Univ. of Minn.
`Bio-Medical
`Library
`
`~-~"=':"=:~~----
`
`CAN JOURNAL OF HOSPITAL PHARMACY
`
`An overview of antiepileptic drug therapy
`
`Supplement to the
`American Journal of Hospital Pharmacy
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2088 - 1/13
`
`

`
`Critical issues Symposium
`
`Critical issues in the treatment of epilepsy
`
`GREGORY L. HOLMES
`
`Abstract: Classification of
`seizure types and evaluation
`and treatment of seizure dis(cid:173)
`orders are discussed.
`Once the diagnosis of a sei(cid:173)
`zure is made, the seizure type
`must be identified; this will
`help in determining the
`treatment. In partial seizures,
`the electrical discharge occurs
`focally, while generalized sei(cid:173)
`zures involve both cerebral
`hemispheres simultaneously.
`Magnetic resonance imaging
`is the preferred test in the
`
`evaluation of patients with
`seizures, although computed
`tomography and electro(cid:173)
`encephalography can also be
`helpful. Selection of an anti(cid:173)
`epileptic drug (AED) is based
`on efficacy, toxicity, and, to a
`lesser degree, cost. Adverse
`reactions occur in up to SO%
`of patients. First-line AEDs
`include carbamazepine, etho(cid:173)
`suximide, phenobarbital,
`primidone, phenytoin, and
`valproic acid. Serum AED
`concentrations can be help-
`
`ful in managing patients
`with epilepsy. The serum
`concentrations required to
`control seizures or resulting
`in toxicity may vary among
`patients. Most seizures are
`manageable with oral AEDs.
`Medications of choice in sta(cid:173)
`tus epilepticus include diaze(cid:173)
`pam, lorazepam, phenytoin,
`and phenobarbital.
`The key to treating epilep(cid:173)
`sy is correct diagnosis of the
`seizure type and, when possi(cid:173)
`ble, the type of epilepsy.
`
`Most patients with epilepsy
`respond to one of the first(cid:173)
`line AEDs; second-line agents
`may be useful in patients
`who do not respond to one
`or a combination of the first(cid:173)
`line agents.
`
`Index terms: Anticonvul(cid:173)
`sants; Blood levels; Epilepsy;
`Toxicity
`Am J Hosp Pharm. 1993;
`SO(Suppl S):SS-16
`
`T he first priority in evaluating a patient with a
`
`suspected seizure disorder is to be as certain as
`possible that the patient indeed has seizures. 1'2
`Many disorders can be confused with seizures, includ(cid:173)
`ing breath-holding attacks, pallid infantile syncope,
`night terrors, somnambulism, syncope, rage attacks,
`migraines, cardiac arrhythmias, pseudoseizures, and
`movement disorders such as tics and chorea. 2 It is a
`serious mistake to inappropriately label someone as
`having epilepsy or seizures, because the social conse(cid:173)
`quences and risks of antiepileptic drug (AED) use are
`great. 3
`The second task is to determine the seizure type. This
`is critical, since the type of seizure to a great extent
`determines the type of evaluation and treatment a
`patient will receive.
`Seizures are divided into two basic groups: partial
`and generalized. 4 Partial seizures involve only a por(cid:173)
`tion of the brain at onset and can be further divided
`into those involving unimpaired consciousness (sim(cid:173)
`ple pattial) and those with impaired consciousness
`(complex partial). Both types can spread, resulting in
`generalized tonic-clonic seizures. Generalized seizures
`are those in which the first clinical changes involve
`both hemispheres. There is usually impairment of
`consciousness during generalized seizures, although
`some of these seizures, such as the myoclonic type,
`
`may be so brief that impairment of consciousness can(cid:173)
`not be assessed.
`
`Partial seizures
`Simple partial seizures. The signs or symptoms
`of simple partial seizures depend on the focus of the
`seizure. 5 Seizures involving the motor cortex most com(cid:173)
`monly consist of rhythmic or semirhythmic clonic
`activity of the face, arm, or leg. There is usually no
`difficulty in diagnosing this type of seizure. Seizures
`with somatosensory, autonomic, and psychic symp(cid:173)
`toms (hallucinations, illusions, deja vu) may be more
`difficult to diagnose. 2 Psychic symptoms usually occur
`as a component of a complex partial seizure. Simple
`partial seizures can occur at any age.
