CURRENT MEDICAL RESEARCH AND OPINION VOL. 25, NO. 9, 2009, 21792189 2009 Informa UK Ltd.

0300-7995 doi:10.1185/03007990903116867 All rights reserved: reproduction in whole or part not permitted

REVIEW

Division of Cardiovascular and Medical Sciences, Department of Medicine and Therapeutics, University of Glasgow, Glasgow, UK

Address for correspondence: Peter A. Meredith, Division of Cardiovascular and Medical Sciences, Department of Medicine and Therapeutics, University of Glasgow, The Western Infirmary, Glasgow G11 6NT, UK. Tel.: 44 141 2112748; Fax: 44 141 2112748; pam1v@clinmed.gla.ac.uk

Keywords (MeSH): Amlodipine Biological availability Cardiovascular agents Drug toxicity Generic drugs Therapeutic equivalency

ABSTRACT

Background and scope: Whether generic drug products are truly therapeutically identical and interchangeable with their innovator counterparts is still a matter of debate. This review discusses the controversies related to the criteria for bioequivalence and therapeutic equivalence. These concerns are illustrated by using the calcium antagonist amlodipine besylate (innovator drug) versus amlodipine maleate (generic), indicated for the treatment of hypertension and angina pectoris, as an example. Methods: English-language publications were searched in Medline and EMBASE to retrieve all references on amlodipine maleate and literature related to the regulatory guidelines for bioequivalence and therapeutic equivalence to August 2008. Websites from the European and US regulatory authorities were also consulted. Findings: According to regulatory definitions, generic drug products need to be identical to their reference with respect to the active substance, the route of administration as well as quality standards. In contrast to innovator drugs, which have to demonstrate their clinical efficacy

and safety, generics are considered therapeutically equivalent based on simple bioequivalence testing. In addition, bioequivalence is established with a disputable study method (single dose in a small group of healthy subjects) and statistics (broad acceptance intervals). Consequently, a potential negative impact of alternative salt forms or excipients on the clinical profile of a drug may remain undetected. To exemplify this, although amlodipine maleate is known to contain (degradation) impurities with (potential) biological activity, it is found per definition bioequivalent to its innovator drug, amlodipine besylate. However, only two clinical studies compared the antihypertensive and safety profiles of both drugs up to 3 months, without CV event endpoints. Conclusions: The validity of the current criteria for interchangeability of generic and innovator drugs remains controversial and may compromise the response and/or safety of patients. In the case of amlodipine, thorough longterm clinical investigations of commercial amlodipine maleate salt preparations including hard endpoints may be needed to justify their use.

Introduction
By definition, a generic is a drug product the active substance of which is no longer patent- and/or exclusivity-protected. As the product is considered to be
Article 5021/411859

interchangeable, it needs to demonstrate bioequivalence with the innovator brand product1,2. Generics represent true market competitors of innovator drugs. However, despite regulatory demands of bioequivalence, they can still differ from the innovator drug
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Peter A. Meredith

C No op y Un t au fo rig t ht di hor r S sp ize a la d le 20 y, us vi e o ew p r 09 ro C an h d p ibi om In fo rin ted m r t a . Au e rc ma si th ng or i UK le is al ed co py us Dis Lim fo ers tr i rp c i er an bu ted so d na ow tio l u nl n

Potential concerns about generic substitution: bioequivalence versus therapeutic equivalence of different amlodipine salt forms

Table 1. Definitions of terms related to interchangeability or substitution of innovator drugs by generics as documented by international regulatory authorities4,5
Drug products Pharmaceutical alternatives EMEA4 Medicinal products that contain the same active moiety but differ in chemical form (salt, ester, etc.) of that moiety or in the dosage form or strength Pharmaceutical equivalents Same active ingredient Same amount Same dosage form that meets the same or comparable standards of strength, quality, purity and identity Bioequivalents Pharmaceutical equivalents/alternatives having similar bioavailabilities* after administration in the same molar dose, to such a degree that their effects, with respect to efficacy and safety, will be essentially the same FDA5 Drug products that contain the same therapeutic moiety, but differ in salt, esters or complexes of that moiety or in dosage form or strength Same active ingredient(s) Identical in strength or concentration Same dosage form Same route of administration Pharmaceutical equivalents/alternatives without significant difference in the rate and extent to which the active substance becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study Therapeutic equivalents Pharmaceutical equivalents/alternatives for which bioequivalence is demonstrated and containing excipients generally recognised as not influencing safety and efficacy and complying with labelling requirements Products having the same therapeutic moiety or active substance and which clinically show the same efficacy and safety
*Defined as the rate and extent to which the active substance or active moiety is absorbed/delivered from a pharmaceutical form and becomes available at the site of action/in the general circulation

