The Generic Alternative in Schizophrenia - Springer Link

CNS Drugs 2004; 18 (12): 769-775 1172-7047/04/0012-0769/$31.00/0

CURRENT OPINION

 2004 Adis Data Information BV. All rights reserved.

The Generic Alternative in Schizophrenia Opportunity or Threat? Philippe Nuss,1 David Taylor,2 Marc De Hert3 and Martina Hummer4 1 2 3 4

ˆ Psychiatry Department, Hopital St Antoine, Paris, France Pharmacy Department, Maudsley Hospital, London, UK University Psychiatric Centre St Jozef, Catholic University of Louvain, Kortenberg, Belgium Department of Biological Psychiatry, Innsbruck University Clinics, Innsbruck, Austria

Abstract

Pharmacological treatment of schizophrenia often requires careful dosage titration to achieve satisfactory symptom control whilst minimising the risk of adverse effects. Relapses requiring hospitalisation are an important potential source of additional cost for the health service and any inadequate symptom control increases the indirect costs of schizophrenia relating to, for example, the need for sheltered accommodation or intensive social services support. The availability of generic drugs is widely regarded as an opportunity to reduce expenditure on drug costs and deploy limited resources more widely and effectively. However, generic drugs may differ from branded drugs in their formulation and may not show precise bioequivalence with the branded product. This may have consequences for the pharmacokinetic profile of the generic drug. A higher maximum plasma concentration (Cmax) could lead to increased or emergent adverse effects, whereas a decreased absorption or minimum plasma concentration (Cmin) may result in a reduced therapeutic effect. For example, plasma levels of clozapine are critical to therapeutic response. Symptom aggravation occurred in approximately 10% of patients switched from branded to generic clozapine in a small, randomised, crossover study. Patients with schizophrenia may also show suspicion and hostility regarding their treatment. This may result in unwillingness to take an unfamiliar medication and decreased compliance, thus increasing the risk of a relapse. Thus, great care should be taken by psychiatrists when switching patients with schizophrenia from branded to generic antipsychotic drugs; this entails monitoring clinical outcome closely and adjusting the treatment in case of symptom aggravation or emergence of adverse effects.

Schizophrenia is a chronic debilitating mental disorder that is associated with a lifetime risk of about 1% in the adult population and usually develops during adolescence or early adulthood.[1] Treatment involves long-term drug therapy with multiple

adjustments of treatment regimens and often frequent episodic hospitalisation, if not long-term institutional care, and consumes significant public health service financial resources. However, appropriate pharmacotherapy allows many patients to be treated

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in the community, thus avoiding the need for more costly hospitalisation or institutionalisation. As for other illnesses, national healthcare systems have sought to reduce the drug-related costs of schizophrenia by switching from branded drugs to generic alternatives.[2] In principle, generic drugs should provide some reduction in cost without any reduction in the quality of care. However, in some patient populations and therapeutic areas, generic substitution is not without risk, and it has been suggested that generic substitution of some psychotropic medications should be considered in this way.[3] 1. Generics and Public Health Policy The end of the patent life of a medicine heralds an opportunity for the introduction of non-branded or generic versions of previously patented medications. Such generic alternatives are invariably less expensive than the branded original because the manufacturers do not have to pay the considerable costs associated with the research, development and registration of the drug. The main advantage of generic drugs from a public health system perspective is the scope for cost reduction. A lower drug bill allows limited healthcare resources to be more widely distributed. However, public drug reimbursement policies determine which participants in the health system have a financial incentive to use generic drugs. In countries such as the UK, where all drugs are fully reimbursed apart from a fixed prescription charge, the real cost of the drug is invisible to the patient. On the other hand, in other countries that practise a reference pricing system, whereby different versions of a given drug are all reimbursed at a fixed price corresponding to the bottom end of the range, the patient pays the difference between the reference price and the real cost of the drug. In such systems, the patient has a clear financial interest in the prescription of a generic drug as opposed to a branded drug. In certain countries, for example Germany and the UK, physicians have control over a fixed prescription budget, and their allocation of this budget will need to take into account unit drug costs in order to satisfy the needs of their patients. For  2004 Adis Data Information BV. All rights reserved.

