A Summary of Antiseizure Medications Available in the United

A Summary of Antiseizure Medications Available in the United States: 4

th

Edition

Revised April 1, 2024

David G. Vossler, MD, FAES, FACNS, FAAN

1

and Barry E. Gidal, PharmD, FAES

2

of the AES Treatments Committee

Department of Neurology, University of Washington

1

, Seattle, Washington, USA; and

University of Wisconsin School of Pharmacy

2

, Madison, Wisconsin, USA

Introduction: The current review summarizes the most commonly used antiseizure medications (ASMs) available for prescription in the United States and is an

update to the AES 2018

1

and 2020 summaries. Information on rarely prescribed ASMs may be found elsewhere.

2

Tables 1-3 present the major pharmacologic

properties of commonly used ASMs to assist clinicians with providing care for persons with epilepsy and to facilitate the training of healthcare professionals.

Background: Two and one-half decades ago, the choice of ASMs was relatively limited. Beginning in August 1993 in the United States, the first new ASM in

approximately 15 years was approved by the US Food and Drug Administration (FDA). Since then, a panoply of ASMs have been approved. The vast majority of

these ASMs are in new drug classes, and many have novel mechanisms of action. Furthermore, most of the newer ASMs have pharmacokinetic properties that

are different from those of older ASMs.

Target Audience: Now that more than 30 ASMs are available in the United States, it can be challenging for epileptologists, neurologists, pharmacists, nurses,

trainees, and other healthcare professionals to quickly access and cross-reference information needed in clinical practice to optimally select and use these

medications. The American Epilepsy Society Treatments Committee provides this summary as a tool to help meet this need. It is the sincere hope of the authors

and the American Epilepsy Society that providers will find this document to be a beneficial reference tool in the advanced care of people with epilepsy.

Sources: Data for these summaries were obtained in January 2024 from the most recent FDA-approved prescribing information (PI) for each ASM available in the

FDA’s searchable database, Drugs@FDA: FDA-Approved Drugs.

3

Additional notes:

• Among PIs for all ASMs approved since 1993, the PIs for carbamazepine, divalproex, and phenytoin were substantially more detailed than PIs for other older

drugs. Phenobarbital is no longer listed on the FDA website, but an older PI was used to obtain FDA-approved information.

4

In instances where PIs lacked

important data, ASM pharmacology texts were used to supplement the information in the PIs.

5,6

• Serum level ranges are based on the clinical experience of American Epilepsy Society (AES) Treatments Committee members.

• PIs use the former terminology “partial onset seizures”; Table 1 uses the current terminology “focal onset seizures.”

7

• Regulatory language for approval of monotherapy versus adjunctive treatment has changed over the past decades.

8

• In Table 1, all drugs are approved for monotherapy and adjunctive treatment unless otherwise stated.

• Phenytoin maintenance dosing in Table 1 is from the PI, but modern research and experience indicate that adult dose requirements vary considerably from

200 to 600 mg/day. We advise that the reader consult modern sources for recommended maintenance dosing.

9

• Important: Actual practice of providers may differ substantially from official approved indications, doses, dose frequency, and other parameters.

Precautions for ASMs:

• All ASMs confer an elevated risk of suicidal ideation and behavior and an increased risk of teratogenesis.

• All women becoming pregnant while taking ASMs (also called antiepileptic drugs or AEDs), are encouraged to enroll themselves with the North American

Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334 or visiting www.aedpregnancyregistry.org.

10

• In the United States, report ASM adverse events to www.fda.gov/medwatch.

11

Important Notes:

• This document is not intended to constitute treatment recommendations but instead to provide an easy reference listing of products on the market.

• PI information is updated on an ongoing basis, and the FDA database PI sources for each ASM should be consulted for the most current information.

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations

.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

adrenocortico-

tropic

hormone

(ACTH)

IM injection

(80 U/mL)

Epileptic spasms

Monotherapy

Younger than 2 y

Stimulates

adrenal

gland to

secrete

cortisol,

corticostero

ne,

aldosterone,

and several

weakly

androgenic

steroids

Not adequately

characterized

t

1/2

= 0.25 h (IV)

N/A

Multiple

regimens

Manufacturer:

75 U/m

2

IM bid

for 2 wk, then

taper over 2

wk to avoid

adrenal

insufficiency

N/A

New infections or

worsening of

latent infections,

adrenal

insufficiency,

Cushing syndrome,

salt and water

retention,

hypertension,

paralytic ileus,

hypokalemic

alkalosis, gastric

ulcers, GI bleeding,

weight gain, bowel

perforation, fever,

behavior or mood

disturbances (e.g.,

irritability)

Contraindications:

IV use, and use with

congenital or other

infections, recent

surgery,

uncontrolled

hypertension, or

sensitivity to porcine

proteins

Do not administer

with live or live-

attenuated vaccines

Long-term use:

worsened diabetes

or myasthenia

gravis, cataracts,

glaucoma, loss of

endogenous ACTH,

osteoporosis,

decreased growth

DDI not studied

Consider weekly to

twice weekly BP

and glucose

monitoring,

monitoring

electrolyte levels

intermittently

(hypokalemia), and

treatment with a

histamine 2 (H2)

blocker

Hypothyroidism

and hepatic

cirrhosis may result

in enhanced effect

brivaracetam

(BRV)

Tablet, oral

solution

10 mg/mL,

IV solution

50 mg/5 mL

Schedule V

Focal onset in

patients 1 month

and older.