Pharmaceutical equivalents, expected to have the same clinical effect and safety profile when administered to patients as described in the labelling

and amongst themselves in a number of potentially important aspects. This review intends to provide a broad overview of the controversies in regulations and, associated herewith, the potential differences between generics and innovator drugs, and their relevance to clinical practice. This is further illustrated by using the calcium antagonist amlodipine, which is registered for the treatment of cardiovascular (CV) diseases, such as hypertension and angina pectoris, and exists in two salt forms including amlodipine besylate (the salt used in the innovator brand Norvasc, Istin and Amlor*) and amlodipine maleate (the salt used in some generics), as an example.

(amlodipine besylate, amlodipine maleate, equivalence, guidelines, salt) terms. In addition, bibliographies of retrieved publications were screened for complementary publications. The search criteria with respect to bioequivalence and therapeutic equivalence were not intended as the basis for a systematic literature review on the respective topics. However, this review is systematic in the sense that it does include all available literature (within the above-mentioned limits) about amlodipine maleate. Websites from the European and American regulatory authorities were consulted as well.

Regulatory definitions of equivalence and similarity Methods

Literature searches were performed in August 2008 in Medline and EMBASE, without limits for publication date but with limits for full-text English-language publications and using MeSH (amlodipine, biological availability, drug stability, drug toxicity, generic drugs, therapeutic equivalency) as well as free text Although in slightly different wording, both the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) define the terms pharmaceutical alternatives and pharmaceutical equivalents in the same way (Table 1). Generics, either alternatives or equivalents, are formulated to contain the same active ingredient as the

*Norvasc, Istin and Amlor are registered trade names from Pfizer

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New drug application (NDA): Innovator drug product

Abbreviated new drug application (ANDA): Generic drug product*

product quality requirements that are similar to those for new drug applications (NDA), data on (non-) clinical safety and efficacy are not obligatory (Figure 1)8,9.

Preclinical (animal) studies Clinical studies Bioavailability

Chemistry Manufacturing Controls Labelling Bioequivalence Testing

Assessment and criteria for bioequivalence

Despite differences in bioequivalence assessment methods across countries10, the guidelines from the World Health Organization (WHO) state that a minimum of 12 healthy adult volunteers from 18 to 55 years of age and of normal body weight should be included in a cross-over study2. In practice, bioequivalence studies are usually conducted as randomised, two-period, twosequence cross-over studies in 1824 normal, healthy and relatively young volunteers. Usually a single dose of the generic or innovator drug product is administered under standardised conditions (with respect to diet, fluid intake, exercise and timing of drug administration). The standardised population and protocol are used to ensure a low inter-subject variability, which makes it more likely that any observed deviation in bioequivalence beyond the allowable statistical variation is due to formulation differences rather than to person-related factors11. Furthermore, the received wisdom suggests that single-dose studies are generally more sensitive than multiple-dose studies in the assessment of the systemic release of the active compound11. Because food co-administration with oral formulations may influence bioequivalence6,11, it is recommended5 (for example, for extended-release formulations) or obligatory4 (in case of food interaction by the reference drug) to perform additional testing with the products ingested together with a standardised meal. The pharmacokinetic effects of the drugs are evaluated and statistically analysed, using primarily the area under the plasma concentration versus time curve (AUC) and the maximum plasma concentration (Cmax)4,5. These variables are deemed to provide the most accurate indication of the extent and rate of drug absorption (bioavailability) and exposure4,5. Additional possible variables include the time to reach the maximum plasma concentration (tmax)4,5, the terminal half-life (t)4,5, the elimination rate constant (z)5 and, in specific instances, the urinary excretion rate (Ae)4. Regulatory authorities stipulate bioequivalence if the 90% confidence intervals (CIs) for the ratio generic:innovator drug of the AUC and Cmax fall within an acceptance interval of 0.801.254,5. Being asymmetrical, because log transformed data are used in the comparison12, this has been termed the 20%/25% rule13. However, more stringent (tighter) limits may be required for critical-dose drugs4, which have a
Potential concerns about generic amlodipine maleate Meredith 2181

