Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 108/216
`
`

`
`ith drug failures, the major question becomes whether to change
`medications, and if so, whether to institute a cross-taper or to add a
`second medication to the first. A drug failure may be due to intolerance of
`adverse effects or to lack of efficacy. lnthis case, his first drug failure was
`actually lamotrigine due to the rash risk~ In most cases with rash, the likely
`offending agent must be immediately discontinued (see Chapter 12), elim(cid:173)
`inating that decision. In fact, in most cases of intolerability, the offending
`AED should be discontinued or reduced, because side effects can be more
`disabling than the seizures themselves. We must always aim for the modern
`goal of "no seizures, no side effects."
`In this case, the patient appeared to tolerate a moderate dose oflevetirac(cid:173)
`etam, and it appeared to decrease seizure frequency, but it was only partially
`effective. The dose was increased until side effects were noted, and yet a
`seizure still occurred. He was compliant with medications, but if he was
`having problems with missed or late doses, using the extended-release
`formulation could be considered.
`It is important to specifically screen for side effects, particularly as
`recommended maximal doses are reached, though the recommended dose
`range may be exceeded as specific patients may be fast metabolizers or may
`be on concomitant medications that reduce effects. As doses increase, or
`when polytherapy begins, drawing peak or trough drug levels may help
`guide dosing, but the paramount guide is the patient and his or her reported
`or elicited side effects, including mood, irritability, and cognitive abilities.
`For instance, if the patient had no side effects at a dose of 3,000 mg/day, he
`may be part of the small percent that improve on 4,000mg/day, though this
`is not common practice. Occasionally seizures appear to worsen on very
`high doses of AEDs, although this is controversial.
`Complete seizure freedom is the goal. Another medication can be added
`to the lower, tolerated dose of levetiracetam or a cross-taper can be designed
`to attempt monotherapy of another AED. The choice has been debated and
`studied, and there is no clear right or wrong answer. There are a few factors
`to consider.
`
`1. Adding a second agent may not increase protection, but it.
`also may not increase the likelihood of new or additive
`side-effects.
`
`9S
`
`WHAT DO I DO NOW? EPILEPSY
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 109/216
`
`

`
`a. A study of 157 patients showed no difference in efficacy or side
`effects in patients randomized to adjunctive therapy or
`(
`alternative monotherapy (Beghi et al., 2003).
`b. A multicenter study (n = 809) studied similar endpoints and
`. concluded it was instead an individual's susceptibility, the type
`of AED, and the skill of the practitioner that had the greatest
`impact on side effects (Canevini et al., 2010).
`2. Alternative monotherapy (cross-titration) may be best iF.
`a. The first AED failed due to intolerability
`h. The patient is planning a pregnancy in the near future
`3. Adding a second agent may be best iF.
`a. The patient had at least a partial response and had no adverse
`effects at a lower dose
`h. The consequences of another seizure in the short term are
`very high
`4. ~ts: the total healthcare costs of dual therapy compared to
`switching to another monotherapy treatment were higher, primarily
`due to the costs of providing two AEDs (Lee et al, 2005).
`5. The fact that this initial AED failure pccurred decreases the chances
`of seizure freedom (see Table 16.1).
`5a. (Mohanraj & Brodie, 2006), more patients became seizure-free
`when the combination involved a sodium channel blocker
`(considered to include carbamazepine, phenytoin, lamotrigine) and
`
`I
`
`TABLE HH Percentage Chance of Remission with Sequential Regimens In
`Patients with Newly Diagnosed Epilepsy (n = 780) Falling Treatment Because
`of Lack of Efficacy or Adverse Effects
`
`Lack of efficacy
`
`Adverse effects
`
`All causes
`
`First drug
`
`Second schedule
`
`Third schedule
`
`21
`
`8
`
`4
`
`From Mohanraj & Brodie, 2006.
`
`42
`
`17
`
`14
`
`26
`
`11
`
`9
`
`16. AED FAILURES
`
`99
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 110/216
`
`

