Treatment of Convulsive
`
`and Nonconvulsive
`
`Status Epilepticus
`Trudy Pang, MD
`*
`Lawrence J. Hirsch, MD
`
`Address
`
`'Comprehensive Epilepsy Center, Columbia University, Neurological
`Institute, Box NI-135, 710 W. 168th Street, New York, NY 10032, USA.
`E-mail: ljh3@columbia.edu
`
`Current Treatment Options in Neurology 2005, 7:247—259
`Current Science Inc. ISSN 1092-8480
`Copyright © 2005 by Current Science Inc.
`
`Opinion statement
`
`Status epilepticus (SE) should be treated as quickly as possible with full doses of medica-
`tions as detailed in a written hospital protocol. Lorazepam is the drug of choice for initial
`treatment. If intravenous access is not immediately available, then rectal diazepam or
`nasal or buccal midazolam should be given. Prehospital treatment of seizures by emer-
`gency personnel is effective and safe, and may prevent cases of refractory SE. Home treat-
`ment of prolonged seizures or clusters with buccal, nasal, or rectal benzodiazepines
`should be considered for all at-risk patients. Nonconvulsive SE is underdiagnosed. An
`electroencephalogram should be obtained immediately in anyone with unexplained alter-
`ation of behavior or mental status and after convulsive SE if the patient does not rapidly
`awaken. Delay in diagnosis of SE is associated with a worse outcome and a higher likeli-
`hood of poor response to treatment. For refractory SE, continuous intravenous midazolam
`and propofol (alone or in combination) are rapidly effective. Randomized trials are
`needed to determine the best treatment for SE after lorazepam.
`
`Status epilepticus (SE) is a medical and neurologic
`emergency. Overall, mortality is approximately 17% to
`23% [1,2]. An additional 10% to 23% of patients who
`survive SE are left with new or disabling neurologic def-
`icits [2,3]. The varied presentation of nonconvulsive SE
`(NCSE) can lead to misdiagnosis or delayed treatment.
`This article will review the recent literature pertaining to
`early, efficient recognition and management of SE.
`
`DEFINITION AND CLASSIFICATION
`
`Status epilepticus has traditionally been defined as con-
`tinuous or repetitive seizure activity persisting for at
`least 30 minutes without recovery of consciousness
`between attacks [4]. Recent revisions of this definition
`gradually shortened the duration of SE. Because isolated
`seizures rarely last more than 5 minutes, the current
`operational definition of SE is 5 minutes or more of
`continuous seizures or two or more discrete seizures
`with incomplete recovery of consciousness between sei-
`
`zures [5]. From a clinical standpoint, the most practical
`definition is any patient who is still seizing.
`There are many different types of SE. The simplest
`classification scheme divides SE into two major types:
`convulsive and nonconvulsive, based on whether or not
`there is rhythmic jerking. Generalized convulsive status
`epilepticus (GCSE), including generalized tonic-clonic,
`myoclonic, tonic, and clonic, is more easily recognized
`than NCSE. However, as GCSE continues, the overt symp-
`toms usually evolve into subtler features, such as subtle
`twitching of the face or limbs, or nystagmus [6]. Some
`patients may not show any motor symptoms of seizure
`and therefore have nonconvulsive status epilepticus. It is
`this group of patients who often evade early diagnosis
`because NCSE has protean manifestations, ranging from
`slight alteration of consciousness to coma. In the inten—
`sive care unit (ICU), most seizures are nonconvulsive and
`would not be noticed without electroencephalography
`(EEG) [70-]. Some clinicians attempt to classify NCSE
`AQUESTIVE EXHIBIT 1107 Page 0001
`AQUESTIVE EXHIBIT 1107 Page 0001
`
`

