Does one size really fit all?

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Reena Popat MPharm IPresc

Acting Principal Pharmacist,
Renal and Urology Services,
Barts and the London NHS Trust, UK

Healthcare costs across Europe continue to rise dramatically. According to the World Bank, public expenditure on healthcare in the EU could jump from 8% of GDP in 2000 to 14% in 2030.(1) Hence the need to create savings is ever more important. The use of generics is one such way health economies are saving money; it is estimated that €30bn savings(2) are made annually by the use of generics. With many blockbuster drugs, for example atorvastatin and seretide, reaching the end of their patents, more savings will continue to be achieved.

Recently, across Europe the patents of the most commonly prescribed immunosuppressants in transplantation have expired and generics are now available at competitive prices. Pressure is growing on the transplant community to begin the process of prescribing generics, and this has sparked much debate, most crucially around the calcineurin inhibitors ciclosporin and tacrolimus.

Calcineurin inhibitors (CNIs) are classified as narrow therapeutic index (NTIs) drugs and display the following characteristics:(3,4)

• A narrow therapeutic range
• Serious clinical consequences if concentrations are too low or high
• Require blood monitoring
• Require individualised dosing based on plasma concentration
• Show steep concentration response relationship for efficacy, safety or both
• Formulation-dependant bioavailability differences may affect safety and efficacy
• Pharmacokinetic variability can have a significant impact on safety and efficacy.

As such, simply switching NTIs without monitoring is not possible due to the multitude of characteristics they exhibit. Particularly with the CNIs, the risk of low blood levels can result in graft rejection and potential loss of functioning graft whilst high blood levels can result in nephrotoxicity. It is therefore important for us as pharmacists to understand the generic approval process and the evidence behind generic CNIs in order to evaluate the effect on our transplant patients.

The extent to which generics replicates these NTI characteristics are determined through bioequivalence testing. Bioequivalence is defined as when the ‘rate and extent of absorption of the test drug does not show significant difference from the rate and extent of absorption of the innovator drug when administered at the same molar dose of therapeutic ingredient under similar experimental conditions in either the same or multiple doses.'(5) Bioequivalence is determined by pharmacokinetic studies and the process is regulated by government bodies such as the Food and Drug Administration (FDA) in the US and the European Medicines Evaluation Agency (EMA) in Europe.

The generic approval process
Generics are required to fulfil the following criteria:
Active ingredient(s)

• Dosage form
• Route of administration
• Strength/concentrations
• but may be different in:
• Shape
• Scoring
• Release mechanisms
• Excipients
• Packaging
• Expiration time

This can be incredibly confusing for patients who are counselled on the importance of their medication and the need to stay on a particular formulation from the time of transplant.

In addition, the approval process for generics itself has caused further concern. The process is similar in both the US and Europe and requires the company manufacturing the generic to perform a two-way crossover study with 24 to 36 healthy adults. An oral dose is administered of the test and reference product (in this case the CNI) (Figure 1) and pharmacokinetic parameters are then evaluated. This is performed by creating a plasma concentration curve (Figure 2) that is used to determine the rate and extent of absorption. The key parameters assessed are the area under the curve (AUC) and the time to reach maximum concentration (Cmax).

When the means of AUC and Cmax for the generic are compared to the reference product, the 90% confidence interval of the ratio of the means has to be within the acceptance limits of 80-125%. But this was challenged as being too wide when considering the nature of NTIs and the risks involved. The EMA have accepted this and in January 2010 changed the acceptance limits in which the confidence intervals of the ratio of the means must fall for all NTIs to be in the range of 90-111%. The example in Figure 3 shows the importance of the bioequivalence limits. You can see that only one product is deemed bioequivalent, while all others are not. Should the intervals have been as previous, product B would also have been deemed to be bioequivalent. What is important to note here is that to some degree there will be differences in bioequivalence, and crucially the company manufacturing the generic formulation does not need to carry out any tests to compare its drug to another generic. Should patients be switched from one generic NTI to another, there is the potential for clinically important fluctuations in levels.

This process of bioequivalence testing is the crux of the problem. The tests do not take into consideration the unique pharmacokinetic profile characteristics of transplant recipients or the effect of concurrent conditions or drug therapy and fed and fasted states – all of which can significantly alter the pharmacokinetic profile of a drug. Hence the fundamental question is, does bioequivalence testing currently performed translate into therapeutic equivalence?