`
`a drug with multiple mechanisms of action (considered gabapentin,
`topiramate, valproic acid) (36o/o) compared to other combinations
`(7o/o, p= 0.05).
`
`Further Reading
`Beghi E, et al. Adjunctive therapy versus alternative monotherapy in patients with partial
`epilepsy failing on a single drug: a multicentre, randomlsed, pragmatic controlled
`trial. Epilepsy Res. 2003;57(1):1-13.
`
`100
`
`WHAT DO I DO NOW? E:PIL£PSY
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 111/216
`
`

`
`canevlni MP, et al. Relationship between adverse effects of antleplleptlc drugs, number of
`coprescrlbed drugs, and drug load In a large cohort of consecutive patients with
`drug-refractory epilepsy. £pl/epsla. 2010;51(5):797-804.
`French JA, Faught E. Rational polytherapy. £pllepsla. 2009;50(Suppl 8):63-68.
`Kwan P, Brodie MJ. Epilepsy after the first drug falls: substitution or add-on? Seizure.
`2000;9(7):464-468.
`Lee we, et al. A cost comparison of alternative regimens for treatment-refractory
`partial seizure disorder: an ~onometrlc analysis. Clln Ther. 2005:27(10):
`1629-1638.
`Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: response to sequential treatment
`schedules. £ur J Neurol. 2006;13(3):m-282.
`
`.J
`
`16. A.ED fAILURES
`
`101
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 112/216
`
`

`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 113/216
`
`

`
`There are multiple reaso~s to make changes to a medication regimen.
`
`Most are for medication failures, but occasionally they are initiated to
`reduce th.e overall medication burden in well-controlled patients and to
`reduce the potential for teratogenicity.
`This case represents a common hut relatively simple situation. There is a
`need to avoid valproate in pregnancy, and there are several medications that
`appear to have significantly lower risks of major malformations and cogni(cid:173)
`tive outcomes in the baby (see Chapter 19). In this case, larn.otrigine was
`chosen. Because valproate inhibits glucuronidation, lamotrigine is cleared
`about half as quickly ~d thus the initial titration to begin lamotrigine is
`half as fast, starting with 25 mg every other day for 2 weeks, increasing to
`25 mg daily for 2 weeks, then to 25 mg BID for 1 week.
`If valproate is added to a patient on a steady dose of lamotrigine, the
`dose ofla~otrigine will eventually need to be reduced, possibly as much as
`halved. Monitoring for side effects and obtaining levels of both medications
`during, this period are advisable (Table 17.1).
`Conversely, it is well known that medications that induce liver enzymes
`will increase clearance of other liver-metabolized medications. Enzyme(cid:173)
`inducing AEDs (EIAED) include phenytoin, phenobarbital, carbarn.(cid:173)
`azepine, primidone, and (at doses over 400 mglday) topiramate. Rufinamide
`may also induce some enzymes at high doses. Oxcarbazepine has minimal
`to no interactions with other AEDs though does affect oral contraceptives
`(see chapter 18). Sometimes rapid metabolism can result in worse neuroM
`toxicity despite similar or lower levels of the AED. Carbarn.azepine epoxide
`is considered the cause of neurotoxic side effects, and its level is increased
`with increased metabolism, despite decreasing carbamazepine levels. This
`. toxic epoxide is also increased with coadministration of valproic acid, which
`inhibits the metabolism of the epoxide. Primidone is a prodrug that is
`metabolized to phenobarbital, and increasing this process will lower primi(cid:173)
`done but inc~ phenobarbital· levels.
`Phenytoin indtiees lamotrigine metabolism to a greater extent than
`carbamazepine. Thus, lamotrigine dosing should be decreased by 50-75o/o
`after stopping phenytoin, whereas the decrease in lamotrigine 4ose should
`be 25-50% with carbarn.azepine discontinuation; essentially complete
`withdrawal of the EIAED is required prior to the change in lamotrigine
`levels occurring , showing induction is an all-orMnone phenomenon rather
`
`1~ DRUG-DRUG INT£RACTJONS:AED9
`
`103
`
`II
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 114/216
`
`

