system. Pharmacists are integral advocates for the use of generic medications and can increase utilization by educating providers and patients about the efficacy, safety, and lower cost of generics. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
Phillips et al
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Notes 1. Grupo Tecnimede, Sintra, Portugal (Lot number not provided) 2. Roche Registration Ltd. Welwyn Garden City, United Kingdom (Lot number not provided) 3. Ivax and Medis (City, Country and lot number not provided) 4. Ivax, Prague, Czech Republic (Lot number not provided) 5. Hoffman LaRoche (City, Country and lot number not provided) 6. Medis, Tunisa (Lot number not provided) 7. Hoffman LaRoche, Switzerland (Lot number not provided) 8. Recalcine Pharmaceuticals, Santiago, Chile (Lot number not provided) 9. Roche Pharmaceuticals, Basel, Switzerland (Lot number not provided) 10. Teva pharmaceuticals, Israel (Lot number not provided) 11. Roche pharmaceuticals (City, Country and lot number not provided) 12. Medis laboratories, Tunisa (Lot number not provided) 13. Hoffmann-La Roche Switzerland (Lot number not provided) 14. Teva pharmaceuticals (City, Country and lot number not provided) 15. Roche pharmaceuticals (City, Country and lot number not provided) 16. No information provided 17. Apotex pharmaceuticals (City, Country and lot number not provided)
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Considerations; 2003. Web site. http://www.fda.gov/downloads/ Drugs/ . . . /Guidances/ucm070124.pdf. Published March 2003. Accessed June 12, 2014. Food and Drug Administration Abbreviated New Drug Application (ANDA): generics. Web site. http://www.fda.gov/ Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand Approved/ApprovalApplications/AbbreviatedNewDrugApplication ANDAGenerics/default.htm. Accessed May 24, 2015. Davit B, Nwakama P, Buehler G, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the Unites States Food and drug administration. Ann Pharmacother. 2009;43:1583-1597. van Gelder T, Gabardi S. Methods, strengths, weaknesses, and limitations to bioequivalence tests with special regard to immunosuppressive drugs. Transpl Int. 2013;26(8): 771-777. Health Canada Guidance Document Conductance and Analysis of Comparative Bioavailability Studies; 2012. Web site. http://www. hc-sc.gc.ca/dhp-mps/alt_formats/pdf/prodpharma/applic-demande/ guide-ld/bio/gd_cbs_ebc_ld-eng.pdf. Published May 22, 2012. Accessed June 12, 2014. Health Canada Guidance Document Comparative Bioavailability Standards: formulations used for systemic effects; 2012. Web site. http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/prodpharma/ applic-demande/guide-ld/bio/gd_standards_ld_normes-eng.pdf. Published May 22, 2012. Accessed June 12, 2014. European Agency for the Evaluation of Medicinal Products Evaluation of Medicines for Human Use. Committee for Proprietary Medicinal Products Note for Guidance on the Investigation of Bioavailability and Bioequivalence; 2001. Web site. http://www.ema.europa.eu/docs/en_ GB/document_library/Scientific_guideline/2009/09/WC500003008. pdf. Published July 26, 2001. Accessed June 12, 2014. European Agency for the Evaluation of Medicinal Products Evaluation of Medicines for Human Use. Committee for Proprietary Medicinal Products Note for Guidance on the Investigation of Bioavailability and Bioequivalence; 2010. Web site. http:// www.ema.europa.eu/docs/en_GB/document_library/Scientific_ guideline/2010/01/WC500070039.pdf. Published January 20, 2010. Accessed June 12, 2014. European Medicines Agency Questions & Answers: positions on specific questions addressed to the pharmacokinetics working party; 2013. Web site. http://www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2009/09/WC500002963. pdf. Published February 13, 2013. Accessed July 17, 2013. Almedia S, Filipe A, Neves R, et al. Mycophenolate mofetil 500 mg tablet under fasting conditions: single-dose, randomizedsequence, open-label, four-way replicate crossover, bioequivalence study in healthy subjects. Clin Ther. 2010;32(3):556-574. Masri M, Andrysek T, Rizk S, et al. The roles of generics in transplantation: TM-MMF versus CellCept in healthy volunteers. Transpl Proc. 2004;36:84-85. Masri M, Rizk S, Attia M, et al. Bioavailibality of new generic formulation of mycophenolate mofetil MMF 500 mg vs CellCept in healthy adult volunteers. Transpl Proc. 2007;39:1233-1236. Videla C, Godoy C. Converting to a generic formulation of mycophenolate mofetil in stable kidney transplant recipients: 1 year of drug surveillance and outcome. Transplant Proc. 2007;39:602-605.
