Epilepsy

Ibrahim Sales, Pharm.D.Assistant Professor of Clinical Pharmacy

King Saud Universityisales@ksu.edu.sa

Epilepsy - a disorder

• Chronic recurrent tendency to have seizures• 4 -7 cases per 1,000 people• 80% unknown cause– 5% developmental disorders– Head trauma, stroke

• Profound social impact– Limits driving, education, work– Dependence on caregivers

Age-Related Incidence

PediatricPerinatal and neonatal insults; genetic susceptibility

AdultIdiopathic traumaComplex febrile seizuresStatus epilepticus

ElderlyIdiopathicCerebrovascular accidentsNeurodegenerative disordersTumors

Medication-induced Seizures

• Tramadol, buproprion, theophylline, lithium• Antidepressants, antipsychotics• Amphetamines, cocaine• Imipenem, excessive doses of other beta-

lactams

Classification Overview

Seizures

Partial

Simple

Complex

Secondarily generalized

Primary Generalized

Tonic-Clonic

Absence

Myoclonic

Atonic

Treatment Principles

• Verify it was actually a seizure• Identify & Classify type of seizure to select

appropriate therapy• Determine risk of subsequent seizure– Fix underlying reversible causes first

• Design patient – specific plan– Type of seizure, ADE’s of drugs, cost / compliance

Treatment Principles

• Goal: Eliminate (control) seizures without adverse effects from the treatment

• Begin with a single drug• Increase dose slowly until – Seizures are controlled – Adverse effects that are unacceptable develop

• Try an alternative monotherapy before using combination therapy

Pharmacokinetic Issues

• Mechaelis – Menten Metabolism: Phenytoin– Metabolism saturates as concentrations increase

• Protein Binding: Phenytoin, Valproate– Free drug is active drug; altered in:• Kidney failure, hypoalbuminemia; Neonates, pregnant

women; Critically ill, or other highly bound drugs

• Autoinduction: Carbamazepine– Increases rate of own metabolism over time– Start small, titrate carefully

Carbamazepine• Spectrum

– Good for partial & secondarily generalized TC– Worsens absence or myoclonic seizures

• Dosing & PK– Adults and children over 12 years of age-Initial: Either 200 mg b.i.d. for tablets and XR tablets,

or 1 teaspoon q.i.d. for suspension (400 mg/day). Increase weekly by adding up to 200 mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations. Dosage NTE 1000 mg daily in children 12 to 15 years of age, and 1200 mg daily in patients >15 years of age 1600 mg daily max in adults

– Maintenance: Adjust dosage to the minimum effective level, usually 800 to 1200 mg daily– Serum levels 4-12 mcg/mL (lower in combo)– Induces metabolism of other drugs & itself

• serum levels fall over weeks

• Adverse Effects– Acute: Diplopia, drowsiness, nausea & sedation– Chronic: Aplastic anemia, hyponatremia, hypochloremia, leucopenia, osteoperosis & rash (SJS)

especially HLA-B*1502 allele

Oxcarbazepine

• Spectrum– As effective / useful as carbamazepine

• Dosing– Immediate-release:

Initial dose: 300 mg orally twice a day, increased by increments of 300 mg per day every third day as clinically indicatedMaintenance dose: 300 to 1,200 mg orally twice a dayMaximum dose: 1,200 mg orally twice a day Adverse effects

– Somnolence, dizziness, diplopia, ataxia, N/V– SJS & TEN*– More hyponatremia

* Toxic epidermal necrolysis

Oxcarbazepine Dosing • Adjunctive Therapy:

Immediate-release:Initial dose: 300 mg orally twice a day, increased by increments of up to 600 mg per day at approximately weekly intervals as clinically indicatedMaintenance dose: 300 mg to 1,200 mg orally twice a dayMaximum dose: 1,200 mg orally twice a day