Figure 1. Comparison between regulatory requirements for NDAs with innovator versus ANDAs with generic drug products (adapted from Basak et al.8) *pharmaceutical equivalent

innovator drug. However, they may differ in characteristics such as shape, size, colour, scoring configuration (i.e., debossed line across the planar surface of a tablet), release mechanisms (immediate, modified, etc.), excipients (dyes, flavours, preservatives, binders, fillers, lubricants, disintegrants, etc.), manufacturing, expiration time, packaging, and, within certain limits, labelling3. Despite the permit of distinct types of excipients that are supposed to be inert, these need to occur in a similar ratio to the active ingredient in the generic drug as in the reference listed drug, i.e. the innovator drug1. By definition, bioequivalence implies the absence of a significant difference in the rate and extent of absorption (i.e., bioavailability) when administered at the same molar dose (Table 1)4,5. When drugs are bioequivalent, essential similarity is assumed and indeed has been assured by the FDA6. This is defined as satisfaction of the criteria of having the same qualitative and quantitative composition in terms of active substances, of having the same pharmaceutical form, and of being bioequivalent unless it is apparent in the light of scientific knowledge that the medicinal product differs from the original product as regards safety and efficacy4. Paradoxically, the EMEA guideline incorporates two declarations about therapeutic equivalence (Table 1)4, which suggests that pharmaceutically equivalent products can clearly be considered therapeutically equivalent based on bioequivalence studies alone, whereas additional (pre)clinical data may be required for a pharmaceutical alternative to be considered therapeutically equivalent7. These definitions are reflected in the regulatory requirements for application of generic drug products. For pharmaceutical equivalents, these are referred to as abbreviated new drug applications (ANDAs)8. The sponsor of an ANDA must provide information to prove bioequivalence of a pharmaceutically equivalent generic drug product with the reference drug product (Figure 1), which per definition implies therapeutic equivalence8. In contrast, apart from mainly

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narrow therapeutic index (i.e., small difference between minimum effective concentration (MEC) and minimum toxic concentration (MTC); e.g. immunosuppressants, antiepileptics, cardiac glycosides such as digoxin or anticoagulants such as warfarin)12. This is because a relatively small change in systemic concentration can produce marked changes in pharmacodynamic response, in terms of reduced efficacy or the occurrence of adverse events11. Conversely, the EMEA (but not the FDA) allows a prospectively defined broadening of the 90% CI to, e.g. 0.751.33 for Cmax only, in the case of highly variable drugs (i.e., within-subject variability 430%) and lack of toxicity associated with Cmax14,15. The need to evaluate tmax for establishing bioequivalence differs between regulatory bodies. This in part relates to the lack of an agreed statistical approach to the analysis of tmax data which, unlike the continuous variables AUC and Cmax, is a discrete variable dependent upon the sampling schedule defined in the protocol. Thus, in contrast to the FDA, the EMEA only requests tmax statistics in case of a clinically relevant claim for rapid release/action or signs related to adverse events4.

Controversies about interchangeability

The EMEA has made no clear statements surrounding the interchangeability issue of bioequivalent drugs. The FDA has acknowledged that about 20% of innovator and generic drugs available in the US cannot be considered bioequivalent and are therefore not freely interchangeable11. However, somewhat paradoxically, they have stated that there are no documented examples of a generic product manufactured to meet its approved specifications that could not be used interchangeably with the corresponding innovator brand name drug product16. This suggests that physicians need to have no concerns when patients are switched from an innovator product to a generic product or between generic products. However, it may be reasonable to express concerns about switching or interchangeability because of bias in the concept and assessment of bioequivalence, and in the regulatory criteria for therapeutic equivalence, which lead to questioning relative therapeutic quality10.

Issues related to the validity of bioequivalence studies

In general, data from bioequivalence studies are submitted to the health authorities for regulatory purposes
2182 Potential concerns about generic amlodipine maleate