16 20. Sunder-Plassman G, Reinke P, Rath T, et al. Comparative pharmacokinetic study of two mycophenolate mofetil formulations in stable kidney transplant recipients. Transplant Int. 2012; 25(6):680-686. 21. Kuypers D, Le Meur Y, Cantarovich M, et al. Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation. Clin J Am Soc Nephrol. 2010;5:341-358. 22. Abdallah T, Ounissi M, Cherif M, et al. The role of generics in kidney transplant: mycophenolate mofetil 500 versus mycophenolate: 2-year results. Exp Clin Transplant. 2010;4:292-296. 23. Rutkowski B, Bzoma B, Debska-Slizien A, et al. Immunosuppressive regimens containing generic mycophenolate mofetil (Myfenex) in de novo renal transplant recipients- preliminary results of 6-month observation. Ann Transplant. 2011;16(4): 74-80. 24. Hulbert A, Pilch N, Taber D, et al. Generic immunosuppression: deciphering the message our patients are receiving. Ann Pharmacother. 2012;46:671-677. 25. Al Ameri M, Whittaker C, Tucker A, et al. A survey to determine the views of renal transplant patients on generic substitution in the UK. Transpl Int. 2011;24:770-779. 26. Bentley T, Hanson S, Hauboldt R, et al. 2011 U.S. organ and tissue transplant cost estimates and discussion Milliman Research Report. Web site. http://publications.milliman.com/research/health-rr/pdfs/ 2011-us-organ-tissue.pdf. Published April 30, 2011. Accessed June 12, 2014. 27. Tschida S, Aslam S, Khan T, et al. Managing specialty medications services through a speciality pharmacy program: the case
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of oral renal transplant immunosuppressant medications. J Manag Care Pharm. 2013;19(1):26-41. Alloway R, Isaacs R, Lake K, et al. Report of the American Society of Transplantation conference on immunosuppressive drugs and the use of generics immunosuppressants. Am J Transplant. 2003;3:1211-1215. Harrison J, Schiff J, Coursol C, et al. Generic immunosuppression in solid organ transplantation: a Canadian perspective. Transplantation. 2012;93:657-665. van Gelder T. Advisory Committee on Generic Substitution. European Society for Organ Transplantation Advisory Committee recommendations on generic substitution of immunosuppressive drugs. Transpl Int. 24:1135-1141. Cutler C, Kesselheim A, Gabardi S, et al. Generic immunosuppression in hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011;17:285-290. Uber P, Ross H, Zuckermann A, et al. Generic drug immunosuppression in thoracic transplantation: an ISHLT educational advisory. J Heart Lung Transplant. 2009;28:655-660. Kasiske B, Zeier M, Chapman J, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. 2010;77(4):299-311. Thomson Reuters Micromedex Clinical Evidence Solutions [Internet]. Thomson Reuters. RED BOOK Drug References; c2014. Web site. http://thomsonreuters.com/products_services/ healthcare/healthcare_products/clinical_deci_support/micromedex_ clinical_evidence_sols/med_safety_solutions/red_book/. Updated weekly. Accessed November 15, 2014.
Is There Evidence to Support Brand to Generic Interchange of the Mycophenolic Acid Products?
