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Abstract

Generic drugs: Th e benefi ts and risks of making the switch When is it safe to substitute a generic drug for a brand-name medication, and when should a switch be avoided? Here's a look at the evidence. E ach year, Americans save an estimated $8 billion to $10 billion at retail pharmacies by purchasing generic drugs rather than brand-name medications, the US Food and Drug Administration (FDA) reports. 1 Th e lower cost, of course, is the key advantage of generics. But the very reason for the cost savings—the fact that generic drugs do not have to undergo the large, expensive clinical trials that are required for approval of brand-name medications—gives rise to questions about the quality and safety of generics. Are these concerns justifi ed? Under what circumstances is it safe to prescribe generics, or to substitute a generic for a brand-name drug? Are brand-name drugs always better? To answer these questions, we conducted a thorough evidence review, which included numerous randomized controlled trials (RCTs) and case reports, as well as a single meta-analysis that assessed the benefi ts and risks of generics. Generics: On the positive side Safety and effi cacy. Our literature search yielded little evidence that generic drugs are less safe or less eff ective than their brand-name equivalents. Th e meta-analysis, for example , 2 included 47 studies (38 of 47 were RCTs) covering 9 subclasses of cardiovascular medications. In trials involving beta-blockers, diuretics, calcium channel blockers, antiplate-let agents, statins, angiotensin-converting enzyme inhibitors, and alpha-blockers, no evidence of superiority of brand-name drugs vs generics was found. 2 ❚ Cost. Generic drugs typically cost 30% to 60% less than their brand-name counterparts, 3 and widespread use of ge-nerics has the potential to reduce the price of other brand-name drugs by creating more competition.
634 THE JOURNAL OF FAMILY PRACTICE
|
NOVEMBER 2010
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VOL 59, NO 11
Generic drugs:
e bene ts and risks
of making the switch
When is it safe to substitute a generic drug for a brand-
name medication, and when should a switch be avoided?
Here’s a look at the evidence.
Each year, Americans save an estimated $8 billion to
$10 billion at retail pharmacies by purchasing generic
drugs rather than brand-name medications, the US
Food and Drug Administration (FDA) reports.1 e lower
cost, of course, is the key advantage of generics. But the very
reason for the cost savings—the fact that generic drugs do not
have to undergo the large, expensive clinical trials that are re-
quired for approval of brand-name medications—gives rise
to questions about the quality and safety of generics.
Are these concerns justi ed? Under what circumstances
is it safe to prescribe generics, or to substitute a generic for a
brand-name drug? Are brand-name drugs always better? To
answer these questions, we conducted a thorough evidence
review, which included numerous randomized controlled tri-
als (RCTs) and case reports, as well as a single meta-analysis
that assessed the bene ts and risks of generics.
Generics: On the positive side
Safety and ef cacy. Our literature search yielded little evi-
dence that generic drugs are less safe or less e ective than
their brand-name equivalents.  e meta-analysis, for ex-
ample,2 included 47 studies (38 of 47 were RCTs) covering
9 subclasses of cardiovascular medications. In trials involving
beta-blockers, diuretics, calcium channel blockers, antiplate-
let agents, statins, angiotensin-converting enzyme inhibitors,
and alpha-blockers, no evidence of superiority of brand-
name drugs vs generics was found.2
Cost. Generic drugs typically cost 30% to 60% less than
their brand-name counterparts,3 and widespread use of ge-
nerics has the potential to reduce the price of other brand-
name drugs by creating more competition.
Another plus: Patients taking generic drugs appear to be
Pawel Lewek, MD;
Przemyslaw Kardas,
MD, PhD
The First Department of
Family Medicine, Medical
University of Lodz, Poland
pawel.lewek@umed.
lodz.pl
Dr. Kardas reported that he
receives research support from
Polpharma SA and serves as
a consultant to Boehringer
Ingelheim, Egis
Pharmaceuticals, and
Polpharma SA. Dr. Lewek
reported no potential con ict of
interest relevant to this article.
