medications for epilepsy management in the ambulatory setting

Medications for epilepsy management in the ambulatory setting

Elizabeth Flatley, PharmD, BCACPTCH APP Conference 2019

Disclosure I have nothing to disclose

Objectives1. Identify appropriate initial medication regimens to manage

epilepsy/common seizure disorders in children

2. Formulate a plan to monitor pediatric patients on common seizure medications

Definitions*Seizure: a sudden stereotyped episode that presents with a change in motor activity, sensation, behavior, and/or consciousness caused by abnormal electrical discharge in the brain

*Epilepsy: Any of the following o ≥ 2 unprovoked seizures occurring within 24 hours o 1 unprovoked seizure and a recurrence risk*o Diagnosis of an epilepsy syndrome

*Status Epilepticus: single seizure lasting ≥ 20 minutes or recurrent shorter seizures without recovery of consciousness between**

*Resolved epilepsy occurs for patients who had an age-dependent epilepsy syndrome and are past the age of said syndrome or patients who are seizure free for the last 10 years with no medication for at least 5 years

American Academy of Pediatrics. National Coordinating Center for Epilepsy. Epilepsy Overview. https://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/Coordinating-Center-on-Epilepsy/Pages/Epilepsy-Overview.aspx. Accessed February 18, 2019. American Academy of Pediatrics (AAP). Epilepsy Compendium: A Compilation of Resources for Providing Care To Children and Youth With Epilepsy (CYE). Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475-82.

Causes of Seizures *Many causes when cortical neurons discharge abnormally in synchrony

*Identified in under 20% of children with seizures

American Academy of Pediatrics. Seizures Overview. https://www.aap.org/en-us/Documents/echo_session%201_seizures_overview.pdf

Dipiros. Epilepsy . Page 3-4.

Provoked

• CNS infection

• Trauma

• Metabolic

abnormality

• Toxic exposure

• Fever

• Stroke

Unprovoked Other/Mixed

• Brain malformation

• Genetic disorders

• Disorders of

metabolism

• Trauma or previous

infectious injury of

brain

• Neoplasm

https://www.aap.org/en-us/Documents/echo_session%201_seizures_overview.pdf

Increase Seizure risk

Hyperventilation (absence seizures)

Sleep

•Excessive sleep •Sleep deprivation Sensory stimuli Emotional stress

Hormonal changes

Medications/drugs:

•Theophylline•Alcohol •High dose phenothiazines•Maprotiline•Bupropion •Substances of abuse/ street

drugs

Perinatal injuries and small gestation weight at birth


Pathophysiology• Excessive excitation in group of cortical neurons • Disordered inhibition in group of cortical neurons Cause

• Functional deficits• Especially in memory

• Change neuronal circuitry • Increase susceptibility to further seizures • Destruction of neurons• Brain damage

Effects of continued seizure activity

• Control with Antiepileptic Drugs (AED)• Stabilize neuronal membranes• Depress synaptic transmission • Reduce nerve conductance

Medication treatment


Seizure Evaluation

American Academy of Pediatrics. Seizures Overview. https://www.aap.org/en-us/Documents/echo_session%201_seizures_overview.pdf

• Obtain a detailed description of event(s)• Perform general physical exam and neurologic exam• Obtain an EEG

To establish diagnosis and categorize seizure type:

• Obtain a detailed description of event(s)• Collect past and recent medical history • Ask about family history • Collect appropriate labs

Identify possible etiology & determine likelihood of recurrence:

• Safety precautions• Rescue medication • Preventive medication

Formulate treatment plan

U.S. Epilepsy Prevalence

Zack MM, Kobau R. National and state estimates of the numbers of adults and children with active epilepsy — United States, 2015. MMWR. 2017;66:821–825. DOI: 10.15585/mmwr.mm6631a1. html

In 2015, 1.2% of the U.S. population had active

epilepsy. This accounts for about 3 million adults and

470,000 children nationwide.

Scheffer IE, Berkovic S, Capovilla G et al. ILAE classification of the epilepsies: position paoer of the ILAE Commision for Classification and Terminologi. Epilepsia; 1-10, 2017. doi: 10.1111/epi.13709.

International League Against Epilepsy (ILAE)

2. Level of awareness

during seizure

3. Other features

1. Onset: where seizures begins in the

brain

*

*Seizure already determined to be epileptic in nature

Scheffer IE, Berkovic S, Capovilla G et al. ILAE classification of the epilepsies: position paoer of the ILAE Commision for Classification and Terminologi. Epilepsia; 1-10, 2017. doi: 10.1111/epi.13709.

Can omit awareness in some instances

(i.e. neonate)

Aura: symptoms a person may

feel at start of a seizure

Focal to bilateral: starts on one

side of the brain and spreads to

both sides

Motor: some kind of

movement occurs during

event

Aware: aware of self & event throughout

seizure

Focal: originate within 1

hemisphere of the brain

Generalized:engage both

hemispheres of the brain

Treatment Plan Safety Precautions

Rescue Medication

Preventative Medication

Safety

American Academy of Pediatrics. Family Education and Support. https://www.aap.org/en-us/Documents/echo_session_5_family_education_support.pdf

Firs

t Aid Make a

seizure safety plan Provide instructions on when to call EMS

Activ

ities Water

SportsPhysical activity

Environment

Driv

ing Not allowed if

seizure not controlled

Com

orbi

ditie

s Children with epilepsy have increased risk of mental health and learning disorders

Resources:Epilepsy Foundation: A seizure safe environment

Rescue Medication

For prolonged or recurrent seizures

Use when :

• Multiple seizures

within a short time or

seizure lasting more

than 3 minutes*

Non-oral routes

• Rectal diazepam

• Clonazepam wafer

• Intranasal midazolam

Implement seizure

safety plan and

follow up per MD

instructions

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137

Vassler DG, Weingarten M, Gidal BE. Current Review in Clinical Science: Summary of Antiepileptic Drugs available in the United States of America. American

Epilepsy Society. July 2018.

Rescue

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Diazepam. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. Accessed December 27, 2017. .

