Article Text
Abstract
Generic immunosuppression is not a new phenomenon to solid organ transplantation; however, clinical and patient safety concerns have been raised with the introduction onto the market of multiple brands of generic ciclosporin, tacrolimus and mycophenolate mofetil. In the UK there are significant national drivers to support efficiency savings within the National Health Service (NHS) and thus allow reimbursement back into clinical services to continually improve quality of patient care. The use of generic immunosuppression to release such savings must be given serious consideration. In the UK, many transplant centres have safely implemented the use of generic tacrolimus and mycophenolate mofetil brands into clinical practice in both de novo and established renal transplant recipients.
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The use of generic immunosuppression is not a new phenomenon to transplant communities. Prednisolone tablets are a long-standing and widely used generic preparation. In the early 1990s, when generic versions of azathioprine became available, some patients and clinicians expressed concerns about whether these would be as effective as branded Imuran. The ensuing years have not provided us with any evidence of clinical problems and transplant patients have become accustomed to receiving packets of azathioprine and prednisolone tablets with a different livery when they get their prescription dispensed.
Before the advent of generic ciclosporin and tacrolimus formulations the transplant community had already experienced managing a therapeutic conversion with a narrow therapeutic index (NTI) immunosuppressant. In the mid 1990s Neoral-ciclosporin was launched to replace the then patent-protected Sandimmun-ciclosporin, which was to be withdrawn from the market. It was known that Neoral formulations were not bioequivalent with Sandimmun and some units implemented supervised conversion programmes for their transplant recipients with additional blood-level monitoring. After some negotiations with the drug manufacturer, Sandimmun-ciclosporin capsules and liquid remained available in the UK, on a named patient basis, for a small minority of transplant patients who were unable or unwilling to switch to Neoral-ciclosporin.
In 1999, the first generic ciclosporin product (Sang-CyA) was launched in the UK by Sangstat; however, this was voluntarily withdrawn the following year without attracting much use. It took a further 10 years before another generic ciclosporin product was marketed again in the UK. It must be noted that all the UK available generic ciclosporin products (eg, Capimune, Deximune, Capsporin) were tested prior to implementation of revised criteria for NTI drug bioequivalence, which was applied by the European Medicines Agency (EMA) from 2010.1 These new guidelines tightened the acceptance intervals for bioequivalence so that 90% CIs of the average Cmax and AUC(0-∞) + (0-t) of the generic formulation to the innovator formulation should lie within 90% to 111%. The specific bioequivalence data for each generic product, termed a Public Assessment Report for medicines, are available from the Medicines and Healthcare products Regulatory Agency (MHRA) website.2
Generic tacrolimus products, in contrast, were tested using the revised, stricter bioequivalence criteria. June 2010 saw the introduction of the first UK available alternative branded generic tacrolimus product (Adoport, Sandoz). Like Prograf, Adoport is an immediate-release product intended for twice daily administration and it shares the same licensed indications. It is in similar size capsules of the same strengths as Prograf and it contains much the same excipients, differing only in the colour and printing ink used on the hard gelatin capsule (Sandoz Ltd. Appearance and excipient comparison of Prograf vs Adoport. Document dated 3/5/10. Personal communication). The licensing bioequivalence studies (with Prograf) show that the 90% CIs of mean AUC & Cmax of test versus reference ratio's are within the 0.9 to 1.11 limits required for critical-dose drugs. In the case of the 0.5 mg capsule, the initial study of 46 subjects, which was powered to meet the previous limits of 0.8 to 1.25, was repeated with 219 subjects and met the new stricter standard.3
Initially, there was considerable unease within the UK transplant community about the potential for unfettered substitution of Prograf with the lower priced generics. This was primarily because of concerns that some patients may be ‘outliers’ to the 90% CI of mean AUC (risking rejection or toxicity) but also originated from an extrapolation of UK ciclosporin experience.
Generic Sandoz tacrolimus (Sandoz, Princeton, New Jersey, USA) had been available in the US since August 2009 and at the point of UK Adoport launch an investigator-led study was presented in abstract form at the 2010 American Transplant Congress.4 Fifty-five transplant recipients on stable Prograf doses were converted to Sandoz tacrolimus on a mg:mg basis. The mean of the last three whole-blood Prograf trough levels was compared for each patient with the first level deemed at steady-state after conversion. The median change in trough level was just +4.7% (range −98% to +67%). Although the majority of patients remained within ±2 ng/mL of the average preconversion level, one in six had levels >±5 ng/mL difference. There were no reported clinical events but two new adverse-reactions were noted in two subjects. Dose changes were made in 31% of patients (10 down, 7 upwards).