PRACTICE
PRACTICE
RECOMMENDATIONS
RECOMMENDATIONS
Do not authorize the phar-
macy to switch patients from
a brand-name antiepileptic
drug to a generic without
your approval. C
Use caution when switch-
ing a patient to a generic
modi ed-release formulation,
which may not have the same
pharmacokinetic pro le as its
brand-name counterpart. C
Consult the FDAs
Orange Book: Approved Drug
Products with  erapeutic
Equivalence Evaluations,
available at http://www.
accessdata.fda.gov/scripts/
cder/ob/default.cfm for details
on generic substitution. C
Strength of recommendation (SOR)
G ood-quality patient-oriented
evidence
Inconsistent or limited-quality
patient-oriented evidence
Consensus, usual practice,
opinion, disease-oriented
evidence, case series
A
B
C
635
JFPONLINE.COM VOL 59, NO 11 | NOVEMBER 2010 | THE JOURNAL OF FAMILY PRACTICE
more willing to continue therapy than those
taking brand-name medications.4 Lower co-
pays are a key factor. In 1 recent study of pa-
tients with hypercholesterolemia or diabetes,
those taking generics had greater adherence
compared with patients receiving brand-
name drugs.5
Quality. It is important to note that
many generic medications are produced
under the license of the manufacturer of
the original brand-name product, with the
lower-cost equivalent often introduced after
the drug’s patent has expired. Even when dif-
ferent manufacturers produce the branded
product and the generic, strict standards ex-
ist to guarantee the quality of generic drugs.
The journey to market—
the similarities, the differences
Both brand-name and generic medications
undergo similar new drug application (NDA)
procedures.  e manufacturers of both are
required to submit detailed evidence of the
chemistry, manufacturing, controls, labeling,
and testing processes. From there, brand-
name and generic products take divergent
paths to market.
New nongeneric drugs must undergo
rigorous animal and human studies, includ-
ing large RCTs comparing the e cacy of the
new product with that of a placebo and care-
fully tracking side e ects. Bioavailability test-
ing is required, as well. For generic drugs, the
process is known as an abbreviated new drug
application (ANDA), and bioequivalence
studies are su cient.1,6
e bioequivalence studies required for
a new generic are based on pharmacokinetic
parameters, most notably, the area under
the plasma concentration curve (AUC)—a
measure of overall drug exposure—and the
maximal plasma concentration (Cmax). If AUC
and Cmax are within an acceptance range
(0.80–1.25 of the brand-name product pa-
rameters), the therapeutic equivalence of a
generic drug is substantiated.7,8
Concerns about testing,
formulation
Opponents of widespread use of generics
point out that they are tested on only a few
young, healthy individuals, compared with
the large numbers of patients who participate
in clinical trials of the original drug.
Bioequivalence
According to guidelines from the World
Health Organization (WHO), 18 to 24 healthy
TABLE
Generic substitution of antiepileptic agents:
Where the American Academy of Neurology stands18
The AAN opposes:
generic substitution of anticonvulsant drugs for the treatment of epilepsy without the attending
physician’s approval.
generic substitution of anticonvulsants for patients with epilepsy at the point of sale without prior
consent of both the physician and the patient.
state and federal legislation that would impede the ability of physicians to determine which
anticonvulsant drugs to prescribe for the treatment of patients with epilepsy.
The AAN believes:
formulary policies should recognize and support physician autonomy in prescribing, and patients in
accessing, the full range of anticonvulsants for epilepsy.
The AAN supports:
legislation that would require informed consent of physicians and patients before generic
substitutions of anticonvulsants are made at the point of sale.
The AAN recognizes:
that different strategies may be appropriate in using anticonvulsants for the treatment of
conditions other than epilepsy. According to the
World Health
Organization,
18 to 24 healthy
adult volunteers
are generally
considered
suf cient for a
bioequivalence
study.
636 THE JOURNAL OF FAMILY PRACTICE | NOVEMBER 2010 | VOL 59, NO 11
In a study
comparing
Tegretol with
3 generic
formulations of
carbamazepine,
1 of the generics
was not
bioequivalent.
adult volunteers are considered su cient for
a bioequivalence study.9 e number of par-
ticipants may be greater, however, if absorp-
tion or clearance of the drug is highly variable.