these reasons, physicians may also have a financial interest in prescribing generic drugs. Similarly, pharmacists in certain countries are rewarded financially for replacing brand drug prescriptions with generics unless this is specifically prohibited by the physician on the prescription. In countries with private healthcare systems, managed healthcare plans may mandate prescription of the least expensive generic alternative.[4,5] 2. Equivalence of Generic Drugs Generic drugs contain the identical active principle as the branded drug, at an identical dose. However, the formulation of the drug can be different, and this explains why there may be several different generic versions of the same branded drug. Apart from the macroscopic differences in formulation (shape, colour, etc.), there are important microscopic and chemical differences in formulation that may have consequences for the clinical effectiveness of the drug. These include the choice of excipient with which the active principle is incorporated in the finished drug product, the particle size of the active principle and the crystalline (or amorphous) form of the active principle. These parameters influence the rate at which the dose form disintegrates and the rate at which the active substance disperses and dissolves in the gastrointestinal tract. The rate and extent of disintegration, dispersion and dissolution affects the rate, and potentially the extent, of absorption of the drug molecule from the gastrointestinal tract and, in extreme cases, may change whether the drug substance is liberated in the stomach (which is an acid milieu) or the intestine (an alkaline milieu). For these reasons, manufacturers of generic drugs are obliged to demonstrate that their new formulations are bioequivalent to the original product in healthy volunteers.[6-9] 2.1 Bioequivalence

The licensed use of generic medicines is based on the principle of bioequivalence, that is that they are substantially bioequivalent to their branded predecessor. Bioequivalence is measured in studies in healthy volunteers, although there is some discusCNS Drugs 2004; 18 (12)

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sion as to whether such studies are directly applicable to the use of drugs in the intended patient population.[10]

For many drugs this difference in the effective dose is clinically insignificant, but it may become important where drugs have a narrow therapeutic index or where the prescriber has made efforts to titrate the patient’s dose with precise care. Concern has been raised that for some medication classes used to treat disorders with a relapsing-remitting course, the difference between branded and generic drugs could be sufficient to provoke relapse.[8,10] A higher Cmax could lead to increased or emergent adverse effects, whereas a decreased absorption or minimum plasma concentration (Cmin) may result in a reduced therapeutic effect. The principle is illustrated in figure 1, in which drug 2 represents a hypothetical branded drug and

16 Peak plasma

Although definitions for bioequivalence in the context of generic medicine vary between countries, WHO recommendations require that the ratio of the mean area under the concentration-time curve (AUC; total drug exposure) to peak plasma concentration (Cmax) for the two substances falls in the range 0.8–1.25.[10] However, this is the ‘average’ bioequivalence and this value has been criticised because it does not sufficiently take into account differences between individuals.[11] Put simply, this means that the effective dose received by an average patient after administration of a generic drug could be 25% higher or 20% lower than in the case of the branded medication.

Drug 1 Drug 2 Drug 3

18 14 12 10 8 6 4 2 0 0

1

2 4 6 8 12 Time after administration (h)

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24

Fig. 1. Comparison of pharmacokinetic properties of three ‘bioequivalent’ drugs.

drugs 1 and 3 represent generic alternatives. The Cmax and the AUC from 0 to 24 hours (AUC24) for these three agents are broadly similar and fall within the currently accepted definition of bioequivalence, but they have quite different profiles. Although the difference between the branded drug and the generic drug is noticeable, the difference between drug 1 and drug 3 is even more striking. In effect, drug 1 could have a Cmax and AUC more than 50% higher than that of drug 3. However, this degree of difference between generic products is possible with current regulations. The use of average bioequivalence as the standard for generic drugs has been criticised on a number of grounds (see Meredith[7] for a comprehensive review) and the principal arguments are illustrated in table I.