The presented data indicated that interchanging Prograf and Adoport might lead to loss of carefully established therapeutic blood levels in a minority of recipients. It did not, however, suggest that Adoport could not be introduced as the de novo tacrolimus product and by 2011 some UK renal transplant units had begun commencing new patients on this brand. The driver for this was a national tender within the National Health Service (NHS) for immediate-release tacrolimus products, which resulted in significantly lower acquisition costs for Adoport compared with Prograf both within English hospitals and in primary care.
When this initial investigator-led study was presented in full (n=70) the results showed little difference in mean daily tacrolimus dose or trough-level, before and after conversion when compared with a control arm. However, fewer dose adjustments were required in the control arm when compared with the patients who switched product, highlighting that any conversion must be accompanied by blood-level monitoring.5 Alloway et al6 showed in their 2012 paper that Sandoz tacrolimus also met US & European bioequivalence standards when pharmacokinetic analysis was undertaken in a kidney transplant population. This answered a key criticism of even the stricter regulatory framework for generic medicines, namely that they are largely performed in cohorts of otherwise healthy young men and don't match the clinical demographic.
In 2010, the White Paper ‘Equity and excellence: Liberating the NHS’7 set out the government's vision for the future of the NHS. Quality, Innovation, Productivity and Prevention (QIPP) work streams would support the NHS to make efficiency savings, which could be reinvested back into the service to continually improve quality of care. One of these work streams was medicine use and procurement. As stated, in 2011, there was a national NHS tender for tacrolimus. A first draft National Kidney Care QIPP plan document was released in the summer of 2011 and was then incorporated into the Kidney Care Commissioning plan for 2012–2013.8 This document highlighted the opportunities to improve quality and effective use of funding by seeking the best value in immunosuppression spend. Once some UK transplant centres had started to use generic tacrolimus de novo then commencing supervised switch programmes to convert existing patients on Prograf to branded generic tacrolimus was a logical next step.
A survey conducted by the UK Renal Pharmacy Group of its members at 24 transplant centres in July 2012 found that of the 16 centres responding, no centre was using a generic ciclosporin in solid organ transplantation patients but it was being used in other specialities, for example, dermatology and haematology. Generic tacrolimus, as Adoport, was, however, being used by some centres and remains the only branded generic being used in transplant recipients in the UK.
Despite little transplant use, many branded generic tacrolimus products remain available. Safeguards, to ensure patients receive the correct product, must be implemented when introducing generic tacrolimus into clinical practice. One example is the requirement for brand prescribing to avoid inadvertent switching between the different tacrolimus brands available. Only the innovator product (Prograf, Astellas), with a recommended twice daily dosing regimen, was licensed in the UK when, in 2007, the modified-release capsule (Advagraf, to be taken once daily in the morning) was marketed for adults. There was very limited clinical use of ‘specials’ manufactured tacrolimus liquids as questions had already been raised about the reproducibility of blood levels. Astellas launched the immediate-release granules for oral suspension (Modigraf) in 2009 with the clear caveat that it is not-bioequivalent with Prograf and offering dose conversion recommendations.
Since 2008, the UK MHRA/Commission on Human Medicines has used the Drug Safety Update to issue one ‘Stop press’, four ‘Advice’ notes and a letter to Healthcare professionals relating to oral tacrolimus prescribing.
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In December 2008, after the launch of Advagraf, it identified that serious errors had occurred with patients receiving the incorrect formulation.9
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In January 2009, it offered the advice that ‘immediate-release Prograf and modified-release Advagraf are not interchangeable without therapeutic monitoring under the close supervision of a transplant specialist’.10
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In February 2010, with the launch of Modigraf, they again advised about the vigilance required because of the difference in bioavailability to Prograf and reiterated that, ‘oral tacrolimus formulations or regimens should not be altered without careful therapeutic monitoring by a transplant specialist’.11
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In May 2010, just before the launch of the first branded generic immediate-release competitor, they summarised their advice that the three different formulations should not be switched in an unsupervised manner. Confusingly, this implied that bioequivalent immediate-release tacrolimus capsules were perhaps interchangeable. At this juncture, they did recommend that oral tacrolimus should be prescribed as either by recommended International Non-proprietary Name plus form, release characteristics and strength or by brand name with strength.12
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This advice was simplified to the current ‘prescribe and dispense by brand-name only’ in May and June 2012.13
This same safe prescribing advice is also included in the British National Formulary under Tacrolimus.14
Patient education and involvement in the issues are also vital to the process of safe generic immunosuppression prescribing. In the UK, an independent group of multidisciplinary healthcare professionals, using educational grants from the Pharmaceutical Industry, was set up ahead of introduction of generic ciclosporin to provide advice to healthcare workers and patients about the safety and efficacy of generic immunosuppression in transplant recipients. This group is called Efficacy and Safety of Prescribing In Transplantation (ESPRIT) and has published recommendations as well as resources, such as patient information leaflets, clinic posters and formulation identification cards. For more information, access their website at http://www.esprit.org.uk.