Extended-release:Initial dose: 600 mg orally once a day for one week, increased by increments of 600 mg per day at weekly intervals as clinically indicatedMaintenance dose: 1,200 to 2,400 mg orally once a dayMaximum dose: 2,400 mg orally once a day

Lamotrigine• Spectrum

– Generalized Tonic-Clonic, Partial – +/- Myoclonic (may worsen in infancy)– Depression, Bipolar

• Dosing & PK– Ranging from 25mg initially – 700mg daily depending on sz type– Adjunct therapy: 25 mg po at bedtime for week 1, 25 mg po BID for week 2,

and then 50 mg po BID– OC’s decrease lamotrigine levels

• Adverse effects– Better tolerated than carbamazepine, phenytoin– Dizziness, ataxia, somnolence, headache, diplopia, nausea, vomiting, rash,

insomnia– Severe / life threatening rash (usually in 1st 2 months) especially with VPA (start at

lower dose)

Lamotrigine• Added to an Antiepileptic Drug Regimen Containing Valproic Acid:

Weeks 1 and 2: 25 mg every other dayWeeks 3 and 4: 25 mg every dayUsual maintenance dose: 100 to 400 mg/day (1 or 2 divided doses). To achieve maintenance, doses may be increased by 25 to 50 mg/day every 1 to 2 weeks. The usual maintenance dose in patients adding lamotrigine to valproic acid alone ranges from 100 to 200 mg/day.

• For patients receiving enzyme-inducing AEDs but not valproate:Initial dose: 50 mg orally once a day for 2 weeks, then increase to 50 mg orally twice a day for 2 weeks.Maintenance dose: 150 to 250 mg orally twice a day.Dose may be increased by 100 mg/day every week.Maintenance doses as high as 700 mg/day have been used.

LamotrigineEscalation regimen for lamotrigine extended release:For use in Primary Generalized Tonic-Clonic and Partial Onset Seizures

Treatment with lamotrigine is introduced based on concurrent medications.

Weeks 1 and 2:For patients not taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Valproate: 25 mg dailyFor patients taking Valproate: 25 mg every other dayFor patients taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and not taking Valproate: 50 mg daily

Weeks 3 and 4:For patients not taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Valproate: 50 mg dailyFor patients taking Valproate: 25 mg dailyFor patients taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and not taking Valproate: 100 mg daily

Week 5:For patients not taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Valproate: 100 mg dailyFor patients taking Valproate: 50 mg dailyFor patients taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and not taking Valproate: 200 mg daily

Week 6:For patients not taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Valproate: 150 mg dailyFor patients taking Valproate: 100 mg dailyFor patients taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and not taking Valproate: 300 mg daily

Week 7:For patients not taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Valproate: 200 mg dailyFor patients taking Valproate: 150 mg dailyFor patients taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and not taking Valproate: up to 400 mg daily

Maintenance Range (Week 8 and onward):For patients not taking Carbamazepine, Phenytoin, Phenobarbital, Primidone or Valproate: 300 mg to 400 mg dailyFor patients taking Valproate: 200 mg to 250 mg dailyFor patients taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and not taking Valproate: 400 mg to 600 mg daily

Dose increases at week 8 or later should not exceed 100 mg daily at weekly intervals.

Levetiracetam

• Spectrum– GTC, Myoclonic, Partial +/- Absence

• Dosing & PK– PO & IV formulations– Monotherapy: initiated with 1000 mg daily (500 mg twice daily) and

increased by 1000 mg/day every two weeks up to 3000 mg/day– Adjunct: 250 mg po at bedtime for week 1, 250 mg po BID for week 2,

and then 500 mg po BID

– No significant interactions• Adverse effects

– Dizziness, somnolence; depression– Little cognitive effects

Phenytoin

• Spectrum– As effective as CBZ for GTC & partial– Clinical utility limited by PK, ADE’s…

