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CLINICAL PRACTICE

Prescribing generic antiepileptic drugs: Issues and


concerns for nurse practitioners
Megan Weigel Barrett, DNP, ARNP, FNP-c, MSCN

Baptist Neurology, Jacksonville


Beach, Florida

Keywords
Neurology; pharmacology; safety
clinical decision-making; epilepsy;
antiepileptic drugs; generic drugs.
Correspondence
Megan Weigel Barrett, DNP, ARNP,
FNP-c,
MSCN, Baptist Neurology, 1370 13th
Avenue South, Jacksonville Beach, FL
32250.
Tel: 904-249-1041;
Fax: 904-249-9764;
E-mail: mrweigel@ufl.edu
Received: August 2008;
accepted: February 2009 doi:
10.1111/j.1745-

Disclosures The author reports no conflicts of interest.

Abstract
Purpose: To educate prescribing clinicians about bioequivalent standards for
therapeutic equivalence of brand and generic antiepileptic durgs (AEDs) as more
generic drugs come to market, and to increase awareness of practice and safety
issues surrounding the use of these drugs for people with seizures. Data sources:
Information was gathered from a search of the scientific literature as well as the
authors clinical experience.
Conclusions: Controversy exists regarding the therapeutic equivalence of brand and
generic AEDs, even when bioequivalent standards are satisfied. Generic AEDs have
been associated with breakthrough seizures and adverse events that may outweigh
cost savings encouraged by third-party payors. Further research is needed
comparing brand to generic drugs in a rigorous manner in order to make a consensus
statement regarding the safety and equivalency of generic AEDs for all patient
populations.
Implications for practice: Generic AEDs may be safely prescribed in certain
situations if clinicians are aware of ethical, legal, and practice issues surrounding
their use. Sufficient time should be spent educating patients, caregivers, and
pharmacists about implications of a switch made without the knowledge of the
patient and/or prescriber.

7599.2010.00511.x

Epilepsy is a common neurological condition with an


estimated worldwide prevalence between 0.5% and 1%
(Duncan, 2003). In the United States, more than 2 million
people have epilepsy, 200,000 new cases are diagnosed per
year, and costs of care are approximately $12.5 billion (Frank
et al., 2004; Zachry, Doan, Clewell, & Smith, 2008).
Traditionally, epilepsy has been managed with the use of
antiepileptic drugs (AEDs). Selection of an AED is a
complex process determined by seizure type, side effect, and
long-term safety profiles of medication, concurrent
medication therapy, and general health state (Trescher &
Lesser, 2004). While approximately two-thirds of patients
with newly diagnosed epilepsy will become seizure-free with
the first or second drug tried, breakthrough seizures do occur
(Frank et al.; Heaney & Sander, 2007). Recurrent,
unprovoked seizures in those with epilepsy pose significant
safety hazards and have serious adverse effects on quality of
life.
AEDs such as phenytoin, phenobarbital, and
carbamazepine have been prescribed and available in generic
form for decades. Most require therapeutic drug monitoring
300

as well as safety monitoring due to their longterm side-effect


profile. The advent of second-generation AEDs in the 1990s
brought better-tolerated drugs with safer long-term sideeffect profiles to market (Frank et al., 2004). Several of these
drugs have just recently, or will soon, become available in
generic forms (Blier, 2007; Crawford, Feely, Guberman, &
Kramer, 2006; Heaney & Sander, 2007; Makus &
McCormick, 2007). In an effort to control costs, third-party
payors encourage the use of first- and second-generation
AEDs available in a generic form; however, switching from
brand to generic, between generic forms, or from generic to
brand has been associated with a higher risk of breakthrough
seizures, side effects, and toxicity (Meyer, 1998).
Over half of people with epilepsy report breakthrough
seizures as very or extremely disruptive (Haskins,
Tomaszewski, & Crawford, 2005). The social and personal
consequences of breakthrough seizures are well documented
(Blier, 2007; Borgherini, 2003; Crawford et al., 2006; Makus
& McCormick, 2007; Andermann, Duh, Gosselin, & Paradis,
2007). Patients on multidrug