What is the evidence so far?
There have been numerous studies evaluating the efficacy of generic immunosuppressants in transplant Recipients, some of which are summarised below.

Ciclosporin
Ciclosporin has been off patent since the mid-nineties. One of the most poignant mistakes was made by a company manufacturing SangCya—a ciclosporin oral solution that was licensed to be taken with apple or orange juice (SangStat Medical Corporation, 2000). After licensing, it was found that, when given with apple juice, its absorption diminished relative to Neoral.(6) As a result, the FDA recalled the product. Since this time there has been a stream of positive studies published using Sigmasporin, Apimune and Equorel. All these generics have been found to be safe and effective in transplant recipients. These were all licensed prior to the tighter bioequivalence standards, and therefore caution needs to be exercised on conversion to a generic from Neoral.

Tacrolimus
Prograf, the innovator tacrolimus preparation, came off patent in Europe last year but has been available as a generic in the US since 2009. Numerous studies evaluating the use of generic tacrolimus in transplant recipients have been conducted as its use is more widespread than ciclosporin.

McDevitt-Potter et al studied the effect of converting stable transplant recipients from brand to generic tacrolimus on a mg:mg basis. Seventy patients (37 kidney, 28 liver and 5 multi-organ transplant patients) were evaluated, with mean daily doses of tacrolimus before and after generic conversion of 4.4mg and 4.5mg, respectively. Fifteen  patients (21%) required dose adjustments: seven upwards and eight downwards. Mean trough concentrations were 5.8 and 5.9ng/ml before and after conversion, respectively. Three out of four patients reverted to the innovator drug due to spontaneous adverse drug reactions (nausea, mouth sores, rash  and vision disturbances). The authors concluded that, when switching to generic tacrolimus, post conversion monitoring is prudent, as patients may require dose adjustments.(7)

Momper et al similarly evaluated converting transplant patients from branded to generic tacrolimus. One hundred and three patients were evaluated (48 liver and 55 kidney transplant patients). Generic substitution of tacrolimus with the Sandoz generic formulation resulted in an average reduction of 15.9% and 11.9% in the concentration/dose ratio in liver and kidney patients, respectively, following conversion from the innovator product, Prograf. In addition, in those patients who remained on the same tacrolimus dosing regimen over the observational period, actual mean tacrolimus concentrations declined by an average of 1.98ng/ml in liver patients and 0.87ng/ml in kidney transplant patients following the switch. They too concluded that generic substitution appeared to be safe when done in conjunction with vigilant monitoring.(8)

Finally, Abdulnour et al compared generic tacrolimus and Prograf drug levels in a paediatric kidney transplant programme. Four patients with stable renal allografts in their paediatric programme were inadvertently switched to generic tacrolimus. Retrospective analysis was performed pre and post tacrolimus switch with regards to trough levels and serum creatinine. None of the patients had experienced rejection prior to the switch. Post switch, three patients had similar creatinine levels, but one patient experienced acute rejection soon after switching, with immediate marked rise in creatinine, and required treatment with methylprednisolone. Unfortunately, the kidney function did not return to its baseline level prior to the rejection episode.(9) While analysis was performed in only four patients, the evidence alerts us to the fact that inadvertent switching from branded to generic tacrolimus may have serious consequences on graft function/survival.

European guidelines
All the studies published to date stress the importance of close monitoring when converting patients to a generic CNI. As a result, the European Society of Organ Transplantation  highlighted the specific concerns of the transplant community and issued a set of guidelines for safe conversion of patients to branded
generic CNIs.

