Parkinsonism and Related Disorders 17 (2011) 308e312
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders
journal homepage: www.elsevier.com/locate/parkreldis
Review
Generic versus branded pharmacotherapy in Parkinson’s disease:
Does it matter? A reviewq
Criscely L. Go a,1, *, Raymond L. Rosales b,1, Peter Schmidt c,1, Kelly E. Lyons d,1,
Rajesh Pahwa d,1, Michael S. Okun a,1
a
Department of Neurology, University of Florida, McKnight Brain Institute, Movement Disorders Center, 100 S. Newell Drive, Gainesville, FL 32611, USA
University of Santo Tomas Hospital, Department of Neurology and Psychiatry, España, Manila, Philippines
National Parkinson Foundation, Miami, FL, USA
d
Department of Neurology, University of Kansas Medical Center, Parkinson’s Disease and Movement Disorder Center, Kansas City, KS, USA
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 October 2010
Received in revised form
2 February 2011
Accepted 4 February 2011
There is an ongoing debate about generic drug use for a multitude of conditions including epilepsy,
psychosis, hypertension, post-organ transplantation, and several infectious diseases. Most of the concerns
involve drugs with narrow therapeutic indices. There is a heightened attention to health care costs and
macroeconomic policy as well as microeconomic business decisions that may impact the use of generic
drugs. The issues surrounding generic substitution for chronic degenerative conditions such as in Parkinson’s disease (PD) continue to be controversial subjects for physicians, pharmacists, patients, Medicare/
governmental insurance programs, and for private insurance companies. The United States Food and Drug
Administration (FDA) requires that generic drugs meet a standard for bioequivalence prior to market
approval, but this may not translate to therapeutic efficacy or to overall patient tolerance. In this review we
will address issues related to the use of generics versus branded drugs in PD, and the potential impact
substitution of generics may have on patients and on clinicians. Having proper documentation may help in
deciding the appropriate usage of these drugs in PD. Medicare, governmental run health care systems, and
third party insurance companies should in a complex disease such as PD, allow physicians and patients the
chance to properly document the superiority of brand versus generic approaches. Currently, in the U.S, and
in many countries around the world, there is no obligation for payers to respect these types of patient
specific bedside trials, and there has been no standardization of the process.
! 2011 Elsevier Ltd. All rights reserved.
Keywords:
Movement disorders
Generics
Parkinson disease
Dopamine agonist
Levodopa
Pharmacotherapy
Contents
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
2.
Economic impact of Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
3.
Generic drugs and bioequivalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
4.
Generic drugs and Parkinson’s disease: does it matter? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .310
5.
Drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .310
6.
Variations in generics drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .310
7.
Variation in patient response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .310
8.
Patient compliance/adherence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
9.
Financial issues with generics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
10.
Comments/conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
q The review of this paper was entirely handled by the Co-Editor-in-Chief, Z.K. Wszolek.
* Corresponding author. Tel.: þ1 9042637860.
E-mail addresses: crouix_scs@yahoo.com, criscely.go@neurology.ufl.edu (C.L. Go).
1
On Behalf of the National Parkinson Foundation Quality Improvement Initiative.
1353-8020/$ e see front matter ! 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.parkreldis.2011.02.005
C.L. Go et al. / Parkinsonism and Related Disorders 17 (2011) 308e312
1. Introduction
Parkinson’s disease (PD) is a neurodegenerative disorder
affecting both dopaminergic and non-dopaminergic neuronal
systems. The typical motor manifestations include tremor, bradykinesia, and rigidity. Gait, postural instability, cognitive dysfunction, and other axial motor disturbances may occur with advancing
disease. There is usually a good to excellent response to dopamine
replacement therapy (i.e. levodopa or a dopamine agonist),
particularly early in the disease course. Presently, there is still no
cure, nor is there a proven disease modifying therapy. Since its
discovery approximately 40 years ago [1], levodopa has been the
standard medical therapy for PD. However, with disease progression, the response to medication may become increasingly inconsistent. Inevitably, patients usually later in the course of PD will
require higher dosages, more frequent dosing, and the use of
complex drug combinations to treat symptoms and to try to
maintain as much quality of life as possible. Long term levodopa
therapy is associated with motor fluctuations and dyskinesia, and
these two issues may pose a challenge for both specialist and nonspecialist physicians. Additionally, emergence of non-motor
manifestations and comorbidities requiring use of a multitude of
other non-dopaminergic drugs (e.g. SSRIs, antipsychotics, anticholinergics) have a largely unknown impact on levodopa absorption and transport in a PD patient.