Journal of the American Academy of Nurse Practitioners


2010 The Author
Journal compilation 2010 American Academy of Nurse Practitioners

M. W. Barrett
Table 1 Number of generic manufacturers of commonly
used antiepileptic drugs

Brand name, dose

Generic name

Cerebyx, 50 mg/mL

fosphenytoin sodium

Dilantin, 100 mg
Depakote, 500 mg
Depakote ER
Keppra
Lamictal, 200 mg
Neurontin, 300 mg
Tegretol, 200 mg
Topamax
Trileptal, 300 mg
Zonegran

phenytoin sodium
divalproex sodium
divalproex sodium
levetiracetam
lamotrigine
gabapentin
carbamazepine
topiramate
oxcarbazepine
zonisamide

Number
of
generic
manufactur
ers
10
7
13
6
23
1
12
6
18
7
16

AED regimens are at higher risk for such serious events


(Andermann et al.; Blier). It is important to avoid even a
single seizure in a person with long-term control. For these
reasons, providers and patients have expressed concern about
the true therapeutic equivalence of generic AEDs.
In the 1970s, interest in generic drugs increased in order to
decrease the cost of prescription medication (Meyer, 1998).
The current economic environment dictates the continued
need to keep healthcare costs low. While economic pressure
to prescribe cheaper medication exists, patients with epilepsy
expect seizure control (Crawford et al., 2006). Professional
guidelines also dictate that the most tolerable AED for
seizure type with the lowest potential of harm and least
likelihood of negative impact on quality of life be prescribed
(Frank et al., 2004). The lower cost of generic AEDs is a
result of the minimal costs necessary to demonstrate
bioequivalence. They are widely advocated as a safe method
of cost containment, and are expected to have the same
therapeutic efficacy as branded drugs (Bialer, 2007).
Insurance companies put forth guidelines that encourage the
prescribing of generic drugs, pharmacists are often given
incentives to dispense them, and patients want to be
prescribed the best medication for their disease state at the
lowest cost (Crawford et al., 2006). Safe prescribing in this
setting becomes a challenge when there are approximately
119 generic versions of branded AEDs available, an average
of 10 per brand (see Table 1). In a disease state such as
epilepsy, the prescribing clinician must consider these issues,
as well as safety and tolerability of medication and seizure
control when prescribing. After reading this article,
prescribers should feel more comfortable with evidence
supporting the decision to prescribe, or not to prescribe, a
generic AED.

