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: jh3@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 choiceforinitial
`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 personnelis effective and safe, and may prevent casesofrefractory SE. Hometreat-
`mentof prolonged seizures or clusters with buccal, nasal, or rectal benzodiazepines
`should be consideredforall at-risk patients. Nonconvulsive SEis underdiagnosed. An
`electroencephalogram should be obtained immediately in anyone with unexplained alter-
`ation of behavior or mental status and after convulsive SEif the patient does not rapidly
`awaken. Delay in diagnosis of SE is associated with a worse outcome and a higherlikeli-
`hood of poorresponse to treatment. For refractory SE, continuous intravenous midazolam
`and propofol(alone or in combination) are rapidly effective. Randomizedtrials are
`needed to determine the best treatmentfor 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% ofpatients 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.
`Thisarticle will review the recentliterature pertaining to
`early, efficient recognition and managementofSE.
`
`DEFINITION AND CLASSIFICATION
`Status epilepticus has traditionally been defined as con-
`tinuousor repetitive seizure activity persisting for at
`least 30 minutes without recovery of consciousness
`betweenattacks [4]. Recent revisions ofthis definition
`gradually shortened the duration ofSE. Becauseisolated
`seizures rarely last more than 5 minutes, the current
`operational definition of SE is 5 minutes or more of
`continuousseizures or two or morediscrete seizures
`with incomplete recovery of consciousness between sei-
`
`zures [5]. From a clinical standpoint, the mostpractical
`definition is any patient whoisstill seizing.
`There are many different types of SE. The simplest
`classification schemedivides SE into two majortypes:
`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-
`tomsusually evolve into subtler features, such as subtle
`twitching of the face or limbs, or nystagmus[6]. Some
`patients may not show any motor symptomsofseizure
`and therefore have nonconvulsivestatus epilepticus.It is
`this group of patients whooften evadeearly diagnosis
`because NCSEhas protean manifestations, ranging from
`slightalteration of consciousness to coma.In the inten-
`sive care unit (ICU), mostseizures are nonconvulsive and
`would notbe noticed without electroencephalography
`(EEG) [7¢e]. Some clinicians attemptto classify NCSE
`AQUESTIVE EXHIBIT 1107 Page 0001
`AQUESTIVE EXHIBIT 1107 Page 0001
`
`

`

`248
`Epilepsy
`SSeee
`
`basedonits site of onset; however, practically, it often is
`notpossible to distinguish between NCSE ofgeneralized
`onset and NCSEofpartial onsetwith bilateral spread.
`
`Nonconvulsive seizures and NCSE are much more
`common than previously recognized, particularly in
`patients whoare in theintensive care unit. Risk factors for
`nonconvulsive seizures or NCSEincludeseverely impaired
`mental status of any cause, young age (<18 years), prior
`clinical seizures or remote epilepsyrisk factors, and ocular
`movement abnormalities (sustained deviation, nystag-
`mus, or hippus) [7¢e,10]. In one study, more than 50% of
`96 comatose patients undergoing continuous EEG moni-
`toring had nonconvulsive seizures [7ee].
`Anyfluctuating or unexplained alteration in behav-
`ior or mental status warrants an EEG andconsideration
`of NCSE. Delays in the recognition of NCSE are associ-
`ated with poor outcome and lessen the likelihood of
`successfulseizure control [11].