• Dosing & PK– See following pages

• Adverse effects– Concentration dependent Nystagmus, Drowsiness, ataxia

& diplopia.– Chronic Gingival hyperplasia, facial coarsening, rash,

hepatitis, hypersensitivity, cognitive impairment

Phenytoin - Levels

• Therapeutic range is whatever takes to control seizures, limited by adverse effects

• Therapeutic range: Usually 10-20 mcg/mL = free levels of 1-2 mcg/mL

• Level - specific adverse effects:> 20 mcg/mL Nystagmus, Drowsiness>30 mcg/mL Ataxia>40 mcg/mL Mental status changes, coma50-60 mcg/mL Exacerbate seizures, precipitate GTC

Phenytoin - Dosing

• Loading dose 10 - 20 (15) mg/kg PO or IV– Oral doses need to be divided– IV doses need to be given slowly (only in monitored bed)

• Do not exceed the infusion rate of 50 mg/min– Therapeutic levels last 12 - 24 hours.

• May check trough at 18 -24 hours

• Maintenance dose 3 - 6 mg/kg/day – Average 300 - 400 mg; consider drug interactions– Total dose QHS OK if Dilantin,

• Must divide Q8h for oral liquid (per tube) or IV

Phenytoin - Kinetics

Absorption - Oral – Saturable absorption at doses > 300mg– Tube feedings decrease absorption– Release depends on dosing form– Only Dilantin ER Caps recommended for Q Day

Phenytoin - Kinetics (2)

Distribution -• Free phenytoin is active drug • Highly protein bound to Albumin • Uremia alters binding, displaces phenytoin• Must correct measured phenytoin levels for

Hypoalbuminemia & / or Renal Failure (BUN>50).– Medcalc for hypoalbuminemia, double level for RF.– PhenC = Phen / [(0.2* x Alb) + 0.1] * use 0.1 in RF– RF = renal failure = GFR < 10

Phenytoin - Kinetics (3)

Metabolism & Elimination• Long half-life (24 hours) with saturable metabolism– Small increase in dose may cause profound increase in

concentrations– In overdose, clearance is further delayed– Takes > 5-7 days (up to 28) on same dose & stable on

interacting meds to reach steady state

Phenytoin - Kinetics (4)

Metabolism & Elimination• Hepatically eliminated enzyme inducer– Metabolism inhibited (levels increased) by

• Isoniazid, sulfonamides, amiodarone, azole antifungals, cimetidine, erythromycin, valproic acid

– Metabolism induced (levels decreased) by• Rifampin, phenobarbital, carbamazepine; folic acid

– Induces metabolism (chews up) other drugs• Folate, Carbamazepine, oral contraceptives, lamotrigine,

cyclosporine & tacrolimus, valproic acid

– Warfarin: increased then decreased effect

Valproate

Valproic acid (Depakene), Divalproex Sodium (Depakote)• Spectrum

– Very broad: GTC, Partial, Absence. Also Bipolar disorder

• Dosing & PK– Oral & IV 15 mg /kg /day (+/- loading) & titrate up– Levels 50 – 100 mcg/mL – Fewer (but still has) drug interactions

• Adverse Effects– Drowsiness, Nausea, sedation & tremor– Hyperuricemia, hepatotoxicity, osteoperosis, pancreatitis, weight

gain

Felbamate

• MOA: Prolongation of the inactive state of sodium channels

• Indications: NOT INDICATED AS FIRST LINE TREATMENT; monotherapy or adjunctive therapy in the tx of partial seizures, w/ or w/o generalization

• Black box warning– Aplastic anemia– Hepatic failure

Felbamate

• Dosage forms: 400 and 600mg tablets; Oral suspension 600mg/5mL

• Dosage:– Monotherapy: Initiate at 1200mg/day divided into 3 or 4 doses;

increase in 600mg increments every 2 weeks to 2400mg/day; 3600mg daily max

– Adjunctive: Initiate at 1200mg/day divided into 3 or 4 doses while reducing AEDs by 20% (PHT, VPA, PHB, CB); increase by 1200mg increments every week to 3600mg daily max