`
`NC
`
`NC
`
`NC
`
`NC
`
`NC
`
`NC
`
`NC
`
`NC
`
`LCM, LTG
`ZNS, PGB,' RFN· I
`TC?B, LVT, OXC,
`GBP", TPM•,
`
`NC
`
`NC
`
`?
`
`NC
`
`NC
`
`NC
`
`1' mild
`
`+I-
`
`CBZ-E 1'50-60%
`. .120-30%, but
`
`CBZ-E 1' 100o/o
`
`'
`
`'
`
`?
`
`1'100-150%
`
`1'3D-50%
`
`1'50-80%
`
`1'30-50°A,
`
`1'50-80%
`
`NC
`
`NC
`
`NC
`
`1'100-150%
`
`.!.mild
`
`NC
`
`NC
`
`?
`
`?
`
`FBM
`
`. VPA
`
`Inhibitor:
`
`oxc
`
`CBZ
`
`TABLE 17-1 Effects of AEDs on Serum Concentrations of Other AEDs
`
`+I-
`+/-
`
`NC
`
`.!.mild
`
`.150%
`
`NC
`
`NC
`
`.!.
`
`.!.
`
`J.
`
`J.
`
`(
`
`+I-
`+I-
`
`J.mild
`
`.!.SO%
`
`NC
`
`J.15%
`
`.!.
`
`Phenytoin
`
`Phenobarbital
`
`Oxcarbazepi,ne
`
`Levetiracetam
`
`Lamotrigine
`
`Lacosamide
`
`Gabapentin
`
`Felbamate
`
`Ethosuximde
`
`increase
`J., CPZ-E may
`
`Carbamazepine
`
`J.
`
`Benzodiazepines
`
`Inducers: PB,
`
`of the AED to the right .
`adminfstratron
`level of AED below with PHT
`What happens to the
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 115/216
`
`

`
`oxcarbazeplne; RFN, ruflnamlde; ZNS, zonisamide. +/· = variable, NC = no change, ? = unknown.
`carbamazepine epoxide; PB, phenobarbital; VPA, valprolc acid; GBP, gabapentln; LCM, lacosamide; LTG, lamotrlgine; TGB, tiagablne; LVT, levetiracetam; OXC.
`table represents the effects on each druQ/class in the top row when the AED listed on the left is added. PHT, phenytoin; CBZ, carbamazeptne; CBZ·E,
`Note: Some of these interactions have not been directly studied, but probable effects can be Inferred frol)'l known drug properties. The effects shown in the
`"'Gabapentln ')'laY significantly Increase the elimination time of felbamate.
`•Toplramate >400 mg/day and ruflnamide 4Q-50 mg/kQ/day appear to have inducing properties.
`
`NC
`
`NC
`
`NC
`NC
`
`NC
`
`dose-dependent
`'t25-60%
`
`i
`NC
`
`?
`
`?
`
`dose-dependent
`'t 15-70o/o
`
`NC
`
`+/~
`
`NC
`
`,I; mild
`
`NC
`
`,1;
`
`NC
`
`,1;33-50%
`
`,1;33-50%
`
`,1;
`
`,1;50%
`
`,1;
`
`,1;50%
`
`Zonisamide
`
`Vlgabatrin
`
`Valproate
`
`Tiagablne
`
`Topiramate
`
`,1;1()-30%
`
`,1;25-46%
`
`Rufinamlde
`
`ratios
`PEMA/PRM
`'tPB/PRM
`
`ratios
`PEMA/PRM
`'tPB/PRM
`
`NC
`
`NC
`
`NC
`
`Primidone
`
`Pregabalin
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 116/216
`
`