`
`ETIOLOGY
`The most frequentcauseofSE is a prior history ofepi-
`lepsy (22% to 26%). However, morethanhalfof epi-
`sodes of SE occur in patients withoutprior seizures. In
`these patients, stroke (19% to 20%) is the most fre-
`quentcause, 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 unknowncauses (2% to 15%)
`[2;8, Class III; 9]. Metabolic etiologies include: low
`CONSEQUENCESOF STATUS EPILEPTICUS
`glucose, calcium, sodium, magnesium and phosphate
`Patients who presentwith a first episode of SE areat
`(the latter particularly in alcoholic patients); high glu-
`increased risk for developmentof epilepsy compared
`cose, osmolality, blood urea nitrogen or creatinine;
`with those withasingle, brief first episode of seizure
`medication toxicity (theophylline, imipenem, iso-
`[12]. Status epilepticus after stroke has been shown to
`niazid [treat with pyridoxine], clozapine, cyclosporine
`be associated with a much higher mortality, indepen-
`and related drugs, fentanyl, meperidine, pro-
`dent of stroke size and location [13]. In GCSE and
`poxyphene, bupropion, and high dose intravenous
`NCSE,longseizure duration and delay to diagnosis are
`[IV] beta-lactam antibiotics); withdrawal from medi-
`independentpredictors of poor outcomeafter control-
`cations and drugs (benzodiazepines, barbiturates,
`ling for etiology [11,14]. There are several reported
`alcohol); and acute intoxication from illicit drugs,
`cases of prolonged nonconvulsive seizures alone caus-
`especially cocaine.
`ing permanent CNSinjury or worsening [15, Class III].
`In patients with intracerebral hemorrhage, nonconvul-
`sive seizures are associated with increased masseffect
`and shift after controlling for hemorrhagesize [16e,
`Class II]. SE also can cause nonneurologic abnormali-
`ties, including acidosis, rhabdomyolysis, renalfailure,
`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.
`
`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 GCSEare expected to awaken
`gradually after the motorfeatures of seizures disappear.
`If the mental status remains depressed 20 to GO minutes
`after the convulsions cease, NCSE must be considered
`and urgent EEGis advised.
`
`Treatment
`General principles
`
`° Early cessation ofseizuresis the key in the managementof SE. Treatment
`strategies should focus onseveral aspects: early termination ofseizure,
`identification of the cause, prevention of seizure recurrence, and treatment
`of secondary complications.
`As summarizedin Table 1, initial steps in the managementofSE involve
`basic life support. Patients should receive 100% oxygen by nasal cannula or
`nonrebreather mask, and may require intubationif there is evidence ofres-
`piratory failure. Patients should not be pharmacologically paralyzed for
`intubation unless continuous EEGis being recorded, or unless absolutely
`necessary. IV access should be established quickly to administer drugs nec-
`essary for seizure control andresuscitation, butrectal, buccal, or nasal ben-
`zodiazepinesshould be givenif there is any delay in obtaining IV access
`(see below). Fever and hypotension should betreated 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
`
`Time, 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, LFTs, AED levels, arterial blood gas; do
`toxicology screen.*
`Thiamine 100 mg IV; give 50 mL D50 IV unless adequate glucose known. Lorazepam 4 mq IV over 2 min; if the
`patientis still seizing, repeat once in 5 min. If there is no rapid IV access, give diazepam 20 mgrectally or
`midazolam 10 mgintranasally, buccally, or intramuscularly.
`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:? 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 clV 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 patientisstill seizing, proceed to cIV mida-
`zolam or pentobarbital; or 3) give IV valproate 40 mg/kg over approximately 10 minutes. If the patientis
`still seizing, give an additional 20 mg/kg over approximately 5 minutes.If the patientisstill seizing, pro-
`ceed to cIV midazolam or propofol; or 4) give IV phenobarbital 20 mg/kg IV at-50.to 100-mq/min. If the
`patientis still seizing, proceed to cIV midazolam, propofol, 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 awakenor if any cIV treatment is used.
`
`*Urine and blood
`'The IV solution of diazepam can begiven rectally if Diastat is not available; the IV solution of midazolam can be given by any of
`these routes
`+Intubation necessary exceptfor 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
`
`Initial pharmacologic therapy
`
`SEOey teeCery
`Benzodiazepines
`
`tory studies shouldbesent (see Table 1). A bedside glucose level should be
`obtained, and 100 mgthiamine and 50 mL. 50% glucose should be admin-
`istered if hypoglycemiais presentorif glucose level is unknown. Other
`components of managementinclude determining whetherthereis a his-
`tory of alcoholor druguse, previous epilepsy, or neurologic insult. A
`description of the seizure at onset shouldbe obtained if witnessed, and
`brain imaging should be doneafter the patientis stable and seizures are
`controlled.For seizures caused by a metabolic abnormality, correcting the
`metabolic problem is moreeffective than antiepileptic drugs (AEDs).