`

`Epilepsy
`248
`m
`
`based on its site of onset; however, practically, it often is
`not possible to distinguish between NCSE of generalized
`onset and NCSE ofpartial onset with bilateral spread.
`
`ETIOLOGY
`
`The most frequent cause of SE is a prior history of epi—
`lepsy (22% to 26%). However, more than half of epi—
`sodes of SE occur in patients without prior seizures. In
`these patients, stroke (19% to 20%) is the most fre-
`quent cause, followed by remote causes (16%), toxic-
`metabolic encephalopathy (12% to 18%), alcohol
`and/or drugs (8% to 15%), tumor (4% to 20%), car—
`diac arrest or hypoxia-ischemia (4% to 12%), infec-
`tion of the central nervous system (CNS) or other
`infection (4% to 7%), traumatic brain injury (2% to
`5%), and idiopathic or unknown causes (2% to 15%)
`[2;8, Class III; 9]. Metabolic etiologies include: low
`glucose, calcium, sodium, magnesium and phosphate
`(the latter particularly in alcoholic patients); high glu-
`cose, osmolality, blood urea nitrogen or creatinine;
`medication toxicity (theophylline, imipenem, iso-
`niazid [treat with pyridoxine], clozapine, cyclosporine
`and related drugs, fentanyl, meperidine, pro-
`poxyphene, bupropion, and high dose intravenous
`[IV] beta-lactam antibiotics); withdrawal from medi-
`cations and drugs (benzodiazepines, barbiturates,
`alcohol); and acute intoxication from illicit drugs,
`especially cocaine.
`
`DIAGNOSIS OF STATUS EPILEPTICUS AND NONCONVUL-
`SIVE STATUS EPILEPTICUS
`
`Early recognition of SE allows for prompt treatment and
`increases the likelihood of treatment success. Typically,
`patients who present with CCSE are expected to awaken
`gradually after the motor features of seizures disappear.
`If the mental status remains depressed 20 to 60 minutes
`after the convulsions cease, NCSE must be considered
`and urgent EEC is advised.
`
`Nonconvulsive seizures and NCSE are much more
`common than previously recognized, particularly in
`patients who are in the intensive care unit. Risk factors for
`nonconvulsive seizures or NCSE include severely impaired
`mental status of any cause, young age (<18 years), prior
`clinical seizures or remote epilepsy risk factors, and ocular
`movement abnormalities (sustained deviation, nystag-
`mus, or hippus) [700,10]. In one study, more than 50% of
`96 comatose patients undergoing continuous EEC moni-
`toring had nonconvulsive seizures [ 7"].
`Any fluctuating or unexplained alteration in behav-
`ior or mental status warrants an EEG and consideration
`ofNCSE. Delays in the recognition of NCSE are associ-
`ated with poor outcome and lessen the likelihood of
`successful seizure control [110].
`
`CONSEQUENCES OF STATUS EPILEPTICUS
`Patients who present with a first episode of SE are at
`increased risk for development of epilepsy compared
`with those with a single, brief first episode of seizure
`[12]. Status epilepticus after stroke has been shown to
`be associated with a much higher mortality, indepen—
`dent of stroke size and location [13]. In CCSE and
`NCSE, long seizure duration and delay to diagnosis are
`independent predictors of poor outcome after control-
`ling for etiology [110,14]. There are several reported
`cases of prolonged nonconvulsive seizures alone caus-
`ing permanent CNS injury or worsening [15, Class III].
`In patients with intracerebral hemorrhage, nonconvul-
`sive seizures are associated with increased mass effect
`and shift after controlling for hemorrhage size [160,
`Class II]. SE also can cause nonneurologic abnormali-
`ties, including acidosis, rhabdomyolysis, renal failure,
`arrhythmias, and aspiration. Fever, hypotension,
`hypoxia, and metabolic abnormalities accelerate sei—
`zure-related neuronal injury and should be corrected
`aggressively. The best way to prevent these adverse
`effects is to stop the seizure activity as soon as possible.
`
`Treatment
`
`General principles
`
`0 Early cessation of seizures is the key in the management of SE. Treatment
`strategies should focus on several aspects: early termination of seizure,
`identification of the cause, prevention of seizure recurrence, and treatment
`of secondary complications.
`
`0 As summarized in Table 1, initial steps in the management of SE involve
`basic life support. Patients should receive 100% oxygen by nasal cannula or
`nonrebreather mask, and may require intubation if there is evidence of res-
`piratory failure. Patients should not be pharmacologically paralyzed for
`intubation unless continuous EEC is being recorded, or unless absolutely
`necessary. IV access should be established quickly to administer drugs nec-
`essary for seizure control and resuscitation, but rectal, buccal, or nasal ben-
`zodiazepines should be given if there is any delay in obtaining IV access
`(see below). Fever and hypotension should be treated concurrently. Labora-
`
`AQUESTIVE EXHIBIT 1107 Page 0002
`AQUESTIVE EXHIBIT 1107 Page 0002
`
`