– Divide doses in half for renal dysfunction• Side effects/counseling points:

– Anorexia, vomiting, insomnia, nausea, headache– Suicidal thinking and behavior

Ethosuximide

• MOA: Binds to T-type voltage sensitive calcium channels

• Indications: Absence epilepsy

Ethosuximide

• Dosage forms: Oral suspension 200mg/5mL• Dosage:

– Initial dose for 3 to 6 years is 250mg; 6 years and older is 500mg daily; increase daily dose by 250mg every 4 to 7 days

– Dosages exceeding 1.5mg daily should be divided– 20mg/kg/day is the optimal dose– Therapeutic levels: 40 to 100mcg/mL

• Side effects/counseling points:– Anorexia, vomiting, insomnia, nausea, weight loss, diarrhea,

drowsiness, headache, hiccups, behavioral changes / psychosis. Rare: severe SJS, SLE

Lacosamide

• MOA: Sodium channel blockade (slow and selective)

• Indication: Adjunct, substitution monotherapy or monotherapy for partial-onset seizures in patients with epilepsy in patients ≥ 17 years old

• Pharmacokinetics:– Not affected by food– Renally eliminated; 300mg/day max for CrCl <

30mL/min and mild-moderate liver disease– IV formulation: pH 3.5 - 5

Lacosamide• Dosage forms:

– Tablet 50, 100, 150, and 200mg– Solution: 10mg/mL– IV solution: 200mg/20mL single-use vial

• Dosage:– Oral adjunct: 50mg twice daily, increase weekly by 100mg/day in two divided doses

up to 200 to 400mg/day– Oral monotherapy: after 3 days of adjunctive therapy withdrawal previous

antiepileptic drug– IV: Same as oral, infuse over 30 to 60 minutes– Loading dose: IV or oral: 200mg followed by 100mg in 12 hours then continue twice

daily – medical supervision• Controlled substance: Schedule V• Side effects/counseling points: Headache, nausea, diplopia, PR interval

increase (minimal)

Rufinamide

• MOA: Prolongation of the inactive state of sodium channels

• Indications: Adjunct treatment of seizures associated with Lennox–Gastaut syndrome (LGS) in adults and children ≥ 4 years old

• Pharmacokinetics:– Food increase bioavailability– Protein bound 34%– Metabolized via enzymatic hydrolysis (not CYP450 dependent)– Elimination is 85% renal– Plasma half-life is 6-10 hours

Rufinamide

• Dosage forms: 100, 200, and 400mg tablets• Dosage:

– Children: 10mg/kg/day in two divided doses. Increase by 10mg/kg every other day to a target dose of 45mg/kg/day given in two equally divided doses

– Adults: 400-800mg/day in two equally divided doses. Increase by 400-800mg every other day to a target dose of 3200mg/day in two equally divided doses

– Should be taken with food– Dose adjustment not necessary for CrCl < 30mL/min

• Side effects/counseling points:– Shortened QT interval, headache, somnolence

Ezogabine

• MOA: Activates voltage-gated potassium channels• Indication: Adjunct therapy for partial-onset seizures in

adults (≥ 18 years) who have responded inadequately to several alternative treatments and benefits outweigh the risk of retinal abnormalities and potential decline in visual acuity

• Pharmacokinetics:– Not affected by food– Renally elimiated; 600mg/day max for CrCl < 50mL/min– Moderate liver disease (Child-Pugh 7-9) max 750mg/day– Severe liver disease (Child-Pugh >9) max 600mg/day

Ezogabine

• Dosage forms: 50, 200, 300, and 400mg tablet• Dosage: 100mg TID, increase by max of 150mg/day

every week until at maintenance dose of 200-400 mg TID• Side effects/counseling points:– Somnolence, dizziness, confusion