Inhibits

synaptic

vesicle

protein

SV2A

F ~100%

Protein binding

<20%

Metabolism:

1st - hydrolysis,

2nd - CYP2C19

hydroxylation,

CYP2C9

hydrolysis then

renal excretion

t

1/2

= 9 h

Children:

<11 kg = 0.75-

1.5 mg/kg bid

11-20 kg =

0.5-1.25 mg/kg

bid

20-50 kg =

0.5-1 mg/kg

bid

≥50 kg =

25-50 mg bid

Adults:

50 mg bid

Children:

<11 kg = 0.75-3

mg/kg bid

11-20 kg =

0.5-2.5 mg/kg

bid

20-50 kg =

0.5-2 mg/kg

bid

Children> 50

kg, use adult

dosing

Adults:

25-100 mg bid

Not

establish-

ed

Somnolence,

fatigue, N/V,

dizziness,

irritability,

aggression, anger,

agitation,

tearfulness,

depression, mood

swings, anxiety,

psychotic

symptoms,

disturbance in gait

and coordination,

and decreased

WBC count

Bronchospasm,

Angioedema

In all stages of

hepatic impairment

reduce BRV dosage

No adjustments

required in renal

insufficiency

Not recommended

in patients requiring

hemodialysis

Rifampin decreases

BRV by 45%;

EIASMs decrease

BRV by 19%-26%

BRV increases PHT

by 20% (via

CYP2C19) and CBZ-

epoxide by 198%

(via inhibition of

epoxide hydrolase)

No added efficacy

when combined

with LEV

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

cannabidiol

(CBD)

Oral solution

100 mg/mL

Seizures

associated with

LGS, tuberous

sclerosis complex,

or Dravet

syndrome

At least 1 y

Unclear

Does not

interact at

CB1 or CB2

receptors

Potential

targets

include

blockade of

orphan G

protein-

coupled

receptor 55

(GPR55);

agonist at

transient

receptor

potential

vanilloid

receptor

(TRPV1);

modulation

of

adenosine-

mediated

signaling

Low F, but

meals can

increase by 4-

fold

Tmax = 2.5-5 h

Extensively

metabolized,

principally via

CYP3A4 and

CYP2C19

7-OH-CBD

metabolite

appears to be

active

Protein binding

>90%

High-fat meals

increase extent

of absorption

>4- to 5-fold

Elimination t

1/2

~60 h; effective

t

1/2

~17 h

LGS and Dravet

syndrome:

5 mg/kg/d

divided bid x 1

wk. Then may

increase to 10

mg/kg/d

divided bid

Tuberous

sclerosis

complex:

5 mg/kg/d

divided bid x 1

wk. Increase as

tolerated

weekly by 5

mg/kg/d

divided bid

LGS and Dravet

syndrome:

10-20 mg/kg/d

divided bid

Tuberous

sclerosis

complex:

25 mg/kg/day

divided bid for

tuberous

sclerosis

complex

Not

establish-

ed

Somnolence/

sedation that may

be increased with

concomitant CLB,

potentially due to

increase in N-des-

methylclobazam

Elevated

transaminase level

(>3x upper limit of

normal),

particularly at

higher CBD doses

and with

concomitant VPA

Decreased

appetite, weight

loss, diarrhea,

vomiting, rash,

fever, infections,

insomnia, sleep

disorder,

hematologic

abnormalities,

increased

creatinine

Hypersensitivity

reactions include

pruritis, erythema,

and angioedema

Obtain baseline

serum ALT, AST and

total bilirubin levels

in all patients

Obtain periodic liver

enzyme levels,

especially if patient

is receiving higher

dose CBD or

concomitant VPA

with or without CLB

Artisanal

formulations of CBD

are not biopharma-

ceutically equivalent

and should not be

substituted

Dose should be

reduced in patients

with moderate to

severe hepatic

impairment

Drugs that inhibit

or induce CYP3A4

or CYP2C19 may

alter CBD kinetics -

clinical relevance

unclear

CBD inhibits

CYP2C19, so it

increases the

N-desmethyl-CLB

level by 3-fold and

increases DZP

CBD may inhibit

CYP2C9 (increasing

PHT, and may

increase

anticoagulant

effect of warfarin),

CYP2B6, CYP2C8,

and CYP1A2, and

UGT1A9 and

UGT2B7 substrates

May increase EVL

levels several-fold

May use with

ketogenic diet

May administer via

non-polyvinyl

chloride feeding

tubes

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

carbamazepine

(CBZ)

IR/ER tablet,

ER capsule,

chewable

tablet,

suspension

100 mg/5 mL

Focal onset,

GTCS, mixed (not

absence) seizure

types

May aggravate

absence or

myoclonic

seizures in

generalized

epilepsies

Enhance

rapid

inactivation

of Na

+

channels;

block L-type

Ca

2+

channel

F = 70% (ER

formulations

may be less),

Protein binding

= 76%

Metabolism:

CYP3A4 to CBZ

10,11 epoxide;

hydroxylated

and conjugated

metabolites

found in urine

more than

feces

Time-

dependent

clearance

(autoinduction)

t

1/2

= 25-65 h

initially, then

t

1/2

= 12-17 h

after

autoinduction is

completed

3-5 wk later

Children:

< 6 y =

10-20 mg/kg/d

divided doses

2-4x daily

Adults:

2-3 mg/kg/d

divided bid or

tid

Children:

<35 mg/kg/d

Adults:

Increase every

2-3 wk up to

2400 mg/d

(divided tid or

4x/d for IR; bid

for ER)

4-12

mcg/mL

Sedation, diplopia,

ataxia, dizziness,

blurred vision,

incoordination,

hyponatremia,

N/V, increased

intraocular

pressure, fever,

chills, elevated

ammonia,

decreased T3, T4,

increased LFTs

Low WBC counts,

pancytopenia

Lowers 25-OH

vitamin D levels

and serum calcium

leading to osteo-

porosis

Avoid in

porphyrias

Contraindications:

bone marrow

suppression; with

use of nefazadone,

boceprevir, or

delavirdine; in

hypersensitivity to

TCAs; with MAOIs

(serotonin

syndrome)

SJS and TEN

(increased with

HLA-B*1502,

10x increase with

Asian ancestry),

aplastic anemia,

agranulocytosis,

DRESS, rash (SJS,

TEN, rash, and

DRESS moderately

associated with

HLA-A*3101)

Arrhythmias and

other cardiovascular

disorders; Use with

caution in 2

nd

and

3

rd

degree heart

block

Induces CYP1A2,

CYP2B6, CYP2C9,

CYP2C19, and

CYP3A4, affecting

OCs, warfarin, and

many other drugs

CBZ metabolism is

inhibited by drugs

which inhibit

CYP3A4 (e.g.

macrolides, azol

antifungals) and

grapefruit juice

VPA and BRV can

inhibit epoxide

hydrolase and

increase CBZ-

epoxide.