`

`Treatment of Convulsive and Nonconvulsive Status Epilepticus Pang and Hirsch
`
`249
`
`Table 1. Treatment protocol for status epilepticus in adults
`
`wT
`
`ime, min
`
`Action
`
`0 to 5
`
`6 to 10
`
`10 to 20
`20 to 60
`
`60
`
`Diagnose; give supplemental 02; check ABC; obtain IV access; begin EKG and blood pressure monitoring;
`draw blood for basic metabolic panel: Mg, Ca, phosphate, CBC, Ll-Ts, AED levels, arterial blood gas; do
`toxicology screen.*
`Thiamine 100 mg IV; give 50 mL 050 IV unless adequate glucose known. Lorazepam 4 mg IV over 2 min; if the
`patient is still seizing, repeat once in 5 min. If there is no rapid IV access, give diazepam 20 mg rectally or
`midazolam 10 mg intranasally, buccally, or intramuscularly.T
`If seizures persist, begin fosphenytoin 20 mg/kg IV at 150 mg/min, with blood pressure and EKG monitoring.
`If seizures persist, give one of four options:i 1) give cIV midazolam at a loading dosage of 0.2 mg/kg; repeat
`0.2 to 0.4 mg/kg boluses every 5 minutes until seizures stop, up to a maximum total loading dose of 2 mg/
`kg. Initial cIV rate is 0.1 mg/kg/hr. cIV dose range: 0.05 - 2 mg/kg/hr. If still seizing, proceed to cIV pro-
`pofol or pentobarbital; or 2) give cIV propofol at a loading dosage of 1 to 2 mg/kg. Repeat 1 to 2 mg/kg
`boluses every 3 to 5 minutes until seizures stop, up to maximum total loading dose of 10 mg/kg. Initial cIV
`rate is 2 mg/kg/h. cIV dose range is 1 to 15 mg/kg/h. If the patient is still seizing, proceed to cIV mida-
`zolam or pentobarbital; or 3) give IV valproate 40 mg/kg over approximately 10 minutes. If the patient is
`still seizing, give an additional 20 mg/kg over approximately 5 minutes. If the patient is still seizing, pro-
`ceed to cIV midazolam or propofol; or 4) give IV phenobarbital 20 mg/kg IV at 50 to 100 mg/min. If the
`patient is still seizing, proceed to cIV midazolam, propofoi, or pentobarbital.
`Give cIV pentobarbital at a loading dosage of 5 to 10 mg/kg at up to 50 mg/min; repeat 5 mg/kg boluses
`until seizures stop. Initial cIV rate should be 1 mg/kg/h. cIV dose range is 0.5 to 10 mg/kg/h; tradition-
`ally titrated to suppression-burst on EEG. Begin EEG monitoring as soon as possible if patient does not rap-
`idly awaken or if any cIV treatment is used.
`
`*Urine and blood
`1The IV solution of diazepam can be given rectally if Diastat is not available; the IV solution of midazolam can be given by any of
`these routes
`tIntubation necessary except for valproate
`ABC— airway, breathing and circulation; AED—antiepileptic drug; CBC—complete blood count; cIV—continuous intravenous; EEG—elec-
`troencephalogram; EKG—electrocardiogram; IV—intravenous; LFT—liver function test
`
`tory studies should be sent (see Table 1). A bedside glucose level should be
`obtained, and 100 mg thiamine and 50 mL 50% glucose should be admin-
`istered if hypoglycemia is present or if glucose level is unknown. Other
`components of management include determining whether there is a his-
`tory of alcohol or drug use, previous epilepsy, or neurologic insult. A
`description of the seizure at onset should be obtained if witnessed, and
`brain imaging should be done after the patient is stable and seizures are
`controlled. For seizures caused by a metabolic abnormality, correcting the
`metabolic problem is more effective than antiepileptic drugs (AEDS).
`
`' First line medications control SE in 80% of patients when initiated within 30
`minutes, but in 40% if started after 2 hours of onset [3;8, Class III]. For practi-
`cal purposes, treatment should be started after 5 minutes of continuous sei-
`zure activity. Our protocol for treatment of SE in adults is shown in Table 1.
`
`Initial pharmacologic therapy
`
`its
`
`,
`
`. ,
`
`”W .
`'2 «i,
`
`5435,
`
`Benzodiazepines
`
`0 Benzodiazepines are potent, parenterally available medications with a
`rapid onset of action and are the preferred initial therapy. Their mechanism
`of action involves binding to high affinity sites on the y-aminobutyric acid
`(GABA) receptor, resulting in hyperpolarization of the neuronal cell mem-
`brane and decreased neuronal firing [17].
`
`AQUESTIVE EXHIBIT 1107 Page 0003
`AQUESTIVE EXHIBIT 1107 Page 0003
`
`