• Rare: Urinary retention, prolonged QT interval

• Black box warning:– Retinal abnormalities– Retinal pigment dystrophies– Baseline and every 6 month eye exam

Clobazam

• MOA: a 1,5-benzodiazepine; enhances GABA via enhanced Cl - conductance through GAGA-A receptors

• Indication: Adjunct therapy LGS in age ≥ 2 years• Pharmacokinetics:

– Food does not affect absorption– Highly protein bound (80-90%)– Substrate of 2C19, oxidative metabolism and sequential

glucuronidation, inducer 3A4, inhibitor 2D6– 82% eliminated by kidney, and 11% by feces– Active metabolite: N-desmethylclobazam (norclobazam)– T1/2: 36 to 42 hours, N-desmethylclobazam: 71 to 82 hours

Clobazam• Dosage form: 5, 10, 20mg tablet; 2.5 mg/mL oral suspension• Dosage:

– < 30kg: 2.5mg twice daily; increase to 5mg twice daily in one week, then 10mg twice daily at week two

– > 30kg: 5mg twice daily, increase to 10mg twice daily in one week then 20mg twice daily at week two

• Dose adjustments:– Hepatic impairment (Child-Push 5 to 9) Geriatric, CYP 2C19 poor metabolizers:

initial 5mg once daily, titrated no faster than every 7 days to 10 to 20mg/day in 2 divided doses; max dose of 20 to 40mg per day on day 21

– Concomitant use with CYP2C19 inhibitors; may require clobazam dose reduction

• Side effects/counseling points: Somnolence (perhaps less than other benzos), fever, drooling, lethargy, constipation

Perampanel• MOA: Non-competitive antagonist of AMPA on postsynaptic neurons• Indication: Adjunct therapy for PS w or w/o secondary generalized

seizures• Pharmacokinetics:

– Effects of food: unchanged AUC; decreased Cmax 28 to 40%; delayed Tmax 2 to 3 hours

– Liver metabolism extensive CYP 3A4/5– t1/2: 105 hours; hepatic impairment 305 hours (mild); 295 hours (moderate

impairment)– Mild liver disease: 2mg once daily at bedtime; may increase dose by 2mg/day

every 2 weeks to a max of 6mg/day– Moderate liver disease: 2mg once at bedtime; may increase dose by 2mg/day

every 2 weeks to a max of 4mg/day; severe impairment, use not recommended– Renal: mild/moderate impairment no dosage adjustment, just monitor; severe

impairment, use not recommended

Perampanel• Dosage forms: 2, 4, 6, 8, 10, 12mg tablets• Dosage:

– Without enzyme inducing AEDs: 2mg at bedtime initially; increase by 2mg/day weekly up to 4-8mg at bedtime; max 12mg at bedtime

– With enzyme inducing AEDs: 4mg at bedtime initially; increase by 2mg/day weekly up to 12mg at bedtime max

– Dose titration every two weeks in the elderly– Max dose of 6mg in mild hepatic impairment, 4mg in moderate hepatic

impairment, avoid in severe impairment (renal or hepatic)• Side effects/ counseling points: Irritability (4 to 12%) Headache (11 to

13%) Hostility, aggression (1 to 3% of patients at 8-12mg), homicidal ideation, dizziness (16-43%), somnolence (9 to 18%), fatigue (8 to 12%)

• Black box warning:– Serious or life threatening psychiatric and behavioral adverse reactions

Eslicarbamazepine Acetate• MOA: Unknown, but thought to involve sodium channel blockade• Indication: Adjunct treatment of partial-onset seizures• Pharmacokinetics:• Prodrug metabolized to eslicarbazepine

– Not affected by food– Metabolized 91% hepatically via hydrolytic 1st pass metabolism,

intestinal (minor) active– Eslicarbazepine (major) active, (R)-licarbazepin and oxcarbazepine