301

Prescribing generic antiepileptic drugs

Brand and generic bioequivalence and


AEDs
The purpose of the Food and Drug Administration (FDA)
bioequivalence studies is to compare the bioavailability of
generic products, referred to as test, and brand products,
referred to as reference. Bioavailability involves the rate and
extent of drug absorption. The population for bioequivalence
studies is typically 2426 healthy volunteers. Immediaterelease drugs are administered in a single-dose crossover
design in the fasting state. Controlled-release drugs are
administered in single-dose and multi-dose crossover
designs, and food effects are considered. Tmax (rate of
absorption), Cmax (a function of the rate and extent of
absorption, the maximum concentration of drug reached in
the plasma), and AUC (area under the curve, how much drug
is absorbed) are calculated (Andermann et al., 2007; Bialer,
2007; Blier, 2007; Crawford et al., 2006; Meyer, 1998;
Wilner, 2004). If generic and brand drugs are bioequivalent, a
90% confidence interval (CI) between 80% and 125% of the
Cmax and AUC occurs. In other words, one is 90% confident
that the true mean of the AUC or Cmax is between 0.8 and
1.25 of the reference standard.
The FDA makes recommendations on bioequivalence
following testing in the form of ratings. An A rating
indicates interchangeability between generic and brand, and a
B rating indicates substitution is not recommended. Ratings
such as AA and AB may also be given (Meyer, 1998). In
general, AB ratings (indicating equivalence based on a
human bioequivalence study) are considered sufficient for
safety purposes. Clinically, concerns are noted that
bioequivalence and therapeutic efficacy are not necessarily
the same (Bialer, 2007; Blier, 2007; Borgherini, 2003;
Hatton, 2007; Makus & McCormick, 2007; Wilner, 2004).
Additionally, the standard is criticized because small
populations of healthy patients are studied, rather than the
population for whom the drug is intended (Meyer). Despite
what is discussed in the literature and anecdotally, no
rigorous scientific data exist yet to prove the current system
fails.
Smaller studies, however, do exist, and their results raise
concern. Over 20% of cases of loss of efficacy with
carbamazepine can be traced to decreased serum levels after
switching to generic forms (Crawford et al., 2006). When
brand lamotrigine was switched to generic, breakthrough
seizures were documented in the majority of patients, and the
majority also regained control after switching back to brand
(Andermann et al., 2007; Bialer, 2007; Makus &
McCormick, 2007). In another case review study, 50 patients
controlled on brand phenytoin, valproic acid, carbamazepine,
gabapentin, or zonisamide experienced breakthrough seizures
or increased seizure frequency after a switch to generic. The
majority of

Prescribing generic antiepileptic drugs

M. W. Barrett

301

patients whose therapeutic drug levels were known had lower


levels at the time of the breakthrough event (Berg et al.,
2008b).
Since 1980, the FDA has published Approved
Products
with
Therapeutic
Equivalence
Evaluation, referred to as The Orange Book, to list drug
ratings (FDA, 2008). Drugs marketed before 1938 are not in
the book. The ratings must be read with caution, because
different dosage forms of medications, that is, capsules and
tablets, are not considered to be therapeutically equivalent by
the FDA (Meyer, 1998). Questions and concerns are raised in
the literature about excipients in drugs, for example,
preservatives and buffers, being considered inactive (Bialer,
2007; Borgherini, 2003; Hatton, 2007; Makus & McCormick,
2007; Wilner, 2004); use of different salts among generic
AEDs affecting serum drug concentrations (Bialer); and
individual variation in drug metabolism among treated
patients (Blier, 2007).
When drugs have a narrow therapeutic index (NTI),
nonlinear kinetics, and poor solubility in water, as many
AEDs do, a low threshold for suspicion is valid (Andermann
et al., 2007; Blier, 2007; Borgherini, 2003; Burkhardt et al.,
2004; Crawford et al., 2006; Makus & McCormick, 2007).
Based on reported FDA bioequivalent testing standards for
generic drugs, providers, pharmacists, and patients should
feel assured that the same results and safety profile occurs
with generic AEDs (Bialer, 2007; Wilner, 2004). However,
clinically measurable differences in drug performance should
not be ignored, and should cause the method of
bioequivalence testing to be questioned (Walson, 2003).
Understanding these concepts is of utmost importance in
epilepsy care because of the number of generics available for
each AED. Switching between generics or offbrand without
prescriber and patient notification can cause undue risk
because of the lack of consistency among generic forms as
companies enter and exit the market (Bialer, 2007; Heaney &
Sander, 2007). For the majority of therapeutic areas, plasma
concentration fluctuations of 20% are insignificant (Crawford
et al., 2006). In epilepsy, however, such a drop could be
enough to cause seizure recurrence (Blier, 2007).