`
`¢ First line medications control SE in 80% ofpatients wheninitiated within 30
`minutes, but in 40%if started after 2 hours of onset [3;8, Class III]. For practi-
`cal purposes, treatment should bestarted after 5 minutes of continuous sei-
`zure activity. Our protocolfor treatmentof SEin adults is shown in Table1.
`
`Benzodiazepines are potent, parenterally available medications with a
`rapid onsetof action andarethepreferredinitial therapy. Their mechanism
`of action involves bindingto highaffinity sites on the y-aminobutyric acid
`(GABA)receptor, resulting in hyperpolarization of the neuronalcell mem-
`brane and decreased neuronalfiring [17].
`
`AQUESTIVE EXHIBIT 1107 Page 0003
`AQUESTIVE EXHIBIT 1107 Page 0003
`
`

`

`Epilepsy
`250
`eee
`
`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 managementofSE. 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 eM HRARARSNSmmRONO
`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 importantrole 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).
`
`Alternative routes of administration of benzodiazepines
`* Alternative modes of administration are particularly importantin patients
`withoutIV access in varioussettings. Prompt treatment by caregivers out-
`side the hospital can shorten the duration ofseizure, prevent progression to
`SE, and possibly reduce the need for emergency room visits (potentially
`lowering health care costs). Rectal, IM, buccal, and IN all are alternatives
`which have been showntoeffectively and rapidly control seizures [19e,
`Class I; 20;21,22, Class III; 23;24-26, ClassI]. 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 randomizedtrial involving patients with seizure clus-
`ters, a single doseofrectal diazepam gel decreased seizure frequency signif-
`icantly and increased the chance ofseizure freedom after treatment
`compared with placebo (55% vs 34%)[26, Class]. In children, IM mida-
`zolam has been shownto stop seizures more rapidly than IV diazepam
`becauseof earlier administration [24, Class I].
`* 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 midazolamis effective in aborting prolonged seizures in
`adults and children [22, Class Il; 27¢, Class I]. Scott et al. [19¢, Class I]
`found that in children with seizures lasting more than 5 minutes, buccal
`midazolam wasaseffective 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 morelikely 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 prolongedauras, simple partial seizures, or clusters with
`recovery between seizures.
`
`Comparison of benzodiazepines
`
`* Recentstudies investigating out-of-hospital treatment of SE found benzodi-
`azepines to be safe and effective when administered by paramedicsfor 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%ofpatients 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 randomizedtrial compar-
`ing 4 mg IV lorazepam to 10 mg IV diazepam,SE wascontrolled in 89%of
`patients in the lorazepam group, compared with 76% in the diazepam
`group,andthere were nosignificantdifferencesin side effects [30 Class I].
`¢ Theclinical bottom line is that when IV accessis available, IV lorazepam
`shouldbeinitiated asfirst-line therapy, andif possible, in the prehospital
`phase.If widely practiced, this type of treatment could have a major impact
`on the prevention ofrefractory status epilepticus. Whenever obtaining IV
`access would delay administration of AEDssignificantly, diazepam should
`be given rectally (0.2 to 0.5 mg/kg for SE; usually 20 mg for an adult), or
`midazolam shouldbe given nasally, buccally, or intramuscularly (0.2 to 0.3
`mg/kg; usually 10 to 15 mgfor an adult). Patients with a history of pro-
`longedseizuresoracuterepetitive seizures should be offered rectal diaz-
`epam,ornasal or buccal midazolam for out-of-hospital use.