but published very infrequently17. Although these data are usually available either on the website of regulatory authorities or obtainable under the Freedom of Information Act in the US (for US submitted data), their reduced accessibility precludes easy evaluation and peer review by the scientific community. Conclusions about equivalence are in general based on relatively small-scale, single-dose, healthy volunteer studies. Thus, by definition, steady-state concentrations of drugs are not achieved in these studies. For most chronic conditions, however, there is a requirement for maintenance of steady-state drug levels to achieve therapeutic benefit11. In most instances the drug plasma concentrations at steady state are higher with maintenance therapy than those attained after a single dose18 and indeed, in some instances, may be several fold higher. Thus, data are obtained under conditions that may not be (fully) relevant to the practical clinical situation. This could also be an issue since apparently inert compounds (e.g., excipients), impurities and/or potential accumulations of active metabolites might affect the pharmacokinetics of the drug when administered during maintenance therapy11. In addition, the characteristics of a homogenous group of healthy study subjects may differ in such an extent from the target patient population, e.g. elderly people with several co-morbidities and subjected to poly-pharmacy in the treatment of hypertension and/or ischaemic heart disease, that extrapolation may not be justified11. Physiological changes associated with age, interactions with concomitant medication and/or the existence of co-morbidities may affect drug pharmacokinetics. Hence, drug evaluation in healthy persons may not accurately reflect the drugs behaviour in real life clinical practice11. Examples are oral procainamide hydrochloride, of which the absorption differs between healthy persons and patients with acute myocardial infarction (MI)19, and a generic verapamil product that was shown to be bioequivalent to its branded counterpart in young and healthy subjects but not in elderly patients20. Furthermore, the regulatory limits of 0.81.25 for bioequivalence establishment have been criticised since this means that drugs theoretically could differ by about 20% with respect to the extent and/or rate of absorption (Figure 2)1. This is considerably less stringent than the 5% standard for innovator brand name products21. For narrow therapeutic range drugs, these rules can be adapted4,5. Small differences in bioavailability may become a particular issue when the drug is relatively insoluble in water, exhibits non-linear kinetics and/or it concerns a modified-release formulation11,13. In fact there is also a fundamental problem since true bioequivalence implies the same effect (i.e., therapeutic

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14

Mean plasma concentration (ng/mL)

12 10 8 6 4 2 0

Test drug product Cmax 12 ng/mL Reference drug product Cmax 10 ng/mL Test drug product Cmax 8.5 ng/mL

125%

80%

10

12

Time after dose (h)

Figure 2. Illustrative example of the permitted range4,5 for the pharmacokinetic variables (e.g., Cmax) of fictive test drug products

equivalence) of two products in an individual patient13. However, this is not measured in practice since bioequivalence studies measure the mean parameters for the generic and innovator drug products in subject groups, which merely indicate average equivalence in bioavailability13. This approach has been indicated as insufficient for assessing interchangeability22. Other approaches such as the individual or population bioequivalence may be more suitable and accurate11 since these investigate, in addition to the average bioequivalence, the equality of the distribution of bioavailability within (i.e., intra-individual) or across (i.e., interindividual) subjects, respectively11. However, these alternative approaches are not favoured by regulatory authorities and are only allowed under special circumstances23.

Issues related to the regulations concerning therapeutic equivalence

An important consideration with regard to the statement of therapeutic equivalence based on bioequivalence assessment only is that excipients do not necessarily need to be identical. However, it has been clearly established that excipient selection plays an important role in product stability and performance1 and, as such, differences in excipients could lead to a distinct therapeutic and safety/tolerance profile11,24. In addition, some differences related to the operating conditions in the manufacturing process, e.g. the compression pressure and type of machine (alternative or rotating), can have a marked impact on the shelf-life of drug tablets1. These changes are unlikely to be detected by bioequivalence studies. It is well recognised that not all drugs within the same therapeutic class are interchangeable with respect

to outcome25. Whilst this lack of interchangeability may be associated with a number of factors, it is reasonable to suggest that this principle may also be applicable to generics and innovator drugs. For example, all antihypertensive drugs are licensed on the basis that they lower blood pressure (BP) and it is assumed that for any given identical BP reduction they will be equivalent by way of influencing hard endpoints, i.e. reducing the risk of (non-) fatal stroke, MI and heart failure. However, this assumption may not hold good if, for example, a generic contains an alternative salt form of the drug. It has thus been proposed to determine interchangeability of drugs in (long-term) head-to-head comparisons using the occurrence of clinical events as the primary endpoint25. In that regard, while it is not necessarily directly applicable to all generic products, it is worthy of note that the regulatory requirements for biosimilars (i.e., follow-on biologics, generics of biotechnology-derived medicinal products) may be more suitable for generics than the current guidelines. Guidance documents for biosimilars, issued by EMEA, advocate pre-clinical and clinical testing prior to market authorization26.