`Complex partial seizures. Complex partial sei(cid:173)
`zures ( CPSs), formerly called temporal lobe or psychomo(cid:173)
`tor seizures, are among the most common seizure types
`encountered in both children and adults. 2 CPS may be
`preceded by a simple partial seizure, which may serve as
`a warning to the patient (i.e., an aura) of more severe
`seizures. The aura may enable the clinician to deter(cid:173)
`mine the cortical area where the seizure is beginning.
`By definition, patients have impaired consciousness
`during CPS; thus, the patient either does not respond to
`commands or responds in an abnormally slow manner.
`While CPSs may be characterized by simple staring and
`
`GREGORY L. HOLMES, M.D., is Director of the Clinical Neurophysi(cid:173)
`ology Laboratory and Epilepsy Program, Hunnewell 2, Children's
`Hospital, 300 Longwood Avenue, Boston, MA 02115, and Associ(cid:173)
`ate Professor of Neurology, Harvard Medical School, Boston, MA.
`Based on the proceedings of a symposium entitled "Issues for
`the 1990s: Antiepileptic Drugs and Pharmacy Practice," held De(cid:173)
`cember 10, 1991, in New Orleans, LA, and sponsored by the
`College of Pharmacy, University of Minnesota, under an unre(cid:173)
`stricted educational grant from Roche Laboratories, a division of
`Hoffmann-La Roche Inc.
`
`Dr. Holmes is on the speaker's bureau for Parke-Davis, Abbott
`Laboratories, Carter-Wallace Laboratories, Hoffmann-La Roche
`Inc., and Ciba-Geigy Corporation and has served on advisory
`committees for Abbott Laboratories, Carter-Wallace Laboratories,
`Hoffmann-La Roche Inc., and Ciba-Geigy Corporation. He re(cid:173)
`ceived an honorarium from Roche Laboratories for his participa(cid:173)
`tion in the symposium and for manuscript preparation.
`
`Copyright© 1993, American Sodety of Hospital Pharmacists,
`Inc. All rights reserved. 0002-9289/93/1202-00SS$03.00.
`
`Vol SO Dec 1993 Suppl 5 Am] Hosp Pharm 55
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2088 - 2/13
`
`

`
`Symposium Critical issues
`
`impaired responsiveness, behavior is usually more com(cid:173)
`plex during the seizure. Automatisms (involuntary motor
`activity) are common during the period of impaired
`consciousness in CPS. Automatic behavior is quite vari(cid:173)
`able and may consist of activities such as facial grimac(cid:173)
`ing, gestures, chewing, lip smacking, finger snapping,
`and repeating phrases; the patient does not recall this
`activity after the seizure. 6.7 Although duration varies,
`CPSs usually last from 30 seconds to several minutes, in
`contrast with absence seizures, described below, which
`usually last less than 15 seconds. 8 Most patients have
`some degree of postictal impairment, such as tiredness
`or confusion.
`
`Generalized seizures
`Generalized tonic-clonic seizures. There is rare(cid:173)
`ly any difficulty in correctly diagnosing generalized
`tonic-clonic (GTC) seizures (formerly called grand mal
`seizures). The only caution is that toddlers with breath(cid:173)
`holding attacks and adults and children with syncope
`may have brief GTC seizures at the end of the attack9;
`because these seizures are brief, they should not be
`treated with AEDs.
`Some patients may have a simple partial seizure
`(aura) preceding loss of consciousness. As the seizure
`spreads in the cortex, it develops into a GTC seizure or,
`more specifically, a simple partial seizure with second(cid:173)
`ary generalization. 10 Loss of consciousness usually oc(cid:173)
`curs simultaneously with the onset of a generalized
`stiffening of flexor or extensor muscles (tonic phase).
`Following the tonic phase, generalized jerking of the
`muscles (clonic activity) occurs. A GTC seizure is almost
`always associated with deep postictal sleep.