In patients with

hepatic

impairment,

monitor CBZ

concentration

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

cenobamate

(CNB)

Tablet

Schedule V

Focal onset

Adults

Enhance

rapid and

slow

inactivation

of Na

+

channels;

inhibits non-

inactivating

persistent

Na

+

current;

positive

allosteric

modulator

of GABA

A

ion channel

F = 88%,

Protein binding

= 60%

Metabolism:

glucuronidation

by UGT2B7 and

oxidation by

multiple CYP

isozymes

Tmax = 1-4 h

t

1/2

= 50-60 h

12.5 mg/d

weeks 1 and 2

25 mg/d

weeks 3 and 4

50 mg/d

weeks 5 and 6

100 mg/d

weeks 7 and 8

150 mg/d

weeks 9 and

10

200 mg/d;

may increase

by increments

of 50 mg/d

every 2 wk up

to 400 mg/d

maximum

10-35

mcg/mL

Somnolence and

fatigue, especially

when used with

CLB (see DDIs) –

consider reducing

CLB and other

sedating ASMs

Dizziness, ataxia,

diplopia, blurred

vision, vertigo,

especially

combined with

other sodium-

channel blocking

ASMs – consider

reducing those

ASMs

Cognitive

dysfunction, N/V,

constipation,

decreased

appetite,

hyperkalemia

(K

+

> 5 mEq/L)

Shortening of QT

interval

Contraindication:

Familial short QT

syndrome

DRESS (multiorgan

hypersensitivity)

occurred in 3 of 953

patients in initial

trials using rapid up

titration, but in 0 of

1339 adults using

approved slow

titration

Caution should be

exercised when

used with drugs

which shorten the

QT interval (eg, RUF)

Mild to moderate

renal or hepatic

impairment: Use

caution and reduced

dose

Severe renal or

hepatic impairment:

Use is not

recommended

CNB inhibits

CYP2C19, so PHT

increases 70-84%,

PB increases

34-37%, and

N-desmethyl-CLB,

and possibly LCM,

increases

substantially

CNB induces

CYP3A4, so CBZ

decreases 23%

CNB induces

glucuronidation, so

LTG decreases 21-

52%

PHT induces CNB

metabolism, so

CNB level

decreases 28%

CNB can decrease

effectiveness of

OCs and may

decrease

midazolam and

bupropion levels

CNB increases the

omeprazole level 2-

fold

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

clobazam

(CLB)

Tablet,

oral suspension

(2.5 mg/mL),

oral film

Schedule IV

LGS

Adjunctive Tx

At least 2 y

GABA

A

receptor

agonist;

binds

between

α and γ

subunits

CLB is a 1,5-

BDZ (all

other BDZs

are 1,4)

F = 100%

Protein binding

= 85%

Tmax = 0.5-4 h

Metabolized by

N-demethyl-

ated CYP3A4 to

N-desmethyl-

CLB, which is

metabolized to

inactive

metabolite by

CYP2C19

t

1/2

= 36-42 h;

71-82 h for

metabolite

≤30 kg =

5 mg/d for at

least 1 week

>30 kg =

5 mg bid for at

least 1 week

≤30 kg = up to

10 mg bid

>30 kg = up to

20 mg bid

CLB: 30-

300 ng/ml

N-

desmethyl

CLB: 300-

3000

ng/ml

Rash, sedation,

fever, URI, drool-

ing, constipation,

urinary tract

infection,

insomnia,

irritability,

depression,

dependence,

withdrawal

effects, vomiting,

ataxia, bronchitis,

pneumonia

With BDZs assess

each patient’s risk

for abuse, misuse,

and addiction

DRESS, SJS, and TEN

Use with opioids can

cause profound

sedation, respiratory

depression, coma,

and death

Use lower dose in

elderly, known

CYP2C19 poor

metabolizers, and

those with mild or

moderate liver

failure. Not studied

in patients with

severe hepatic or

renal impairment

Weak CYP3A4

inducer, so may

affect OCs

CLB inhibits

CYP2D6 (e.g.,

dextromethorphan)

CBD, CNB, STP,

ethanol and

CYP2C19 inhibitors

(e.g., fluconazole,

fluvoxamine,

omeprazole) inhibit

CLB metabolism

clonazepam

(CZP)

Tablet,

ODT tablet

Schedule IV

LGS, myoclonic

and absence

seizures

No age specified

GABA

A

receptor

agonist;

binds

between

α and γ

subunits

F = 90%

Protein binding

= 85%

Tmax = 1-4 h

CYP3A4 reduces

7-nitro group;

4-amino

derivative is

acetylated,

hydroxylated,

and glucuron-

idated; metabo-

lites are renally

excreted

t

1/2

= 30-40 h

Children:

≤10 y or ≤30 kg

= 0.01-0.03

mg/kg/d,

not to exceed

0.05 mg/kg/d

given in 2-3

divided doses

Adults:

<1.5 mg tid

Children:

0.1-0.2

mg/kg/d

Adults:

<20 mg/d

0.04-0.07

mcg/mL

Sedation; ataxia,

dizziness; hyper-

salivation;

respiratory

depression;

porphyrogenic;

impaired cognition

or motor skills;

agitation, anxiety,

irritability, anger,

nightmares,

hallucination,

psychoses,

depression,

dependence,

tolerance

With BDZs assess

each patient’s risk

for abuse, misuse,

and addiction

Use with opioids can

cause respiratory

depression, coma,

and death

Contraindications:

acute narrow angle

glaucoma,

significant liver

disease, sensitivity

to BDZs

Use caution in

patients with renal

impairment and

underlying

respiratory

impairment

Worsened or new

TCS

VPA + CZP may

cause absence SE;

withdraw all BDZs

gradually to help

avoid SE

CBZ, LTG, PB and

PHT decrease CZP

levels ~38%

Oral antifungal

agents (eg,

fluconazole) may

inhibit CZP

metabolism

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

eslicarbazepine

acetate

(ESL)

tablet

Focal onset

At least 4 y

Enhances

Na

+

channel

rapid

inactivation;

blocks

hCav3.2 Ca

2+

channel;

enhances K+

conductanc

e

F = 90%

Protein binding

= 40%

ESL acetate

hydrolyzed to

ESL; renal

excretion as ESL

and ESL

glucuronide

t

1/2

= 13-20 h

Children:

11-21 kg = 200

mg/d

22-31 kg = 300

mg/d

32-38 kg = 300

mg/d

>38 kg = 400

mg/d

Adults:

400 mg/d

Given once

daily

Children:

11-21 kg =

400-600 mg/d

22-31 kg =

500-800 mg/d

31-38 kg =

600-900 mg/d

>38 kg = 800-

1600 mg/d

Adults:

800-1600

mg/d

Possibly

10-35

mcg/mL

(as OXC

MHD)

1%-1.5%

hyponatremia

(<125 mmol/L);

dizziness,

sedation, cognitive

disturbance,

blurred vision,

diplopia, HA, N/V,

disturbance in gait

and coordination,

tremor; elevated

ALT, AST and

bilirubin;

pancytopenia,

leukopenia,

agranulocytosis;

decreased T3 and

T4 levels.

SJS and TEN

(increased risk with

HLA-B*1502),

angioedema, DRESS,

anaphylaxis

Obtain baseline liver

enzyme and

bilirubin levels.

In moderate to

severe renal

impairment reduce

dose 50%.

Has not been

studied in severe

hepatic impairment

EIASMs induce ESL

metabolism

ESL induces OCs,

statins, and

S-warfarin

ESL inhibits

CYP2C19, so it

increases CLB and

PHT levels

ethosuximide

(ESM)

Capsule (gel),

oral solution

Absence

Affects low-

threshold,

slow, T-type

Ca

2+

thalamic

currents

F ~ 93%

Metabolism:

CYP3A4 and

CYP2E1

clearance may

be nonlinear at

higher doses

(saturable)

t

1/2

~ 30 h

(children),

~ 60 h (adults)

Children:

3-6 y =

250 mg/d

Children &

Adults:

6+ y =

250 mg bid

Children:

optimal is

20 mg/kg/d

Adults:

1500 mg

divided bid or

tid

40-100

mcg/mL

N/V, abdominal

pain, anorexia,

weight loss,

diarrhea, sedation,

dizziness, ataxia,

leukopenia, HA,

behavior changes,

sleep disturbance,

depression,

hyperactivity,

irritability,

psychosis,

hallucinations,

gingival

hypertrophy,

tongue swelling

SJS, rash, DRESS,

leukopenia,

agranulocytosis,

pancytopenia,

eosinophilia,

thrombocytopenia,

systemic lupus

erythematosus

Abnormal liver and

renal function tests

Use cautiously in

patients with renal

or hepatic disease

Monitor CBC and

CMP tests

May increase TCS

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

everolimus

(EVL)

Tablets for

suspension

Tuberous

sclerosis complex-

associated focal

Adjunctive Tx

At least 2 y

mTOR

inhibitor

Protein binding

= 74%

Intake of fatty

foods can

reduce systemic

exposure

20%-30%

CYP3A4

substrate

T

1/2

= 30 h

5 mg/m

2

once

daily

New dose =

current dose

multiplied by

(target

concentration

divided by

current

concentration)

Target:

5-15

ng/mL

Stomatitis (>30%),

non-infectious

pneumonitis

Bacterial, fungal,

viral, and proto-

zoal infection,

including

opportunistic

infection; avoid

live vaccines

Myelosuppression,

embryofetal

toxicity, pneu-

monia, irregular

menses, fever,

diarrhea, rash,

lymphedema,

radiation

sensitization

Impaired wound

healing,

hypersensitivity

(anaphylaxis,

dyspnea, flushing,

chest pain,

angioedema), renal

failure, increased

risk of angioedema

with ACE inhibitor,

hyperglycemia,

thrombocytopenia,

neutropenia,

anemia, hyper-

cholesterolemia,

hypertriglycerid-

emia, increased

LFTs, embryofetal

toxicity

Reduce dose in

severe hepatic

impairment

EVL increases CBZ,

CLB, and OXC levels

~10%

Avoid P-pg & strong

CYP3A4 inhibitors

CBD can increase

EVL plasma levels,

so monitoring of

level is recommen-

ded and may

require lowering

EVL dose.