The areas of concern raised were:(10)

• The guidelines for bioequivalence testing from 80-125% to the stricter range of 90-111% was implemented in January 2010. Before this time, ciclosporin generics had already been marketed in Europe. Not only are these preparations still available, they were not tested in fed and fasted states despite recommendations from  the Committee for Human Medicinal Products of the EMA.
• Generic formulations are not necessarily bioequivalent to each other. If substitution where to be allowed between various generic formulations, there may still be fluctuations in levels that may be clinically relevant.
• Prescribers may not be aware of alternative dispensing by pharmacists to the patient. In countries such as the UK, pharmacists are encouraged to dispense generics when no brand is specified. Whilst this does not apply to NTIs, there are occasions where pharmacists have given generic brands of NTIs. In the case of generic substitution, the pharmacist should contact the prescriber to confirm the brand and to make sure the prescriber is aware of any substitution should extra monitoring be required.
• Discount contracts between the pharmaceutical manufacturers and health insurance companies force pharmacists to frequently change the dispensed formulation. Health insurance in many European countries have contracts renewed 6-12 monthly with pharmaceutical manufacturers. Hence often pharmacists have no alternative other than to dispense the formulation produced by the cheapest manufacturer recruited by a particular insurance company. This may lead to uncontrolled switching between brands in the community.
• Providing patients with different generic formulations will lead to confusion and errors. As there is no requirement for generic formulations to have similar appearance as the brand drug, patients may become confused with their medication. This may alarm patients if not appropriately counselled and negatively affect adherence.

Thus the recommendations for safe conversion to generic formulations are:(10)

• Those drugs that do not meet the stricter bioequivalence should not be used as transplant immunosuppression. The use of these generics should be discouraged unless they prove bioequivalence to today’s standards.
• Substitution of the brand name drug for a generic formulation should only be initiated by specialist transplant centres. When patients are switched to a generic, this should be done under close supervision with appropriate monitoring. Where there are issues with insurers and pharmacists are required to dispense the cheapest formulation, this should be reported to the transplant specialist team.
• Consecutive switching should be avoided between brands and patients should be counselled when they are switched, to be aware of the change in packaging and tablet appearance.
• Prescribing of CNIs should be by brand and any omission to do so should be confirmed with the prescriber. Thus prescribers who wish to continue using an original product for their transplant patients must explicitly prescribe it.

Generics CNI immunosuppression can be used safely but initiation requires close monitoring and patients need to be counselled appropriately and involved in the generic substitution process: the risk of not doing so may lead to graft rejection or worse graft loss. Equally important is the need to educate patients. In the UK, for example, the national kidney foundation are working hard to promote patients’ querying packaging that looks different and the importance of staying on one formulation, unless told otherwise by their transplant team.

Conclusions
The information we have to date does lend itself to suggest that generic NTIs can be used safely if the switch over is managed within a specialist hospital setting and with appropriate monitoring. Unfortunately, it is apparent that patients are inadvertently being switched without the knowledge of the transplant teams. This can, of course, have potentially serious consequences for our transplant recipients. Pharmacists are central to ensuring that patients remain on the appropriate brand and, where this is not possible, have a responsibility to contact the prescriber should extra monitoring be required. We also need to be active in counselling patients and making sure they too are aware of the formulation they should be taking and to query their prescriptions when alternative formulations are dispensed.

References

1. Economic Intelligence Unit. The Future of Healthcare in Europe 2011.
2. European Generic Medicine Association. www.egagenerics.com/gen-geneurope.htm
3. Sabatini S et al. Drug substitution in transplantation: a National Kidney Foundation White Paper. Am J Kidney Dis 1999;33(2):389–97.
4. Kahan BD. Considerations concerning generic formulations of immunosuppressive drugs. Transplant Proc 1999;31(3):1635–41.
5. Alloway RR et al. Report from the American Society of Transplantation Conference on immunosuppressive drugs and the use of generic immunosuppressants. Am J Transplant 2003;3(10):1211–15.
6. SanStat Medical Corporation (2000) SangCya (CyclosporineOral Solution) Dear Healthcare Professional Letter Jul 2000. www.fda.gov/Safety/MedWatch/SafetyInformation/  safetyAlertsforHumanMedicalProducts/ucm175740.htm
7. McDevitt-Potter LM et al. A multicentre experience with generic Tacrolimus conversion. Transplantation 2011;92(6):653–7.
8. Momper JD et al. The impact of conversion From Prograf to generic Tacrolimus in liver and kidney transplant recipients with stable graft function Am J Transplant 2011;11(9):1861–7.
9. Abdulnour HA et al. Comparison of generic tacrolimus to Prograf drug levels in a pediatric kidney transplant programme: Brief communication.Pediatric Transplantation 2010; 14(8):1007–11.
10. European Society for Organ Trasnplantation Advisory Committee on Generic Substitution of Immunosuppressive Drugs. March 2011.