Diazepam- rectal (Diastat® AcuDial™ )

Indication Treat status epilepticus in children and adults for initial outpatient therapy

Mechanism GABA-A receptor agonist, enhances inhibitory effect of endogenous GABA

Dosing 2-5 years: 0.5 mg/kg6-11 years: 0.3 mg/kg≥12 years and Adults: 0.2 mg/kgRound up to the nearest 2.5 mg increment, max: 20 mg/doseCan repeated in 4-12 hours if needed

Adverse Effects (AE) Sedation, dizziness, depression, fatigue, motor and cognitive impairment, paradoxical reactions, tolerance/withdrawal with prolonged use

Monitoring Seizure resolution, sedation

Formulations Twin pack of 2.5mg, 10mg, 20mg; Rectal gel, available as 5mg/mL (delivers doses or 5, 7.5, 10mg) (other formulations injection, solution, tablet)

Drug-drug interactions (DDI)

Additive CNS agents, Inhibitors of CYP2C19 (cimetidine) and CYP3A4 (azoles) can decrease clearance; inducers of 2C19 (rifampin) and 3A4 (carbamazepine, phenobarbital, phenytoin, dexamethasone) can increase elimination

Clinical Pearls CIV controlled substance; Rectal gel not recommended under 6 months due to additional ingredients in product (including ethanol 10% and propylene glycol) ; CI in narrow angle glaucoma

AdministrationDiastat® [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals LLC; 2016

Disposal:• Pull plunger all the way up until

completed removed from syringe body

• Point over sink or toilet• Replace plunger into syringe

body and push plunger until it stops

• Flush toilet or rinse sink until gel no longer visible

• Discard all used material in garbage can in safe space away from children

Seizure Prevention Medication

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Academy of Pediatrics. Medication Management of Epilepsy. https://www.aap.org/en-us/Documents/echo_session_6_medication_management_epilepsy.pdf

Initiate daily preventative medication for:

Occurrence of second seizure

Patient with elevated risk for seizure recurrence

Neurologic deficit present

EEG with clear epileptiform activity

Patient/family consider risk unacceptable

Brain imaging with structural abnormality

https://www.aap.org/en-us/Documents/echo_session_6_medication_management_epilepsy.pdf

General Medication ConsiderationsStarting Medication

Based on epilepsy type/syndrome, age, comorbidities, side effect profile, access, lifestyle, patient/family preference

Changing Medication

Usually for adverse effects/unable to tolerate, lack of efficacy

Adding Medication

Events continue despite optimal dose first line medication ; combination therapy only if attempts at monotherapy not resulting in seizure freedom

Stopping Medication

Patient/provider decision, based on risk recurrence, long term control

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Academy of Pediatrics. Medication Management of Epilepsy. https://www.aap.org/en-us/Documents/echo_session_6_medication_management_epilepsy.pdf

Medications by Seizure Type/Syndrome

Case 1: KR *KR is a 10 year old right-handed male (NKDA, 26.8kg) with complex congenital heart disease/heterotaxy syndrome (TAPVR s/p multiple procedures on chronic

anticoagulation), recent onset/ recognized epilepsy (March 2018) associated with bilateral mesial temporal sclerosis, and learning/memory difficulties.

*EEG normal (6/2018). ; MRI (6/2018) was significantly motion degraded but revealed bilateral mesial temporal sclerosis.

*Semiology is consistent with mesial temporal seizures (aura- fear, nausea; ictus - confusion, cough, vomiting)

*Etiology possibly due to early hypoxic-ischemic insult affecting highly sensitive bilateral mesial temporal structures, related to underlying cardiac abnormality.

*Epilepsy Type/Syndrome: Focal structural - bilateral MTS

*Plan per neurology: Suspect his paroxysmal events are due to complex partial seizures (temporal lobe epilepsy). Advised treatment with a daily AED. While preference would be a narrow spectrum agent such as Oxcarbazepine/Aptiom, given that he is on multiple medications (including diuretics for cardiac condition) initiating alternate therapy to prevent dropping sodium further.

Levetiracetam started 6/2018 as follows:

WEEK AM PM

1 1/2 tablet (125 mg) 1/2 tablet (125 mg)

2 1 tablet (250 mg) 1 tablet (250 mg)

3 (Goal Dose) 2 tablets (500 mg) 2 tablets (500 mg)

https://medicine.umich.edu/dept/pediatrics

Case 1: KR Questions1. What is the mechanism of action of this therapy for partial seizures?

2. How would you counsel parents on medication administration?

3. What labs would you monitor?

Focal seizures*Seizures start in one area of the brain

*Replaces partial term

* Aware seizures often brief, lasting seconds to less than 2 minutes

*Impaired awareness can last 1-2 minutes

*Many treatment options are available, including medications, dietary therapy, surgery, and devices

Epilepsy Foundation. Focal Onset Aware Seizure. https://www.epilepsy.com/learn/types-seizures/focal-onset-aware-seizures-aka-simple-partial-seizureshttps://www.webmd.com/epilepsy/treat-epilepsy-seizures-16/slideshow-epilepsy-overviewUptoDate. https://www.uptodate.com/contents/image?imageKey=NEURO%2F77659&topicKey=NEURO%2F2231&search=focal%20seizure&source=outline_link&selectedTitle=1~150

https://www.epilepsy.com/learn/types-seizures/focal-onset-aware-seizures-aka-simple-partial-seizures

https://www.webmd.com/epilepsy/treat-epilepsy-seizures-16/slideshow-epilepsy-overview

Focal seizuresFirst Line Second Line Alternatives, Refractory, and/or Adjunct

Carbamazepine Levetiracetam Brivaracetam Phenytoin

Oxcarbazepine Clobazam Pregabalin

Lamotrigine Eslicarbazepine Primidone

Felbamate Tiagabine

Gabapentin Topiramate

Lacosamide Valproic acid

Perampanel Zonisamide

Phenobarbital

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018American Academy of Pediatrics. Medication Management of Epilepsy. https://www.aap.org/en-us/Documents/echo_session_6_medication_management_epilepsy.pdf

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Carbamazepine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. Accessed December 27, 2018.

Carbamazepine(Carbatol, Epitol, Equetro, Tegretol, TegretolXR®)

Indication Focal and generalized tonic clonic seizures, mixed seizure types

Mechanism Enhances Na+ channel rapid inactivation; block L-type Ca2+ channel

Dosing* -<6 years: start 10-20 mg/kg/day divided 2-3 times daily as IR tablets or 4 times daily as suspension• Maximum recommended daily dose: 35 mg/kg/day

-6-12 years: start 100 mg twice daily or 50 mg of suspension 4 times daily • Maximum recommended daily dose: 1000 mg/day (age 6-15)

-Adolescents: Initial: 200 mg twice daily • Maximum recommended daily dose: 1200 mg/day (age > 15)

AE Nausea, vomiting, hyponatremia, lethargy, dizziness, headache, hypersensitivity , diplopia, ataxia, low WBC count, decreased T3, T4, increased LFTs

Monitoring Serum carbamazepine level: 4-12 mcg/mL unless concomitant anticonvulsant; HLAB*1502 genotype for some, CBC, serum iron, LFTs, ophthalmic exam, UA, Lipi panel, TFTs, serum sodium

Formulations Extended release capsule, oral suspension, tablet, chewable tablet, extended release tablet

DDI MANY (Induces CYP1A2, 2B6, 2C9/19 and 3A4)- Oral contraceptives, warfarin; inhibited by macrolides

Clinical Pearls Indications for bipolar disorder, chronic pain syndromes (trigeminal neuralgia) ; do not use for absence seizure

* Lexicomp dosing

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Oxcarbazepine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com.