12,13

Monitor CBC,

glucose, and renal

function

periodically

Withold for at least

1 week before

elective surgery

felbamate

(FBM)

Tablet,

Suspension

(600 mg/5 mL)

Refractory focal:

Adults

LGS:

Adjunctive Tx

At least 2 y

Enhance Na

+

channel

rapid

inactivation;

blocks Ca

2+

channel,

inhibits

NMDA

receptor;

potentiates

GABA

A

conduc-

tance

F = 90%,

Protein binding

= 23%

40%-50%

excreted in

urine

unchanged;

remainder

hepatically

metabolized to

multiple

metabolites

and conjugates

t

1/2

= 22 h

Children:

15 mg/kg/d

divided tid or

4 x/d

Children &

Adults:

14+ y =

1200 mg

divided tid or

4 x/d

800-1200 mg

tid

60-100

mcg/mL

HA, insomnia, N/V,

abdominal pain,

anorexia, weight

loss, facial edema,

anxiety, acne,

rash, constipation,

diarrhea,

increased SGPT,

hypophospha-

temia, rhinitis,

infection,

somnolence,

ataxia, dizziness,

tremor

Aplastic anemia,

hepatic failure

Contraindications:

history of blood

dyscrasia or hepatic

dysfunction

Decreased clearance

and increased t

1/2

in

renal impairment

Monitor full

hematologic and

LFTs before,

frequently during,

and after treatment

Hepatic enzyme

inhibitor: Increases

CBZ-epoxide, PB,

PHT, and VPA levels

EIASMs CBZ, PB and

PHT decrease FBM

level

FBM decreases the

progestin in OCs

but not the

estradiol

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

fenfluramine

(FFA)

Oral solution

(2.2 mg/mL)

LGS, Dravet

syndrome

At least 2 y

Both FFA

and nor-FFA

increase

serotonin

(5HT) levels,

and are

agonists at

5HT

1D

,

5HT

2A,

5HT

2B

,

5HT

2C

, 5HT

4

receptors

thereby

increasing

GABA

signaling

FFA may be

positive

modulator

of sigma-1

receptors

thereby

decreasing

glutamate

signaling

F ~ 68-74%

Protein binding

= 50%

Tmax = 3-5 h

No effect of

food; may be

given via

feeding tube

Metabolized

(75%) via

CYP1A2, 2B6 &

2D6 to active

metabolite,

nor-FEN.

CYP2C9, 2C19 &

3A4 may play

minor role in

metabolism

t

1/2

= 20 h

0.1mg/kg bid

If not taking

STP:

0.1-0.35 mg/kg

bid (max =

26 mg/d total)

If taking STP

and CLB:

0.1-0.2 mg/kg

bid (max =

17 mg/d total)

Not

estab-

lished

Decreased

appetite, weight

loss, diarrhea,

somnolence,

fatigue, sedation,

lethargy, abnormal

echocardiogram,

serotonin

syndrome

hypertension, angle

closure glaucoma

Mandatory REMS

program for:

valvular heart

disease, pulmonary

artery hypertension

Echocardiogram is

required at baseline,

every 6 months on

treatment, and 3-6

months after

stopping FFA

Contraindication:

To avoid serotonin

syndrome, do not

use within 14 days

of MAOI and use

with caution with

other serotonergic

drugs

Dose adjustment

needed in severe

renal impairment &

mild, moderate &

severe hepatic

impairment.

STP and CLB can

increase FFA levels

and decrease levels

of nor-FFA

Strong CYP1A2 and

2D6 inhibitors

increase FFA levels

Strong CYP3A4,

CYP1A2, CYP2B6

inducers can

reduce FFA levels

5HT1A, 1D, 2A & 2C

receptor antago-

nists (e.g. cypro-

heptadine) may

reduce FFA efficacy

Serotonergic

agents (e.g. SSRIs,

SNRI, TCA, MAOIs,

trazodone,

dextromethorphan)

increase risk of

serotonin

syndrome

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

gabapentin

(GBP)

Capsule,

tablet,

refrigerated

oral solution

(250 mg/5 mL)

Focal onset

Adjunctive Tx

At least 3 y

Binds

presynaptic

α

2

-δ subunit

of voltage-

activated

Ca

2+

channel

to modulate

Ca

2+

current

Saturable oral

absorption via

L-amino acid

transferase:

F = 60% at

900 mg/d,

34% at

2400 mg/d,

and 27% at

4800 mg/d total

Protein binding

= 3%

Renal excretion

t

1/2

= 6 h

Children:

3-11 y =

10-15 mg/kg/d

divided tid

Children &

Adults:

12+ y =

300 mg tid

Children:

3-4 y =

40 mg/kg/d

divided tid

5-11 y =

25-35 mg/kg/d

divided tid

Children &

Adults:

12+ y = 600 mg

po tid, but may

increase up to

2400-3600

mg/day

4-8.5

mcg/mL

Drowsiness,

sedation, fatigue,

driving

impairment,

ataxia, dizziness,

nystagmus,

diplopia,

peripheral edema,

weight gain

Neuropsychiatric

changes

(emotional,

aggression,

cognitive and

concentration

problems,

hyperkinesia) in

children aged 3-12

DRESS, anaphylaxis,

angioedema

Respiratory

depression when

used with CNS

depressants,

including opioids, or

in the setting of

respiratory

impairment:

consider initiating

GBP at lower dose,

monitoring patients,

and adjusting dose

Reduce dose in renal

impairment, and in

hemodialysis

GBP concentration

is increased by

morphine

GBP decreases

hydrocodone

exposure

Magnesium/

aluminum antacids

decrease GBP level

20%

ganaxolone

(GNX)

oral suspension

(50 mg/mL),

Schedule V

Cyclin-dependent

kinase-like 5

(CDKL5)

Deficiency

Disorder

At least age 2

Positive

allosteric

modulator

(PAM) of

GABA

A

receptor

F = 99%

Protein binding

= 50%

Tmax = 2-3 h

Metabolized by

CYP3A4/5,

CYP2B6,

CYP2C19, and

CYP2D6

T

1/2

= 34 h

Must be taken

with food

Children:

< 28 kg = 6

mg/kg three

times daily (18

mg/kg/day)

Children &

Adults:

> 28 kg = 150

mg three times

daily (450 mg

daily)

Must be taken

with food

Children:

< 28 kg = 21

mg/kg three

times daily (63

mg/kg/day)

maximum

Children &

Adults:

> 28 kg = 600

mg three times

daily (1800 mg

daily)

maximum

Not

estab-

lished

Somnolence and

sedation (may be

potentiated by

CNS depressants,

including opioids,

antidepressants,

and alcohol),

pyrexia, salivary

hypersecretion,

and seasonal

allergy

Reduce dose in

hepatic impairment

Ganaxolone

exposures when

given in renal

insufficiency

(creatinine

clearance <90

mL/min) are not

expected to be

clinically significant

Avoid concomitant

use with strong or

moderate CYP3A4

inducers (e.g., CBZ,

PHT, PB, and PRM).