PD incidence is known to increase with age [2], and as the
population continues to age, the prevalence of PD will therefore
increase. The progression of PD and its psychosocial consequences
usually have a demonstrable impact on patients’ health related
quality of life [3,4]. The increase in the aged population, will stress
health care utilization and also increase prescription drug use.
Private and public insurers, as well as policy makers have been
recently examining different strategies to lower health care costs.
Reducing health care related expenses is a compelling force for
the use of generics as substitutes for branded products. The cost of
medications creates both an economic burden for payers, and for
patients, as the direct patient payment is typically a function of the
total cost of the medication. Various reports have extensively
examined the effects of generic substitution among patients with
epilepsy [5e7], psychosis [8e10] organ transplant [11] and cardiac
disorders [12], but no report has looked in depth into PD. This
review article will examine the relevant issues pertaining to the use
of generic drugs in the treatment of PD.
2. Economic impact of Parkinson’s disease
PD is a chronic disease that often requires long term treatment
with medications. In a study performed by Noyes et al. in 2006 [13],
health related expenditures in PD patients were two times higher
than the average American without PD (>65 years old). Medicare
beneficiaries with PD tended to use more health care related
services than beneficiaries without PD [14].
Medicare plays a major role in the U.S. health care system
accounting for 23% of the total national health care spending [14]
and its spending is influenced by prices of health care services,
increasing volumes of patients, and the use of new services and
new technologies. Drug prices for brand name products may
increase as a result of economic inflation, and Medicare may have
a difficult time compensating and adjusting for this change.
Medicare may attempt to lower its spending by decreasing the
amount paid to physicians, or alternatively by strategies such as
increasing the requirements to use generic medications. The hope
is that by the increased use of generic formulations, Medicare
spending will be reduced in 2011 [15].
309
The number of PD cases in the US has been estimated at 340,000
in 2005, and is predicted to double by 2030. Estimating the number
of undiagnosed and misdiagnosed patients, some estimates put the
total number as high as 1 million [16]. According to a study done by
O’Brien et al. [17], the annual economic cost of PD in the United
States is approximately $10.8 billion, and 58% of this is direct
medical costs. Skilled nursing costs are the single largest line item
at $4.4 billion (41%) [17] and prescription drugs are second at
$1.5e$2.4 billion (14%e22%). A study by Winter et al. [18] revealed
that patients may use up to 43% of their income to shoulder drug
costs. With the new U.S. health insurance law this may change with
less out of pocket expenses. Additionally, in Italian [19] and German
cohorts [20], it was found that the highest co-payments made by
PD patients were for their antiparkinsonian drugs, and for medical
equipment. These financial burdens have pushed insurance
companies and the government health care systems toward generic
formulations.
3. Generic drugs and bioequivalence
In an effort to reduce health related expenditures, many insurance companies have turned to generic substitution. Generic drugs
are typically available at a fraction of the cost of branded forms.
Currently, there are multiple pharmaceutical companies that
manufacture a generic formulation of carbidopa/levodopa (i.e.
Actavis US, Sandoz and Teva Pharmaceuticals among others).
Dopamine agonists, monoamine oxidase inhibitors and anticholinergics are also available through various generic brands.
The manufacturers of a generic formulation must show that
there is an “essential similarity” between the generic formulation
and the commercially available branded originator. The US Food
and Drug Administration (FDA) must approve whether a generic
drug formulation is bioequivalent with its branded counterpart [21]
before it can be marketed in the US. The basic assumption in bioequivalence is that the two (generics and brand) products are
pharmaceutically equivalent, and that their bioavailabilities (rate
and extent of availability) after being administered in the same
molar dose are similar such that their efficacy and safety, can be
expected to be the same. Pharmaceutical equivalents [22] mean
that the two drugs have the same active ingredients, are of the
same dosage form, route of administration and are identical in
strength or concentration. The regulatory limits applied in bioequivalence studies require that the areas under the drug concentration versus time curves (AUC ratio of generics versus brand) be
within 90% confidence intervals and the maximum plasma
concentrations (Cmax ratio between generics versus brand) fall
within 80e125% [8,21]. These integral measures by definition do
not consider that different rates of drug delivery may impact
efficacy.