Oxcarbazepine(Trileptal®)

Indication Focal seizures, monotherapy or adjunctive therapy, tonic clonic seizures

Mechanism Enhances Na+ channel rapid inactivation; block Ca2+ channel; enhances K+ conductance

Dosing 2-16 years: start 8-10 mg/kg/day in 2 divided doses, maximum 300 mg twice daily; maintenance/max dose depends on weight≥17 years: 300 mg twice daily for week 1 then add no more than 300 mg BID each week (range 1200 mg – 2400 mg)

AE Blurred vision, dizziness/uncoordinated/fatigue, nausea, diarrhea or constipation, dyspepsia, hyponatremia, risk SJS/TEN especially with HLA-B*1502

Monitoring Efficacy, CNS depression, CBC, serum sodium , serum level: 10-35 mcg/mL as MHD

Formulations Suspension (300mg/5mL), tablet (150, 300, 600 mg) , 24 hour extended release tablet (150, 300, 600mg)

DDI CNS depressants ; Cyp3A4 metabolite; Induces CYP3A4 (reduces estrogen level at higher doses); inhibits CYP2C19

Clinical Pearls IR and XR formulations are NOT bioequivalent and NOT interchangeable on a mg/mg basis ; IR are interchangeable on a mg per mg basis however ; Due to a higher drug clearance, children 2-4 years of age may require up to 2x dose per body weight compared to adults, dose adjust for renal failure ; TID dosing can improve tolerability


American Epilepsy Society. July 2018

Lamotrigine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com.

Lamotrigine

(Lamictal®)

IndicationLGS, primary generalized tonic clonic seizures, focal seizures, adjunct therapy, absence seizures

MechanismEnhances Na

+

channel rapid inactivation; inhibits Ca2+

channel; activates postsynaptic HCN channels

DosingBased on age, weight, indication, concomitant medications

Weight based range: 0.15- 1.2 mg/kg/day

AEDizziness, headache, diplopia, ataxia, nausea, vomiting, somnolence, insomnia in high doses, aseptic

meningitis, rash/hypersensitivity

MonitoringHypersensitivity (RASH), CBC with differential, liver and renal functions, mood changes/suicidality, serum level

of lamotrigine : 4-20 mcg/mL; serum levels of concurrent anticonvulsants

FormulationsOral tablet (25, 100, 150, 200 mg), chewable tablet (5, 25mg), ODT (25, 50, 100, 200 mg), extended release

tablet (25, 50, 100 , 200, 250, 300 mg )

DDICNS depressants, Enzyme inducing AEDs, rifampin, oral contraceptives decrease level, pregnancy decreases

level, inhibits dihydrofolate reductase ; valproic acid inhibits lamotrigine

Clinical PearlsAlso indicated for bipolar disorder/ mood stability; avoid with sodium channel defects (Dravet syndrome) as

can worsen epilepsy

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Levetiracetam. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com..

Levetiracetam(Keppra®)

Indication Myoclonic seizures with juvenile myoclonic epilepsy (JME); focal seizures; tonic-clonic seizures

Mechanism Inhibits synaptic vesicle SV2A protein; partially inhibits N-type Ca2+ currents

Dosing 1 to <6 months: Start 7 mg/kg/dose twice daily; in clinical trials mean daily dose 35 mg/kg/day≥6 months and Children <4 years: Start 10 mg/kg/dose twice daily; in clinical trials mean daily dose 47 mg/kg/day≥4 years <16 years: Start 10 mg/kg/dose twice daily; maximum of 30 mg/kg/dose twice daily or total 3,000 mg/day; in clinical trials mean daily dose 44 mg/kg/day; older pediatric patients and adults (eg, weight >50 kg): Initial fixed dose of 500 mg twice daily is suggested

AE Somnolence, fatigue, asthenia, dizziness, depression, behavioral change (aggression, irritability), ataxia, infection, anemia, leukopenia, thrombocytopenia, diastolic blood pressure change in patients <4 years

Monitoring Efficacy, CNS depression, psychiatric and behavioral symptoms, diastolic BP in patients <4 ; serum levetiracetam level: 20-50 mcg/mL

Formulations IV solution (regular and PF), oral solution (100 mg/mL), tablet, orally disintegrating tablet (ODT), 24 hour extended release tablet (oral range from 250-1000 mg tablets)

DDI CNS depressants

Clinical Pearls Dose adjustment required with renal impairment

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Brivarecetam. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. .

Brivaracetam(Briviact®)

Indication Focal seizures (monotherapy or adjunct)

Mechanism Inhibits synaptic vesicle SV2A protein

Dosing ≥4 and <16 years: 11 to <20 kg: Initial: 0.5 to 1.25 mg/kg/dose twice daily; maximum daily dose: 5 mg/kg/day20 kg to <50 kg: Initial: 0.5 to 1 mg/kg/dose twice daily; maximum daily dose: 4 mg/kg/day≥50 kg: Initial: 25 to 50 mg twice daily; maximum daily dose: 200 mg/day

AE Sedation, nausea, vomiting, dizziness, suicidal ideation, anger, psychosis

Monitoring CBC with differential, liver and renal function, mood symptoms

Formulations IV solution preservative free (50mg/5mL), oral solution 10mg/mL (contains methylparaben, raspberry flavor), oral tablet – 10, 25, 50, 75, 100 mg

DDI Dose adjustment for concomitant use with rifampin; CNS depressants, AED interactions: carbamazepine, phenytoin

Clinical Pearls CV controlled substance; CYP2C19 poor metabolizers ; dose adjustment for hepatic impairment; IV formulation only approve for ≥ 16 years

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Clobazam. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com..

Clobazam(Onfi®; Sympazan®)

Indication Lennox-Gastaut syndrome; monotherapy/adjunct for generalized or focal seizures

Mechanism GABAA receptor agonist, binds between a and g subunits (1,5 benzo)

Dosing age ≥ 2 years ≤30 kg: Start 5 mg once daily for ≥1 week, can then increase to 5 mg twice daily for ≥1 week, then increase to 10 mg twice daily thereafter (max: 20 mg/day)>30 kg: Initial: 5 mg twice daily for ≥1 week, may then increase to 10 mg twice daily for ≥1 week, then increase to 20 mg twice daily thereafter (max: 40 mg/day)

AE Sedation, fever, infection (URI/UTI/pneumonia), drooling, constipation, Insomnia, irritability, depression, dependence/withdrawal effects, vomiting, ataxia

Monitoring Respiratory and mental status; CBC; liver and renal function, serum clobazam level: 0.25-0.75 mcg/mL

Formulations Oral film (5, 10, 20 mg); Tablets (10, 20 mg); oral suspension (2.5mg/mL – berry flavor ; use provided syringe and adapter for dosing)

DDI CNS depressants, major substrate of CYP2C19 (thus fluconazole, fluvoxamine, omeprazole inhibit metabolism), inhibits CYP2D6 weakly, induced CYP3A4 weakly

Clinical Pearls CIV controlled substance; Taper off by 5-10 mg/week if stopping ; different dose titration in hepatic impairment and CYP2C19 poor metabolizers

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Eslicarbazepine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com.