`

`Epilepsy
`250
`R
`
`Lorazepam
`
`Standard dosage 4 to 8 mg given intravenously (0.1 mg/kg). Onset of action is 3 to 10 minutes
`Duration of antiepileptic effects is 12 to 24 hours (slower redistribution than diaz-
`epam). Elimination half-life is 14 hours.
`
`Contraindications Hypersensitivity to drug.
`Main drug interactions Increased sedation with other CNS depressants. Lorazepain is highly protein-bound.
`Main side effects Sedation of several hours, occasional respiratory depression, hypotension.
`Special points Lorazepam is the drug of choice in the initial management of SE. It has several
`important advantages over diazepam, which has been used traditionally. Diazepam
`has a much shorter duration of antiepileptic action (approximately 15 to 30 min-
`utes), but its elimination half life of 30 hours is twice that of lorazepam, making it
`less optimal. However, the rectal preparation of diazepam can be valuable when IV
`access is not available.
`
`Midazolam Wan-w saw-mmmmmm“em“..mmm
`Give when there is no immediate IV access; see below for continuous IV drip for
`refractory SE.
`
`Standard dosage 0.2 to 0.3 mg/kg intramuscular (IM), intranasal (IN), or buccal. Onset of action is
`1 to 5 minutes.
`
`Contraindications Hypersensitivity to drug.
`Main drug interactions Increased sedation with other CNS depressants
`Main side effects Sedation, occasional respiratory depression, cardiac arrest, hypotension.
`Special points Midazolam is a water-soluble drug in acidic environments, thereby allowing for an
`intramuscular preparation in addition to the IV form [18]. It is lipid-soluble in
`physiologic pH ranges and is able to penetrate the brain to exert its anticonvulsant
`effects. When IV access cannot be established, buccal, IN or IM midazolam plays
`an important role in seizure control. Buccal and IN forms in particular are good
`alternatives for out-of-hospital settings. Continuous IV midazolam also plays a key
`role in refractory SE (discussed below).
`
`.4.“
`
`“WM
`
`w
`
`.
`
`.7...
`
`Alternative routes of administration of benzodiazepines
`0 Alternative modes of administration are particularly important in patients
`without IV access in various settings. Prompt treatment by caregivers out-
`side the hospital can shorten the duration of seizure, prevent progression to
`SE, and possibly reduce the need for emergency room visits (potentially
`lowering health care costs). Rectal, 1M, buccal, and IN all are alternatives
`which have been shown to effectively and rapidly control seizures [190,
`Class I; 20;21,22, Class III; 23;24—26, Class 1]. Currently, rectal diazepam
`gel (Diastat, Xcel Pharmaceuticals, San Diego, CA) available in prefilled
`syringes, is the only version approved by the United States Food and Drug
`Administration. In a randomized trial involving patients with seizure clus-
`ters, a single dose of rectal diazepam gel decreased seizure frequency signif-
`icantly and increased the chance of seizure freedom after treatment
`compared with placebo (55% vs 34%) [26, Class]. In children, IM mida-
`zolam has been shown to stop seizures more rapidly than IV diazepam
`because of earlier administration [24, Class I].
`0 Buccal and IN midazolam are easier to administer than rectal medications
`and are more socially acceptable. Two prospective studies have shown that
`IN or buccal midazolam is effective in aborting prolonged seizures in
`adults and children [22, Class III; 270, Class 1]. Scott et al. [190, Class I]
`found that in children with seizures lasting more than 5 minutes, buccal
`midazolam was as effective as rectal diazepam. In a recently presented ran-
`domized trial in children presenting to the emergency room with acute
`tonic-clonic seizures, buccal midazolam was more likely to stop seizures in
`
`AQUESTIVE EXHIBIT 1107 Page 0004
`AQUESTIVE EXHIBIT 1107 Page 0004
`
`