Journal of Pharmacy Practice 2017, Vol. 30(1) 9-16 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190015585758 journals.sagepub.com/home/jpp
Karen Phillips, PharmD, BCPS1, Prabashni Reddy, PharmD, MMedSc, RPh1, and Steven Gabardi, PharmD, FAST, FCCP, BCPS2
Abstract The uptake of generic immunosuppressants lags comparatively to other drug classes, despite that the Food and Drug Administration (FDA) uses identical bioequivalence standards for all drugs. Transplant societies acknowledge the cost savings associated with generic immunosuppressants and support their use following heart, lung, kidney, or bone marrow transplantation. Seven studies of the pharmacokinetics or clinical efficacy of generic mycophenolate mofetil compared to the innovator product are published; all studies and products were ex-United States. Three studies did not demonstrate any pharmacokinetic differences between generic and innovator products in healthy subjects, achieving FDA bioequivalence requirements. Two studies in renal allograft recipients demonstrated no difference in area under the curves between generic and innovator products, and in one, the maximum concentration (Cmax) fell outside the FDA regulatory range. Two studies revealed no difference in acute organ rejection or graft function in renal allograft recipients. Patient surveys indicate that cost is a barrier to immunosuppressant adherence. Generics present a viable method to reduce costs to payers, patients, and health care systems. Adherence to immunosuppressants is crucial to prevent graft failure. An affordable regimen potentially confers greater adherence. Concerns regarding the presumed inferiority of generic immunosuppressants should be assuaged by regulatory requirements for bioequivalency testing, transplant society position statements, and pharmacokinetic and clinical studies. Keywords bioequivalence, generic, mycophenolic, pharmacokinetics, transplant
Background Generic dispensing rates are approximately 80% in the United States and present an important means to reduce drug costs and control overall health care expenditures.1 Despite the lower cost of generics, the uptake of generic immunosuppressants has lagged behind other drug classes. For example, based on retail pharmacy claims data, generic mycophenolate mofetil, approved in 2008, comprised 33.5% of the market share for the transplant drug class (as determined by Express Scripts) in 2013.2 The use of generic immunosuppressants in transplant recipients has been debated, as many of the immunosuppressants are considered by the medical community to have a narrow therapeutic index (NTI).3,4 Mycophenolic acid is an inhibitor of inosine monophosphate dehydrogenase, which results in selective inhibition of T- and B-lymphocyte proliferation. There are currently two mycophenolic acid products available, mycophenolate mofetil and entericcoated mycophenolic acid. Despite being the same parent compound, they do not have the exact same indications. Mycophenolate mofetil is approved for the prevention of organ rejection in renal, cardiac, and hepatic transplant, while enteric-coated
mycophenolic acid is approved for prophylaxis of organ rejection only in patients receiving renal transplant.5,6 Despite their different indications, these products are used nearly interchangeably for all solid organ transplant recipients but also in an unlabeled manner for management of several autoimmune disorders, such as system lupus erythematosus. The purpose of this review is to assess the place in therapy of the generic mycophenolic acid products for use in organ transplantation. Generic mycophenolic acid products include mycophenolate mofetil tablets and capsules and mycophenolic acid tablets, and a generic is not available for mycophenolate mofetil intravenous. A generic was recently approved in November 2014 for the oral solution. This article will
1 2
Partners HealthCare, Needham, MA, USA Brigham and Women’s Hospital, Boston, MA, USA
Corresponding Author: Karen Phillips, Partners HealthCare, 115, 4th Avenue, Needham, MA 02494, USA. Email: [email protected]
10 summarize regulatory requirements for generic approvals and position statements regarding generic immunosuppressants from transplant societies. Additionally, a summary of mycophenolic acid pharmacokinetics and clinical and patientreported outcome data comparing generic to branded formulations will be provided. The potential for cost savings, as identified at Partners HealthCare, is also reviewed.
Methods The English-language literature in the Ovid (Medline), Cochrane Databases of Systematic Reviews, and Health Technology Assessment was searched using the search terms mycophenolate, mycophenolic acid, mycophenolate mofetil, CellCept1, Myfortic1, heart or cardiac, lung, liver or hepatic, renal or kidney, bone marrow transplant, hematopoietic stem cell transplant, stem cell transplant, and generic. Web sites for the Food and Drug Administration (FDA), European Medical Association (EMA), and Health Canada were searched to obtain regulations regarding bioequivalency testing requirements and generic substitution. Articles were considered for inclusion if these were randomized controlled trials, clinical practice guidelines, observation studies, or pharmacokinetic analyses relevant to mycophenolic acid and applicable to transplant recipients. Additional relevant articles were also identified via manual review of the bibliographies of the articles that were reviewed. A total of 23 abstracts were identified and, following review, 9 relevant studies were selected for inclusion. Abstracts were excluded if they were protocols included in the Cochrane Database of Systematic Reviews or were irrelevant to transplant recipients.