Eslicarbazepine(Aptiom®)

Indication Focal seizures (as monotherapy or adjunct)

Mechanism Enhances Na+ channel rapid inactivation; blocks HCav3.2 Ca2+ channel; enhances K+ conductance

Dosing Age ≥4 years: -11 to 21 kg: Start 200 mg once daily; max: 600 mg/day-22 to 31 kg: Start 300 mg once daily; max: 800 mg/day-32 to 38 kg: Start 300 mg once daily; max: 900 mg/day->38 kg: Start 400 mg once daily; max: 1,200 (1,600) mg/day

AE Hyponatremia, dizziness, sedation, diplopia, headache, N/V, tremor, ataxia, allergic reaction (SJS & TEN increased with HLA-B*1502), angioedema, DRESS, anaphylaxis

Monitoring Efficacy, LFTs, serum sodium and chloride, symptoms CNS depression, vision changes, periodic TFTs, serum eslicarbazine level possibly: 10-35 mcg/mL

Formulations Tablet (200, 400, 600, 800)

DDI Induces CYP3A4 (induces metabolism of oral contraceptives, statins, warfarin), inhibits CYP2C19 (increases phenytoin), Enzyme inducing AED induce metabolism

Clinical Pearls Dose adjustment for renal impairment, avoid in severe hepatic impairment and stop if hepatic impairment occurs during therapy

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Felbamate. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com.. .

Felbamate(Felbatol®)

Indication Focal seizures, monotherapy or adjunct ; adjunct in LGS*

Mechanism Enhances Na+ channel rapid inactivation; blocks Ca2+ channel; inhibits NMDA receptor, potentiates GABAAconductance

Dosing Adults: Start 1,200 mg/day in 3 or 4 divided doses; increase dose in 1,200 mg/day increments at weekly intervals; maximum daily dose: 3,600 mg/day≥4 years : Start 15 mg/kg/day in 3 or 4 divided doses, increase weekly by 15mg/kg/day to max of lesser of 45mg/kg/day or 3,600 mg per day

AE Aplastic anemia, hepatic failure (>6 cases/75,000 patients/year) , headache, insomnbia, nausea, vomiting, abdominal pain, anorexia/weight loss, facial edema, rash, hypophosphatemia, rhinitis, infection, ataxia, dizziness, tremor, anxiety, acne, SGPT, sedation

Monitoring Efficacy, CBC with differential and platelets, LFTs, mood change/suicidality, serum felbamate level: 60-100 mcg/mL

Formulations Suspension 600mg/5mL ; tablets (400mg, 600 mg)

DDI CYP3A4 inducers/inhibitors (decreases progestin in contraceptives), dose adjustment of many concomitant AED required on initiation, CNS depressants

Clinical Pearls Not first-line treatment; only for patients who respond inadequately to alternatives with benefits > risk ; contraindicated with hepatic impairment

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Gabapentin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com.

Gabapentin(Neurontin®)

Indication Focal seizures, adjunct therapy

Mechanism Binds presynaptic a2 -d subunit of Ca2+ channel to modulate Ca2+ current & ¯ glutamate, NE, and substance P release

Dosing 3-12 years: start 10 to 15 mg/kg/day divided into 3 doses daily; Usual dose:Age 3 to 4 years: 40 mg/kg/day divided into 3 doses daily 5-12 years: 25 to 35 mg/kg/day divided into 3 doses daily≥12 : start 300 mg 3 times daily; usual maintenance dose: 900 to 1,800 mg/day divided into 3 doses daily; doses up to 2,400 mg/day divided into 3 doses daily are well tolerated long-term

AE Drowsiness, sedation, fatigue, ataxia, dizziness, nystagmus, diplopia, peripheral edema, fever, viral infection, nausea, vomiting, tremor , rare but serious: DRESS , anaphylaxis, angioedema, neuropsychiatric changed in children 3-12 years

Monitoring Renal function, weight, behavior, signs and symptoms of suicidality , serum gabapentin level: 4-8.5 mcg/mL

Formulations Oral capsule (100mg, 300mg, 400mg) , oral solution 250 mg/5mL , oral tablet (600mg, 800mg)

DDI CNS depressants, Mg/Al containing antacids decrease gabapentin level by 20%

Clinical Pearls Also indicated for neuropathic pain ; dose adjustment required for renal insufficiency



Lacosamide. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com.

Lacosamide

(Vimpat®)

IndicationFocal seizure

MechanismEnhances Na

+

channel slow inactivation

Dosing≥4 -17 years:

11 to <30 kg: start 1 mg/kg/dose by mouth twice daily; maintenance: 3 to 6 mg/kg/dose twice daily

30 to <50 kg: start 1 mg/kg/dose twice daily by mouth; maintenance: 2 to 4 mg/kg/dose twice daily

≥50 kg: start 50 mg by mouth twice daily ; Maintenance: Monotherapy: 150 to 200 mg twice daily ; Adjunctive therapy: 100 to 200 mg twice daily

AEDizziness, ataxia, diplopia, headache, nausea, prolong PR interval, increase risk cardiac arrhythmias,

hypersensitivity, blurred vision, suicidal ideation

MonitoringECG (in select patients), hepatic and renal function, mood , heart rate and blood pressure (IV) , serum

lacosamide level: 4-12 mcg/mL

FormulationsIV solution (200mg/20mL), oral solution (10mg/mL – contains aspartame, methylparaben, propylene glycol-

strawberry), oral tablet (50, 100, 150, 200 mg)

DDI Strong Cyp3A4 inhibitors, Class III antiarrythmics, bradycardia causing medications, lidocaine, orlistat, QT-

prolonging Class IA and IC antiarrythmics

Clinical PearlsNot recommended with severe hepatic impairment, use caution with renal impairment; injection for age 17 and

up only

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Perampanel. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com.

Perampanel(Fycompa®)

Indication Focal seizures as adjunct or monotherapy; primary generalized tonic-clonic seizures

Mechanism Selective noncompetitive antagonist of AMPA glutamate receptor

Dosing ≥4 years : start 2 mg once daily at bedtime, can titrate weekly as needed to maximum 12 mg daily at bedtime *start with 4 mg dose if on moderate or strong CYP3A4 inducer

AE BBW – dose related neuropsychiatric events (aggression, anger, HI) ; dizziness , fatigue, irritability, ataxia, anxiety, falls, nausea, mental status change hypersensitivity, weight gain, rash, blurred vision

Monitoring Efficacy, mental status/suicidality (at least 1 month after stopping), weight

Formulations Suspension (mg/mL), tablets (2, 4, 6, 8, 10, 12 mg)

DDI CNS depressants; phenytoin; oral contraceptives

Clinical Pearls C-III controlled substance; dose adjustment for hepatic impairment

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Phenobarbital. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. .