`

`Treatment of Convulsive and Nonconvulsive Status Epilepticus Pang and Hirsch
`
`251
`
`less than 10 minutes than rectal diazepam, and had a similar (slightly
`lower) rate of respiratory depression [28, Class I]. In select patients, these
`forms of benzodiazepines also can confer the ability of patients to treat
`themselves during prolonged auras, simple partial seizures, or clusters with
`recovery between seizures.
`
`Comparison of benzodiazepines
`
`Recent studies investigating out—of-hospital treatment of SE found benzodi—
`azepines to be safe and effective when administered by paramedics for out-
`of-hospital SE in adults [29”, Class I]. In this study, 59% of patients with
`SE treated with IV lorazepam in the field were no longer seizing on arrival at
`the emergency department, compared with 43% of patients treated with IV
`diazepam, and 21% in the placebo group. Respiratory and circulatory com-
`plications were higher in the placebo group (22.5%) than in the diazepam
`and lorazepam groups (10% to 11%). In an older randomized trial compar-
`ing 4 mg IV lorazepam to 10 mg IV diazepam, SE was controlled in 89% of
`patients in the lorazepam group, compared with 76% in the diazepam
`group, and there were no significant differences in side effects [30 Class I].
`The clinical bottom line is that when IV access is available, IV lorazepam
`should be initiated as first—line therapy, and if possible, in the prehospital
`phase. If widely practiced, this type of treatment could have a major impact
`on the prevention of refractory status epilepticus. Whenever obtaining IV
`access would delay administration ofAEDs significantly, diazepam should
`be given rectally (0.2 to 0.5 mg/kg for SE; usually 20 mg for an adult), or
`midazolam should be given nasally, buccally, or intramuscularly (0.2 to 0.3
`mg/kg; usually 10 to 15 mg for an adult). Patients with a history ofpro-
`longed seizures or acute repetitive seizures should be offered rectal diaz-
`epam, or nasal or buccal midazolam for out-of-hospital use.
`
`Most patients who respond to first-line agents also will require mainte-
`nance therapy with a second-line agent because the risk of recurrence is
`high. Additionally, second-line therapy must be initiated quickly when
`patients continue to seize despite treatment with benzodiazepines. The
`longer SE persists, the higher the risk for developing refractory status epi-
`lepticus. If convulsions are successfully abated but patients fail to improve
`in their mental status, there is a high probability of ongoing subclinical sei-
`zures or NCSE. Such cases warrant additional treatment. DeLorenzo et al.
`[31, Class II] found subclinical electrographic seizure activity in 48% of
`patients after control ofconvulsive SE, including NCSE in 14%. Towne et al.
`[320, Class III] found that among 236 comatose patients with no current or
`past evidence of seizures, 8% showed electrographic seizures. In the Veteran
`Affair Cooperative study, 20% of convulsive SE patients whose movements
`stopped with treatment still were seizing as shown by EEC [33", Class 1].
`Therefore, EEG is mandatory for all patients who do not wake up quickly
`after cessation of clinical SE, and for all patients with unexplained coma.
`
`Second-line pharmacotherapy
`
`Phenytoin
`
`‘MWymmc—nwvvuAWHMVV “WWW/a. ..M_.~.mn m, .mawm...“ vavmw/maw “twang.
`'rnwmi my... MW v4
`The primary mechanism of action of phenytoin is inhibition of high-frequency“
`repetitive neuronal firing by blocking voltage-dependent sodium channels [34]. It
`is the most commonly used second-line therapy in status epilepticus.
`Standard dosage 20 mg/kg load given intravenously. The maximum infusion rate is 50 mg/min. Max-
`imal effect is achieved in 20 to 25 minutes.
`
`AQUESTIVE EXHIBIT 1107 Page 0005
`AQUESTIVE EXHIBIT 1107 Page 0005
`
`