Regulatory Criteria For Generic Drug Approval Food and Drug Administration Generic drug manufacturers must submit an Abbreviated New Drug Application to the FDA to gain approval of a generic medication. In order for a generic product to be deemed a therapeutic equivalent to the innovator product, it must be pharmaceutically equivalent and demonstrate bioequivalence in healthy subjects based on a single-dose, nonreplicate crossover study conducted under fasting conditions which is effective to assess the release of the drug from its formulation and subsequent systemic effects. Bioequivalency testing in healthy individuals is more likely to expose potential differences between formulations compared to a more variable end user population. It is generally accepted that when bioequivalence criteria are achieved in healthy subjects, the relative exposure in end users will be the same for both the brand and the generic. Conducting additional tests in end user populations will not necessarily confer additional knowledge or risks. Clinical trials demonstrating safety and efficacy are not required.7,8
Journal of Pharmacy Practice 30(1) Bioequivalence. Bioequivalence is demonstrated by equivalent systemic levels of the rate and extent of absorption of the generic product compared to the innovator product. The core assumption in bioequivalence testing is that the two products will have comparable pharmacokinetic profiles, thereby conferring similar therapeutic profiles. The FDA bioequivalence criteria require that the 90% confidence intervals (CIs) for the geometric, not arithmetic, mean rate, and extent of absorption (maximum concentration [Cmax] and area under the curve [AUC]) of the generic product must lie between 80% and 125% of the innovator product.9,10 Despite the FDA requirements for bioequivalence studies to be conducted by generic manufacturers, the results are not generally published. If a generic drug meets the strict FDA standards for bioequivalence, it can substituted for the innovator product with the full expectation that safety and efficacy are the same as the innovator product.4 Misinterpretation of bioequivalency CIs has contributed to misconceptions of generic equivalency. The range of bioequivalency CIs incorporates both inter- and intrapatient variability and is interpreted to mean that there may be a difference of 20% to þ25% in the rate and extent of absorption. These limits are not considered to be clinically significant. If a generic drug varied by 20% below or 25% above the innovator drug, then the CIs would fall outside the acceptable range of 80% to 125%.4,10,11 Pharmaceutical equivalence. The FDA considers a generic as a pharmaceutical equivalent if the formulation has the same route of administration (eg, oral and injectable), dosage form (eg, tablet and capsule), strength, and active ingredients. Inactive ingredients (eg, dyes and binding agents), dosage form shapes, and tablet scoring do not have to be identical to the brand product. Generic manufacturing processes must be congruent with the FDA’s good manufacturing regulations as required for the innovator product and must attain batch requirements for identity, strength, purity, and quality. If a generic product can demonstrate the above-mentioned criteria, then it is considered pharmaceutically equivalent to the innovator product.9 Immunosuppressant approval criteria. The FDA does not designate drugs as NTI during the approval process nor has a consensus definition for NTI been established in the United States or globally.4 The FDA defines narrow therapeutic range as ‘‘drug products containing certain drug substances subject to therapeutic drug concentration or pharmacodynamic monitoring, and/or where product labeling indicates a narrow therapeutic range designation.’’ The agency has not established a list of medications that are considered to be narrow therapeutic range drugs.8 Whole blood therapeutic drug monitoring (TDM) is used as a surrogate marker of immunosuppression with cyclosporine, tacrolimus, sirolimus, and everolimus. In the case of the mycophenolic acid products, TDM is not the standard of care in the United States and is therefore not used regardless of brand or generic medication choice. The FDA refutes the notion that because a drug is commonly referred to as an NTI by the medical community, it should therefore require different bioequivalency or generic substitution
Phillips et al criteria. The agency affirms that the statistical parameters for bioequivalency testing exclude the potential for therapeutic nonequivalence. The FDA issued the following position statement regarding evaluations of therapeutic equivalences which are: ‘‘prepared to serve as public information and advice to state and health agencies, prescribers, and pharmacists, to promote public education in the areas of drug product selection and to foster containment of health costs.’’ The current acceptable bioequivalence limits have proven to be satisfactory for drugs that are commonly considered NTI.4