Salt form of a drug as critical factor

Alternative salts of approved drug substances are considered as new chemical entities by the EMEA and FDA7. Nevertheless, the registration procedure for those medicinal products may be facilitated by the use of previous (clinical) experience with the salt type, under certain conditions7. An abbreviated application, popularly known as the 505 b(2) filings (or the hybrid NDA), can be submitted when it is known that
Potential concerns about generic amlodipine maleate Meredith 2183

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the alternative salt type does not lead to a change in the pharmacokinetics, pharmacodynamics and/or toxicity of the active substance, which could change its efficacy and/or safety profile7. Approximately half of all active substances for therapeutic use are administered as salts (instead of free bases or acids)7. Synthesis of alternative salt forms of a drug is a well-known method for optimising its physicochemical properties, such as solubility, hygroscopicity, (thermal) stability, dissolution, flowability, degradation pathways, etc., without modifying its structure7. However, because these characteristics determine how the drug is handled by the body, it needs to be emphasised that the salt may also affect the drugs biological characteristics (pharmacokinetics and pharmacodynamics) and as such its clinical and other performances27. To date, there is no reliable way of predicting exactly the effects of changing the salt form of an active substance27. Generic drug product manufacturers often incorporate a different salt of an approved innovator drug in order to submit a special ANDA7 containing bioequivalence data, and obtain market approval prior to patent expiry of the innovator drug28. It is reasonable to suggest that these generic drugs should not automatically be regarded as pharmaceutical equivalents of the innovator drug but as pharmaceutical alternatives, i.e. a distinct chemical entity of the same active substance. It would logically follow that therapeutic equivalence for those generic drugs cannot be established on bioequivalence data alone and additional pre-clinical and/or clinical data may be required before they can be routinely applied in clinical practice7.

gastrointestinal irritation and ulceration by particular salt forms of alprenolol in an animal oesophageal test model were attributable to a higher solubility31. Changing salt forms may also affect drugdrug interactions as shown by the analgesic propoxyphene hydrochloride, which caused aspirin instability27.

Impact on stability and optimal formulation

The hygroscopicity and hydrophobicity of a salt may affect the stability of the active drug moiety, particularly when the drug is susceptible to hydrolytic degradation27. Furthermore, a low melting point of a particular salt may result in plastic deformation of the drug and subsequent caking or aggregation of the active substance7. This negatively affects the dose uniformity and other characteristics of solid dosage forms and hence, may be critical for the optimal formulation and large-scale manufacturing7.

Impact on the development of impurities with biological activity

Chemical impurities associated with the synthesis process of a particular drug salt or resulting from instability may produce intrinsically toxic effects upon drug use7. Therefore, the impurity concentration in drug products needs to stay below the International Conference on Harmonisation (ICH) safety qualification thresholds32,33. Instability associated with changing the salt form of a drug is exemplified by amlodipine maleate (Figure 3)11. Unlike the besylate salt (Figure 3), amlodipine maleate undergoes degradation, which results in the formation of chemical impurities7. One of them is formed by Michael addition of the unsaturated maleic acid with the primary amine group of amlodipine7. This reaction occurs during the salt-formation step of the active
(a)

Impact on absorption, tolerability and safety

Solid-state polymorphism, defined as the ability of the drug to exist in distinct ordered arrangements and/or conformations of the molecules in the crystal lattice, can have an impact on bioavailability due to solubility changes29. Salts differ in their aqueous solubility and dissolution rate, which affects the in vivo absorption characteristics of the drug and, in turn, its pharmacokinetics and biological properties27. While this underscores the need for bioequivalence studies, those studies may not detect tolerability or safety problems. For example, the conjugate anions or cations from salt-forming agents may react with salts and induce toxic effects7. This was apparent in pre-clinical toxicity studies where nephrotoxicity with pravadoline maleate was observed and this was attributed to the formation of maleic acid by the maleate anion30. Changing the salt form can also have other unpredictable effects. For example,
2184 Potential concerns about generic amlodipine maleate

Cl MeOOC N H

COOEt O

COO COO

NH3+

(b)
O Cl MeOOC N H COOEt O S O O

NH3+

Figure 3. Chemical structures of (a) amlodipine maleate and (b) amlodipine besylate