The development of a brand name formulation requires the
demonstration of pharmacokinetics, efficacy, safety and tolerability. This must be performed in healthy subjects, and also in the
target patient population. The development of a generic equivalent
however, requires only the demonstration of bioequivalence with
brand name counterparts and testing is done only in healthy
subjects [23]. The fact that the generics are not tested on PD
patients has the potential to result in a “relative therapeutic inequivalence,” because of the uniqueness of the PD population. For
example, PD patients often experience slow absorption of their first
orally-administered dose of medication in the morning due to low
gastric motility [24]. PD patients often use multiple drugs (i.e.
dopamine agonists, anticholinergics, psychotropics) which may
amplify differences between generic and branded formulations.
Issues regarding drugedrug interactions with the different
formulations of carbidopa/levodopa (extended release, immediate
310
C.L. Go et al. / Parkinsonism and Related Disorders 17 (2011) 308e312
release), dopamine agonists, monoamine oxidase inhibitors, and
anticholinergics have not been addressed by simple bioequivalence
studies.
The FDA approval of these drugs is based on the assumption that
demonstrating simple bioequivalence is sufficient to indicate
comparable clinical tolerability and efficacy. It is common practice
to ensure that antiparkinson medications be administered on
a strict schedule in order to optimally manage plasma concentrations. Since bioequivalence, does not consider variability in solubility over time, this may translate into a noncomparable efficacy
especially in a complex disease such as PD. Adding to this issue is
that variation in bioequivalence tests may differ as regulatory
policies change [8].
4. Generic drugs and Parkinson’s disease: does it matter?
There are very few available reports from either patients or
physicians that address the question of the “essential similarity” of
generic drugs. There are few anecdotal reports of generic drugs
resulting in difficulty in PD. Whether the lack of information has
been influenced by reporting biases from physicians and or
patients, adverse events, or lack of efficacy due to disease
progression remains unknown.
PD has a multitude of motor and non-motor symptoms, which
can be complex and require meticulous assessment and comprehensive treatment. It is not uncommon to use combinations of
drugs to optimize symptom control. Physicians and patients
commonly work together to develop a reasonable, and often
empirical combination of treatment approaches tailored to each
patient. Blood levels of levodopa are correlated with the emergence
of many symptoms including cardinal motor manifestations, on/off
fluctuations, anxiety, mood symptoms [25] and these can all impact
quality of life [26]. Patients may also experience “freezing” or
dyskinesia, and these symptoms may be particularly influenced by
even subtle fluctuations in serum levodopa level.
Pahwa et al. [27] published a small study on the pharmacokinetic differences between Sinemet (brand) and Atamet (generic
carbidopa/levodopa). This study involved a single dose of Sinemet
in 30 patients all with idiopathic PD (10 previously untreated
patients, 10 with early disease and 10 with motor fluctuations/
dyskinesia). This pilot study suggested that the generic formulation
of carbidopa/levodopa (Atamet) given in a single dose was bioequivalent. In another open label conversion study of 86 PD
patients [28] on Sinemet who were switched to generic carbidopa/
levodopa, majority of the patients (69%) either preferred generic
carbidopa/levodopa or had no preference. Patients who did not
tolerate generic carbidopa/levodopa had more advanced disease
and more off time, dose failures and orthostatic hypotension. This
study suggested that a subgroup of patients might not be well
controlled with generic medications, and may need either higher
doses of a generic preparation or the use of brand medication.
5. Drug interactions
Drugedrug interactions may affect both pharmacokinetics and
pharmacodynamics. In a pharmacokinetic interaction, one drug
may affect the absorption, elimination and distribution of another
drug. Interactions that trigger hepatic (or renal) metabolism may
affect pharmacokinetics thus resulting in a lack of efficacy. Similarly, when pharmacodynamic drug interactions occur, two drugs
may have additive or alternatively antagonistic pharmacological
effects. Non-linear pharmacodynamic effects of plasma concentration have been previously found in drugedrug interactions
involving levodopa [29]. Such non-linear pharmacodynamic effects
are not addressed through bioequivalence as defined in the
regulatory framework. Since generic drugs require only bioequivalence studies, drugedrug interactions are unknown [21].