If these are

unavoidable, do

not exceed max

GNX dose

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

lacosamide

(LCM)

Tablet (IR &

ER),

oral solution

(10 mg/mL),

IV solution

(200 mg/20 mL)

Schedule V

Focal onset:

Monotherapy

At least 1 mo

Primary GTCS:

Adjunctive Tx

At least 4 y

Enhances

Na

+

channel

slow

inactivation

F = 100%

Demethylated

by CYP3A4,

CYP2C9, and

CYP2C19;

95% renally

excreted, 40%

as LCM/60% as

metabolites

t

1/2

= 15 h

Children:

11-49 kg =

1 mg/kg bid

Children &

Adults:

50+ kg =

50 mg bid

17+ =

100 mg bid in

monotherapy,

and

50 mg bid

in adjunctive

Tx

Children:

11-29 kg =

3-6 mg/kg bid

30-49 kg =

2-4 mg/kg bid

Children &

Adults:

Adjunctive Tx:

50+ kg or at

least 17 y =

100-200 mg

bid

Monotherapy:

50+ kg or at

least 17 y =

150-200 mg

bid

4-12

mcg/mL

Dizziness, ataxia,

diplopia, HA,

nausea, dose-

dependent

prolongation of PR

interval, atrial

fibrillation, atrial

flutter, and

ventricular

arrhythmias

Bradycardia, AV

block and

ventricular

tachyarrhythmia,

rarely resulting in

asystole, cardiac

arrest and death.

This occurs mostly in

proarrhythmic

conditions or when

taken with

medications that

affect cardiac

conduction (sodium

channel blockers,

beta-blockers,

calcium channel

blockers, or

potassium channel

blockers) or that

prolong the PR

interval (eg, sodium

channel blocker

ASMs)

For these instances

and in 2nd- or 3rd-

degree block,

obtaining an EKG

before treatment

and once reaching

steady state LCM

dose is

recommended

Syncope (especially

with diabetes),

DRESS

May “load” with

200 mg oral or IV

LCM dose

reduction may be

needed in patients

with renal or

hepatic impairment

and those who are

taking drugs that

strongly inhibit

CYP3A4 or CYP2C9

or CYP2C19

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

lamotrigine

(LTG)

Tablet

(standard,

chewable-

dispersable,

orally

disintegrating,

and ER)

Focal onset:

Adjunctive Tx and

conversion to

monotherapy

At least 16 y

Focal onset, LGS,

primary GTCS:

Adjunctive Tx

At least 2 y

Enhances

Na

+

channel

rapid

inactivation;

inhibits Ca

2+

channels;

activates

postsynaptic

HCN

channels

F = 98%

Protein binding

= 55%

Glucuronidated

to inactive

metabolite

t

1/2

= 25 h, 13 h

with EIASMs,

and

70 h with VPA

25 mg every

2nd day (with

VPA only)

25 mg/d

50 mg/d (with

EIASMs only)

For adults, and

children >12 y:

50-100 mg bid

with VPA alone

75-200 mg bid

without VPA or

EIASMs

150-250 mg

bid with

EIASMs

For children

ages 2-12 y:

See PI for

weight-based

dosing

4-20

mcg/mL

Dizziness, HA,

diplopia, ataxia,

tremor, nausea,

vomiting,

somnolence,

insomnia in high

doses; aseptic

meningitis (rare)

Rash, SJS, TEN,

DRESS

Hemophagocytic

lymphohistocytosis

(rare)

Blood dyscrasias

May widen EKG

QRS. Avoid in 2° and

3° heart block. Use

caution with

ventricular

arrhythmias, cardiac

disorders and

channelopathies

(e.g., Brugada

syndrome)

EIASMs (CBZ, CNB,

PB, PHT, PRM),

ethinyl estradiol ,

rifampin, and

ritonavir decrease

LTG level 40-50%

Pregnancy

decreases LTG level

~50%-67%

VPA increases LTG

level >2-fold

Reduce dose in

moderate-severe

hepatic impairment

levetiracetam

(LEV)

IR/ER tablet,

orally

disintegrating

tablet, oral

solution (100

mg/mL), IV

solution

(500 mg/5 mL)

Focal onset:

At least 1 month

Myoclonic in JME:

Adjunctive Tx

At least 12 y

Primary GTCS:

Adjunctive Tx

At least 6 y

Inhibits

synaptic

vesicle

protein

SV2A;

partially

inhibits

N-type Ca

2+

currents

F = 100%

PPB <10%

Enzymatic

hydrolysis (non-

CYP) to inactive

metabolite

~66% renally

eliminated

unchanged

t

1/2

= 7 h

Children:

1-5 mo =

7 mg/kg bid

6 mo - <4 y =

10 mg/kg bid

4 - <16 y =

10 mg/kg bid

Children &

Adults:

16+ y:

500 mg bid

Children:

1 - <6 mo =

21 mg/kg bid

6 mo - <4 y =

25 mg/kg bid

4 - <16 y =

30 mg/kg bid

Children &

Adults:

16+ y:

1500 mg bid

(myoclonic

JME & primary

GTCS)

or

500-1500 mg

bid (focal

onset)

20-50

mcg/mL

Irritability, anger,

aggression,

depression,

suicidal ideation,

psychotic

symptoms (esp. in

children)