(minor) active– Moderate inhibitor of CYP2C19, inducer of CYP3A4– Renal elimination > 90% as eslicarbazepine and glucuronide

metabolites– t1/2: 13-20 hours

Eslicarbamazepine Acetate• Dosage forms: 200, 400, 600, 800mg tablets• Dosage:

– 400mg daily; increase to 800mg after one week. Max dose of 1200mg– Moderate to severe renal impairment: 200mg daily; increase to 400mg

after two weeks. Max dose of 600mg– Hepatic impairment: mild to moderate, no change; severe, not

recommended– Not recommended with oxcarbazepine – Eslicarbazepine is inducible

• Side effects/counseling points:– Dizziness, somnolence, N/V, headache, diplopia, fatigue, vertigo, ataxia,

blurred vision, tremor– Suicidal behavior/ideation, dermatologic reactions (SJS)

Special Populations

• Elderly– Age-related changes– Protein binding, distribution, decreased enzyme

inducibility, elimination change– May require alteration in dosing and monitoring– Drug accumulation due to reduced clearance and

increased sensitivity

Therapeutic Considerations in the Elderly

• No interactions with other drugs or with other AEDs• Minimal to no protein binding • Good adverse effect profile • Few effects on cognitive function • One or two administrations daily • Can be introduced quickly until it reaches therapeutic levels • No blood controls required • Psychoactive benefits (to treat concomitant agitation,

aggression or anxiety, if present) • Easy-to-swallow pill • Easy-to-identify pill

AED Concerns

• Drug-drug interactions• Bone health– Decrease bone mineral density and alter bone

mineral metabolism– Enzyme-inducing AEDs

Patient Education

• Seizure record– Frequency and duration– Precipitating factors– Times occurred– Presence of an aura– Ictal and postictal activity– Medications (past and present)

Pregnancy

• Give 1-4 mg folic acid daily to all women of child-bearing potential

• Use monotherapy & lowest possible dose• Use AED that worked best before pregnancy– Valproate = higher risk of congenital anomalies, lower IQ’s

• Monitor AED levels every month & titrate dose• Monitor AED levels post partum & titrate dose

Switching & Stopping

• Switching– Start new drug at low dose & slowly titrate up to usual

minimum effective dose– Taper off the old drug as continue titrating up the new one

while monitoring closely

• Stopping if– Seizure free for 2 – 5 years– Normal neurological exam– Normal IQ– Single type of partial or generalized seizure– Normal EEG with treatment

Status Epilepticus

• Seizures lasting > 5 minutes or 2 seizures without regaining consciousness in between

• Can be convulsive or non-convulsive (detect by EEG)• Medical emergency• Supportive care• Goals of therapy

– Therapy is started with emergent initial therapy (Step 1), then– Urgent control therapy (Step 2), and then – Treatment of refractory status epilepticus if seizure activity

has continued

Emergent initial therapy (Step 1):

Benzodiazepines• Advantages: rapid onset of action and ease of

administration• Disadvantages: short duration of action and CNS

(assessment of consciousness) and respiratory depression

• IV administration or non-IV options • If the seizure has not stopped within 5–10 minutes,

a second dose of a benzodiazepine may be administered

Emergent initial therapy (Step 1):Lorazepam DOC for IV administration• Longer duration of action (fewer repeat doses ; less frequent seizures)

– Lorazepam 0.1 mg/kg (maximum 4 mg) IV given at a rate of 2 mg/min. Administer a second dose after 5–10 minutes if needed

Diazepam • Fast acting and crosses the blood–brain barrier (lipid solubility), but rapidly redistributes

to the more abundant fatty tissue• Duration in the CNS ~30 minutes• Option of rectal administration

– Diazepam 5 to 10 mg IV; may be repeated at 10 to 15 minute intervals up to a maximum dose of 30 mg

– Diazepam 0.2 mg/kg (maximum 20 mg) per rectum. If a second dose is needed, it may be administered after 5–10 minutes

Midazolam DOC for intramuscular (IM) administration of a benzodiazepine• Hydrophilic and lipophilic (rapid absorption into the bloodstream and CNS)

– Midazolam 0.2 mg/kg (maximum 10 mg) IM. If a second dose is needed, it may be administered after 5–10 minutes.