Table I. Restrictions of bioequivalence studies[7] Single range of bioequivalence

Drugs with a narrow therapeutic index (e.g. antiepileptics) or for which small changes in plasma levels (e.g. immune suppressants) would have serious consequences should have a narrower definition of bioequivalence

Bioequivalence provides comparable clinical efficacy and safety

Little research available to support the assumption

Significance of differences between healthy populations (generic bioequivalence studies) and patient populations (clinical trials)

Healthy volunteer and patient populations vary in a variety of ways, and there is little evidence to support the assumption that studies in the former predict safety and efficacy in the latter. For many classes of drug, doses appropriate for studies in healthy volunteers are lower than those used in patients

Lack of multiple-dose studies

Bioequivalence studies are restricted to single-dose studies, but most drugs are used in a multiple-dose paradigm

Drugs with significant inter-individual differences in pharmacokinetics

Some drugs exhibit considerable variability in pharmacokinetics and drug metabolism between individuals. This is not reflected in average bioequivalence data


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3. Generic Medications in Schizophrenia Many older psychoactive medications, including TCAs and some antipsychotics, are now available in both branded and generic form. Whilst the introduction of generics has been successful and cost saving in some therapeutic areas, the nature of psychiatry requires that special consideration be made before switching a patient to a generic alternative. In schizophrenia, lack of insight, cognitive difficulties, poor compliance and the unstructured lives of certain patients may compromise successful switching of medications to or between generics.[12,13] 3.1 Compliance

Compliance is key to good outcomes in treating schizophrenia, and the introduction of atypical antipsychotics has gone some way to improving this.[14] However, despite excellent results in clinical studies, patients commonly do less well than expected in real-world situations. Under these circumstances, optimising compliance is critical to outcome. An important determinant of compliance is patient satisfaction with treatment.[15] In particular, emergence of extrapyramidal symptoms has been associated with an increased likelihood of spontaneous treatment discontinuation by the patient.[16] Despite apparent bioequivalence (see section 2.1), the Cmax of a generic antipsychotic drug may be elevated compared with the branded product at the same dosage, resulting in an increased risk of adverse events, particularly for those drugs where these are strongly dose dependent. Patients and their families may be reluctant to accept cosmetic, physical or functional changes in medication or even a name change, even when the principle of generic medication is well explained.[8] Patients and their carers frequently invest considerable faith in their medication and, bioequivalence notwithstanding, might perceive the switch to a generic version of their familiar medication to be a change in treatment. Although this is to some extent true for all medications, there are certain features of schizophrenia that militate against good compliance. First, the symptoms of schizophrenia may include cognitive difficulties and suspicion of or  2004 Adis Data Information BV. All rights reserved.

hostility to change in general, and this needs to be taken into account.[12] This is a particularly important issue for patients with well developed paranoia and delusions. Such patients may not readily accept recommendations about treatment from their physicians or caregivers as they may consider that these are not in their best interest or are potentially harmful. Switching to a generic drug by the pharmacist may even be construed within the patient’s delusional system as a poisoning attempt. Even when they do receive a prescription for a new drug, they may decide not to take the medication. In addition, the social integration of patients with schizophrenia is frequently suboptimal, attenuating a beneficial effect of the patient’s caregivers in maintaining compliance. Education of patients and families therefore has an important role in ensuring continued compliance after a switch to a generic, although neither psychiatrists nor pharmacists necessarily have the time to invest in this. In some cases, when patients are stabilised on medication, maintaining a regimen that is subjectively consistent to the patient can assist in optimising compliance and therefore be cost saving in the long-term. Although generic medications may offer drug-acquisition cost savings compared with the branded alternatives, these costs are relatively small compared with the costs of inpatient treatment and institutional care,[17] and poor compliance is recognised as a significant cost driver in the treatment of schizophrenia as a result of the increased risk of hospitalisation.[18] 3.2 Attitudes to Generic Medication