Economic issues
M. W. Barrett

Containment of healthcare expenditures is a major goal of


government and third-party payors (Blier, 2007; Duh et al.,
2007; Heaney & Sander, 2007; Wilner, 2004). The initial cost
savings with the use of generic AEDs may be offset by the
need for increased doses of generic AEDs as well as
increased utilization of medical services when switches are

made (Duh et al.; Schacter, n.d.; Zachry et al., 2008). A


greater number of total medical visits and lengthier hospital
stays have been reported with generic AED use (LeLorier et
al., 2008). Additionally, a study of 416 cases and 1248
controls found an association between increased incidence of
epilepsy care received in the hospital (emergency department
[ED] or inpatient care) and recent AED switch involving
generics (Zachry et al.). Needs such as frequent laboratory
testing and more frequent or longer office visits for education
and monitoring purposes to decrease the likelihood of
adverse events do increase medical expenditures (Haskins et
al., 2005; Heaney & Sander, 2007).
In order to truly realize economic benefit from generic
AED prescribing, front-end interventions are necessary.
Mechanisms should be in place at the provider level to
increase monitoring frequency if a patient desires to switch to
a generic AED; at the pharmacy level in education provision
if a brand is switched to generic or generic forms are
switched; and at the patient level in recognition of a different
form of medication and communication with the prescriber
and pharmacist (Liow et al., 2007).

Clinical concerns
A major problem with generic prescribing lies not in the
generic medication itself, but in the lack of awareness that
switches are made at the pharmacy level among generics or
from brand to generic. Such changes should prompt the
prescriber to initiate more frequent office or laboratory
monitoring. Data suggest that neurologists may
underestimate the frequency of generic substitution, thus
undermining those needs (Haskins, Tomaszewski, &
Crawford, 2005). Most states allow a pharmacist to substitute
generic medication unless Brand Only (or a similar phrase
depending on the state) is written on the prescription
(http://professionals.epilepsy.com/
page/statutes
by
pharmacists.html). Unless a patient physically brings
medication to an office visit or calls the office, the prescriber
may not know that a medication form change has occurred
that would necessitate more vigilant monitoring.
Concerned anecdotal opinions of the use of generic AEDs
are supported by provider surveys. In a European telephone
survey of general practitioners, neurologists, and
Prescribing generic antiepileptic drugs

epileptologists, Haskins et al. (2005) found that 65% of


physicians reported brand-name prescribing; 55% opposed
generic substitution without physician consent; and 38% of
neurologists believed that patients had breakthrough seizures
because of a switch to a generic drug. A survey of 312 French
neurologists (Biraben, DeToffol, Semah, & Rouad, 2007)

reported a majority had discomfort with generic substitution;


one-third reported breakthrough seizures or new adverse
events after switches to generics; and 70% reported extra
time needed for phone consultations with patients. Wilner
(2004) described results of a survey of 301 neurologists.
Breakthrough seizures after a switch to generic were reported
by 67.8% of respondents, and 56% reported an increase in
adverse events. Breakthrough seizures after a switch between
generics were reported by 32.5%, and 26.6% reported an
increase in adverse events. In a survey of 550 adult patients
with epilepsy and 606 physicians who treat epilepsy, 88% of
physicians noted concern about an increase in breakthrough
seizures when switching from brand to generic or among
generics, and 49% were extremely or very likely to request
brands not be switched (Berg et al., 2008a).
General disagreement exists between AED prescribers
and the FDA about bioequivalent standards being sufficiently
narrow, pharmacy substitution without prescriber approval,
and the use of healthy participants in bioequivalence studies
(Blier, 2007; Duh, Andermann, Paradis, Weiner, Manjunath,
& Cremieux, 2007; Heaney & Sander, 2007; Wilner, 2004).
The American Academy of Neurology position statement on
coverage for anticonvulsant drugs (2007) supports the use of
generic AEDs if safety and efficacy are not compromised,
avoidance of switching between generic forms is exercised,
pharmacokinetic information is available, pharmacists inform
patients and prescribers about changes, organizations that
encourage or mandate generic substitution have mechanisms
in place to address responsibility if problems occur, and
further research is undertaken (Liow et al., 2007).
At present, the following commonly prescribed AEDs are
available in generic forms: carbamazepine, divalproex
sodium,
ethosuxamide,
gabapentin,
lamotrigine,
levetiracetem, oxcarbazepine, phenobarbital, phenytoin,
primidone, topiramate, valproic acid, and zonisamide (see
Table 1). The advantages of generic drug use include use of
uniform names and lower prices. In addition to more serious
problems previously discussed, more simple consequences
include the different appearance of medications and
difficulties contacting generic manufacturers (Borgherini,
2003). At the pharmacy level, different forms of generics can
be combined and dispensed. Such occurrences have resulted
in breakthrough seizures and toxicity anecdotally (Heaney &
Sander, 2007).
Given the risk for serious and even fatal events to occur in
patients with epilepsy when medication switches are made
without provider awareness, the clinician has a responsibility
to provide education to the patient with epilepsy before such
an event occurs. Best practices for prescribing AEDs for
patients with epilepsy are described in Table 2 (Anderson,
2008; Bishop, 2006; Liow et al., 2007). Not all switches to
generics are harmful, but the generic form should remain the
same for a given patient
Table 2 Best practices for generic AED use in patients with
epilepsy