`Absence seizures. Absence seizures, formerly called
`petit mal, are usually characterized by an abrupt cessa(cid:173)
`tion of activity and a change of facial expression with a
`blank gaze.s,n,Iz The seizures are short, rarely lasting
`over 30 seconds, and are never associated with an aura
`or postictal impairment. Like CPS, absence seizures are
`frequently associated with automatic behavior.
`Absence seizures almost always begin during child(cid:173)
`hood, typically between three and six years of age.
`While they occasionally continue into adulthood, they
`are most prevalent during the first 10 years of life. In
`most patients with absence seizures, the results of a
`neurologic examination are normal.
`Hyperventilation is a useful diagnostic tool in cases
`where absence seizures are suspected. 2 Three minutes of
`hyperventilation in an untreated patient with absence
`seizures is likely to induce an absence seizure. Hyper(cid:173)
`ventilation in a patient with GTC or myoclonic seizures
`may occasionally induce a seizure. Partial seizures are
`rarely precipitated by hyperventilation. Photic stimula-.
`tion (blinking lights), usually administered during the
`electroencephalogram (EEG), may also result in a GTC,
`absence, or myoclonic seizure.
`At times it may be difficult to differentiate absence
`
`56 AmJ Hosp Pharm Vol SO Dec 1993 SupplS
`
`seizures from partial complex seizures, since both are
`associated with a change in facial expression, staring, and
`automatic behavior. Table 1 shows the diagnostic fea(cid:173)
`tures of absence seizures and complex partial seizures.
`Clonic seizures. Clonic seizures are similar to GTC
`seizures, but are characterized by rhythmic or semi(cid:173)
`rhythmic contractions of a group of muscles. These
`contractions can involve any muscle group, although
`the arms, neck, and facial muscles are most commonly
`involved. Clonic seizures are much more common in
`children than adults.
`Myoclonic seizures. Myoclonic seizures are char(cid:173)
`acterized by sudden, lightning-like contractions of
`muscle groups. The contractions, which can occur in
`any muscle group, are quicker than those seen with
`clonic seizures. Myoclonic seizures may be dramatic,
`causing the patient to fall to the ground, or subtle,
`resembling tremors. Because of the brevity of the sei(cid:173)
`zures, it is not possible to determine whether conscious(cid:173)
`ness is impaired. Myoclonus may occur as a component
`of an absence seizure or at the beginning of a GTC
`seizure.
`Tonic seizures. Tonic seizures are brief (usually less
`than 60 seconds) and characterized by the sudden onset
`of increased tone in the extensor muscles. 13-15 If stand(cid:173)
`ing, the patient typically falls to the ground. There is
`impairment of consciousness during the seizure, al(cid:173)
`though the brevity of the seizure may make this diffi(cid:173)
`cult to assess. Tonic seizures are frequently seen in
`patients with Lennox-Gastaut syndrome, which con(cid:173)
`sists of a mixed seizure disorder, mental retardation,
`and a slow spike-and-wave EEG pattern. 16-18 The sei(cid:173)
`zures usually occur more frequently at night.
`Atonic seizures. Atonic seizures are rare and are
`usually confined to childhood. 13,14 They are character(cid:173)
`ized by the sudden loss of muscle tone. These seizures
`
`Table 1.
`Comparison of Clinical and EEG Features in Absence
`and Complex Partial Seizures8
`
`Clinical Variable Absence Seizures
`
`Frequency/day
`Duration
`
`Usually multiple
`Usually <10 sec
`Rarely >30 sec
`No
`Common
`No·
`
`Aura
`Automatisms
`Postictal
`impairment
`Activation
`Hyperventilation Frequent
`Photic
`Common
`stimulation
`EEG findings
`Between
`seizures
`During
`seizures
`
`Usually normal
`
`Generalized
`spike-waves
`
`aEEG
`
`electroencephalogram.