`
`* Most patients whorespondtofirst-line agents also will require mainte-
`nance therapy with a second-line agent because the risk of recurrenceis
`high. Additionally, second-line therapy must beinitiated quickly when
`patients continueto seize despite treatment with benzodiazepines. The
`longer SE persists, the higher the risk for developingrefractory status epi-
`lepticus. If convulsions are successfully abated but patients fail to improve
`in their mentalstatus, there is a high probability of ongoing subclinical sei-
`zures or NCSE. Such cases warrant additional treatment. DeLorenzo etal.
`[31, Class II] found subclinical electrographic seizure activity in 48% of
`patients after control of convulsive SE, including NCSE in 14%. Towneetal.
`[32¢, Class III] found that among 236 comatosepatients with no currentor
`past evidence ofseizures, 8% showedelectrographic seizures. In the Veteran
`Affair Cooperative study, 20% of convulsive SE patients whose movements
`stopped with treatmentstill were seizing as shown by EEG [33¢e, Class I].
`Therefore, EEG is mandatory forall patients who do not wake up quickly
`after cessation ofclinical SE, andforall patients with unexplained coma.
`
`Se Cuil
`
`Phenytoin
`
`The primary mechanism ofaction of phenytoin is inhibition of high-frequency
`repetitive neuronalfiring 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
`See
`
`Contraindications
`
`Main drug interactions
`
`Main side effects
`
`Special points
`
`Fosphenytoin
`
`Standard dosage
`
`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%). Phenytoin maydisplace other drugs that are pro-
`tein-bound and increasefree 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 jzg/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 is a phenytoin prodrug without the propylene glycol carrier and has
`fewerside 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.
`Lowerrisk of hypotension than phenytoin (5% to 15%, rate dependent). Arrhyth-
`mias and respiratory depression are rare. Decreased consciousness, transient prun-
`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-
`tionsstill 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 toad or 4 hours after IM delivery to allow complete conversion
`to phenytoin.
`
`Phenobarbital
`
`PUTERMSRENNEREEROAanecM noncomwoSPORE AA YE AERAAR RSEEMCTEABAnnonat
`
`Phenobarbital is one of the long acting barbiturates that act by potentiation of y-
`aminobutyric acid (GABA) and by interfering with sodium and potassium transport
`across the cell membrane.
`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 yxg/mL initially, but some patients may need
`higher levels.
`
`Standard dosage
`
`Contraindications
`Main drug interactions
`
`Main side effects
`
`Special points
`
`AQUESTIVE EXHIBIT 1107 Page 0006
`AQUESTIVE EXHIBIT 1107 Page 0006
`
`

`

`Treatment of Convulsive and Nonconvulsive Status Epilepticus Pang and Hirsch
`
`253
`
`Valproate
`
`Although currently not approved 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 ofdifferent 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.
`Standard dosage 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].
`Contraindications Hypersensitivity to drug, severe liver dysfunction, thrombocytopenia.
`Major drug interactions 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.
`Main side effects Hepatotoxicity (including fatal), thrombocytopenia, pancreatitis. Hypotension is
`rare but has been reported [39].
`Special points Target serum levels are 70 to 140 g/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.
`
`
`Comparisonof initial treatment options for status epilepticus
`* Only a few prospective randomizedtrials have been done comparingtreat-
`mentstrategies for SE; some werediscussed above. The largest prospective
`study wastheVA Status Epilepticus Cooperative study [33¢¢, Class I],
`which was a randomized, double-blind, multicentertrial that compared
`four IV treatments: lorazepam, diazepam followed by phenytoin, phe-
`nobarbital, and phenytoin alone. In generalized convulsive SE, lorazepam
`was foundto be mosteffective (65% for lorazepam alone vs 58%for phe-
`nobarbital, 56% for diazepam plus phenytoin, and 44% for phenytoin
`alone). The difference wasstatistically significant between lorazepam and
`phenytoin only. For subtle SE, nostatistical difference was found between
`the groups andthe responserate was poor.All four treatment arms had
`similar complicationrates.