`

`Epilepsy
`252
`xx
`
`Contraindications
`
`Main drug interactions
`
`Main side effects
`
`Special points
`
`Hypersensitivity to drug, heart block. Use caution if there is impaired liver or
`renal function.
`
`Highly protein-bound (>90°/o). Phenytoin may displace other drugs that are pro-
`tein-bound and increase free levels of other drugs. Also induces hepatic metabo-
`lism of many medications, including other AEDs.
`Cardiac arrhythmias (bradycardia, ectopic beats), hypotension, hepatotoxicity,
`pancytopenia, phlebitis, soft tissue injury from extravasation, purple glove syn-
`drome, allergy including Stevens-Johnson syndrome.
`During and after SE, the target free-phenytoin level should be 1.5 to 2.5 pg/ml,
`equivalent to a total phenytoin level of 15 to 25 pg/mL in the presence of normal
`protein binding. Daily serum levels should be followed. Free phenytoin levels can
`become very high in patients with low albumin (malnutrition, critical illness, liver
`insufficiency) or those who are on other highly protein-bound drugs such as ben-
`zodiazepines and valproate. It cannot be mixed with glucose or dextrose because
`of precipitation and should not be given in small peripheral veins or IM.
`
`Fosphenytoin
`
`
`
`
`
`
`
`Fosphenytoin is a phenytoin prodrug without the propylene glycol carrier and has
`fewer side effects. It is quickly dephosphorylated to phenytoin when given IM or
`IV. IV fosphenytoin is preferred to IV phenytoin because of its water solubility and
`normal pH, thereby allowing more rapid administration with less irritation of veins,
`less hypotension during administration, no risk of skin necrosis or purple glove
`syndrome with extravasation, and compatibility with all IV fluids. It is dosed as
`phenytoin-equivalents.
`
`20 mg/kg load given intravenously. The maximum infusion rate is 150 mg/min
`(three times the rate of phenytoin). If patients continue to seize after receiving 20
`mg/kg, an additional 5 to 10 mg/kg may be given. It also can be given intramus-
`cularly, with low therapeutic levels reached in 30 minutes and peak levels in 2
`hours, but this is too slow for convulsive SE. The elimination half-life is 10 to 15
`minutes (for conversion to phenytoin).
`See phenytoin.
`See phenytoin.
`
`Lower risk of hypotension than phenytoin (5% to 15%, rate dependent). Arrhyth-
`mias and respiratory depression are rare. Decreased consciousness, transient pruri-
`tus (in as many as 50% of awake patients, not an allergic reaction; often in the
`groin; possibly attributable to phosphate load) also are possible. Cardiac complica-
`tions still can occur with fosphenytoin. Blood pressure and electrocardiograms
`should be monitored well after infusion ends because phenytoin is effectively still
`being loaded for more than 15 minutes after the end of the infusion. Otherwise the
`side effects are the same as phenytoin.
`See phenytoin for target serum levels. Serum phenytoin levels should be obtained
`2 hours after an IV load or 4 hours after IM delivery to allow complete conversion
`to phenytoin.
`
`Standard dosage
`
`Contraindications
`
`Main drug interactions
`Main side effects
`
`Special points
`
`Phenobarbital
`WWW. “mm.“mma..m.VW/.m»mmm~m.¢mwwmWV N ,
`»
`WWW” m, ‘ WW u umWVr‘ an... m...» c mm,“ WWW/mm. .......mm...-~mw .»mmm~,ww—m.wu
`Phenobarbitafis one of the long acting barbiturates that act by potentiation of ye
`aminobutyric acid (GABA) and by interfering with sodium and potassium transport
`across the cell membrane.
`
`Standard dosage
`
`Contraindications
`
`Main drug interactions
`
`Main side effects
`
`Special points
`
`15 to 20 mg/kg given intravenously. The maximum infusion rate is 50 to 100 mg/
`min. The elimination half life is 72 hours.
`
`Hypersensitivity to drug, severe liver dysfunction.
`Increased respiratory depression, sedation, and hypotension are possible, espe—
`cially when given in conjunction with benzodiazepines.
`Respiratory depression (patients often need intubation), prolonged sedation,
`allergy including Stevens-Johnson syndrome, blood dyscrasias.
`Target serum levels are 30 to 45 pg/mL initially, but some patients may need
`higher levels.
`
`AQUESTIVE EXHIBIT 1107 Page 0006
`AQUESTIVE EXHIBIT 1107 Page 0006
`
`