`
`Complex Partial
`Seizures
`
`Rarely >1-2
`Usually >90 sec
`Rarely <30 sec
`Frequent
`Frequent
`Frequent
`
`Rare
`Rare
`
`Spikes/sharp waves;
`may be normal
`
`Focal discharges
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2088 - 3/13
`
`

`
`are very brief, lasting seconds, and are rarely associated
`with any significant postictal impairment. If truncal
`tone is involved, the patient falls to the ground. Most
`children who suddenly fall during a seizure, however,
`are experiencing a myoclonic or tonic seizure. If only
`the neck extensors are involved, the patient's head may
`drop briefly. During atonic seizures lasting more than a
`few seconds, consciousness is impaired. Atonic seizures
`are frequently seen in patients with other seizure types.
`In addition, there may be an atonic component of
`absence seizures.
`
`Epileptic syndromes
`After identifying the seizure type, the clinician should
`determine whether the patient has an epileptic syn(cid:173)
`drome. An epileptic syndrome is a cluster of signs and
`symptoms customarily occurring together. 2,19 Since cer(cid:173)
`tain syndromes are associated with specific genotypes,
`proper identification may allow the physician to coun(cid:173)
`sel patients as to the genetic risks for their offspring. In
`addition~ identifying a syndrome helps in determining
`appropriate therapy and prognosis. Although it is be(cid:173)
`yond the scope of this discussion to cover all epileptic
`syndromes, a review of one example, juvenile myoclon(cid:173)
`ic epilepsy OME), demonstrates ·why syndrome identifi(cid:173)
`cation is useful.
`]ME is a familial disorder that typically begins in
`the second decade of life and is characterized by mild
`myoclonic seizures, GTC seizures, donie-tonic-clonic
`seizures (a variation of GTC seizures in which there is
`an initial clonic phase), or, occasionally, absence sei(cid:173)
`zures. The interictal EEG in this disorder is easily
`discerned from those seen with other forms of gener(cid:173)
`alized epilepsies.20,21 The characteristic EEG features
`are fast (3.5-6 Hz) spike-and-wave or multiple spike(cid:173)
`and-wave complexes. This pattern contrasts with the
`3~Hz spike-and-wave complexes seen in classic ab(cid:173)
`sence seizures and the slow (1.5-2.5 Hz) spike-and(cid:173)
`wave complexes of Lennox-Gastaut syndrome. The
`epileptiform discharges of ]ME may be activated· by
`photic stimulation. If ]ME is suspected and the waking
`EEG is normal, it is imperative that a sleep-deprived
`EEG be obtained, since the abnormality may be present
`only during sleep deprivation.
`Identification of this syndrome is important for sev(cid:173)
`eral reasons. While myoclonic seizures may be associat(cid:173)
`ed with degenerative disease, JME is benign. Once the
`diagnosis of JME is established, the physician does not
`need to perform neuroimaging procedures such as mag(cid:173)
`netic resonance imaging (MRI) or computed tomogra(cid:173)
`phy (CT) or tests for neurodegenerative diseases. ]ME
`responds extremely well to treatment with valproic
`acid, so identification of this syndrome also enables the
`clinician to prescribe the proper AED. (Although the
`seizures respond well to valproic acid, the disorder
`persists throughout the patient's life, and withdrawal of
`AEDs is usually not possible.) Finally, identification of
`
`Critical issues Symposium
`
`]ME in a large number of patients has enabled investiga(cid:173)
`tors to establish hereditary patterns for this syndrome
`and has led to research linking it to chromosome locus
`6p21.3.22-24
`In summary, identification of a patient's epileptic
`syndrome often helps the clinician determine the type
`and extent of the workup required, guides him or her in
`selecting the proper AED, allows counseling of the
`patient as to the extent of the genetic risk for his or her
`offspring, and assists in establishing the prognosis.
`
`Evaluation
`The history and neurologic examination remain the
`cornerstones of neurologic diagnosis. As mentioned
`above, it is important to determine by history whether
`the patient has had a seizure and, if so, what type. In
`general, if there is uncertainty about the diagnosis, it is
`usually best to withhold treatment and wait for another
`attack before embarking on an extensive (and expen(cid:173)
`sive) workup and initiation of AED therapy.
`After diagnosing a seizure, the clinician must deter(cid:173)
`mine· its underlying or precipitating cause. The initial
`workup is partly determined by the patient's condition.