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ingredient, as well as during manufacturing and storage of the drug product34. Stability studies with experimental formulations demonstrated that up to 2% of this impurity was formed34. Although the clinical significance is unknown, this impurity has a demonstrated biological activity that is distinct from amlodipines34. Ligand-binding and enzymatic tests on the pure (499%) degradation product (at 100 nM) showed a range of molecular and tissue effects, which included depression of contraction of isolated heart tissue34. In addition, high-performance liquid chromatography analysis revealed six impurities, ranging from 0.43 to 1.42%, in a laboratory batch of amlodipine maleate bulk drug35. Furthermore, two major degradation products were detected after stressing commercial (un)packaged amlodipine maleate tablets but not amlodipine besylate tablets, which supports a distinct stability profile between both preparations36. Consequently, this unique and intrinsic instability and the resulting (biologically active) degradation products of amlodipine maleate militate against the presumed equivalence of maleate and besylate salts of amlodipine7. The new impurities and degradation products that could arise as a consequence of changing the salt form of a drug could potentially also possess genotoxic properties. The EMEA Committee for Medicinal Products for Human Use has recently issued a guideline on the limits of genotoxic impurities37. This guideline describes a general framework and practical approaches on how to deal with genotoxic impurities in new active substances. While the subject of a change in the salt form of an existing active substance/authorised product is not explicitly addressed, the guideline does relate to new applications for existing active substances (i.e., where assessment of the route of synthesis, process control and impurity profile does not provide reasonable assurance that no new or higher levels of genotoxic impurities are introduced as compared to products currently authorised in the EU containing the same active substance) and to variations to existing marketing authorisations. The situation in the US, Canada and Japan is unclear as similar guidelines do not currently exist.

reducing systemic BP38,39. Besides its action as peripheral and coronary vasodilator38, it relieves angina as well by, as yet, partly elucidated mechanisms, including reduction of the myocardial oxygen demand and coronary tone/spasm leading to restoration of myocardial blood flow38,39. Amlodipine was eventually developed by Pfizer as a besylate salt and is marketed in tablet form for oncedaily administration (2.5510 mg) under the trade names Norvasc (US, most countries in Europe), Istin (UK, Ireland) and Amlor (Belgium, France) since 1992. These amlodipine products are indicated for the treatment of hypertension, chronic stable angina and vasospastic (i.e., Prinzmetals or variant) angina3942. The clinical profile of amlodipine has been extensively studied, in the development phase as well as post-approval, with respect to its pharmacology and long-term safety and efficacy including hard endpoints. This safety and efficacy database is almost exclusively associated with amlodipine besylate with a relative paucity of data for other salt forms. A recent meta-analysis showed superiority of amlodipine besylate over other antihypertensive drugs or placebo in CV protection against stroke (odds ratio 0.81, p50.0001 and 0.63, p 0.06, respectively)43. Significant risk reductions by amlodipine besylate treatment were also found for MI as outcome43. The results are very compelling in that they are based on more than 78 000 patients and cover the two largest trials in hypertension, ALLHAT and ASCOT43. So far, the database documenting the clinical experience for amlodipine besylate includes over 600 000 randomised patients in approximately 800 clinical studies44.

Comparison of amlodipine maleate with amlodipine besylate

The patent for amlodipine expired in most European countries in 2004, while its patent in the US lasted to 2007. Despite this patent protection, a number of generic amlodipine maleate-containing products became available throughout Europe (Germany, Sweden, UK, etc.)45,46, Korea47 and South Africa48, but not in the US. Since 2007, generic formulations of amlodipine besylate have also been introduced worldwide. The original development process for the drug amlodipine was initiated with the maleate salt form but this was eventually discontinued because of a number of concerns including inherent instability7,34 and tablet manufacturing issues (problems with adhesion to tabletting machinery)34,49. Published reports of nephrotoxicity of maleic acid in rodents were also taken into account50,51. Toxicity was later confirmed by animal studies with maleate alone and pravadoline maleate30,52 (see also Impact on absorption,
Potential concerns about generic amlodipine maleate Meredith 2185

The historical perspective of amlodipine besylate versus amlodipine maleate

Clinical evidence with amlodipine besylate
As a dihydropyridine-type calcium antagonist, amlodipine acts by relaxing the vascular smooth muscles, decreasing peripheral vascular resistance and hence

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Table 2. Outcome of one bioequivalence study between amlodipine besylate (Norvasc) and amlodipine maleate17
Variable Amlodipine besylate (Norvasc) 328.85 7.28 Amlodipine maleate 312.04 7.21 90% CI ratio 0.851.06 0.761.06 Significance level p 0.42 p 0.88