One issue particularly pertinent to PD is the common need to
address high rates of depression [30,31], anxiety [32] and psychosis
[33] which may require the use of a psychotropic. Most pharmacokinetic interactions with psychotropics [34,35] (antidepressants and
antipsychotics) involve changes in the activity of major drugmetabolizing enzymes (i.e. the cytochrome P450 (CYP) monooxygenases and/or uridine diphosphate-glucuronosyltransferases
(UGT)) [36]. Although psychotropics are unlikely to interfere with the
elimination of other drugs, co-administration with inhibitors or
inducers of the major enzymes responsible for their metabolism may
modify plasma concentrations, and lead to clinical adverse effects by
altering drug levels. The increased and unpredictable variability of
plasma concentrations from generic drugs results in a higher probability of exposing concentration-dependent drugedrug interactions. Additionally, elderly individuals, due to physiologic changes
related to aging, usually experience decreased hepatic activity and
protein binding [37] which places them at higher risk for developing
drug related side effects. This situation may also be applied to the use
of drugs other than psychotropics in PD such as memory enhancers,
anticholinergics, and drugs used to treat other comorbidities and
symptoms.
6. Variations in generics drugs
Despite the FDA’s stringent requirements in setting bioavailability and preparation similarity, the generic formulations are not
entirely identical to brand [5,6,38]. Active ingredients contained in
the generic formulation may be the same as the branded, but may
be present in a different form, which the FDA refers to as pharmaceutical alternatives. Pharmaceutical alternatives [22] may have
different salts, esters, or complexes of the active moiety or may be
different in dosage forms or strengths (i.e. salt in amlodipine can be
besylate or camsylate, ferrous sulfate or gluconate). The form may
have different absorption characteristics and solubility properties
[8] and these differences may explain differences in clinical efficacy
and safety [8]. In a study by Olling et al. [39], four generic formulations of carbamazepine showed different absorption characteristics that were related to the occurrence of side effects (e.g.
dizziness). Finally it should be kept in mind that bioequivalence
studies are conducted on one batch (or lot) of a branded drug, and
do not account for batch variability, or for country to country
differences.
Furthermore, varying types of excipients may be present among
brand and generic drugs. Excipients are additives that aid in
stabilizing the tablet (or any formulation) [40] and are known to
play an important role in governing the release of the active
pharmaceutical ingredient required for the desired therapeutic
effect. These excipients may affect absorption and bioavailability of
drugs. Some of these excipients have been known to invoke allergic
reactions or even intolerance [41,42].
Many of the generic drugs are compared to brand, but never
compared against other generics. The decision for their use ends up
being that all generic brands are interchangeable when they pass
the bioequivalence test. Ultimately comparing each brand/generic
with every other brand/generic in formal human studies would be
difficult, not to mention, costly and may even be ethically
questionable.
7. Variation in patient response
From a pharmacogenetic perspective, variability in response to
medications and susceptibility to many of the drug related
complications such as motor fluctuations, hallucinations, daytime
C.L. Go et al. / Parkinsonism and Related Disorders 17 (2011) 308e312
sleepiness and dyskinesia, may be influenced by genes, particularly
those coding for signaling pathways for drug-metabolizing
enzymes, drug receptors and for proteins [43,44]. In a study performed by Arbouw et al. [45], positive associations were found in
the development of levodopa induced dyskinesia and the presence
of polymorphisms in the receptor DRD2 gene, the DAT (dopamine
transporter) gene and m1 opioid receptor (OPRM1) gene. Similarly,
motor fluctuations were associated with the DRD2 gene polymorphism. Recently, altered ABCB1 (p glycoprotein) expression,
a transport protein affecting drug absorption and elimination, was
shown to impair drug efflux across gastrointestinal linings and the
bloodebrain barrier [46]. Among the antiparkinsonian drugs,
levodopa, bromocriptine, pergolide and pramipexole are known
ABCB1 substrates [47], and rely on active transport across the blood
brain barrier. Antidepressants are another class of drugs which
have been widely utilized in PD and these drugs are also susceptible
to ABCB1 related drug efficacy changes. Inter-individual variability
has been described in ABCB1 expression and functionality [48,49],
and it is unknown if there is a difference in how generics and
brands are handled by this system.