There is little information available about attitudes of psychiatric patients and the psychiatric healthcare delivery chain to generic drugs. There is a general perception that prescribers resist the pressure to prescribe generics unless there is a significant incentive to do so, and clearly, there are concerns about generic medications when they are used in dose-critical situations.[19] However, more subtle forces may be at work; many prescribers receive some or most of their information about specific medications from the respective manufacturers’ repCNS Drugs 2004; 18 (12)


resentatives and sometimes branded manufacturers are seen as a better resource in this respect,[20,21] although not everyone agrees.[22] In this sense, certain physicians see the manufacturers of a branded medication as part of the care delivery chain and are reluctant to switch to non-branded prescribing. Generic substitution by pharmacists is vigorously resisted by certain prescribers.[8,23,24] In common with physicians, pharmacists believe that generic substitution is advisable only up to a point and express concerns about the use of generic drugs in critical or high-risk situations.[25,26] More generally, whilst some pharmacists might view generic substitution at the point of dispensing as an appropriate activity, it takes their focus away from the merits and demerits of particular drugs and requires them to become more involved in the overall healthcare provision system; for some, this causes conflict.[27] In the community pharmacy setting, some pharmacists may be reluctant to change the medication for a patient with schizophrenia because they do not feel that they have the time or resources to explain from behind the counter the merits of a switch to a generic drug. 3.3 Bioequivalence of Generic versus Branded Antipsychotics

Despite the assumption that average bioequivalence equals clinical equivalence, there are very few studies which have attempted to verify that this is the case for psychotropic drugs. A literature review[8] has uncovered a number of cases where bioavailability, pharmacokinetic parameters and clinical efficacy were substantially different with generic products than with the branded medication. As the oldest of the atypical antipsychotics, clozapine is the best studied in terms of clinical efficacy and safety after a switch from branded to generic prescribing. Many of the issues raised in the preceding sections apply to this antipsychotic. These include, in particular, the need for multiple-dose studies (the half-life of clozapine increases with multiple doses) and the need to undertake bioequivalence studies in patients (schizophrenic patients are able to tolerate clinical doses of clozapine that are intolera 2004 Adis Data Information BV. All rights reserved.

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ble to volunteers; this results in the use of artificially low doses in bioequivalence studies).[12] A pharmacokinetic study in 21 schizophrenic patients established on clozapine treatment for at least 3 months revealed statistically and clinically significant differences in pharmacokinetic parameters between the branded and generic products.[28] Whilst the concentration-time curves were similar in shape and fell within the +25%/–20% guidelines, plasma clozapine levels were consistently lower in patients receiving the generic product compared with those given the branded product. Statistical analysis of these small differences suggested a systematic bias toward lower drug exposure (AUC) for the generic versus the branded product. The log Cmax ratio at steady state indicated a statistically significant difference between the two products and fell outside the +25%/–20% guidelines. There were also statistically significant differences in the peak-trough concentrations of clozapine. These results suggest that a switch from the branded to the generic product would need careful monitoring for symptom control to be maintained. A randomised study in 45 patients with schizophrenia stabilised on branded clozapine has examined the clinical effects of a switch to generic clozapine.[29] In this study, patients were randomised to two groups: patients in group A were switched to the generic product, whilst those in group B remained on branded clozapine. After 8 weeks, patients in group A were returned to branded clozapine and those in group B were switched to generic clozapine. The switch to generic clozapine resulted in relapse in five patients (approximately 10%) and a worsening short of full relapse in nine patients (figure 2). Two patients worsened after the switch from generic to branded clozapine. There were statistically significant differences in favour of branded clozapine on the Clinician’s Global Impression Improvement score and the Brief Psychiatric Rating Scale. The study authors recommended that patients being switched to generic clozapine be monitored carefully. On the other hand, a naturalistic outpatient study in 20 schizophrenic patients failed to find any signifCNS Drugs 2004; 18 (12)

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Branded clozapine Generic clozapine Symptom aggravation

Acute relapse

Sustained relapse

0

5

10

15

Number of patients (n = 49)

Fig. 2. Clinical outcome in patients randomised to branded or generic clozapine. The graph shows the number of patients experiencing sustained or acute relapse and symptom aggravation when receiving branded or generic clozapine (data are taken from Kluznick et al.[29]).