Mean AUCt (hng/g) Mean Cmax (ng/g)

tolerability and safety). This historical perspective provides compelling support for concerns regarding the presumed safety of commercial amlodipine maleate formulations in humans and for the need for thorough clinical investigations of its therapeutic use. Only a limited number of bioequivalence studies have been performed with amlodipine maleate, of which only one has been published17. There are two published clinical reports on the efficacy and safety of an amlodipine maleate formulation in patients with essential hypertension47,53 but with no equivalent studies in stable coronary artery disease. An open-label, randomised, two-period cross-over trial investigated the bioequivalence of a single dose of 10 mg amlodipine maleate (from Omicron Pharma) versus amlodipine besylate (Norvasc from Pfizer) in 24 healthy volunteers (aged 2445 years) over a 144-h period17. Based on the absence of a statistically significant difference in the values of AUC and Cmax between both formulations and because the CI limits for amlodipine maleate (Table 2) fell within the accepted ranges by EMEA (applying wider limits for Cmax of 0.751.33), this formulation was considered bioequivalent to Norvasc. The authors of this study suggested that both salt forms could be used interchangeably in clinical practice because the plasma kinetics of amlodipine would depend on the properties of the molecule itself. However, it should be noted that the two salt forms would not be considered bioequivalent in the US, where the broader range for Cmax (0.751.33) of highly variable drugs14,15 as applied in this study, would not be acceptable. In addition, since plasma concentrations of amlodipine have been shown to be much higher under steadystate conditions18 and because high BP often affects elderly persons (in whom the pharmacokinetics of amlodipine were found different54,55), there is a cogent argument to suggest that bioequivalence should have been evaluated in multiple-dose studies in elderly patients. The efficacy and safety of both amlodipine besylate and maleate were assessed in two multi-centre, randomised controlled trials. An 8-week, double-dummy, non-inferiority study in Korean patients (n 118) by Park et al.47 compared Norvasc (from Pfizer) with amlodipine maleate from undisclosed origin.
2186 Potential concerns about generic amlodipine maleate

(a)
Change in siDBP (mmHg) compared to baseline in ITT population
2 months n = 117 RCT47 3 months n = 245 RCT53

9 months n = 202 openlabel extension study53

0 2 4 6 8 10 12 14 16 18 20
p eq p = 0.322

0.001

Amlodipine besylate

Amlodipine maleate

(b)
Amlodipine besylate Incidence of adverse events (%) in ITT population 45 40 35 30 25 20 15 10 5 0 2 months n = 117 double-dummy RCT47 3 months n = 245 double-blind RCT53
p = 0.169

Amlodipine maleate
p > 0.05

Figure 4. Outcome of short-term (a) efficacy and (b) safety comparisons between amlodipine maleate and besylate (510 mg) in two multi-centre, double-blind, randomised controlled trials47,53. ITT, intention-to-treat; RCT, randomised controlled trial; siDBP, sitting diastolic blood pressure

A 6-month, open-label, non-comparative extension study after a 3-month double-blind set-up in Polish patients (n 250) by Makowiecka-Ciesla et al.53 studied Norvasc (Pfizer) and Tenox (Krka d.d., Slovenia). Both studies included patients with mild-to-moderate hypertension and applied a washout period of 2 weeks (with or without placebo) after which patients received 510 mg once daily of either amlodipine besylate or amlodipine maleate47,53. In the study by Park et al.47, amlodipine maleate was considered noninferior to amlodipine besylate according to prespecified criteria related to sitting diastolic BP values (Figure 4a). The non-inferiority margin was arbitrarily