Health Canada Health Canada regulations are consistent with the FDA in regard to study design and enrolled population of healthy subjects for bioequivalency testing. It is expected that conclusions will be consistent in the end user population; furthermore, it may be difficult to conduct the studies in end users secondary to disease progression. Bioequivalency criteria are nearly identical to the FDA’s range for the 90% CIs for both Cmax and AUC, with the exception of critical dose drugs (eg, cyclosporine, sirolimus, and tacrolimus) where the 90% CIs must lie between 90% and 112%. No modifications to the CI criteria for the mycophenolic acid products have been established.11,12
European Medical Association Similarly, the EMA relies on pharmacokinetic data in lieu of therapeutic outcomes when assessing the equivalence between a generic and a innovator product. This agency’s regulations are consistent with FDA in regard to study design and population enrollment for bioequivalency studies. Their requirements for pharmaceutical equivalence and bioequivalence are identical to the FDA’s criteria. One exception is that the agency designates the acceptable bioequivalence range of the CIs for immunosuppressants on an individual basis. However, no modifications to the CI criteria for the mycophenolic acid have been mandated. Despite the EMA’s requirements of a narrower 90% CI of 90% to 111.11% for cyclosporine and tacrolimus, generic manufacturers have attained these goals.13-15
Position Statements From Transplantation Societies Six transplantation societies have issued position statements regarding the use of generic immunosuppressants, three from general transplantation organizations and three from diseasespecific groups. Five support the use of generic immunosuppressants, provided adequate monitoring is available. The Canadian Society of Transplantation recommends that generic immunosuppressants should be used with caution until further data are available. However, the panel recommends that if generic substitution occurs, the patient must be educated about the generic alternative and that pharmacists should be involved in the direct care of the patient to provide education, drug monitoring, and assess medication adherence. While TDM is recommended
11 by some societies for NTI immunosuppressant drugs, none of the mycophenolic acid products are classified as NTI drugs, and TDM is not recommended for these agents (Table 1).
Pharmacokinetic Studies Five pharmacokinetic studies utilizing generic mycophenolate mofetil were identified, of which three studies enrolled healthy subjects in concordance with regulatory standards for bioequivalency studies.16-18 The remaining two studies were conducted in stable renal allograft recipients.19,20 All studies were conducted outside the United States using generic products manufactured outside the United States; however, some of the manufacturers produce generics for use in the United States. There have not been any published studies with enteric-coated mycophenolic acid compared to the innovator product.
Healthy Subjects Pharmacokinetic parameters of a generic formulation were compared to CellCept in 103 healthy volunteers. These patients were randomized to receive 500 mg of generic mycophenolate mofetil (note 1) or CellCept (note 2) in a 4-way crossover study. A single 500 mg dose of the randomized treatment was administered followed by a 14-day washout, and the alternate treatment was provided and the cycle was repeated.16 Blood samples were obtained during each testing period and were analyzed in accordance with the FDA’s guidelines for bioanalysis. Pharmacokinetic analysis was congruent with guidelines promulgated from the FDA, Health Canada, and the EMA. The 90% CIs for the Cmax (85.94%-106.63%) and AUC (97.42%100.59%) for the generic product were within the range of 80% to 125% which meets the criteria for bioequivalence from the 3 regulatory agencies.9-11,13 Two additional pharmacokinetic studies in healthy adults (n ¼ not reported [NR]) also demonstrated a similar AUC and Cmax of mycophenolate mofetil (note 3) to CellCept. The least squares mean values, following a single 1-g dose, for the AUC0-t (mg h/mL) were 23.68 versus 24.35 and Cmax (mg/mL) 19.83 versus 18.91 for mycophenolate (note 4) and CellCept (note 5), respectively (P ¼ NR).17 The second study reported the least squares mean values, following a single 500-mg dose, for the AUC0-t (mg h/mL) as 11.65 versus 11.06 and Cmax (mg/mL) 12.20 versus 11.68 for mycophenolate mofetil (note 6) compared to CellCept (note 7), respectively (P ¼ NR). The authors report that the products achieved the FDA standards for bioequivalence, however, the 90% CI were not included in the publications.18 These additional studies provide supporting evidence that generic formulations of mycophenolate mofetil are bioequivalent to CellCept.