icant differences in scores on the Positive And Negative Symptom Score Scale and the Beck Anxiety Inventory after a switch from branded to generic clozapine.[30] However, this smaller study lacked the randomised crossover methodology of the previously described study. A randomised parallel group study in schizophrenia of branded versus generic fluphenazine also failed to show any significant clinical differences between the products.[31] 4. Discussion It is clear that generic drugs may differ from their branded counterparts; widely accepted guidelines recognise that strict equivalence between branded and generic medications is unattainable and permit a degree of liberty in the definition of bioequivalence. Under many circumstances, the demonstrable differences in pharmacokinetics and clinical efficacy between branded and generic medications are of little import, but it is clear that in some situations the differences can be clinically significant. Schizophrenia may be one of the circumstances in which great care and close monitoring is needed when switching a patient from a branded to a generic medication. Physicians can invest a great deal of care in titrating drug dosage and optimising the treatment of schizophrenic patients, with extended  2004 Adis Data Information BV. All rights reserved.

remission in a stabilised patient being a worthy reward. As well as the medical consequences of poor compliance and inadequate symptom control, there are also financial consequences due to the increased rate of intervention in the case of deterioration of symptoms. If care is not taken to ensure that the patient remains compliant with the generic drug after switching and that symptoms continue to be well controlled, there is a risk that the patient may need to be hospitalised. In such cases, any saving in medication cost would be cancelled out by the cost of hospitalisation. Moreover, patients with well controlled symptoms living in the community generate lower indirect costs than patients with poorly controlled symptoms or those at risk for relapse who may need to be accommodated in sheltered housing or receive regular follow-up from the social services or community nurses. Thus, although switching a patient from a branded drug to a generic alternative may save the difference in the cost of acquisition of the two products, in certain cases, this must be done with extreme care and consistent monitoring. Indeed, the degree of care required is no less than that of switching from, say, one atypical antipsychotic to another; in general, most physicians would prefer not to switch a stabilised patient with schizophrenia between drugs unless there were convincing clinical reasons to do so. Perhaps the same argument should be applied to the risk-benefit balance involved in the switch from branded to generic antipsychotics. Acknowledgements This paper is the result of discussions regarding the issues associated with generic switching in schizophrenia. The authors would like to acknowledge Stefan Leucht (Klinik and Poliklinik für Psychiatrie und Psychotherapie der Technischen Universitatät München, Munich, Germany) for his contribution to the development of this article. The preparation of this review was supported by an unrestricted educational grant from Sanofi-Synthelabo.

References 1. Jablensky A. Epidemiology of schizophrenia: the global burden of disease and disability. Eur Arch Psychiatry Clin Neurosci 2000; 250: 274-85

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2. Meredith PA. Generic drugs: therapeutic equivalence. Drug Saf 1996; 15: 233-42 3. Colaizzi JL, Lowenthal DT. Critical therapeutic categories: a contraindication to generic substitution? Clin Ther 1986; 8: 370-9 4. Ess SM, Schneeweiss S, Szucs TD. European healthcare policies for controlling drug expenditure. Pharmacoeconomics 2003 ; 21 (2): 89-103 5. Kanavos P, Reinhardt U. Reference pricing for drugs: is it compatible with US health care? Health Aff (Millwood) 2003 May-Jun; 22 (3): 16-30 6. European Agency for the Evaluation of Medicinal Products. Note for guidance on the investigation of bioavailability and bioequivalence. London: EMEA, 2001 Jul 26 (CPMP/EWP/ QWP/1401/98) 7. Meredith P. Bioequivalence and other unresolved issues in generic drug substitution. Clin Ther 2003; 25: 2875-90 8. Borgherini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther 2003; 25: 1578-92 9. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry: average, population, and individual approaches to establishing bioequivalence, draft guidance August 1999 [online]. Available from URL: http:// www.fda.gov/cder/guidance/1716dft.htm [Accessed 2004 Jul 5] 10. World Health Organization. Multi-source pharmaceutical products: WHO guideline on registration requirements to establish interchangeability. Geneva: WHO, 1996. WHO Technical Support Series no. 863 11. Chen ML, Patnaik R, Hauck WW, et al. An individual bioequivalence criterion: regulatory considerations. Stat Med 2000; 19: 2821-42 12. Cutler NR. Pharmacokinetic studies of antipsychotics in healthy volunteers versus patients. J Clin Psychiatry 2001; 62 Suppl. 5: 10-3 13. Burns T, Chabannes JP, Demyttenaere K. Switching antipsychotic medications: general recommendations and switching amisulpride. Curr Med Res Opin 2002 18 (4): 201-8 14. Lindstrom E, Bingefors K. Patient compliance with drug therapy in schizophrenia: economic and clinical issues. Pharmacoeconomics 2000; 18: 106-24 15. Hellewell JS. Patients’ subjective experiences of antipsychotics: clinical relevance. CNS Drugs 2002; 16: 457-71 16. Robinson DG, Woerner MG, Alvir JM, et al. Predictors of medication discontinuation by patients with first episode schizophrenia and schizoaffective disorder. Schizophr Res 2002; 57: 209-19 17. Genduso LA, Haley JC. Cost of illness studies for schizophrenia: components, benefits, results and implications. Am J Manag Care 1997; 3: 873-7