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set at 4 mmHg for diastolic BP. This value is not based upon an established regulatory precedent and, based upon epidemiological evidence, it could be that such a CI could include BP differences that are clinically relevant for CV outcomes56. Indeed, based upon a meta-analysis of 61 cohort studies supported by a meta-analysis of 147 randomised trials, it can be predicted that a 4 mmHg difference in diastolic BP may be associated with a difference in coronary heart disease events of 20% and a difference in stroke events of 29%57. Furthermore, although not statistically significant, a greater proportion of amlodipine besylate-treated patients obtained adequate BP control (92%) compared to amlodipine maleate (86%). A comparable antihypertensive efficacy of the two formulations was found after 3 months in the study by Makowiecka-Ciesla et al. (Figure 4a)53. Although a statistically significant increase of 0.9 mmHg in BP was seen over the last 6 months with amlodipine maleate (p50.01 for diastolic BP and p50.05 for systolic BP), there was no relevant rise in comparison with baseline values (Figure 4a)53. Safety comparisons in both studies revealed no statistically significant differences between amlodipine maleate and amlodipine besylate (Figure 4b)47,53. However, comparative adverse event recording was only performed up to 3 months47,53. The lack of statistical differences in both studies led the authors to conclude that amlodipine maleate may be an alternative for amlodipine besylate47,53. However, the firm inclusionexclusion criteria, the limited number of patients and the lack of long-term evaluations (43 months) question any generalisation of amlodipine interchangeability. In fact, to establish therapeutic equivalence or non-inferiority of drugs for their antihypertensive effect, a parallel group study with in excess of 600 patients studied for at least 6 months would be required. In addition, because the impact of antihypertensive drugs on hard endpoints (such as the reduction of stroke and MI) is the most important treatment goal, their therapeutic equivalence in these outcomes would best be evaluated in large, long-term, head-to-head clinical studies. One such long-term (median 4.4 years) study was conducted with amlodipine maleate in combination with nutritional-hygienic intervention of randomised, double-blind, placebocontrolled design58. However, the publication reported pooled incidences of major CV events for all antihypertensive study groups in comparison to placebo, which precludes evaluation of amlodipine maleate separately. Furthermore, it remains to be established whether amlodipine maleate is therapeutically equivalent to amlodipine besylate as anti-anginal drug (i.e., alleviating ischaemic pain).

Conclusions
Despite the fact that regulations regarding bioequivalence and therapeutic equivalence have been in place for decades, controversies continue to arise about the presumed interchangeability of generics and innovator drug products based on the criterion of essential similarity. Bioequivalence, as defined by European and American regulatory authorities, implies but does not necessarily guarantee therapeutic equivalence. This may be associated with a number of factors, including the permitted range of bioavailability for generics and the short-term evaluation in a small, young and healthy population. Most importantly, the fact that there is no need for clinical efficacy data with, in case of lifethreatening diseases, hard endpoints or for proof of long-term safety debates the validity of the current criteria and could set patients at risk. It is often suggested that there are no well-documented instances in recent times where problems have arisen with generic products that have been approved by the major licensing authorities. It is acknowledged that some of the concerns raised are not universally applicable to all generic products. Nonetheless, it should also be recognised that, by definition, the only advantage of a generic product is one of cost. While this is clearly of major importance to healthcare delivery throughout the world, it is not a justification for failing to consider the application of complementary approaches59, such as the use of population pharmacokinetics in the target population, to provide further reassurance as to the suitability of alternative generic products. Although generics and their innovator counterparts must contain identical amounts of active substance in the same route of administration as well as meet the same applicable standards for strength, quality, purity and identity, they may differ in, for example, excipients, which are presumed but not proven inert. In addition, despite the allowance of an abbreviated application procedure for alternative salts of marketed drugs, changing the salt form may change the product profile, as has been demonstrated by numerous examples, including amlodipine besylate (innovator) versus maleate (generic variant). Although both formulations have been shown (per definition) bioequivalent in some studies, no long-term clinical head-to-head investigation has been performed as yet. Moreover, due to the (potential) animal nephrotoxicity of maleic acid/maleate and/or biological activity of impurities as a result of degradation or other processes, one has to be aware of untoward clinical implications of amlodipine maleate preparations. More research may be needed to establish true therapeutic comparability and justify switching
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patients from amlodipine besylate to amlodipine maleate.

Transparency
Declaration of funding This study was funded by an unrestricted grant from Pfizer. Although Pfizer was given the opportunity to review the manuscript, the author felt no obligation to address any comments; the views expressed are those of the author and not those of the involved company. Declaration of financial/other relationships P.M. has disclosed that he is a recipient of honoraria for consultancy, advisory board attendance and speaker fees from a number of pharmaceutical companies, including AstraZeneca, Bayer, Boehringer Ingelheim, GSK, MSD, Pfizer and Takeda. All peer reviewers receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed that he/she is a former employee and shareholder of AstraZeneca. Peer Reviewer 2 has disclosed that he/she has been a recipient of grant support from the Attorney General Prescriber and Consumer Education Grant Program. Acknowledgement The author acknowledges medical writing assistance from Ismar Healthcare NV and the unrestricted grant from Pfizer.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com Article CMRO-5021_3, Accepted for publication: 12 June 2009 Published Online: 14 July 2009 doi:10.1185/03007990903116867

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