Stable Renal Allograft Recipients The pharmacokinetics of mycophenolate mofetil (note 8) were compared to CellCept (note 9) in stable renal allograft patients
12
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Table 1. Transplant Societies’ Recommendations for Generic Immunosuppressants. Transplant society
Recommendations for generic immunosuppressants
General transplant societies American Society of Transplantation28 The majority of the committee agreed with adequate monitoring the use of FDAapproved generic immunosuppressants conferred adequate immunosuppression in low-risk patients and strongly supported the availability of cost-effective generic alternatives Canadian Society of Transplantation29 The panel concluded the following: Routine monitoring of mycophenolic acid serum levels is unnecessary regardless of brand or generic drug choice. There is insufficient literature regarding the safety and efficacy of generic immunosuppressants based on the lack of data from randomized controlled trials and the belief that regulatory standards need to be more stringent. Generic immunosuppressants should be used with caution in the setting of solid organ transplant recipients and should not be routinely used, given the pharmacokinetic differences. If generic substitution occurs, a consistent formulation should be used, and patients should be educated about the generic alternative. Pharmacists should be involved in the direct care of the patient to provide education, drug monitoring, and assess medication adherence European Society for Organ The committee recognizes the cost savings associated with the use of generic Transplantation30 immunosuppressants and is not opposed to the use, provided the following parameters are implemented to control generic substitution: Only the transplant physician should initiate the change between a brand and generic formulation. Anytime a formulation is switched close monitoring should occur to ensure attainment of appropriate therapeutic parameters. Avoid repetitive consecutive generic substitutions; product specification is recommended when prescribing. Uncontrolled switching among generics may expose the patient to cycles of overor underexposure secondary to intrapatient variability, which may affect long-term clinical outcomes. Educate patients regarding generic substitution including how to identify when they have received a different generic. The patient should contact the prescriber if a different generic is received. De novo generic use would permit for dose individualization and monitoring during the hospital stay. Switching among generics should be avoided early after transplant when the risk of rejection is highest. The panel does not recommend routine TDM for mycophenolate Organ-specific transplant societies American Society for Blood and Comparative outcome studies of generic immunosuppressants following hematopoietic Marrow Transplantation31 stem cell transplant are not available; therefore, the committee relied on the experience of the American Society of Transplantation, Kidney Disease Improving Global Outcomes, and the International Society for Heart and Lung Transplantation. Although not proven among hematopoietic stem cell transplant recipients, the committee suggested that lower patient copayments associated with generics may promote adherence International Society for Heart and The Society recommends that the following parameters be followed regarding generic Lung Transplantation32 substitution: Additional monitoring may be required. Patients should be educated about the receipt of a generic medication and the potential for a change to the appearance of their immunosuppressant. Transplant centers should develop protocols for education regarding the use of generic immunosuppressants. There were no specific recommendations regarding mycophenolate mofetil or mycophenolic acid Kidney Disease Improving Global In an effort to reduce cost, the committee recommends the use of bioequivalent generic Outcomes33 drugs. It is essential that patients and health care providers be notified of generic substitution Abbreviations: FDA, Food and Drug Administration; TDM, therapeutic drug monitoring.
Publication year 2003
2012
2011
2011
2009
2010
Phillips et al (n ¼ 13) with a mean posttransplant time of 32 months. Five patients were switched from CellCept to mycophenolate mofetil for 60 days and then resumed CellCept for 45 days, at which time all patients changed back to mycophenolate mofetil. Pharmacokinetic parameters were assessed at 15 days and 6 months. There was no difference in exposure to mycophenolic acid (AUC0-6 [mg h/mL] 22.69 vs 24.81 [Pearson ¼ 0.882; P < .25]) in those who received both the generic and the innovator product. There were no dose adjustments or changes in renal function reported.19 The pharmacokinetic parameters (AUC and Cmax) of Myfenax (note 10; generic mycophenolate mofetil) were compared to CellCept (note 11) in 43 stable renal transplant recipients (serum creatinine < 2.3 mg/dL for at least 3 months; population was not further defined). Patients were followed for 112 days with pharmacokinetic assessments occurring over the study period, and all patients were exposed to both the generic and the brand product. On days 1 to 14, patients received either the generic or the brand product. On days 15 to 28, the other respective product was administered and continued until day 112. After day 112, all patients received branded product. The 90% CI for the AUC was found to be within the EMA parameters of 80% to 125%, however, the Cmax was slightly outside the regulatory range (78%-96%). Rates of adverse events were similar between the groups.20 Despite the Cmax falling outside the specified range, most transplant practitioners would argue that this would have limited clinical value as long as the AUCs of the products were similar. The pharmacokinetics of mycophenolate are complex and complicated by betweensubject (eg, comorbidities and concomitant medications) and within-subject variability (eg, renal function and time since transplant). Various methods are available to monitor pharmacokinetics including trough, single, or multiple concentrations and full AUC. Monitoring full AUC provides the best correlation with clinical outcomes.21 Pharmacokinetic studies in healthy patients are required by regulatory agencies for generic drug approval but are generally not published; however, in the case of mycophenolate mofetil three have been published and no differences between generic mycophenolate mofetil and CellCept have been revealed. Despite the lack of regulatory requirements, pharmacokinetic assessments of two different mycophenolate mofetil formulations compared to CellCept in stable renal transplant recipients have been conducted and did not reveal any differences in AUCs; however, the Cmax was slightly outside the EMA regulatory range for one product.19,20
Clinical Trials Although clinical trials are not required for the approval of generic medications by regulatory agencies, two nonUS, single-center studies were identified that compared organ rejection rates between generic mycophenolate mofetil and CellCept in renal transplant recipients.22,23 Clinical trials of mycophenolic acid compared to Myfortic1 have not been published.