PhenobarbitalIndication Generalized tonic clonic and focal seizure, status epilepticus/neonatal seizures

Mechanism Binds GABAA receptors

Dosing • Maintenance dose usually started 12-24 hours after load-Infants: 5-6 mg/kg/day in 1-2 divided doses-1-5 years: 6-8 mg/kg/day in 1-2 divided doses-5-12 years: 4-6 mg/kg/day in 1-2 divided doses-Adolescents: 1-3 mg/kg/day in 1-2 divided doses ; adult max = 240 mg/day

AE Sedation, cognitive slowing, headache, nausea, vomiting, depression, tolerance, decrease REM sleep, hepatic dysfunction, osteoporosis, megaloblastic anemia, with children irritability, hyperactivity, reduced IQRare but serious: SJS, TEN, DRESS, angioedema, respiratory depression

Monitoring CNS status. Efficacy, liver function, CBC with differential, renal function, suicidality; therapeutic phenobarbital range: 15-45 mcg/mL

Formulations Elixir (20mg/5mL) ; tablets (15, 16.2, 30, 32.4, 60, 64.8, 97.2, 100mg); injection solution (65mg/mL; 130 mg/mL) , oral solution (20mg/5mL)

DDI Vitamin D/calcium ; MANY strong inducer of CYP and UGT enzymes (increases metabolism of phenytoin, lamotrigine, oral contraceptives, warfarin) , CNS depressants (synergy with ETOH), elimination decreased by diuretics, alkaline urine and activated charcoal

Clinical Pearls C-IV controlled substance; caution with excipients in some formulations; toxicity possible

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Phenytoin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com.

Phenytoin(Dilantin®)

Indication Focal seizures, status epilepticus, tonic-clonic seizures

Mechanism Stabilizes neuronal membranes by increasing efflux or decreasing influx Sodium channels

Dosing *Common dose range after load: 6 months to 3 years: 8 to 10 mg/kg/day4 to 6 years: 7.5 to 9 mg/kg/day7 to 9 years: 7 to 8 mg/kg/day10 to 16 years: 6 to 7 mg/kg/day

AE Rash, dizziness, ataxia, cognitive slowing, hypertrichosis, lymphadenopathy, hepatotoxicity, suicidal ideation, nystagmus, constipation, change in taste, nausea, vomiting, gingival hyperplasia, decreased platelets & WBC, long term use: peripheral neuropathy and osteomalacia ; allergic reaction

Monitoring CBC with differential, liver function, suicidality, serum phenytoin concentration: 10-20 mcg/mL (~10% free)

Formulations Oral capsule as sodium (30, 100, 200, 300mg) , injection solution (sodium salt – 50mg/mL), oral suspension (125mg/mL), chewable tablet (50mg)

DDI Vitamin D/calcium; MANY interactions; major substrate of CYP2C19, 2C9 and induces CYP1A2, 2B6, 3A4, PGP UGT1A1

Clinical Pearls Phenytoin base contains ~8% more drug than phenytoin sodium; special kinetics, apparent half-life based on age. Steady state in 5-10 days

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Pregabalin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. .

Pregabalin(Lyrica®)

Indication Focal seizures, adjunctive therapy

Mechanism Binds presynaptic a2 -d subunit of Ca2+ channel

Dosing ≥4 years and Adolescents <17 years: 11 to <30 kg: start 3.5mg/kg/day in 2-3 divided doses ; maximum 14 mg/kg/day≥ 30 kg: start 2.5mg/kg/day in 2-3 divided doses; maximum 10 mg/kg/day up to 600 mg in 2-3 divided doses

AE Dizziness and somnolence, dry mouth, ataxia, decreased platelets, hypersensitivity, peripheral edema, prolongation of PR interval , blurred vision, weight gain, suicidal ideation, increased CK, warning: angioedema, hives, dyspnea, wheezing

Monitoring Efficacy, symptoms of myopathy, vision change, weight, mood, platelets, serum pregabalin level: 3-10 mcg/mL

Formulations Oral capsule (25, 50, 75, 100, 150, 200, 225, 300mg), oral solution (20mg/mL)

DDI CNS depressants

Clinical Pearls C-V controlled substance, dose adjustment in renal impairment, in adults labeled for neuropathic pain ; toxicity possible

Primidone(Mysoline®)

Indication Generalized tonic-clonic, psychomotor and focal seizures

Mechanism Metabolized to 2 active metabolites phenobarbital and PEMA; inhibitory transmission

Dosing Weight directed for infants and children <8 years: usual maintenance 10-25mg/kg/day , usual maximum: 500mg/dose ≥8 years : maximum daily dose 2,000 mg/day

*fixed dose titrations also available

Adverse Effects (AE)

Ataxia, drowsiness, emotional disturbance, fatigue, irritability, suicidal ideation, vertigo, morbilliform rash, anorexia, nausea, vomiting, impotence, diplopia, nystagmus, hematologic reactions

Monitoring Efficacy, liver enzymes, CBC with differential, renal function, suicidality ; therapeutic levels : primidone 5-12mcg/mL with phenobarbital therapeutic level for infants/chidlren/adolescents: 15-40 mcg/mL

Formulations Oral tablet (50, 250 mg)

Drug- drug interactions (DDI)

Strong CYP3A4 inducer, weak inducer of CYP2A6, 2B6, 2C9 , inducer of UGT1A1; CNS depressants

Clinical Pearls Toxicity possible; contraindicated with porphyria

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Tiagabine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. .

Tiagabine(Gabitril®)

Indication Focal seizures, adjunct therapy

Mechanism Selective GABA reuptake inhibitor (SGRI)

Dosing 12 to 18 years Patients on enzyme-inducing AED : Initial 4 mg once daily for 1 week, then 8 mg/day given in 2 divided doses for 1 week, then increase weekly by 4 to 8 mg/day; administer in 2 to 4 divided doses per day; titrate dose to response; maximum dose: 32 mg/dayPatients not on enzyme-inducing AED: Lower doses are required; slower titration *Similar dosing over age 18 with higher maximum daily dose

AE Dizziness, lack of energy, nausea, vomiting, sedation, cognitive slowing, anxiety, diarrhea, nervousness, tremor, trouble concentrating, abdominal pain

Monitoring Efficacy, liver function (recommend periodic tests), suicidal ideation, serum tiagabine level: 5-70 mcg/mL

Formulations Oral tablet (2, 4, 12, 16 mg)

DDI CNS depressants; CYP3A4 inhibitors/inducers (phenytoin, carbamazepine, phenobarbital and primidone decrease levels, valproic acid increases free levels)

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Topiramate. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. .