What’s more, the people who volunteer for
generic drug studies cannot smoke or take
concurrent medication. To exclude the pos-
sibility that food coadministration a ects the
generic medication being studied, the FDA
further recommends bioequivalence test-
ing of oral formulations on volunteers eating
standardized meals.8 ese criteria help min-
imize the magnitude of intersubject variabil-
ity and reduce the possibility of bias—which
could be caused by the disease process, con-
current conditions, or medication interac-
tion, rather than by formulation di erences.8
To further minimize the effects of
nondrug-related variation, bioequivalence
studies typically use a crossover design: Half
the subjects receive the test drug  rst, fol-
lowed by the brand-name product, with a
washout period in between.  e other half re-
ceive the drugs in reverse order.10 ( e study
format is altered, as needed, for extended-
release products, topical agents, and drugs
that are not absorbed systemically. A gener-
ic version of cholestyramine, for example,
which acts by sequestering bile salts within
the intestine, would be approved on the basis
of in vitro studies that quantify the binding of
the bile salts.10)
But does this testing mimic the real
world? While possible confounding factors
are controlled for in bioequivalence studies
of generics, critics point out that this is not
the case in the real world.  us, they worry
that when generics are taken by patients
with actual illnesses, concurrent use of other
medications, medical conditions, and the
like may result in di erences in treatment
that did not occur in the highly controlled
environment in which the equivalency stud-
ies were conducted.11
Differences in formulation
Another concern centers on formulation dif-
ferences, which have the potential to a ect
patients taking generic drugs. A generic copy
of a brand-name drug must contain the same
active ingredient, in the identical quantity, as
the branded product—in the same dose for-
mulation and route of administration. It must
also meet standards for strength, purity, qual-
ity, and identity.11
However, the inert ingredients in the ge-
neric version do not have to be the same as
those in the brand-name drug (although the
ratio of inert to active compound must be
similar).12 Because drugs tested in bioequiva-
lence studies are administered in single dos-
es, many experts wonder whether the inert
compounds used in the generics may a ect
the distribution, metabolism, or absorption
of a drug when it is administered in multiple
doses, or whether the serum concentration of
the generic drug may be elevated when it is
taken for long periods.
Proceed with caution
in these situations
For most patients taking most medications,
generic drugs pose no problems, and provide
an opportunity to obtain the same therapeu-
tic bene t at a considerably lower cost. How-
ever, making the switch with certain classes
of drugs, and with drugs that have a narrow
therapeutic range, poses potential problems
and must be done with caution—if at all.
Antiepileptic drugs. e FDA indicates
that many people who are on antiseizure
medications re-experience seizures despite
continued treatment,1 and that switching to a
generic does not increase the risk of treatment
failure.1,13 Nonetheless, there are numerous
reports of di erences between generic and
brand-name antiseizure medications (and
small studies indicating improper seizure
control after switching patients from a brand-
name to a generic antiepileptic drug).14
For example:
Researchers compared the pharmacoki-
netic parameters of Tegretol with 3 generic
formulations of carbamazepine, and found
that 1 of the 3 was not bioequivalent.15
In a crossover study of 18 healthy volun-
teers, 3 generic formulations of carbam-
azepine were all within the acceptable
bioequivalence range, but were absorbed
more rapidly than the brand-name drug.16
Di erences in the bioavailability of brand-
name and generic products have also
been reported with phenytoin, primi-
638 THE JOURNAL OF FAMILY PRACTICE | NOVEMBER 2010 | VOL 59, NO 11
Generic
formulations
of amitriptyline/
perphenazine
and venlafaxine
may not be
interchangeable,
according to
the FDA.
done, and valproic acid, but the di er-
ences were not statistically signi cant.17
e American Academy of Neurology
has issued a set of recommendations con-
cerning the use of generic antiepileptic drugs
(TABLE).18
Narrow therapeutic ratio. e poten-
tial for complications increases in drugs with
a narrow therapeutic ratio, de ned by the
FDA as <2-fold di erence between the medi-
an lethal dose and the median e ective dose,
or between the minimum toxic concentra-
tion and minimum e ective concentration in
the blood.19 e safe and e ective use of such
drugs—carbamazepine, divalproex, lithium,
phenytoin, and warfarin, to name a few—
requires careful dosage titration and patient
monitoring.
Water solubility and nonlinear phar-
macokinetics may present problems in
drugs with a narrow therapeutic ratio,
especially phenytoin.2 e drugs serum
concentration is allowed to range from 8 to
20 mg/L. A concentration above this range
increases the risk for acute cerebellar syn-
drome, delirium, and coma; a concentration
below the range may cause seizures.12
Warfarin is also of particular concern, as
there is always the possibility that a switch
from Coumadin to a generic equivalent could
result in under- or overcoagulation. However,
studies have shown that the use of generic
warfarin in patients previously receiving
Coumadin did not a ect the international
normalized ratio more than continued use of
the brand-name anticoagulant.20,21
Psychotropic agents. ere has been
a number of case reports of problems occur-
ring following a switch from a brand-name
antidepressant to a generic—or from 1 ge-
neric antidepressant to another. (See “Did
a switch to a generic antidepressant cause
relapse?” J Fam Pract. 2008;58:109-114.) In
fact, the FDA cites some psychotropic drugs
for which generic formulations may not be
interchangeable—including amitriptyline/
perphenazine and venlafaxine—and others
for which generic formulations may not be
bioequivalent at all doses.22
Thyroid medication. ere are also
concerns about levothyroxine (LT4) admin-
istration, and major medical societies debate
the use of generic substitution. According to a
recent survey from the American Association
of Clinical Endocrinologists, the American
yroid Association, and  e Endocrine Soci-
ety, clinical use of generic LT4 continues to be
associated with adverse outcomes.23 Most of
the adverse events (89%) reported by survey
respondents were associated with a change,
either from a brand-name drug to a generic
or from 1 particular generic LT4 to another.