13 A total of 18 patients received either mycophenolate mofetil (note 12) or CellCept (note 13). Graft survival at 2 years was 100% in both treatment arms (P¼NR), and there were no differences in the rates of acute rejection or adverse events. There were no significant differences in any of the study parameters between the treatment groups.22 Given the small sample size and selected population, additional long-term studies in the United States with a product available in the United States could be beneficial to substantiate these findings. A preliminary report of clinical outcomes in 34 patients from a transplant center in Poland assessed patients who received generic mycophenolate mofetil (note 14) compared to the pooled group (n ¼ 127) who received CellCept (note 15), Myfortic (note 16), or mycophenolate mofetil (note 17) for 6 months was also published. There was no statistical difference in acute rejection, delayed graft failure, graft loss, or death between treatment groups after six months.23 Outcomes of this study are limited by the small sample size and the short study duration. Additional outcomes were assessed in this trial, however, the methodology and outcomes are not clearly depicted. Further well-controlled, long-term studies would be beneficial to replicate these findings. Equivalent graft function with no apparent difference in adverse events was demonstrated in two randomized trials of patients who received a generic mycophenolate mofetil formulation compared to innovator products or other generic formulations. The generic formulations used in both studies are manufactured outside the United States, however, Teva and Apotex pharmaceuticals produce generic mycophenolate mofetil formulations for use in the United States. Both studies were small scale and of short duration but provide additional support of the efficacy of generic mycophenolate mofetil use in stable renal transplant patients. Outcomes of both studies did not demonstrate a difference in the incidence of acute rejection, graft survival, or adverse events.
Patient-Reported Outcomes Two single-center observational patient surveys assessed transplantation patients’ perceptions about generic medications.24,25 One study, specific to the use of generic immunosuppressants, was conducted in the United States24 and surveyed 255 patients of whom 75% were renal transplant recipients. In the entire cohort, 81 (~33%) patients had changed to a generic immunosuppressant of which 44 were changed to generic mycophenolate mofetil. Three overall domains were included in the survey: demographics, perception of generic conversion, and experience with generic conversion. Cost, equivalency, and provider recommendations were reported as the most common factor regarding perception of generic products. Cost was identified as a barrier to adherence and a reason supporting conversion to a generic. Those who had switched to a generic or had an annual income of less than US$30,000 perceived generics favorably and had a higher belief of equivalency. Ethnicity, income, and previous experience with generics affected the perception of generic products.24
14 The second survey was conducted in renal transplant patients (n ¼ 163) in the United Kingdom.25 The survey was comprised of 36 questions in 3 domains (knowledge of generic substitution, attitude toward generic substitution, and the professionals’ role in generic substitution) which assessed the perception of all generic medications, not just generic immunosuppressants. The majority of patients were aware that generic medications were available, but three-quarters of them were unaware whether they were taking a generic. Level of education, disease severity, and discussing the patients concerns were most influential on the patients’ perception of generics. Reassurance by health care professionals was influential on their perception of generics.25 Patient reported outcome surveys in transplant recipients have demonstrated that provider recommendations influence their perception and decision to use generic immunosuppressants. Cost was identified as a barrier to adherence and a reason supporting conversion to a generic. There are some limitations to these studies including that neither of surveys have been validated and both were subject to recall bias. The outcomes from the UK study may not be applicable, given the differences in the health care systems between countries. The authors from the US study recommended that patients consistently use the same generic formulation following conversion in order to minimize variation and that transplant centers create a standard position on the use of generic products.