`
`than proportional to,dose. The timecou!$e of both induction and de-induc(cid:173)
`tion is theoretically ~elated to the half-life of the EIAED, requiring 5 half(cid:173)
`lives following discon~nuation of the EIAED for de-induction to be complete.
`Half-lives are shown in Appendix II. Hepatic induction of carbamazepine
`on it's own clearance is termed autoinduction. It starts within a week and is
`maximal within 6 weeks. De-autoinduction of carbamazepine has been
`shown to occur wlthin days.
`Other AED-AED interactions are due to protein binding. AEDs that
`are highly protein-bound include phenytoin, valproic acid, and benzodiaz(cid:173)
`epines. Carbamazepine is moderately protein-bound. When administered
`simultaneously within a patient, they compete for protein binding sites,
`thereby increasing each other's free fraction, which is the pharmacologically
`active portion responsible for both therapeutic and toxic effectS. The total
`level measured will not increase, so a free level must be obtained to deter(cid:173)
`mine the degree of the effects.
`Pharmacodynamics refers to the effect at the receptor or functional
`level. Research has been aimed at looking at positive pharmacodynamic
`interactions--that is, AEDs that appear synergistic when used together.
`There are preclinical data to support this theory but it has not yet been
`proven in human epilepsy. The opposite appears to occur, in that AEDs
`with similar side-effect profiles appear more likely to cause side effects when
`used together. This has been shown when combining lacosamide with other
`sodium channel-blocking agents.
`
`106
`
`WHAT DO I DO NOW? EPILEPSY
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 117/216
`
`

`
`further Reading
`Dfaz RA, Sancho J, Serratosa J. Antleplleptlc drug Interactions. Neurologist. 2008;14(6
`Suppi1):SSS-65.
`Patsalos PN, Perucca E. Clinically Important drug Interactions In epilepsy: general
`features and Interactions between antfeplleptlc drugs. Lancet Neural.
`2003;2(6):347-356.
`Anderson GO, Gtdal BE, Messenhelmer JA, Gilliam FG. Time course of lamotriglne
`de-Induction: Impact of step:wlse withdrawal of carbamazeplne or phenytoin.
`"'
`Epilepsy Res. 2002;49(3):211-7.
`
`1~ DRUG-DRUGINT~RACTION~AEDs
`
`t07
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 118/216
`
`

`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 119/216
`
`

`
`About the same time, he noted tingling sensations
`running down the legs. He was worried that the
`Phenytoin was responsible for the leg sensations and the
`change in the warfarin dosing, and he was wondering
`whether this was the best medkation for him.
`
`19. DRUG-DRUG INTERACTIONS: OTHER MEDICATIONS
`
`109
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 120/216
`
`

`
`his patient has multiple medical issues, the most concerning of them
`being atrial fibrillation and the need for warfarin. Phenytoin was not
`the optimal choice due to its significant effects as an enzyme-inducingAED
`(EIAED). In this case, the haematologists continued to ,chase, the INR by
`increasing his warfarin to over twice the original dose. Once the correct dose
`is found, it should not significantly change. However, if he were to become
`de-induced, either through exposure to another medication or by grapefruit
`juice, for instance, he could become severely supratherapeutic in terms of
`INR and phenytoin toxicity; the combination of ataxia and a lack of clotting
`factors could be disastrous. In this case, phenytoin was also contributing to
`peripheral neuropathic symptoms, which could also increase the risk of falls.
`This patient was having flashbacks and frightening nightmares, so AEDS
`with potential for negative behavioral effects were avoided (levetiracetam,
`zonisamide, topiramate). Lamotrigine was chosen to replace phenytoin due
`to its antidepressant and mood-stabilizing effects. Initiation of lamotrigine
`while on phenytoin requires a titration schedule of EIAED regimens with(cid:173)
`out valproic acid: starting with 25 mg BID for 2 weeks, then 50 mg BID
`for 2 weeks. The dose can then be increased by 100 mgl day every 1 to
`2 weeks. Obtaining a therapeutic lamotrigine level is helpful to check
`whether a reasonable serum level has been achieved prior to the phenytoin
`taper. A patient who complains of blurred or double vision, lightheaded(cid:173)
`ness, or tremor is likely lamotrigine toxic; this may be worsened by the
`phenytoin, which can cause similar side effects.
`With the reduction of phenytoin there will be de-induction of the liver,
`and both the lamotrigine level and the INR will climb. The lamotrigine
`level will approximately double, typically once the phenytoin is completely dis(cid:173)
`continued, as the level of induction appears independent of the EIAED level
`(phenytoin or carbamazepine) serum level. The exact timing of de--induction
`for phenytoin has, not been published, but it may be within days to w~ks.
`Loss of auto-induction to carbamazepine may occur within 4 days.
`EIAEDs interact with non-epilepsy-related medications that are also
`metabolized by the liver. This includes statin medications, whose efficacy
`may be significantly reduced. Interestingly, enzyme inducers may, on their
`own, cause elevations in markers of vascular disease. The entire list of inter(cid:173)
`actions is exhaustive and includes antineoplastics, beta blockers, calcium
`channel blockers, immunosuppressants, some neuroleptics and SSRis,
`
`110
`
`WHAT 00 I DO NOW? EPILEPSY
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 121/216
`
`