Modi ed-release formulations
may also pose a problem
Problems may also occur with generics in
modi ed-release formulations, which may
not have the same pharmacokinetic pro les
as their brand-named counterparts.  e
British National Formulary has advised that
prescriptions for modi ed-release diltiazem
hydrochloride, nifedipine, and theophylline
be  lled with the brand-name drug only.24,25
Morever, a recent study concluded that
2 modi ed-release products of methylpheni-
date and nifedipine had concentration pro-
les that strongly diverged during the period
of absorption, although the formulations met
the regulatory criteria for bioequivalence. 26
The type of salt used to form a com-
pound is also important. Salt-joining makes
a hydrophobic molecule hydrophilic; the
result, especially in psychoactive drugs, is
improved kinetics, absorption, or physico-
chemical properties (eg, stability, hygro-
scopicity,  uidity).27 is may be the reason
for di erences identi ed between generic
and brand-name amitriptyline, nortripty-
line, desipramine, and trimipramine.28 To
avoid problems, physicians should prescribe
generics containing the same salt as their
brand-name counterparts.
When in doubt …
Brand-name drugs are, and always will be,
the best proven therapy, because of the
number and extent of clinical trials they go
through. In most cases, however, there is
no evidence-based reason to avoid generic
substitution for patients who cannot a ord
the brand-name drug. When in doubt, con-
sult the FDAs Orange Book: Approved Drug
Products with  erapeutic Equivalence Eval-
640 THE JOURNAL OF FAMILY PRACTICE | NOVEMBER 2010 | VOL 59, NO 11
Clinical use of
generic LT4
continues to be
associated with
adverse
outcomes.
uations, available at http://www.accessdata.
fda.gov/scripts/cder/ob/default.cfm, before
making a switch.
JFP
J FP
CORRESPONDENCE
Pawel Lewek, MD, The First Department of Family
Medicine, Medical University of Lodz,60 Narutowicza
Street, 90-136 Lodz, Poland; pawel.lewek@umed.lodz.pl
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... Although many generic drugs have been shown to be as safe and effective as brand-name medications, randomized controlled trials are required for each drug to confirm that this is the case [6]. AEDs are a type of generic medications that may require more attention on using generic medications due to increasing risk of treatment failure [6]. ...
... Although many generic drugs have been shown to be as safe and effective as brand-name medications, randomized controlled trials are required for each drug to confirm that this is the case [6]. AEDs are a type of generic medications that may require more attention on using generic medications due to increasing risk of treatment failure [6]. Generic carbamazepine may not be equal bioequivalent with the brandname one [6]. ...
... AEDs are a type of generic medications that may require more attention on using generic medications due to increasing risk of treatment failure [6]. Generic carbamazepine may not be equal bioequivalent with the brandname one [6]. Although there has been a generic version of IV LEV (Focale Ò ) available for several years, there have been few clinical studies comparing it with brand-name IV LEV (Keppra Ò ). ...