`

`Treatment of Convulsive and Nonconvulsive Status Epilepticus Pang and Hirsch
`
`253
`
`,VafPfqate,
`
`_,
`
`,.
`
`Although currently notapproved by the United States Food and Drug Administra-
`tion for use in SE, several small case series suggest good efficacy for IV valproate
`in the treatment of different types of SE, including partial onset, nonconvulsive,
`absence, and myoclonic SE [35,36]. In a recent review of 63 patients, IV valproate
`was infused at an average dose of 31.5 mg/kg (range, 10 to 78 mg/kg), an average
`rate of 200 mg/min (range, 200 to 500 mg/min) [37]. An overall efficacy of 63.3%
`was achieved when used as a second, third, or fourth drug. It was well-tolerated
`with hypotension occurring in only three patients.
`20 mg/kg load given intravenously; however, in the presence of enzyme-inducing
`drugs such as phenytoin, phenobarbital, or carbamazepine, higher dosages of 40 to
`60 mg/kg are needed. Maximum bolus rate: approved for rates up to 3 mg/kg/min
`for a total loading dose of up to 15 mg/kg (although we and others give much
`larger loading dosages as above). Faster rates have been well-tolerated, including
`5 to 6 mg/kg/min [35,38].
`
`Hypersensitivity to drug, severe liver dysfunction, thrombocytopenia.
`Because of the interaction between phenytoin and valproic acid, which are heavily
`protein-bound AEDs, it is important to follow unbound (free) leveLs, especially of
`phenytoin, to avoid toxicity.
`Hepatotoxicity (including fatal), thrombocytopenia, pancreatitis. Hypotension is
`rare but has been reported [39].
`Target serum levels are 70 to 140 ug/mL for SE. There is minimal sedation (intuba-
`tion may be avoided); therefore, it is particularly useful for refractory SE in a
`patient who has a "do not intubate" status.
`
`Standard dosage
`
`Contraindications
`
`Major drug interactions
`
`Main side effects
`
`Special points
`
`
` Comparison of initial treatment options for status epilepticus
`' Only a few prospective randomized trials have been done comparing treat-
`ment strategies for SE; some were discussed above. The largest prospective
`study was the VA Status Epilepticus Cooperative study [3300, Class I],
`which was a randomized, double-blind, multicenter trial that compared
`four IV treatments: lorazepam, diazepam followed by phenytoin, phe—
`nobarbital, and phenytoin alone. In generalized convulsive SE, lorazepam
`was found to be most effective (65% for lorazepam alone vs 58% for phe-
`nobarbital, 56% for diazepam plus phenytoin, and 44% for phenytoin
`alone). The difference was statistically significant between lorazepam and
`phenytoin only. For subtle SE, no statistical difference was found between
`the groups and the response rate was poor. All four treatment arms had
`similar complication rates.
`
`Refractory status epilepticus
`
`0 Refractory SE (RSE) is defined as persistent convulsive SE or NCSE despite
`the use of two agents (usually a benzodiazepine plus another drug, typi-
`cally phenytoin). The next step of treatment usually is use of continuous
`drips or high doses of medications that may cause significant sedation, res—
`piratory depression, and hypotension. Patients most often at this point
`have been intubated and transferred to the intensive care unit. The available
`agents include barbiturates (pentobarbital, thiopental, or high dose phe-
`nobarbital), propofol, and midazolam. The traditional treatment algorithm
`suggests loading with phenobarbital at this point, followed by continuous
`IV pentobarbital if that fails. Our preference is to use rapid-acting drips
`(midazolam or propofol) instead of phenobarbital after a patient has failed
`first— and second-line drugs.
`
`AQUESTIVE EXHIBIT 1107 Page 0007
`AQUESTIVE EXHIBIT 1107 Page 0007
`
`