Urgent control therapy (Step 2)• Used to control seizures that did not stop after initial therapy or

to establish therapeutic blood levels of an antiepileptic agent for continued maintenance dosing

Fosphenytoin or phenytoin DOC as a next-line agent due to the lack of CNS depression and a long half-life

– Phenytoin: cardiovascular toxicity when given too rapidly, necessitating slow IV administration and has limited compatibility with other IV fluids

– Fosphenytoin: water-soluble prodrug of phenytoin• Does not contain propylene glycol as an excipient• Can be administered IV more rapidly than phenytoin (prodrug must be

converted by phosphatases to the active phenytoin), it has fewer adverse infusion reactions, and it can be given intramuscularly

Urgent control therapy (Step 2)

Phenobarbital • Phenobarbital is as effective as phenytoin • Slower onset of action and more respiratory depression. • Advantages: reliability and effectiveness in status epilepticus, long

lasting duration of action, and safety in high doses and with rapid administration

• Disadvantages: risk of accumulation because of its long elimination half-life and the potential for sedation, respiratory depression, and hypotension

Valproic acid and levetiracetam • Advantages: lack of cardiovascular effects, both are well tolerated,

and may be converted to maintenance therapy if needed

Urgent control therapy (Step 2)• Phenytoin 20 mg/kg IV at a rate of 50 mg/min. Give repeat doses of 5–10 mg/kg at 30-

minute intervals to a maximum of 1,500 mg (in 24 hours)– If the patient is already on phenytoin, the loading dose can be followed by restarting their daily oral

maintenance dose

• Fosphenytoin 20 mg phenytoin equivalents (PE)/kg at a rate of 100–150 PE/min. May give an additional 5 mg PE/kg– 75 mg fosphenytoin equivalent to 50 mg phenytoin

• Phenobarbital 20 mg/kg IV at a rate of 50–100 mg/min. May give an additional 5–10 mg/kg.

• Valproic acid 20–40 mg/kg IV at a rate of 3–6 mg/kg/min. May give an additional 20 mg/kg.

• Levetiracetam 1,000–3,000 mg IV at a rate of 2–5 mg/kg/min, or over a total of 15 minutes.

Refractory status epilepticus (RSE)

• Initiate 20–60 minutes after Step 2 treatment if clinical seizures have not stopped or the EEG shows persistent epileptiform activity

• Treatment options– Midazolam 0.2 mg/kg IV loading dose (at a rate of 4

mg/ min), followed by an infusion of 0.05–0.4 mg/kg/h– Pentobarbital 5–15 mg/kg IV loading dose followed by

an infusion of 0.5–3 mg/kg/h– Propofol 1–2 mg/kg IV loading dose, followed by an

infusion of 2–10 mg/kg/h

Drugs of Choice for Specific Seizure Disorders

Seizure Type First-Line Drugs Alternative Drugsa CommentsPartial seizures (newly diagnosed)U.S. guidelines •Adults and adolescents:

Carbamazepine•Gabapentin•Oxcarbazepine•Phenobarbital•Phenytoin•Topiramate•Valproic acid

•FDA approved:Carbamazepine•Lacosamide•Phenobarbital•Phenytoin•Topiramate•Valproic acid

U.K. guidelines •Carbamazepine•Lamotrigine

•Levetiracetam•Oxcarbazepine•Valproic acid

ILAE guidelines •Adults:Carbamazepine•Phenytoin•Valproic acid

•Adults:Gabapentin•Lamotrigine•Oxcarbazepine•Phenobarbital•Topiramate

•Children:Oxcarbazepine •Children:Phenobarbital•Phenytoin•Topiramate•Valproic acid