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Introduction Intravenous levetiracetam (IV LEV) is approved for treatment status epilepticus (SE). However, the drug’s high cost must be considered when deciding on a treatment strategy. This study aimed to compare the efficacy of brand-name and generic IV LEV for acute repetitive convulsive seizure (ARCS) or SE. Methods Forty patients aged 18 years or older who had been diagnosed with SE or ARCS were included in this double-blind study. Patients were randomly assigned at a 1:1 ratio (via computer-generated code) to receive either brand-name or generic IV LEV. The primary outcomes were seizure control and the number of seizure exacerbations during the 24 h after drug administration, while the secondary outcomes were electroencephalographic (EEG) findings, serious adverse events, and clinical outcome at hospital discharge. Results Forty patients were randomly assigned administration with either brand-name IV LEV (10 SE and 10 ARCS patients) or generic IV LEV; 7 SE and 13 ARCS patients). There was no significant difference in patients’ baseline characteristics. The seizure control rate was 75% in the brand-name IV LEV group and 65% in the generic IV LEV group (p value: 0.490). Five (25%) patients in the brand-name IV LEV group, and six (30%) patients in the generic IV LEV group developed seizure exacerbations within 24 h after drug administration (p value 0.723). There were no reports of drug-related adverse events. Two of the patients taking brand-name IV LEV and one taking the generic IV LEV died (p value > 0.999). Conclusion Treatment with the generic IV LEV had comparable outcomes with brand-name IV LEV. The generic IV LEV may be an alternative medication for the treatment of SE and ARCS to reduce treatment costs. Trial Registration TCTR20190513001. Funding Great Eastern Drug Company.
... Before registration, as with all medicines, including original medicines, a generic medicine must pass a rigorous registration process and stringent requirements to ensure its quality, safety and efficacy, and it must meet all the required standards (Wonga et al., 2014). According to Kardas and Lewek (2010), generic medications are produced under the license of the original medicine manufacturers. This implies that there should be similarity with original medicines so that the quality, safety and efficacy of the generic medicine are not compromised. ...
... Despite the bioequivalence of generic medicines, they are estimated to be between 10 and 90% cheaper than the original medicines in many countries (Fraeyman et al., 2015;Dylst et al., 2013;Zeng, 2013;Bera and Mukherjee, 2012;Kardas and Lewek, 2010). They are cheaper because their preproduction does not involve research and development costs, as is the case with original medicine (Ahire et al., 2013). ...
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Purpose – Cheaper generic anti-retroviral medicines are encouraged and often prescribed in South Africa for HIV/AIDS treatment. However, the medicines’ acceptance rate is relatively low. This has been attributed to inadequate brand knowledge of the bioequivalence of generic medicines. Studies have examined how brand knowledge structure lead to purchase. The contributions of brand relationship builders (i.e., trust and satisfaction), which are indicators of sustainable purchase are rarely considered. This study adapted Esch, Langner, Schmitt and Geus’ (2006) brand knowledge structure and relationship model to examine the impact of South African young adults’ brand knowledge structure (brand awareness, brand image and brand beliefs) and trust on brand satisfaction and purchase. Design/methodology/approach – Cross-sectional data was quantitatively collected from 207 young adults through self-administered, paper-based questionnaires. Data was analysed with structural equation modelling. Findings – Brand awareness, image, trust and belief in efficacy positively influenced purchase. All these factors, except brand awareness, positively led to satisfaction. The tested adapted model explained 53.0% and 58.5% variances of purchase and brand satisfaction respectively. Practical implications – Considering how much brand knowledge structure and trust explained purchase and satisfaction from the tested model, South African government, pharmaceutical marketers and consumer interest groups should educate young adults about the bioequivalence, safety and efficacy of generic medicines. With greater knowledge of these qualities, satisfaction is gained from purchase decision. Originality/value – Instead of the usual examination of demographic differences in generic medicine beliefs and perception, this study contributes by revealing brand-related drivers of purchase and satisfaction. Keywords – Generic medicine; brand knowledge structure; brand trust; brand satisfaction; purchase decision; South African young adults
... But the fact that generic drugs need not have to go through the large and costly clinical trials that are required for approval of innovator medicines, ultimately leading to lower price of generics, may raise doubt about their efficacy, safety, and quality. 19 But in this study, majority of physicians were found to be comfortable with the efficacy and safety of generic medications in spite of knowing that generic drug manufacturer need not repeat the preclinical and clinical studies required for originator medicines. As a matter of fact there are no ample proofs that generic drugs are less safe or less effective than their brand-name counterparts. ...
... The regulatory body appraises the manufacturer's compliance to the GMP guidelines before the drug is marketed, and the manufacturer need to give detailed information about the facilities it uses for production, packaging, labelling, among others, of the generic drug. 19,20 In this study, majority of doctors did not agree that generic drugs are made in substandard manufacturing facility. Majority of the doctors were found to have a greater trust in generic drugs and they prescribed them to a greater degree. ...
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... In such a case, at least a partial solution of this problem could be provided by a wider use of generic drugs. Current evidence supports this point, proving that more expensive drugs might be safely replaced by their more affordable generic equivalents [5]. ...
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