`
`Refractory status epilepticus
`
`¢ 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 treatmentusually is use of continuous
`drips or high doses of medicationsthat may causesignificant sedation, res-
`piratory depression, and hypotension.Patients most often atthis point
`have been intubated andtransferred to the intensive care unit. The available
`agents include barbiturates (pentobarbital, thiopental, or high dose phe-
`nobarbital), propofol, and midazolam. Thetraditionaltreatment algorithm
`suggests loading with phenobarbitalat this point, followed by continuous
`IV pentobarbitalif thatfails. Our preferenceis to use rapid-acting drips
`(midazolam or propofol) instead of phenobarbitalafter a patienthas failed
`first- and second-line drugs.
`
`AQUESTIVE EXHIBIT 1107 Page 0007
`AQUESTIVE EXHIBIT 1107 Page 0007
`
`

`

`Epilepsy
`254
`__—waseee
`
`* To date, no randomized controlled trials have been donefor second-line
`therapyorfor SE refractory to first- and second-line therapy. The most expe-
`rience exists with continuousinfusions (cIV) of midazolam and propofol.
`There is somepreliminary evidence from two small retrospective series that
`propofolis effective, fast, and easy to use [40,41, ClassIII], but may beasso-
`ciated with a higher mortality than midazolam (but not Statistically differ-
`ent). In a systematic review oftheliterature on treatment of 193 patients
`with RSE, no difference was found in mortality amongthe groupstreated
`with cIV propofol, cIV midazolam, orcIV pentobarbital [42, Class HI].
`Mortality wasrelated 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. [43¢, ClassIII], in which 27
`patients whofailed IV clonazepam and phenytoin therapy were induced
`into burst-suppression pattern on cEEG with cIV propofolat a dose of2.1
`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
`propofoluse and nopatient experienced propofol infusion syndrome. A
`systematic review by Claassenetal. [42, Class III]
`(published before the
`Rossetti propofol study) found no demonstrable difference between propo-
`fol and midazolam forclinical endpoints such as acute treatmentfailure,
`breakthroughseizures, or posttreatmentseizures. Pentobarbital seemed to
`have had a lower frequency ofacute treatmentfailure and breakthroughsei-
`zures, but this was confoundedby twofactors. First, the pentobarbital! was
`infused until background burst suppression was reached, whereasthe other
`two drugs usually weretitrated to seizure control, not burst-suppression.
`Second, mostpatients 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; 44°, Class II]. Hypotension, which
`further complicates the treatmentofthesecriticallyill patients, occurred
`more frequently with pentobarbital(titrated to EEG background suppres-
`sion) than with propofol or midazolam (usually titrated to suppression of
`seizures) [42, ClassIII].
`
`
`
`
`Continuous intravenous antiepileptics for refractory status epilepticus in adults
`¢ All patients on cIV AEDs require continuous EEG monitoring.
`
`Continuous intravenous pentobarbita
`
`Standard dosage 5 to 10 mg/kg bolus. Repeat 5 mg/kg bolusesuntil 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. Theinitial infusion rate is
`0.1 mg/kg/h. The usual maintenance range is 0.05 to 2 mg/kg/h (this is higher
`than dosagesin 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-tife is 1.5 to 3.5 hours initially. With prolonged use, there may be tolerance,
`tachyphylaxis, and significant prolongation ofhalf-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 jon channels.
`1 mg/kg bolus. Repeat 1 to 2 mg/kg boluses every 3 to 5 minutesuntil seizures stop,
`up to maximum loading dose of 10 mg/kg. Initial cIV rate is 2 mg/kg/h. Continuous
`IV dosage rangeis 1 to 15 mg/kg/h. SE usually stops in less than 10 minutes.
`Hypersensitivity to drug; allergy to soybean oil, egg lecithin, or glycerol.
`Sedation lasting 5 to 10 minutes, large lipid load (3000 cal/d) requiring adjust-
`ment of caloric intake, occasional pancreatitis, dose-dependent hypotension, rare
`propofolinfusion syndrome (metabolic acidosis and circulatory collapse). Multi-
`organ failure in children has been reported with prolonged use [46].
`The use of propofol in adults at these dosages for less than 2 weeks with close
`monitoring including acid/base status seems to be safe and