`The patient who arrives at the emergency room with
`status epilepticus (continuous seizure aCtivity) or who is
`comatose or febrile is approached differently from the
`patient who has totally recovered from the seizure by the
`time he or she sees the clinician. Methods for evaluating
`the second type of patient will be discussed here.
`Electroencephalography. When appropriately
`used, the EEG can support the diagnosis of epilepsy,
`localize onset of the seizures, delineate an epileptic
`syndrome, suggest prognosis, and even aid in choosing
`appropriate therapy. Since the routine EEG is noninva(cid:173)
`sive, safe, and relatively inexpensive compared with
`other diagnostic studies, all patients with suspected
`seizures should have one.
`Epileptiform patterns are distinct from the back(cid:173)
`ground activity appropriate for the patient's age and
`state, have an electrical field and configuration indica(cid:173)
`tive of cerebral origin, illustrate characteristic morpho(cid:173)
`logic features, and demonstrate predictable effects with
`activation procedures.25 Many of the patterns observed
`in neonates and young children are far different from
`those seen in adolescents, and the clinician must be
`aware of these age-specific patterns. Infantile spasms,
`early infantile epileptic encephalopathy, early myo(cid:173)
`clonic epileptic encephalopathy, benign rolandic epi(cid:173)
`lepsy, Landau-Kleffner syndrome, and juvenile
`myoclonic epilepsy are among the epileptic syndromes
`with distinct EEG signatures.
`While the value of an EEG in the evaluation of
`children with suspected epilepsy is beyond dispute,
`epileptiform activity on the EEG is rarely diagnostic of
`epilepsy. In a study population of 6497 nonepileptic
`patients, 142 (2.2%) had epileptiform discharges on
`their EEG but only 20 of those patients (14.1 %) eventu-
`
`Vol SO Dec 1993 Suppl 5 Am] Hasp Pharm 57
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2088 - 4/13
`
`

`
`Symposium Critical issues
`
`ally developed seizures. 26 In a separate study of 743
`normal children, 2. 7% showed epileptiform activity on
`the EEG while awake, versus 8.7% during sleep.27 Final(cid:173)
`ly, Cavazzuti et al.28 reported that in a study of 3726
`children, 131 (3.5%) had epileptiform activity on the
`EEG while awake but only 7 of those children ( 5%)
`eventually developed seizures.
`Conversely, a normal EEG does not rule out the
`possibility of epilepsy. In a study of 1824 EEGs from 308
`patients with known seizures who ranged in age from 1
`to 64 years, only 56% had epileptiform activity on the
`first EEG; subsequently, epileptiform activity was seen
`in an additional 26% of the patients. 29
`Neuroimaging. MRI and CT are superior to the
`clinical examination, EEG, and routine skull radiographs
`in the diagnosis of structural lesions of the central ner(cid:173)
`vous system (CNS).30-32 Whether all patients with sei(cid:173)
`zures require MRI or CT scans is still a matter of debate. A
`substantial number of neuroimaging studies show ab(cid:173)
`normal findings in children and adults with epilepsy.
`MRI is more sensitive than CT and is now the preferred
`test in the evaluation of a patient with seizures. 33,34
`MRI and. CT are frequently abnormal in children
`with partial seizures.35-37 Although most abnormalities
`will not alter management of the child, in a small but
`significant percentage an unexpected neoplasm or oth(cid:173)
`er treatable lesion will be discovered. In addition, even
`when the scan does not alter therapeutic management,
`it may offer the clinician" yaluable information regard(cid:173)
`ing the cause of the seizures. 35,37 A normal scan also
`serves to comfort both the physician and family that
`nothing is being missed. Even with a normal scan,
`however, the physician should follow the patient close(cid:173)
`ly because the development of neurologic signs would
`necessitate a repeat study.
`
`Treatment
`The first step in the treatment of seizures is to firmly
`establish the diagnosis. Many nonepileptic conditions
`resemble seizures. If the diagnosis is uncertain, it is better
`to withhold characterization of the patient as having
`epilepsy and initiation of potentially toxic medications.
`
`Since both children and adults who receive medical
`attention after their first partial or generalized seizure
`have only a 40% chance of recurrence, many physicians
`choose not to treat after just the first seizure. 38-42 There
`is a consensus that patients who have had two or more
`seizures should be placed on antiepileptic therapy.