Topiramate(Topamax, Qsymia, Trokendi®)

Indication Infantile spasms, Focal seizures adjunct therapy, Lennox-Gastaut, generalized tonic-clonic

Mechanism Inhibits Na+ channels, kainite receptors and carbonic anhydrase, enhances GABAA

Dosing Varies based on formulation and indication **2 to 16 years for partial or LGS immediate release formulation: start 1 to 3 mg/kg/day (max 25 mg/dose) administered nightly, usual maintenance 5-9 mg/kg/day in 2 divided dosesIn dose response studies in adults -= dose > 400mg/day not shown to have efficacy

AE Paresthesia, anorexia, weight loss, speech and cognitive disturbance, sedation, dizziness, anxiety, abnormal vision, fever, diarrhea, nausea, abdominal pain, URI, acute myopia, glaucoma, visual field defects, hyperammonemia, metabolic acidosis, hyperthermia, kidney stones

Monitoring Efficacy, renal function, electrolytes including periodic bicarbonate levels, eye exam, signs/symptoms of suicidality , serum topiramate level: 7-30 mcg/mL

Formulations 24 hour capsule sprinkle (25, 50, 100, 150, 200 mg), 24 hour capsule (25, 50, 100, 200), sprinkle capsule (15, 25mg), oral tablet (25, 50, 100, 200mg)

DDI CNS depressants, phenytoin and carbamazepine, lithium, progestins, carbonic anhydrase inhibitors

Clinical Pearls Dose adjustment for renal failure, also used for migraine prophylaxis

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Valproic Acid. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. .

Valproic acid(Depacon, Depakote®)

Indication Focal, tonic-clonic, absence, mixed seizure disorder

Mechanism Enhances GABA activity, Inhibits voltage-dependent Na+ and T-type Ca2+ channels, enhances GABA activity

Dosing General: start 10-15 mg/kg/day in 1-3 divided doses; maintenance 30-60mg/kg/day in 2-3 divided doses

AE CNS depression, brain atrophy, thrombocytopenia, liver issues, encephalopathy, hypothermia, allergic reaction, suicidal ideation, pancreatitis, coagulopathy, alopecia, mood changes, ataxia, infection, diarrhea, nystagmus, edema, weight change, constipation, abdominal pain, headache, vomiting, tinnitus

Monitoring Liver enzymes (baseline and within 1st 6 months), bilirubin, serum ammonia, CBC with platelets, serum concentration, mental status/motor and cognitive function, serum valproic acid level: 50-100+ mcg/mL

Formulations Capsule (250mg), delayed release sprinkle capsule (125mg), IV solution (100mg/mL), oral solution (250mg/5mL), delayed release tablet (125, 250, 500 mg), (Age 10+: extended release tablet (250, 500mg))

DDI MANY : CNS depressants, estrogens, phenytoin, salicylates; Metabolized by CYP 3A4

Clinical Pearls Contraindications: hepatic disease, POLG mutation, urea cycle disorders, pregnancy *Boxed warning for hepatotoxicity, patients with mitochondrial disease, fetal risk, pancreatitisValproic acid and derivatives not preferred in patients <2 due to increased risk hepatotoxicityAdminister with food to decrease GI effects – NOT carbonated drinks

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Zonisamide. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. .

Zonisamide(Zonegran®)

Indication Focal seizures-adjunct, infantile spasms ; off label: absence seizures and others

Mechanism Enhances rapid inactivation at Na+ channels, ¯ low-threshold T-type Ca2+ current; binds GABAA ionophore; carbonic anhydrase inhibitor

Dosing ≤16 years: Start 1-2 mg/kg/day in 2 divided doses, usual dose 5-8 mg/kg/day; maximum 12 mg/kg/day> 16 years: Start 100 mg by mouth every day, increase by 100 mg every 2 weeks Usual maintenance 400-600mg/day as 1-2 doses

AE Kidney stones, rash, sedation, anorexia, weight loss, dizziness, ataxia, agitation, psychosis, irritability, speech or language disturbance, depression Warnings: SJS/TEN, DRESS, ¯ WBC, anemia, oligohydrosis and hyperthermia in children, hyperchloremic MA

Monitoring Efficacy, CBC, chemistry, serum zonisamide level: 10-40 mcg/mL

Formulations Capsule (25, 50, 100mg)

DDI carbamazepine, phenobarbital, phenytoin, moderately decrease half life with VPA, carbonic anhydrase inhibitors

Clinical Pearls Do not crush, chew, or break capsule

Case 2: FS FS is a 9 year old female (NKDA; 35.2kg) who presents to neurology clinic for follow up.

PMH symptomatic localization related epilepsy with temporal lobe seizure and GTC. Started on oxcarbazepine in 2/2015 after second seizure occurrence within 1 month time. Patient’s last seizure was on 6/29/17. With last GTC

Neurological exam: unremarkable. Developmentally she is age appropriate.

Iniital MRI brain was consistent with left mesial Temporal sclerosis and repeat MRI brain (6/16/17) showed stable findings.

Her last EEG showed generalized polyspike and slow wave discharges, often with lateralization to left and frontocentral lead-in. Additional, independent epileptiform discharges were occasional observed over the left frontocentral region and very rarely over the right and midline centroparietal regions. Photoparoxysmal response was also present. No clinical or electrographic seizures.

Plan:

-Continue Trileptal 300 mg/5ml, 11 ml BID

-CBC, CMP, Vitamin D level, Trileptal level, PT/PTT

-Diastat 10 mg PRN fpor seizure > 5 minutes

-Seizure precautions including: the need for constant supervision while in the bathtub or any other body of water, no climbing to high places where injury could occur with a fall, always wearing a helmet while bike riding. We discussed emergency seizure management and first aid.

-Call if any seizure or side effects

Case 2: FS QuestionsWhat follow up labs would you obtain?

Major drug drug interactions to look out for?

Generalized tonic-clonic (GTC) seizures

American Academy of Pediatrics. Types of Seizures and Common Epilepsy Syndromes in Children. https://www.aap.org/en-us/Documents/echo_session%202_types_of_seizures_common_epilepsy_syndromes_children.pdf Epilepsy Foundation. Tonic- clonic Seizures. https://www.epilepsy.com/learn/types-seizures/tonic-clonic-seizures

*Type many people think of as a “seizure”

*First is tonic (stiffening) phase: * All the muscles stiffen.* Air being forced past the vocal cords causes a cry or groan.* The person loses consciousness and falls to the floor.* A person may bite their tongue or inside of their cheek. If this happens, saliva may look a bit bloody.