`

`
`
`254 EpilepsyK
`
`0 To date, no randomized controlled trials have been done for second-line
`therapy or for SE refractory to first— and second—line therapy. The most expe-
`rience exists with continuous infusions (clV) of midazolam and propofol.
`There is some preliminary evidence from two small retrospective series that
`propofol is effective, fast, and easy to use [40,41, Class [II], but may be asso-
`ciated with a higher mortality than midazolam (but not statistically differ—
`ent). In a systematic review of the literature on treatment of 193 patients
`with RSE, no difference was found in mortality among the groups treated
`with cIV propofol, cIV midazolam, or cIV pentobarbital [42, Class III].
`Mortality was related to the patient’s age and duration of SE rather than
`AED choice. The safety of propofol was additionally supported in a more
`recent retrospective series by Rossetti et al. [430, Class III], in which 27
`patients who failed IV clonazepam and phenytoin therapy were induced
`into burst-suppression pattern on cEEG with cIV propofol at a dose of 2.1
`to 13 mg/kg/h for 1 to 9 days while continuing clonazepam infusions.
`Seven deaths (23%) were reported but none were attributable directly to
`propofol use and no patient experienced propofol infusion syndrome. A
`systematic review by Claassen et al. [42, Class III]
`(published before the
`Rossetti propofol study) found no demonstrable difference between propo-
`fol and midazolam for clinical endpoints such as acute treatment failure,
`breakthrough seizures, or posttreatment seizures. Pentobarbital seemed to
`have had a lower frequency of acute treatment failure and breakthrough sei-
`zures, but this was confounded by two factors. First, the pentobarbital was
`infused until background burst suppression was reached, whereas the other
`two drugs usually were titrated to seizure control, not burst-suppression.
`Second, most patients on pentobarbital did not have continuous EEG mon-
`itoring. In our experience and others, most breakthrough seizures in RSE
`patients are subclinical (89%), and would be missed in the absence of con-
`tinuous EEG monitoring [31, Class II; 440, Class III]. Hypotension, which
`further complicates the treatment of these critically ill patients, occurred
`more frequently with pentobarbital (titrated to EEC background suppres-
`sion) than with propofol or midazolam (usually titrated to suppression of
`seizures) [42, Class III].
`
`
`
`
`Continuous intravenous antiepileptics for refractory status epilepticus in adults
`0 All patients on CIV AEDs require continuous EEG monitoring.
`
`Continuous intravenous pentobarbita
`
`Standard dosage 5 to 10 mg/kg bolus. Repeat 5 mg/kg boluses until seizures stop. Maximum bolus
`rate is 25 to 50 mg/min (if blood pressure permits). The initial infusion rate is 1
`mg/kg/h. The usual maintenance range is 0.5 to 10 mg/kg/h, traditionally titrated
`to suppression-burst on EEG. The elimination half life is 15 to 60 hours.
`
`Contraindication Hypersensitivity to drug.
`Main side effects Prolonged coma (usually days after infusion is stopped), hypotension (usually
`requires vasopressors), myocardial depression, immune suppression, ileus, allergy
`including Stevens-Johnson syndrome.
`
`
`
`Continuous intravenous midazolam
`
`Standard dosage 0.2 mg/kg bolus. Repeat 0.2 to 0.4 mg/kg boluses every 5 minutes until seizures
`stop, up to a maximum total loading dose of 2 mg/kg. The initial infusion rate is
`0.1 mg/kg/h. The usual maintenance range is 0.05 to 2 mg/kg/h (this is higher
`than dosages in older literature). For breakthrough seizures, an additional bolus
`can be given, and the cIV rate should be increased by 20%. SE usually stops in less
`
`AQUESTIVE EXHIBIT 1107 Page 0008
`AQUESTIVE EXHIBIT 1107 Page 0008
`
`

`

`Treatment of Convulsive and Nonconvulsive Status Epilepticus Pang and Hirsch
`
`255
`
`Contraindications
`Main side effects
`
`than 1 hour. Duration of antiepileptic effects is minutes to hours. The elimination
`half-life is 1.5 to 3.5 hours initially. With prolonged use, there may be tolerance,
`tachyphylaxis, and significant prolongation of half-life, up to days [45].
`Hypersensitivity to drug.
`
`Sedation of minutes to several hours and possibly days with prolonged use, respira-
`tory depression, occasional hypotension.
`
`Continuous intravenous propofol
`
`Starting dosage
`
`Contraindications
`Main side effects
`
`Special points
`
`Propofol is a GABA-A agonist that suppresses seizure activity via GABA-mediated
`inhibition of neuronal firing. Other mechanisms of action include inhibition of the
`N~methyl-D-aspartate receptor and modulation of calcium influx through slow cal-
`cium ion channels.
`
`1 mg/kg bolus. Repeat 1 to 2 mg/kg boluses every 3 to 5 minutes until seizures stop,
`up to maximum loading dose of 10 mg/kg. Initial cIV rate is 2 mg/kg/h. Continuous
`IV dosage range is 1 to 15 mg/kg/h. SE usually sto