`Once the diagnosis is established and the physician
`decides to treat, the next step is to determine which
`AED to use. This decision is based on efficacy and
`possible toxicity. Table 2lists the AEDs used to treat the
`various seizure types.
`Treatment should always be initiated with a single
`AED and the dosage slowly increased until the seizures
`are controlled or until clinical toxicity occurs. If the fitst
`AED does not work, the drug should be slowly tapered
`while a second AED is introduced.· AEDs should never
`be stopped abruptly unless a severe adverse effect oc(cid:173)
`curs. Although it is sometimes difficult to avoid poly(cid:173)
`therapy, the goal should be to have the patient taking a
`single AED. Monotherapy is likely to result in higher
`serum drug concentrations, fewer adverse effects, and
`better control.
`Serum drug concentrations are useful guides in as(cid:173)
`sessing therapy. 2 In general, patients have better seizure
`control when serum concentrations are within the
`usual therapeutic range than when they are below it.
`Likewise, patients with serum concentrations exceed(cid:173)
`ing the upper therapeutic range are more likely to
`experience adverse effects than those with concentra(cid:173)
`tions within the therapeutic range. Phenytoin, pheno(cid:173)
`barbital, carbamazepine, and primidone concentrations
`correlate better with seizure control and toxicity than
`do those of valproic acid, ethosuximide, and clonaze(cid:173)
`pam. It is far more important for the physician to listen
`to and examine the patient after initiating AED therapy
`than to guide therapy strictly by the serum concentra(cid:173)
`tion. If seizures are continuing and the patient is toler(cid:173)
`ating the medication well, the dosage should be
`increased. Conversely, if the patient has persistent ad(cid:173)
`verse effects, the dosage should be reduced.
`Once the patient achieves a serum AED concentra(cid:173)
`tion that controls seizures without producing adverse
`
`Table 2.
`Antiepileptic Drugs (AEDs) of Choice in the Treatment of Epilepsy
`
`Partial Seizures
`
`Generalized Seizures
`
`AED
`
`Simple
`
`Complex
`
`GTca
`
`Absence
`
`Myoclonic
`
`Clonic
`
`Tonic
`
`Atonic
`
`Carbamazepine Carbamazepine Carbamazepine Ethosuximide Valproic acid Valproic acid Valproic acid
`First
`choice Phenobarbital Phenobarbital Phenobarbital Phenobarbital
`Phenytoin
`Phenytoin
`Phenytoin
`Valproic acid
`Primidone
`Primidone
`Primodone
`Valproic acid
`Valproic acid
`Valproic acid
`Second Clonazepam
`Clonazepam
`Clonazepam
`choice Clorazepate
`Clorazepate
`Clorazepate
`
`Acetazolamide Clonazepam Clonazepam Carbamazepine Clonazepam
`Clonazepam
`Clonazepam
`Phenytoin
`
`Valproic acid
`
`a GTC = generalized tonic-clonic.
`
`58 Am] Hosp Pharm Vol SO Dec 1993 Suppl S
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
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`
`. effects, it is important to maintain it. Fluctuation of this
`! concentration, resulting from either noncompliance or
`drug interactions, places the patient at risk for recurrent
`seizures (if the concentration falls) or adverse effects (if
`it rises). Each patient has his or her own therapeutic
`range; the key to successful epilepsy management is to
`keep the patient within that range.
`Epilepsy in most children and adults can be man(cid:173)
`aged with one of the following first-line AEDs: carba(cid:173)
`mazepine, ethosuximide, phenobarbital, primidone,
`phenytoin, or valproic acid.1'2'43 A number of other
`agents are occasionally used in patients who do not
`respond to first-line agents. Agents such as clonazepam,
`clorazepate, methsuximide, and acetazolamide are con(cid:173)
`sidered second-line agents because their efficacy or
`adverse-effect profiles have relegated their use to situa(cid:173)
`tions .in which other medications are not effective. The
`first-line AEDs and two second-line AEDs (clonazepam
`and clorazepate dipotassium) will be discussed here.