*Next is clonic (rhythmic jerking) phase where: * The arms and usually the legs begin to jerk rapidly and rhythmically, bending and relaxing at the elbows, hips, and knees.* After a few minutes, the jerking slows and stops.

*The person’s face may look dusky or a bit blue if they are having trouble breathing or the seizure lasts too long.

*The person may lose control of their bladder or bowel as the body relaxes.

*Consciousness, or a person’s awareness, returns slowly.

*These seizures generally last 1 to 3 minutes. Afterwards, the person may be sleepy, confused, irritable, or depressed.

Generalized tonic-clonic (GTC) seizures



American Academy of Pediatrics. Medication Management of Epilepsy. https://www.aap.org/en-

us/Documents/echo_session_6_medication_management_epilepsy.pdf

First Line Alternatives, Refractory, and/or Adjunct

Valproic acid Carbamazepine Phenobarbital

Lamotrigine Oxcarbazepine Phenytoin

Topiramate

Perampanel

*Note: for absence or myoclonic seizures or if JME

suspected – no carbamazepine, gabapentin, oxcarbazepine,

phenytoin, pregabalin, tiagabine, or vigabatrin

Primidone

KC6 yo male with hx abscnece seizure ??? Being worked up for fragile X – asthma

Or other option VM (SW162912)

Absence seizures *New classification are a type of generalized, non-motor seizure

*Seizure description: Causes a short period of “blanking out” or staring

*Most common in children age 4-14 years

*Childhood absence epilepsy: * Onset frequently 5-9 years* Intellect and neurological exam often

normal * Neuroimaging often normal * EEG: 3 hz generalized spike and wave * Typical absence seizures remit in ~ 4/5

children * Favorable prognostic signs for outgrowing: * Negative family history * Normal background EEG * Normal intelligence

American Academy of Pediatrics. Types of Seizures and Common Epilepsy Syndromes in Children. https://www.aap.org/en-us/Documents/echo_session%202_types_of_seizures_common_epilepsy_syndromes_children.pdf Epilepsy Foundation. Focal Onset Aware Seizure. https://www.epilepsy.com/learn/types-seizures/focal-onset-aware-seizures-aka-simple-partial-seizures

Absence seziures



. American Academy of Pediatrics. Medication Management of Epilepsy. https://www.aap.org/en-


First Line Alternatives, Refractory, and/or

Adjunct

Ethosuximide Valproic acid

Lamotrigine

Clonazepam



Ethosuximide. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com.

.

Ethosuximide(Zarontin®)

Indication Absence seizures

Mechanism Affects low threshold, slow, T-Ca2+ thalamic currents

Dosing -3 to 6 years: start 250 mg orally daily; usual optimal daily dose: 20 mg/kg/day divided BID or TID

-≥6 years and Adolescents: start 500 mg daily; usual optimal daily dose: 20 mg/kg/day divided BID or TID

Max: lesser of 60 mg/kg/day or 2,000 mg/day

AE Blood dyscrasias, abdominal pain, anorexia, diarrhea, sedation, dizziness, ataxia, hyperactivity, ¯ WBC CNS

depression, change in hepatic function and renal function, SLE, myopia, hypersensitivity, GI upset, N/V, weight

loss, hirsutism, urticarial, change in mood (hyperactivity, depression, irritability, psychosis)

Rare but important : SJS, DRESS, pancytopenia, eosinophilia, lupus

Monitoring CBC with differential, platelets, liver and renal function, UA, mood, rash ; serum ethosuximide concentration:

40-100 mcg/mL

Formulations Oral capsule 250mg , oral solution 250mg/5mL (brand and generic for each)

DDI CNS depressants, CYP3A4 substrate

Clinical Pearls Use caution with renal or hepatic disease

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Clonazpeam. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. .

Clonazepam(®)

Indication

Mechanism

Dosing

AE

Monitoring

Formulations

DDI

Clinical Pearls

Infantile spasms

American Academy of Pediatrics. Types of Seizures and Common Epilepsy Syndromes in Children. https://www.aap.org/en-us/Documents/echo_session%202_types_of_seizures_common_epilepsy_syndromes_children.pdf Epilepsy Foundation. Infantile Spasms. https://www.epilepsy.com/learn/professionals/about-epilepsy-seizures/overview-epilepsy-syndromes/infantile-spasms

*Occurrence about 1 in 4,000-6,000 live births

*Three major groups of seizures: * Flexor: flexion of neck, trunk, arms, legs* Extensor: mainly extensor muscle

contractions resulting in abrupt extension of neck and trunk

* Mixed flexor-extensor

*90% begin before 12 months

*85% children with intellectual disability

*Cryptogenic/Unknown etiology

*Symptomatic: * Genetic

* Prenatal * Perinatal * Postnatal

Infantile spasms



Adrenocorticotrophic hormone (ACTH) Valroic acid

Prednisolone Topiramate

Vigabatrin (1st line for tuberous sclerosis)

Benzodiazepines

https://www.actharishcp.com/get-acthar-for-your-patientsAmerican Epilepsy Society. July 2018Corticotropin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. .

Corticotropin/ACTH(HP Acthar®)

Indication Infantile spasms

Mechanism Exact unknown however causes body and central nervous system to produce hormones such as cortisol, corticosterone , and aldosterone which is believed to impact the inflammatory process

Dosing *Multiple dosing strategies have been evaluated Manufacturer labeling infants and children 2 and under: 7 units/m2/dose administered IM twice daily for 2 weeks followed by a 2 week taper

AE Adverse effects largely related to steroid effects (behavior change, decreased glucose tolerance, cushingoid effects, weight gain, fluid retention, infection/lowered immune system) Contraindicate: coadministration live vaccines, primary adrenal insufficiency, many active infections, uncointrolled HTN, heart failure

Monitoring Efficacy, blood pressure, serum glucose, potassium, calcium, intraocular pressure (for therapy >6 weeks), linear growth, HPA suppression

Formulations 80 units/mL injection gel (5mL) – contains phenol

DDI Corticosteroids, immunosupressants, vaccines

Clinical Pearls $$, Only available through specialty pharmacies, dose calculator available through manufacturer with training materials for patients coming soon

Vigabatrin(Sabril®)

Indication Infantile spasms, Adjunct for refractory complex partial seizures

Mechanism Increases GABA through irreversibly inhibiting GABA-T

Dosing Infantile spasms (1-24 months): Start 50mg/kg/day divided twice daily; max 150 mg/kg/day Adjunct for refractory complex partial seizures age 10 and up: -If weight 25-60 kg and age 10-16 years, start 250 mg twice daily; recommended maintenance 1,000mg twice daily-If weight over 60 kg or age over 16, start 500 mg twice daily; recommended maintenance 1,500 mg twice daily

AE Black Box Warning: vision loss, Anemia, CNS depression, edema, peripheral neuropathy, suicidal ideation

Monitoring Ophthalmic exam (baseline, 1 month, then every 3 months), sedation, efficacy, Hgb/HCT, renal function, weight, suicidality, neurotoxicity, peripheral neuropathy, edema

Formulations 500 mg tablet ; 500 mg oral powder packet for solution

DDI CNS depressants

Clinical Pearls Only available through REMS program; $$$; can decrease AST/ALT activity in plasma in up to 90% patients leading to undetectable in some and precluding use of markers for hepatic injury; can increase amino acids in urine leading to false positive for rare genetic metabolic disorders

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Vigabatrin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. .