`
`acetaminophen, and methadone. The increase in metabolism can be
`harmful-for instance, acetaminophen levels may be lower than normal
`but the toxic metabolites will be elevated. Oral contraceptives are decreased
`by the typical enzyme inducers, in addition to oxcarbazepine, topiramate at
`doses higher than 400 mg/day, and rufinamide at higher doses, often to the
`point of ineffectiveness. Women of childbearing age who note spotting
`should use a second method of contraception. Oral contraceptives with
`higher concentrations of estrogens are recommended {above 50 ug) b~t are
`less common on the market these days.
`Commonly used medications may have an impact on AED levels.
`Ibuprofen, protease inhibitors, omeprazole, and tricyclic antidepressants
`increase phenytoin levels. Valproate levels will be reduced by carbapenems
`but increased by macrolides. This may be due to effects in the liver or
`possibly to effects on other mechanisms, such as P-glycoproteili
`
`Further Reading
`Anderson GD, et al. Time course of lamotrlgine de-induction: Impact of step-wise
`withdrawal of carbamazeplne or phenytoin. Epilepsy Res. 2002;49(3):211-217.
`Mintzer s. Metabolic consequences of antlepileptic drugs. Curr Opin Neurol.
`2 010;23(2):164-169.
`Perucca E. Clinically relevant drug Interactions with antleplleptlc orugs. Br J Clin
`Pharmacal. 2006;61(3):246-255.
`
`18. DRUG-DRUG INTERACTIONS: OTHER Mli!:DICATIONS
`
`111
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 122/216
`
`

`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 123/216
`
`

`
`..
`
`any women with epilepsy are concerned with their ability to have
`healthy children. In the past, there were many misconceptions about
`the risks of epilepsy and AEDs for the infant and the pregnant mother.
`However, most women with epilepsy will have healthy babies and uncom~
`plicated pregnancies. Recent data have allowed physicians to better counsel
`women with epilepsy on the risks of teratogenicity of AEDs, the effects of
`seizures on the developing infant, changes in seizure frequency during preg~
`nancy, and the exposure of the infant to AEDs via breast milk (Table 19.1 ).
`
`TABLE 19•1 Antleplleptlc Drugs In Pregnancy and Lactation
`
`Drug
`
`Carbamazeplne
`
`Ethosuximide
`
`Felbamate
`
`Gabapentln
`
`Lacosamlde
`
`Lamotrlglne
`
`Levetlracetam
`
`Oxcarbazeplne
`
`Phenytoin
`
`Phenobarbital
`
`Prlmidone
`
`Pregaballn
`
`Toplramate
`
`Valproate
`
`Vlgabatrln
`
`Zonlsamlde
`
`Risk of major
`malformations or
`neurocognltlve
`Impairment
`
`Changes In serum Breast milk
`levels during
`excretion
`pregnancy
`
`•
`
`•
`
`•
`
`•
`
`•
`
`••
`
`••
`
`••
`
`••
`
`•••
`
`•
`
`•••
`
`•••
`
`•••
`
`••
`
`••
`
`•
`
`••
`
`..t
`
`••
`
`•
`
`•••
`
`•••
`
`• •
`
`• ••
`
`• •
`
`•
`
`•
`
`•••
`
`•
`
`• ••
`
`• lowest: •• moderate: ••• highest: - Insufficient published data
`'Free levels likely unchanged.
`
`19. AEDs IN PREGNANCY AND LACTATION
`
`113
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 124/216
`
`