303

1. Be familiar with your states rules for prescribing brandonly drugs. Write Brand Only, Medically Necessary,
or Dispense as Written on prescriptions when
appropriate.
2. If patient or third-party payor insists on switch, discuss the
risks involved, and the increased level of monitoring
required to ensure patient safety. Document the
discussion.
3. Educate patients to check AED prescription bottles prior to
leaving the pharmacy. If pills look different than usual,
educate them to notify the pharmacist and have the
pharmacist call the prescriber prior to dispensing.
4. Increase frequency of therapeutic drug-level monitoring
and office visits if switching from brand to generic,
generic to brand, or between generic forms.
5. Record breakthrough seizures and adverse events after a
switch.

to increase the therapeutic effectiveness profile (Peruca et al.,


2006).

Conclusion
Most AEDs have a narrow therapeutic range. While generic
switching may work well in other therapeutic areas to
decrease cost without undue harm to the patient, this may not
be the case in the treatment of epilepsy. Medication costs
may decrease, but the impact of breakthrough seizures on the
need for increased medical expenses may outweigh the initial
cost-benefit ratio. Personal economic, health, and
sociobehavioral impacts of breakthrough seizures also need
to be considered when generic switches are made without
prescriber notification.
The consensus in the literature is that more studies are
needed to prove that cost savings of generic drugs are not
offset by increased costs associated with breakthrough
seizures or adverse events (Borgherini, 2003; Haskins et al.,
2005). These studies should be randomized, controlled trials
of generic versus brand AEDs in an affected population of
adequate size (Borgherini; Crawford et al., 2006; Hatton,
2007; Heaney & Sander, 2007). Unfortunately, such studies
may not be possible due to cost, and an argument could be
made that ethical issues would also arise (Miller, Anderson,
Doherty, & Poolos, 2007).
In the meantime, clinicians should focus on educating and
promoting awareness in patients with epilepsy. Patients
should be taught to notify their pharmacist and prescriber if
their pills look different, and they should be monitored more
frequently if a change is made. If a situation arises where a
change was made without the pharmacist notifying the
patient, it would behoove the prescriber to contact the
pharmacist and discuss the concern in order to reduce the risk
of harm to patients. If an

Prescribing generic antiepileptic drugs

M. W. Barrett

303

adverse event or breakthrough seizure occurs as a result of a


change between generic and brand or among generics, it
should be reported using the FDAs MedWatch system
(http://qqq.fda.gov/medwatch). Generic AED prescribing can
be done safely in the appropriate patient if all parties are
notified and arrangements for monitoring therapeutic efficacy
are made.

Acknowledgments
The author wishes to acknowledge Rose Nealis, PNP, PhD,
and Kevin Barrett, MD, for review of the manuscript.

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