The Council of the European Society of Transplantation (ESOT), in November 2010, commissioned an Advisory Committee on generic substitution and this report was made available to members early 2011 and was published at the end of 2011.15 This advice was reflective of that issued by MHRA, but in addition, they recommended that ‘new generic formulations of immunosuppressive drugs that do not fulfil the stricter bioequivalence criteria should not be used. Similarly, the use of already marketed generic immunosuppressants should be discouraged unless they prove to be bioequivalent according to recently updated EMA guidelines.’ The Advisory Committee included in its recommendations mycophenolate products.
The case of the US Eon formulation of ciclosporin is, for example, widely known and quoted, largely due to the work of the ESPRIT group: it was deemed US Food and Drug Administration (FDA) bioequivalent to Neoral despite numbers of study participants achieving AUC and Cmax >20% below or >25% above the reference product. This study was performed under old FDA, bioequivalence 0.8–1.25 limits. Under the 2010 revised stricter EMA guidelines it would not be granted European licensing approval.16
A number of branded and unbranded generic solid dose-form mycophenolate mofetils (but not the enteric-coated sodium salt) also became available in the UK from the beginning of 2011. Their introduction and use followed a more typical pattern seen following the expiry of the patent of an innovator product. Rather than a single brand winning though, this NHS tender resulted in products from different manufacturers being the contract choice for specific geographical areas (and, in at least one area, the 250 mg capsule and 500 mg tablet contracts were to separate companies). Given the acute awareness of tacrolimus issues at this time it is perhaps surprising that generic mycophenolate mofetils were relatively quickly adopted on the back of very significant drug acquisition cost savings. Mycophenolate mofetil was not seen as a critical-dose drug; clinicians had 15 years of experience of reducing doses (in response to both adverse effect and to combination use with immunosuppressants other than ciclosporin) and the monitoring of blood levels has not been routinely undertaken in the UK. In addition, there was already a significant amount of off-label use within hospitals in arguably less critical conditions. A wider understanding of bioequivalence studies, which had often resulted in unease for the calcineurin inhibitors, seemed to offer reassurance in this case. For example, the comparative pharmacokinetic test results for Teva Pharmaceutical Ltd (UK) mycophenolate mofetil showed that drug exposure for both the capsule and tablet met the stricter (0.9 to 1.11 CI limit) criteria despite it not being defined as a critical-dose drug.2
The ESOT Advisory Committee recommendations are not being followed for mycophenolate mofetils, almost certainly because the majority of patients were already taking a generic by the time this advice was published. With large volumes of transplant, mycophenolate mofetil prescribing undertaken in primary care, and NHS prescribing and reimbursement systems that encourage generic use, it is likely that many patients are repeatedly switching between products. Although the risk of patient confusion remains an issue, no widespread clinical problems have yet manifested; a position similar to that of prednisolone and azathioprine.
As of the 1 April 2013, specialised services commissioning arrangements have changed within NHS England. Over the next year or so, this will permit many hospitals to repatriate their transplant patients’ immunosuppression prescribing back from primary care. By doing so, the transplant specialists will again have some control over which products are used, possibly allowing a consistent approach to dispensing of non-brand-prescribed generic products such as mycophenolate mofetil. However, it should not be seen as a return to old practices; it is anticipated that this change will facilitate supervised switch programmes to generic brands where specialist input is required. It is implausible that transplant recipients who remain on ciclosporin products will be switched to brands, which do not meet the tighter bioequivalence criteria. The potential for greatest savings lies with supervised tacrolimus switches. However, there is a risk that despite many tacrolimus brands most English transplant recipients who take this drug may be switched to the current contract choice of Adoport.
Patient safety remains at the core of patient care and of all prescribing and dispensing decisions. Generic immunosuppression is being used widely in the UK. By facilitating specialist supervised and managed switch programmes for generic tacrolimus, safety is maintained throughout and significant costs savings are released, which ensures reinvestment and continued service improvement for patients, from limited NHS resources. However, by narrowing all English transplant use of generic tacrolimus to one brand, are we actually putting all our eggs in one basket?
Footnotes
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Competing interests None.
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Provenance and peer review Commissioned; internally peer reviewed.