`
`In addition, neurologists and obstetricians have been able to identify ways
`to mitigate some of the risks.
`Children of women with epilepsy have higher rates of major congenital
`malformations. These malformations include cardiac defects (tetralogy of
`Fallot, aortic coarctation, ventricular septal defects, valvular defects), geni(cid:173)
`tourinary defects (hypospadias), gastrointestinal defects (imperforate anus,
`esophageal atresia), skeletal anomalies (hip dysplasia, polydactyly, dub foot,
`finger hypoplasia), facial anomalies (cleft palate), and neural tube defects
`(spina bifiru;_), These inFants are also more likely to have microcephaly and
`growth retardation. It is thought that many of these defects are due to in
`utero exposure to AEDs, as women with epilepsy on these medications .
`are 1.12 to 3.92 times more likely to have such malformations compared to
`untreated women. As much of organogenesis occurs early in fetal develop(cid:173)
`ment, it is believed that first-trimester exposure to these drugs carries the
`greatest risk. As many women are already many weeks along when they
`realize they are pregnant, attempts to reduce the risks of anticonvulsant
`exposure to the offspring should ideally occur before conception. As in this
`case, discussion of these risks should occur when women could potentially
`become pregnant-that is, when they become sexually active or are inter(cid:173)
`ested in starting a family.
`There is now sufficient evidence to suggest that some AEDs may be asso(cid:173)
`ciated with higher rates of malformations than others. Valproate use appears
`to have the highest rate of malformations for which there exist sufficient
`pregnancy outcome data-10% in a recent meta-analysis by Meador and
`colleagues. Valproate use also is associated with a 1 o/o to 2o/o risk of neural
`tube defects. Evidence suggests that this may be dose-dependent and less
`common in doses under 1,000 mglday. Data from a large U.K. pregnancy
`registry suggested that other commonly used AEDs have lower rates of mal(cid:173)
`formations when used in monotherapy: carbamazepine 2.2%, lamotrigine
`3.2%, phenytoin 3.7%, phenobarbital4.2%. There are insufficient data for
`other newer AEDs, but preliminary reports from pregnancy registries sug(cid:173)
`gest monotherapy malformation rates for topiramate of 4.8o/o, levetirac(cid:173)
`etam 2.7°..-b, oxcarbazepine 2.4%, and gabapentin 2.0o/o. There are very
`limited data for all other AEDs. It should be noted that the rate of fetal
`malformations ranged from 1.6% to 3o/o in oontrol groups. There is also
`evidence that AED polytherapy increases the rate of malformations,
`
`114
`
`WHAT DO I DO NOW? EPILEPSY
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 125/216
`
`

`
`especially if the regimen includes valproate. MalfOrmation rates appear to
`be dose-dependent for lamotrigine and valproate.
`In addition to the risks of malformations, in utero exposure to some
`AEDs may lead to neurocognitive deficits in childhood. In the NEAD
`study, Meador and colleagues found that children born to women taking
`valproate had lower IQs at 3 years than children born to women taking
`carbamazepine, phenytoin, or lamotrigine.
`While some AEDs may pose a risk to the offspring, seizures are likely
`more dangerous to the mother and offspring. A higher-than-expected rate
`of maternal death occurs in pregnant women with epilepsy, and generalized.
`tonic-clonic seizures and status epilepticus may lead to fetal injury
`and death. Therefore, it is always advisable for women with epilepsy co
`takeAEDs.
`In this case, the patient's seizures are well controlled on valproate, a med(cid:173)
`ication associated with a high rate of malformations. Therefore, as part of
`prepregnancy planning, steps should be taken to limit the risks associated
`with its use. While topiramate, lamotrigine, and levetiracetam- all appro(cid:173)
`priate AEDs for her epilepsy syndrome- were unable to control her seizures,
`it is unknown if she requires such high doses of valproate. The evidence
`suggests that doses below 800 mglday are less likely to be associated with
`malformations or neurocognitive changes. Prior to becoming pregnant, her
`dose of valproate should be lowered to see if her seizures could still be well
`controlled at a lower dose. If she had not been on other appropriate AEDs
`in the past, a controlled cross-titration to another agent associated with a
`low rate of malformations is advisable. In addition, she should take folic
`acid, 2 to 4 mg daily, as several studies have shown lower rates of neural tube
`defects in women with epilepsy, and specifically in women taking valproate,
`who took prenatal folic acid. If the patient is already pregnant and her seizures
`are well controlled, it is usually not recommended to switch medications, as
`most of the adverse effects on fetal development have already occurred and
`the patient risks seizure recurrence during the transition to the unproven
`medication. It is also recommended that women with epilepsy receive prena(cid:173)
`tal care from an obstetrician with experience in managing high-risk pregnan(cid:173)
`cies, if one is available. However, most of the current evidence suggests that
`women with epilepsy are not at a significaiuly higher risk of developing
`pregnancy or delivery complications than other healthy women.
`
`19. AEDs IN PREGNANCY AND LACTATION
`
`115
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 126/216
`
`