`
`First-line AEDs
`Phenobarbital and primidone. Two of the most
`commonly used anticonvulsants are the barbiturates
`phenobarbital and primidone. 2~43 Both are effective in
`the treatment of GTC and partial complex seizures.
`Phenobarbital has been used to treat most seizure disor(cid:173)
`ders, while primidone has been used primarily in com(cid:173)
`plex partial seizures. Phenobarbital is also a first-line
`drug for status epilepticus. 44 It is considered to be an
`effective prophylactic drug for febrile seizures by most
`investigators,45-47 though not all.48 Although physi(cid:173)
`cians have been avoiding phenobarbital recently in
`favor of other anticonvulsants, it remains an inexpen(cid:173)
`sive, effective, and generally safe medication.49,50
`Serum phenobarbital concentrations of 15 to 40 J..Lg/
`mL are usually necessary for a reasonable therapeutic
`effect. 50 Serious adverse effects are usually· produced by
`concentrations exceeding 60 J.Lg/mL. Primidone's ther(cid:173)
`apeutic serum concentration is 5 to 12 J..Lg/mL.49,si,S2
`Primidone is metabolized by the liver to two com(cid:173)
`pounds, phenobarbital and phenylethylmalonamide,
`both of which have anticonvulsant properties. 53 Since
`phenobarbital derived from primidone usually reaches
`pharmacologically relevant concentrations, a pheno(cid:173)
`barbital concentration is obtained when checking the
`serum concentration of primidone.
`By far the most common adverse effect of these
`agents is sedation; however, with continued therapy,
`tolerance to this effect usually develops. In the experi(cid:173)
`ence of most pediatric neurologists, the most common
`adverse effects of the barbiturates are irritability, hyper(cid:173)
`activity, depression, sleep disorders, and cognitive ab(cid:173)
`normalities. 54-56 I have found that over 50% of patients
`or family members will report these effects when close(cid:173)
`ly questioned. Other ·adverse effects, such as rash or
`allergic manifestations, occur in less than 2% of pa(cid:173)
`tients.57 Adverse effects seen with primidone are be-
`
`Critical issues Symposium
`
`lieved to be dose related and usually occur with serum
`concentrations exceeding 15 J..Lg/mL, 58 although some
`patients tolerate concentrations as high as 20 J..Lg/mL.49
`Frequently observed effects include sedation, nausea,
`emesis, diplopia, dizziness, and ataxia. These effects can
`be minimized by initiating therapy at a low dose that is
`then increased to a therapeutic concentration.
`The oral maintenance dosage of phenobarbital in
`children is 2-6 mg/kg/day; the adult dosage is usually
`1.5-3.5 mg/kg/day.59 I do not recommend starting chil(cid:173)
`dren on a dosage higher than 90 mg. The administra(cid:173)
`tion of a loading dose is an effective strategy for reaching
`therapeutic serum concentrations rapidly. 59 Phenobar(cid:173)
`bital's half-life is 75 to 128 hours in adults, 37 to 126
`hours in older children and adolescents, 37 to 73 hours
`in young children, and 42 to 404 hours in neonates. 49
`Because of the long half-life, it takes two to three weeks
`for the drug to reach a steady-state therapeutic concen(cid:173)
`tration. Once-daily dosing, usually at bedtime, is ade(cid:173)
`quate except in infants.
`The usual dose of primidone in children is 5-20 mg/
`kg/day, while the adult dose is 750-1000 mg three or
`four times a day.49 Loading with primidone is not
`recommended. It is recommended that the drug be
`started at a dosage of 1-2 mg/kg at night for four to five
`days, then gradually increased by increments of 1 to 2
`mg/kg every three days until· a therapeutic effect is
`obtained. 49,52
`Frequent routine laboratory monitoring is not nec(cid:173)
`essary with the use of phenobarbital. Since megaloblas(cid:173)
`tic anemia may occasionally occur in patients taking
`primidone, complete blood counts are recommended
`every year.