•Elderly:Gabapentin•Lamotrigine

•Elderly:Carbamazepine

U.S. Expert Panel 2005 •Carbamazepine•Lamotrigine•Oxcarbazepine

•Levetiracetam

Drugs of Choice for Specific Seizure Disorders

Seizure Type First-Line Drugs Alternative Drugsa CommentsPartial seizures (refractory monotherapy)

U.S. guidelines •Lamotrigine•Oxcarbazepine•Topiramate

•FDA approved:Carbamazepine•Lamotrigine•Oxcarbazepine•Phenobarbital•Phenytoin•Topiramate•Valproic acid

U.K. guidelines •Lamotrigine•Oxcarbazepine•Topiramate

Drugs of Choice for Specific Seizure Disorders

Seizure Type First-Line Drugs Alternative Drugsa Comments

Partial seizures (refractory adjunct)U.S. guidelines •Adults:

• Gabapentin• Lamotrigine• Levetiracetam• Oxcarbazepine• Tiagabine• Topiramate• Zonisamide

•Children:• Gabapentin• Lamotrigine• Oxcarbazepine• Topiramate

•FDA approved:Carbamazepine•Gabapentin•Lamotrigine•Levetiracetam•Oxcarbazepine•Phenobarbital•Phenytoin•Pregabalin•Tiagabine•Valproic acid•Vigabatrin•Zonisamide

U.K. guidelines •Carbamazepine•Clobazam•Gabapentin•Lamotrigine•Levetiracetam•Oxcarbazepine•Valproic acid•Topiramate

•Lacosamide•Phenobarbital•Phenytoin•Pregabalin•Tiagabine•Vigabatrin•Zonisamide

Drugs of Choice for Specific Seizure Disorders

Seizure Type First-Line Drugs Alternative Drugsa CommentsGeneralized seizures absence (newly diagnosed)

U.S. guidelines Lamotrigine •FDA approved:Ethosuximide•Valproic acid

U.K. guidelines •Ethosuximide•Lamotrigine•Valproic Acid

•Clobazam•Clonazepam•Levetiracetam•Topiramate•Zonisamide

ILAE guidelines •None •Ethosuximide•Lamotrigine•Valproic acid

U.S. Expert Panel 2005 •Ethosuximide•Valproic acid

•Lamotrigine

Drugs of Choice for Specific Seizure Disorders

Seizure Type First-Line Drugs Alternative Drugsa CommentsPrimary generalized (tonic–clonic)

U.S. guidelines •Topiramate •FDA approved:Lamotrigine•Levetiracetam•Topiramate

U.K. guidelines •In following order:• Valproic acid• Lamotrigine• Carbamazepine• Oxcarbazepine

•Clobazam•Levetiracetam•Topiramate

ILAE guidelines •None •Adults:• Carbamazepine• Lamotrigine• Oxcarbazepine• Phenobarbital• Phenytoin• Topiramate• Valproic acid

•Children:• Carbamazepine• Phenobarbital• Phenytoin• Topiramate• Valproic acid

U.S. Expert Panel 2005 •Valproic acid •Lamotrigine•Topiramate

Drugs of Choice for Specific Seizure Disorders

Seizure Type First-Line Drugs Alternative Drugsa Comments

Juvenile myoclonic epilepsy FDA approved:Levetiracetam (myoclonic seizures)

U.K guidelines •Ethosuximide•Lamotrigine•Valproic acid

•Clobazam•Clonazepam•Levetiracetam•Topiramate•Zonisamide

ILAE •None •Clonazepam•Lamotrigine•Levetiracetam•Topiramate•Valproic acid•Zonisamide

U.S. Expert Panel 2005 •Valproic acid •Levetiracetam•Topiramate•Zonisamide