Journal of Pharmacy Practice 30(1) intravenous to oral mycophenolate mofetil, tablets or capsules only, confers a savings of approximately US$368 per patient per day. We estimate the potential cost reduction of approximately US$33,000 at our health system. Reducing duration of intravenous therapy with the substitution of generic oral mycophenolate at a lower cost would increase the margin for the inpatient stay under the diagnosis-related group payment system. Costs are based on average wholesale price for patients receiving 1 g twice daily. Savings would vary depending on organization size, number of patients, duration of treatment, and volume of mycophenolate mofetil use. The FDA, EMA, and Health Canada have established strict criteria for demonstrating bioequivalence between generic and innovator products. The FDA uses the same bioequivalence standards for all drugs including those which are considered by the medical community to be NTI drugs. None of the agencies have established unique bioequivalency criteria for the approval of the mycophenolic acid products. Generics are considered equally as safe and effective as the innovator product and therefore may be substituted. Concerns regarding the presumed inferiority of generics should be assuaged by regulatory requirements for bioequivalency testing, position statements from leading transplant societies, and local expert opinion.
Conclusion Discussion The FDA approved generic mycophenolate mofetil in October 2008, and there are 10 drug manufacturing companies approved to produce interchangeable generics for CellCept oral solid dosage forms. On January 9, 2014, the FDA approved the first generic enteric-coated mycophenolic acid formulation, and there are currently 3 manufacturers of this generic product. Generic immunosuppressant substitution has the potential for cost reduction for payers, patients, and health care systems. The cost of transplantation is not insignificant. Based on 2011 data, total charges for solid organ and tissue transplants ranged from US$262,900 to US$805,400 per transplant for the 30 days pretransplant to 180 days posttransplant. Total medication charges (including transplant and nontransplant drugs) represented US$18,200 to US$23,300 of that transplant charge.26 Similarly, a 2007 retrospective claims analysis of patients with a history of a renal transplant (n ¼ 2157) using a major US health plan database found transplant-related medication costs to be US$9,991 for the 1-year analysis period.27 Partners HealthCare is comprised of 14 hospitals including academic medical centers, community, and specialty hospitals. Our health system has two solid organ transplant centers. We identified an opportunity to reduce drug costs by optimizing generic oral mycophenolate utilization. We estimate a potential savings (cost difference between generic and innovator product) of approximately US$80,000 if mycophenolate mofetil is substituted for brand name tablets and capsules across the health system.34 Additionally, optimizing the conversion of
Given the pharmacokinetic data, rigorous bioequivalency standards enforced by the FDA, EMA, and Health Canada and support from transplant organizations, we advocate for the use of generic mycophenolic acid products. Advantages of generic utilization include a lower cost burden to payers, patients, and health care systems. Adherence to immunosuppressive regimens is crucial for the prevention of graft failure, and theoretically, a more affordable regimen could confer higher rates of adherence. Increasing the utilization of generic immunosuppressants may reduce the overall health care burden associated with life-saving transplants and can be safely implemented with proper clinical monitoring (eg, complete blood counts and patient adherence). As health care costs continue to escalate, it is imperative that providers continue to be stewards of expenditures and optimize available resources. Increasing generic utilization is an essential component of lowering the overall burden on the health care system. Pharmacists are integral advocates for the use of generic medications and can increase utilization by educating providers and patients about the efficacy, safety, and lower cost of generics. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
Phillips et al
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Notes 1. Grupo Tecnimede, Sintra, Portugal (Lot number not provided) 2. Roche Registration Ltd. Welwyn Garden City, United Kingdom (Lot number not provided) 3. Ivax and Medis (City, Country and lot number not provided) 4. Ivax, Prague, Czech Republic (Lot number not provided) 5. Hoffman LaRoche (City, Country and lot number not provided) 6. Medis, Tunisa (Lot number not provided) 7. Hoffman LaRoche, Switzerland (Lot number not provided) 8. Recalcine Pharmaceuticals, Santiago, Chile (Lot number not provided) 9. Roche Pharmaceuticals, Basel, Switzerland (Lot number not provided) 10. Teva pharmaceuticals, Israel (Lot number not provided) 11. Roche pharmaceuticals (City, Country and lot number not provided) 12. Medis laboratories, Tunisa (Lot number not provided) 13. Hoffmann-La Roche Switzerland (Lot number not provided) 14. Teva pharmaceuticals (City, Country and lot number not provided) 15. Roche pharmaceuticals (City, Country and lot number not provided) 16. No information provided 17. Apotex pharmaceuticals (City, Country and lot number not provided)
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