Dravet Syndrome

Epilepsy Foundation. Focal Onset Aware Seizure. https://www.epilepsy.com/learn/types-seizures/focal-onset-aware-seizures-aka-simple-partialseizures

Dravet Syndrome

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018

.


Topiramate Cannabidiol

Valproic acid

*Do not offer carbamazepine, gabapentin, lamotrigine, oxcarbazepine,

, phenytoin, pregabalin, tiagabine, vigabatrin

Cannabidiol

(Epidiolex®)

Indication Seizure treatment associated with Lennox-Gastaut Syndrome (LGS) or Dravet Syndrome (DS)

Mechanism Exact unknown

Dosing ≥2 years : Start at 2.5 mg/kg/dose twice daily, may increase in 1 week to maintenance dose of 5

mg/kg/dose twice daily

-If additional seizure control needed, may increase weekly by 2.5 mg/kg/dose twice daily

-Maximum: 20 mg/kg/day ; adjust for hepatic impairment

AE Elevated LFTs, CNs depression, hypersensitivity (angioedema, erythema, pruritis), lack of appetitie,

change in mood or behavior, diarrhea

Monitoring Assess ALT, AST, and total bilirubin prior to initiating treatment, with dose changes or the addition of or

changes in hepatotoxic medications

Formulations Oral solution 100mg/mL (100 mL bottle strawberry flavor, contains alcohol, sesame oil)

DDI CYP 2C19 inhibitors (cilostazol, citalopram (max 20mg/day), clopidogrel) , valproate, CNS depressantsa

Clinical Pearls C-V controlled substance; High fat/high calorie meals ↑ extent of absorption


Cannabidiol. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com.

.

Lennox-Gastaut Syndrome

American Academy of Pediatrics. Types of Seizures and Common Epilepsy Syndromes in Children. https://www.aap.org/en-us/Documents/echo_session%202_types_of_seizures_common_epilepsy_syndromes_children.pdf Epilepsy Foundation. Lennox-Gastaut Syndrome. https://www.epilepsy.com/learn/professionals/about-epilepsy-seizures/overview-epilepsy-syndromes/lennox-gastaut-syndrome

*Mixed seizure disorder

*Syndrome always begins in childhood * Usually age 2-8

*Most frequently occurring seizure types: * Tonic* Tonic-clonic* Myoclonic* Atypical absences * “Drop attacks”

* Cognitive dysfunction/ developmental delay present

* Poor prognosis

Lennox-Gastaut Syndrome



American Academy of Pediatrics. Medication Management of Epilepsy. https://www.aap.org/en-



Valproic acid Cannabidiol

Lamotrigine Felbamate

Topiramate

Felbamate

Clobazam

Clonazepam

Rufinamide

NICE. Epilepsies: diagnosis and management (CG137). 2012. Nice.org.uk/guidance/cg137American Epilepsy Society. July 2018Vigabatrin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http:://online.lexi.com. .

Rufinamide(Banzel®)

Indication Adjunct in Lennox-Gastaut syndrome

Mechanism Triazole derivative antiepileptic, prolongs inactive state of sodium channels and limits repetitive firing of sodium-dependent action potentials

Dosing <17 years: start 10 mg/kg/day in 2 equally divided doses; target daily dose of 45 mg/kg/day in 2 doses; maximum daily dose: 3,200 mg/day≥17 years: start 400 to 800 mg/day in 2 equally divided doses; maximum daily dose of 3,200 mg/day in 2 doses (unknown efficacy in lower doses)

AE Dose related shortened QT interval, anemia, leukopenia, increased infection, itch, skin rash, aggressive behavior, change in attention/hyperactivity,

Monitoring Efficacy, CBC, signs of suicidality, consider ECG (especially with other agents which shorten QT int)

Formulations Suspension (40mg/mL); tablets (200, 400 mg)

DDI Weak inducer of CYP3A4; CNS depressants

Clinical Pearls Initial dose adjust with concomitant valproate use; food increased absorption – counsel to take with food

Juvenile Myoclonic Epilepsy (JME)

American Academy of Pediatrics. Types of Seizures and Common Epilepsy Syndromes in Children. https://www.aap.org/en-us/Documents/echo_session%202_types_of_seizures_common_epilepsy_syndromes_children.pdf

* Onset age 12-18 * Seizure description:* Myoclonus early morning/photic

stimulation induced* Generalized convulsive seizures occur

in almost all patients – frequently main symptom

* Co-occurrence of absence seizures in 15-40%

* Prognosis: usually persists for life thus medication withdrawal not recommended

Juvenile Myoclonic Epilepsy (JME)


First Line Second Line

Levetiracetam Valproic acid

Lamotrigine

Topiramate

Zonisamide

Clobazam

BM18 yo emale with PMH JME

On zonisamide

History febrile seizures

Monotherapy

(start from when med new ) –

? Dosing ; monitoring ; would you stop/ how long to continue

Additional ConsiderationsTransition slide to more general concepts ??

Additional or special considerations / summary thoughts – whats a good title for this ?

Mono versus poly therapyInclude trial about how many pt controlled on one med versus require more than 1

Article to include??? Brain and Development

Volume 39, Issue 6, June 2017, Pages 464-469 ; cog and behavioral effects of new antiepileptic drugs in pediatric epilepsy

Epilepsy and Behavior volume 66 January 217 page 74-79 – a two year retrospective evaluation of perampanel in patients with highly drug-resiatnt epilepsy and cognitive impairment .

https://www.sciencedirect.com/science/journal/03877604

https://www.sciencedirect.com/science/journal/03877604/39/6

Long term monitoring-Efficacy

-Suicidality/mood

-Drug interactions

-Bone health/ vitamin D (enzyme inducing AED)

-Renal/hepatic function / CBC

-Vision

***monitoring as a whole – acute and long term with tablesà Use BCACP Epilepsy chapter!!! ???

Refractory epilepsy/ when to stop Study on % respons

Interactions??? General slide or just keep throughout - ? At end can poll audience if theres a certain comorbidity or womens health aspect that theyd like a talk on for next year?

Womens health Women of childbearing potential

Considerations for AED:

-Seizure control

-Risk birth defects

-Method of contraception if desired

-Dose adjustments during pregnancy and after pregnancy

-Medications in breastfeeding

References