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18. Thieda P, Beard S, Richter A, et al. An economic review of compliance with medication therapy in the treatment of schizophrenia. Psychiatr Serv 2003; 54: 508-16 19. Banahan III BF, Kolassa EM. A physician survey on generic drugs and substitution of critical dose medications. Arch Intern Med 1997; 13: 157: 2080-8 20. Iijima H, Kurosaki T, Kamei M, et al. Calculation of drug information necessity factor of generic drugs [in Japanese]. Yakugaku Zasshi 2003; 123: 1039-47 21. Generali JA, Hogan L. A comparison of pharmaceutical manufacturers as a source of drug information to a telephone inquiry: generic vs brand. Drug Inf J 1983; 17: 195-200 22. Thomas M, Lexchin J. Responsiveness to physicians’ requests for information concerning drug interactions: a comparison of brand and generic companies. Soc Sci Med 1990; 31: 153-7 23. Tilyard MW, Dovey SM, Rosenstreich D. General practitioners’ views on generic medication and substitution. N Z Med J 1990; 103: 318-20 24. Brust M, Hawkins CF, Grayson D. Physicians’ attitudes toward generic drug substitution by pharmacists. Tex Med 1990; 86: 45-9 25. Carroll NV, Wolfgang AP. Inherent risk and market acceptance of generic drug products. J Health Care Mark 1989; 9: 48-51 26. Vasquez EM, Min DI. Transplant pharmacists’ opinions on generic product selection of critical-dose drugs. Am J Health Syst Pharm 1999; 56: 615-21 27. Pelton LE, Strutton D, Smith MC. A political economy perspective: why pharmacists may be reluctant to dispense generic medications. J Hosp Mark 1994; 9: 137 28. Lam YW, Ereshefsky L, Toney GB, et al. Branded versus generic clozapine: bioavailability comparison and interchangeability issues. J Clin Psychiatry 2001; 62 Suppl. 5: 1822 29. Kluznik JC, Walbek NH, Farnsworth MG, et al. Clinical effects of a randomized switch of patients from clozaril to generic clozapine. J Clin Psychiatry 2001; 62 Suppl. 5: 14-7 30. Makela EH, Cutlip WD, Stevenson JM, et al. Branded versus generic clozapine for treatment of schizophrenia. Ann Pharmacother 2003; 37: 350-3 31. Verster GC, Joubert G, Stevens M, et al. Generic substitution: comparing the clinical efficacy of a generic substitute for fluphenazine decanoate with the original product. S Afr Med J 1998; 88: 260-2

Correspondence and offprints: Dr Philippe Nuss, Psychiatry ˆ Department, Hopital St Antoine, 184, rue du Faubourg St Antoine, Paris, 75012, France. E-mail: [email protected]

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