`
`During pregnancy, a woman undergoes significant physiological changes
`in blood volume, renal function, and hepatic function. These changes can
`affect the pharmacpkinetics and metabolism of many anticonvulsant drugs.
`Changes in hepatic metabolism can affect drugs metabolized by the cyto(cid:173)
`chrome P450 system. Levels of phenytoin and phenobarbital can decrease
`by 40% to 50% in the third trimester. Pregnancy has an even greater effect
`on glucuronidation, the main elimination mechanism for lamotrigine and
`the active metabolite of oxcarbazepi_ne. Reductions in serum levels of both
`drugs can be up to 30o/o in later stages of pregnancy for some women.
`Although they are mainly cleared by the renal system, levetiracetam and
`topiramate serum levels also decrease, up to 50% in pregnancy. AED serum
`levels should be monitored frequently during pregnancy and dosage adjust(cid:173)
`ments made to keep levels in a range that was adequate for good seizure
`control prior to pregnancy. After ddivery, drug metabolism returns to
`normal levels within 2 to 3 weeks, and pregnant women should be given a
`schedule to reduce their doses after delivery to avoid toxicity.
`Once the baby is born, women with epilepsy are typically encouraged to
`breast-feed their infant due to the cognitive, social, economic, and immu(cid:173)
`nological benefits. Almost all AEDs tested are found in breast milk in some
`quantity, thus exposing the newborn. However, the AED concentration in
`the breast milk is inversely proportional to its degree of protein binding.
`Therefore, drugs such as phenytoin and valproate are found in concentra(cid:173)
`tions significantly lower in breast milk than in the mother's serum. Drugs
`that do not have significant protein binding such as levetiracetam and gaba(cid:173)
`pentin have similar concentrations in the serum and breast milk. In most
`infants, there is no clear clinical effect of AED ~posure via breast milk, as
`the total amounts ingested are low and effectively cleared by their metabolic
`pathways. There is a theoretical concern that in preterm and early term
`infants some metabolic pathways, such as glucuronidation, are less devel(cid:173)
`oped and can lead to a~umulation of drugs cleared by these mechanisms,
`such as lamotrigine and the active metabolite of oxcarbazepine. However,
`no studies to date have clearly demonstrated clinically important effects of
`infant exposure to AEDs via breast milk. However, all breast-feeding women
`with epilepsy should be counseled to monitor their infants for excessive
`sedation or irritability, potential signs that their infant is intoxicated
`byAEDs.
`
`116
`
`WHAT DO I DO NOW? EPILEPSY
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 127/216
`
`

`
`Ul
`
`
`
`Further Reading
`Harden CL, Meador KJ, Pennell PB, et al. Practice Parameter update: Management Issues
`for women with epilepsy-Focus on pregnancy (an evidence-based review):
`Teratogenesis and perinatal outcomes: Report of the Quality Standards
`Subcommittee and Therapeutics and Technology Assessment Subcommittee of the
`American Academy of Neurology and American ERIIepsy Society Neurology.
`2009;73:133-141.
`Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal
`exposure to antlepileptlc drugs.-N Eng/ J Med. 2009;360(16):1597-1605.
`Meador KJ, Reynolds M, Crean S, Fahrbach K, Probst C. Pregnancy outcomes In women
`with epilepsy: A systematic review and meta-analysis of published pregnancy
`registries and conorts. Epilepsy Res. 2008;81(1):1-13.
`Sabers A, Tomson T. Managing antleplleptlc drugs d':Jrlng pregnancy and lactation.
`Curr Opln Neurol. 2009;22(2):157-161.
`
`19. AEDs IN PREGNANCY AND LACTATION
`
`117
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 128/216
`
`