`Phenytoin. Phenytoin has been used as a first-line
`AED for many years.2,3,43,60,61 It has been one of the
`major AEDs used in the treatment of partial seizures. As
`Ramsay62 noted, "The weight of clinical experience over
`the past 50 years has provided the basis for the accep(cid:173)
`tance of phenytoin, despite the fact that no placebo(cid:173)
`controlled trial has been conducted to prove its efficacy."
`Many efficacy studies in patients with partial and gen(cid:173)
`eralized seizures, however, have used phenytoin as the
`comparison drug. 63-66 Phenytoin can be given in a
`single daily dose to patients who can tolerate the ex(cid:173)
`tended-release capsules; it is highly effective and inex(cid:173)
`pensive, and it can also be administered intravenously.
`Phenytoin is supplied in 50-mg chewable tablets (of
`phenytoin) and 30- and 100-mg capsules of phenytoin
`sodium. An oral suspension of the base (30 mg/ 5 mL
`and 125 mg/5 mL) is available. (Throughout this discus(cid:173)
`sion, phenytoin dosages are expressed in terms of either
`phenytoin or phenytoin sodium.) The usual daily dos(cid:173)
`age in the pediatric group is 5 mg/kg. Adults typically
`require 300 to 400 mg/day. Nonlinear pharmacokinet(cid:173)
`ics may complicate dosage adjustment; as serum con(cid:173)
`centrations reach the therapeutic range, for example,
`small adjustments in dosage may yield disproportion-
`
`Vol 50 Dec 1993 Suppl 5 AmJ Hosp Pharm 59
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2088 - 6/13
`
`

`
`Symposium Critical i~sues
`
`ately large changes in phenytoin concentrations. It is
`recommended that once a patient has a serum concen(cid:173)
`tration above 8-10 f,lg/mL, dosage increases should be
`in increments of 25 mg/day.
`Rapid attainment of therapeutic serum concentra(cid:173)
`tions of phenytoin can be achieved in children by
`giving four doses of 5-6 mg/kg every eight hours; in
`adults, 300-400 mg every four to six hours for 24 hours
`is recommended. 61 The serum half-life of phenytoin
`depends on dose and starting concentration because of
`its nonlinear elimination kinetics. 60,61 Patients with
`toxic concentrations of phenytoin will have half-life
`values higher than patients with concentrations near
`the therapeutic range. The half-life is around 22 hours
`(10 to 34 hours) in adults receiving an average dosage,
`and 5 to 18 hours in children.43,61 Twice-daily dosing is
`often required in children, while adults typically do
`well with once-daily dosing. Steady-state therapeutic
`concentrations are achieved 7 to 10 days after initiation
`oftherapy.61 Optimum control without clinical signs of
`toxicity occurs with serum concentrations between 10
`and 20 f,lg/mL. 61 However, some patients require and
`tolerate serum concentrations greater than 20 flg/mL,
`while others attain seizure control with concentrations
`below 10 f,lg/mL.
`Adverse effects of phenytoin include gingival hyper(cid:173)
`trophy, hirsutism, acne, and, in some patients, behavior(cid:173)
`al changes and cognitive dysfunction. 2 At toxic concen(cid:173)
`trations, nausea, emesis, nystagmus, ataxia, and lethargy
`may result; occasionally patients experience increased
`seizures. Phenytoin may cause a mild elevation of liver
`enzymes that does not necessarily require discontinua(cid:173)
`tion of the drug if there is no other evidence of liver or
`systemic disease. More serious adverse effects, which are
`rare, include hematologic abnormalities such as throm(cid:173)
`bocytopenia, anemia, leukopenia, Stevens-Johnson syn(cid:173)
`drome, and lymphadenopathy. Phenytoin has been
`suspected of causing a slightly higher incidence ofcogni(cid:173)
`tive dysfunction than carbamazepine67-69; however,
`much of this may be due to a phenytoin-related de(cid:173)
`crease in motor speed rather than a true cognitive effect.
`Carbamazepine. Carbamazepine now ranks sec(cid:173)
`ond behind phenytoin in frequency of use in the Unit(cid:173)
`ed States. After its efficacy and safety were established in
`the treatment of trigeminal neuralgia, its marketing for
`treatment of epileptic adults was approved by FDA in
`the late 1960s. In 1976, the marketing of c