8. Patient compliance/adherence
Generic drugs may be packaged in various forms depending on
the manufacturers. They may be available in different sizes, shapes,
and even colors, which may differ from the original drug brand.
These variations not uncommonly introduce confusion in an elderly
patient who may be used to reading a brand formulation. Additionally, switching medications has been shown to have an effect
on adherence to therapy and may lead to a worse outcome, especially in those taking multiple medications.
9. Financial issues with generics
The stakeholders in the drug prescription arena (manufacturers
of brand only drugs, brand and generics or generic only drugs)
often have conflicting interests. Most of the government agencies
and insurance companies prefer generics. In a profit driven
economy, pharmacies and insurers opt to select the drugs with the
lowest cost. Moreover, they usually employ a tiered co-payment
system, requiring generic rather than brand.
There is not much debate that generic drugs are cost effective.
The true debate lies in the value of these drugs for specific groups of
patients who have a particular disease, such as PD. Though generics
can provide cost savings, we must ask ourselves whether generics
are appropriate for all PD patients and whether generics always
provide the same safety profile. In a study done by Duh et al. [49] on
topiramate, generic drug use was associated with higher hospitalization rates and longer hospital stays. A similar finding was
reported with anti-arrhythmia drugs [50]. Additionally, some
studies have reported a high percentage of patients returning to
brand drugs [38] after trying a generic formulation. Savings realized by the use of generic drugs can be negated by higher health
care costs if switching from a brand to a generic drug results in
a change in the efficacy or tolerability of the drug. The risks versus
benefits of the use of generic drugs for PD remain to be examined.
10. Comments/conclusion
Whether generic substitution matters in PD, and in which type of
patient it might have a meaningful impact (e.g. early, advanced,
fluctuating, dyskinetic, gender, ethnicity, race, etc,) remains to be
addressed by the health care system. Because of the existence of
conflicting reports on the effects of generic substitution in other
diseases, the PD community should be sensitive that this may be an
311
important issue. Both patients and physicians should be vigilant in
reporting potential adverse events, lack of effectiveness, and other
concerns pertaining to the use of not only generics but also of their
branded counterpart. Having proper documentation may help in
deciding the appropriate usage of these drugs in PD. Studies of
generics versus branded products are very difficult to perform
across a large population of patients. The approach for individual
physicians and patients should be to carefully document in the chart
the benefits and side effects of identical trials prescribed in the
clinic. Also, increasing and decreasing doses and making adjustments to intervals to try to compensate for the differences should be
recorded. These types of empiric trials can provide the detail
necessary to make a reasonable appeal to an insurance company for
a brand name PD drug. In addition, physicians and patients should
be aware that sudden changes in PD symptoms or in medication
response could be due to a transition from a branded to a generic
medication, or due to a switch to a different generic formulation of
the same medication which may be made by a different manufacturer. If generics are utilized, every effort should be made to stick
with a single manufacturer. Early in PD therapy, the use of generic
formulations may be less controversial, and likely better tolerated.
However, as PD patients transition to later stages of disease, and
they utilize multiple doses and more frequent medication intervals,
it will be the burden of the treating physician to document superiority of one over the other. This documentation will be necessary for
constructing the argument for brand or for generic formulations for
both governmental and third party payers. Medicare, governmental
run health care systems, and third party insurance companies
should in a complex disease such as PD, allow physicians and
patients the chance to properly document superiority of one
approach over another. Currently, in the U.S, and in many countries
around the world, there is no obligation for payers to respect these
types of patient specific bedside trials, and there has been no
standardization of the process. One future direction that we can
undertake in our quest for an answer over this prevailing controversy between generics and branded pharmacotherapy in PD is to
pursue pharmacodynamics and pharmacokinetics of these drugs in
patients who have had poor response to the generic drugs in future
research studies. Pharmacokinetic and pharmacodynamic studies
on PD patients will be more economical and goal directed as
compared to studying these interactions on normal healthy individuals since this is a very complex group of patients. Emphasis
should be placed on why these PD patients developed reactions to
these drugs. These types of observations will be critical for us to
identify at risk patients who are considering the switch to a generic.
Additional consideration to the emerging widespread use of generic
dopamine agonists should be explored in future studies.
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