`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 129/216
`
`

`
`tested due to pain at the wrist, likely related to
`contractu res.
`Prior to the stroke, she was up to date with current
`events and very well read. Since the stroke she has been
`unable to read (likely due to left neglect/field cut) and
`behaviorally and verbally disinhibited. She is sleeping
`poorly due to the chronic post-stroke pain. Her family
`reports that she has been irritable and seemed
`depressed, and they are worried about her poor appetite.
`They also note that in the year prior to the stroke, she
`began slowing down, with a bent-over posture and
`shuffling steps. Her medication list includes metoprolol,
`amlodipine, llsinopril, slmvastatin, ranitidine, zolpidem,
`baclofen, oxycodon~. and aspirin.
`
`20 •. TREATMENT OF EPlL!.PSY lN THE ELDERLY
`
`119
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 130/216
`
`

`
`0
`
`eizures in the elderly are comm·on. They can be acute symptomatic-
`for instance, seizures that occur soon after a stroke are considered pro(cid:173)
`voked and may not recur. ·one study showed 13% of patients who had a
`seizure within 1 week of an acute neurological event went on to have another
`in the next 1 0 years. Most in this situation will start an AED to prevent
`recurrence in the recovery period. Long-term AED use is generally not
`recommended, though, and the early EEG is not reliably predictive of long(cid:173)
`term seizure recurrence. Many practitioners opt to treat with an AED
`short-term and at 3 to 6 months, if the EEG is devoid of epileptiform
`discharges and the history does not support seizure recurrence, the AED
`will be discontinued. Others will discontinue AEDs upon discharge from
`the hospital. There are few clear data to support either choice, but the risk
`of treatment includes medication interactions and possibly worsened
`post-stroke recovery due to phenytoin (Dllantin) and phenobarbital.
`When seizures occur more remotely after a known neurologic insult, the
`chance of recurrence is between 50% and 90%, and most clinicians will
`continue AEDs indefinitely. Other risk factors for seizure recurrence are
`hemorrhagic or ischemic strokes that involve cortical areas.
`Numerous studies have shown that the incidence of recurrent, unpro(cid:173)
`voked seizures (thus, epilepsy) increases sharply with age over 65 and is
`greatest in the elderly population compared to all other age groups. This
`will become even more of a problem as the population ages. Cerebrovascular
`disease is by far the most common cause, with 15% of survivors developing
`-seizures within the first 5 years of the stroke. Degenerative diseases, head
`trauma, neoplasms, and CNS infections are far less common antecedents,
`and about 50% of epilepsy cases in the elderly are cryptogenic (an underly(cid:173)
`ing cause is suspected, but etiology cannot be found).
`The choice of medication is particularly important in the elderly and
`should be tailored to the patient, and in particular tolerability. In general,
`enzyme inducers should be avoided due to the multiple other medications
`the patient is likely taking. It is known, for instance, that enzyme-inducing
`AEDs reduce the effectiveness of statin medications and that on their own
`they may promote the risk of cardiovascular disease (see Chapter 18). Bone
`health is another consideration, which appears to be related to· enzyme
`induction (see Chapter 29). Surprisingly, despite numerous guidelines,
`"sub-optimal AEDs," including Dilantin and phenobarbital, were still
`
`120
`
`WHAT DO I DO NOW? EPILEPSY
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 131/216
`
`

`
`initiated in 70% of elderly veterans with neW--onset epilepsy between 2000
`and 2004.
`In the case presented, the patient likely had undiagnosed idiopathic
`Parkinson's dis~ even prior to the stroK.e. Valproate is known to exacer(cid:173)
`bate tremor, rigidity, and bradykinesia and should be avoided in chis and
`most ocher elderly patients as it can bring oui: parkinsonism in p