Somnolence,

fatigue, asthenia,

dizziness,

infection, ataxia,

incoordination,

anemia, pancyto-

penia, leukopenia,

neutropenia,

agranulocytosis,

thrombocytopenia

<4 y: increased

diastolic BP

SJS and TEN; DRESS

(rare), rhabdomyo-

lysis, angioedema,

anaphylaxis

Worsening of

seizures, including in

patients with SCN8A

mutations

Plasma LEV level

may gradually

decrease during

pregnancy

In patients with

renal insufficiency,

dose must be

reduced propor-

tionate to CrCl;

hemodialysis

eliminates 50%

in 4 h

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

oxcarbazepine

(OXC)

Tablet (IR and

ER), oral

suspension

(300 mg/5 mL)

Focal onset

Monotherapy:

At least 4 y

Adjunctive Tx:

At least 2 y

Enhances

Na

+

channel

rapid

inactivation;

modulation

of high-

voltage

activated

Ca

2+

channel;

enhances K+

conduc-

tance

F = 100%

Protein binding

= 40%

OXC is prodrug:

reduced 80% to

S-licarbazepine

and 20% to

R-licarbazepine

(the MHDs), by

hepatic cytosol

enzymes

MHD is

glucuronidated,

then renally

excreted

t

1/2

= 9 h (MHD)

and 2 h (OXC)

Children:

2-16 y =

8-10 mg/kg/d

divided bid,

not to exceed

300 mg bid

Adults:

17+ y =

300 mg bid

(wk 1),

then add no

more than 300

mg bid each

wk

Children 2-16 y

<20 kg =

16-60 mg/kg/d

20-29 kg =

900 mg/d

30-39 kg =

1200 mg/d

40+ kg =

1800 mg/d

(All doses are

divided bid)

Adults:

17+ y =

1200-2400 mg

divided bid

(tid improve

tolerability)

10-35

mcg/mL

(as MHD)

Dizziness,

cognitive

problems,

somnolence,

fatigue nausea,

HA, diarrhea,

vomiting, URI,

constipation,

dyspepsia, ataxia,

incoordination,

nervousness,

pancytopenia,

agranulocytosis,

leukopenia

Hyponatremia

(<125 mmol/L =

2.5% but increases

with age)

SJS and TEN (risk

increases with

HLA-B*1502,

10x increase with

Asian ancestry),

DRESS

Anaphylaxis,

angioedema, cross

hypersensitivity with

CBZ

Mild to moderate

hepatic failure: No

adjustment

Renal failure: Adjust

dose; MHD is not

dialyzable, but

metabolites may be

Induces CYP3A4:

At 1200 mg/d, it

decreases OC

estrogen level

Inhibits CYP2C19:

At >1200 mg/d, the

PHT level increases

40%

CBZ, PB, and PHT

and rifampin

decrease OXC

levels 29%-40%

Unlike CBZ, no

autoinduction or

formation of a

10,11 epoxide

perampanel

(PER)

Tablet, oral

solution (0.5

mg/mL)

Schedule III

Focal onset:

At least 4 y

Primary GTCS:

Adjunctive Tx

At least 12 y

Selective,

non-

competitive

antagonist

of AMPA

glutamate

receptor,

inhibiting

synaptic-

driven influx

of Na

+

F = 100%, but

food delays by

2 h

PPB= 96%

Metabolized by

CYP3A4 and

CYP3A5 to

multiple

inactive

metabolites

T

1/2

= 105 h

(~24 h with

EIASMs)

Children and

Adults:

2 mg qhs

(4 mg with

EIASMs)

Suggest giving

at HS

Children and

Adults:

Increase no

faster than 2

mg/wk (long

t

1/2

suggests

slower

titration every

3-4 weeks)

Minimum =

4-6 mg/day

Higher doses

may be

needed if

taking EIASM

(8-12 mg/day)

Not

estab-

lished

Dizziness, vertigo,

somnolence,

fatigue, irritability,

hostility,

aggression, anger,

HA, ataxia,

anxiety, paranoia,

euphoric mood,

agitation, falls,

nausea, vomiting,

weight gain,

abdominal pain,

ataxia, mental

status changes

Homicidal ideation

(6 in 4368 subjects

in preclinical trials),

suicidal thoughts,

DRESS

Use lower dose in

mild and moderate

hepatic impairment

No dose adjustment

for mild-moderate

renal insufficiency

Not recommended

in severe hepatic or

severe renal

impairment

CBZ, OXC, ESL and

PHT (not PB)

decrease PER

plasma level

PER at 12 mg/d

increases OC

metabolism

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

phenobarbital

(PB)

Tablets, elixir

(4 mg/mL),

IV solution

Schedule IV

Focal onset and

generalized onset

Nonspecific

GABA

A

receptor

binding:

affects both

synaptic

(phasic) and

extra-

synaptic

(tonic)

GABA

A

receptors

F ~95%

PPB = 45%

Hepatically

parahydrox-

ylated and

glucuronidated

25%-50% of

unchanged PB

and its

metabolites are

renally excreted

t

1/2

= 79 h

(110 h in

children and

newborns)

Children:

< 6 y =

3-5 mg/kg/d

6-12 y =

2-3 mg/kg/d

Children &

Adults:

13+ y =

60 mg/d

or 1-4 mg/kg/d

Children:

Infants =

5-6 mg/kg/d

1-5 y =

8 mg/kg/d

6-12 y =

4-6 mg/kg/d

Children &

Adults:

13+ y =

1-4 mg/kg/d

Adult

maximum =

240 mg daily

Taper very

slowly after

chronic use,

because

barbiturate

withdrawal can

cause

convulsions

and delirium

and may be

fatal

15-45

mcg/mL

Sedation, cognitive

slowing, HA,

depression, N/V,

tolerance,

dependence,

confusion,

decreased REM

sleep, hepatic

dysfunction,

osteoporosis,

megaloblastic

anemia with

chronic use,

hypoventilation,

bradycardia, and

hypotension

With pain:

Agitation or

delirium

Children:

Irritability,

hyperactivity,

reduced IQ

SJS, TEN, DRESS,

rash, angioedema,

respiratory

depression,

synergistic effects

with ETOH or

sedatives,

psychological and

physical

dependence

Caution should be

used with

concomitant pain

medications and

CNS depressants

Do not use in

hepatic encephalo-

pathy, porphyria,

marked hepatic

impairment, or

marked respiratory

disease

Elimination is

increased by

diuretics, alkaline

urine and activated

charcoal but is

decreased by VPA

MAOIs prolong the

effects of PB

PB is a strong

CYP3A4 inducer:

It increases the

metabolism of PHT,

LTG, OCs, warfarin,

corticosteroids, and

many other drugs

Monitor CBC and

CMP results

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

phenytoin

(PHT) and

fosphenytoin

(FOS)

PHT:

Delayed-

release (sodium

salt) capsule –

has 8% less PHT

than prompt

(acid) tablet

and suspension

(25 mg/mL)

PHT and FOS:

IV (FOS is

prodrug of PHT

and has higher

molecular

weight due to

PO

4

molecule)

(500 mg PE/10

mL)

Focal onset, GTCS

Convulsive status

epilepticus,

prevention and

treatment of

seizures during

neurosurgery,

and short-term

use when

administration of

oral PHT is not

possible (FOS

only)

Enhances

rapid

inactivation

of Na

+

channels

F ~100% (varies

by formulation)

Protein binding

= 90%-95%

Metabolized by

CYP2C9 and

CYP2C19

Excreted in bile

as inactive

metabolites,

reabsorbed in

intestines, then

renal tubular

secretion

Nonlinear

elimination

(zero order) PK

(saturable at

higher doses)

t

1/2

= Adult:

22 h (7-40 h);

longer at higher

doses and older

age

Children:

5 mg/kg/d

divided bid or

tid

Adults:

300 mg/d

divided tid

Children &

Adults:

IV load for

status

epilepticus:

15-20 mg/kg

(PHT) at

≤50 mg/min or

15-20 mg

PE/kg (FOS) at

≤2 mg

PE/kg/min

(children) or

≤150 mg

PE/min (adult)

IV non-

emergent load:

0-16 y =

10-15 mg

PE/kg (FOS) at

1-2 mg

PE/kg/min or

150 mg PE/min

whichever is

slower

17+ y =

10-20 mg

PE/kg (FOS) at

≤150 mg

PE/min

Children:

4-8 mg/kg/d

divided bid or

tid

6-17 y = up to

300 mg/d

given once

daily or divided

bid or tid

Adults:

6-17 y =

300-600 mg/d

given once

daily or divided

bid or tid

10-20+

mcg/mL

(~10% as

free PHT)

Rash, nystagmus,

incoordination,

dysarthria, ataxia,

cognitive slowing,

gum hyperplasia,

hypertrichosis,

lymphadenopathy,

pseudolymphoma,

lymphoma, Hodgkin

disease, low

patelets,

megalobalastic

anemia,

leukopenia,

pancytopenia,

osteoporosis,

decreased vitamin

D level,

porphyrogenic

IV PHT:

thrombophlebitis,

peripheral

neuropathy,

cerebellar atrophy

IV PHT and FOS may

produce purple

glove syndrome.

FOS may produce

transient burning,

itching and

paresthesia due to

the phosphate load

Decreases T4 level;

increases glucose,

GGT, and alkaline

phosphatase levels

FOS contraindicated

in sinus bradycardia,

sinoatrial block, 2

nd

-

and 3

rd

-degree AV

block and Stokes-

Adams attacks

SJS and TEN

(especially in

patients with

Chinese ancestry

with HLA-B*1502),

DRESS, angioedema,

hepatotoxicity

PHT must never be

given IM or IV in

diluents other than

normal saline or

>50 mg/min

(hypotension,

bradyarrhythmia,

QT prolongation,

ventricular

tachycardia or

fibrillation, asystole

and death)

FOS may be given

IM and IV up to 150

mg PE/min

EKG, respiratory and

blood pressure

monitoring is

essential during IV

PHT and IV FOS

infusion

CNB, ESM, FBM,

OXC, MSM, TPM,

acute alcohol intake,

and many other

drugs increase PHT

levels

CBZ, DZP, VGB,

chronic alcohol

intake and many

other drugs

decrease PHT levels

PB and VPA have

variable effects on

PHT and vice versa;

PHT induces

metabolism of CBZ,

FBM, LTG, OXC,

TPM, and many

other drugs

In SE, the full effect

of IV PHT and FOS is

delayed, so

concomitant

administration of an

IV BDZ is needed

Monitor unbound

(free) serum level in

hepatic or renal

impairment or

hypoalbuminemia

Slow CYP2C9 and

CYP2C19 metabo-

lism occurs in 1%

and 3% of persons,

respectively,

requiring lower

maintenance doses

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

pregabalin

(PGB)

Capsule, oral

solution 20

mg/mL

(Extended

release form

not FDA-

approved for

epilepsy)

Schedule V

Focal onset

Adjunctive Tx

At least age 1

month

Binds pre-

synaptic α

2

-

δ subunit of

Ca

2+

channel

to modulate

Ca

2+

current,

resulting in

decreased

glutamate

concentra-

tion, NE

level, and

substance P

release

F = 90%

Protein binding

= low

Negligible

metabolism,

renal excretion

t

1/2

= 6 h

Children:

<30 kg =

3.5 mg/kg/d

(1 mo to <4 y =

divided tid;

4+ y = divided

bid or tid)

30+ kg =

2.5 mg/kg/d

divided bid or

tid

Adults:

17+ y =

≤150 mg/d

divided bid or

tid

Children:

<30 kg =

14 mg/kg/day

(1 mo to <4 y =

divided tid;

4+ y = divided

bid or tid)

30+ kg =

10 mg/kg/d

divided bid or

tid

Adults:

600 mg divided

bid or tid

Reduce dose

for CrCl ≤60,

mL/min

3-10

mcg/mL

Dizziness,

somnolence, dry

mouth, peripheral

edema, diplopia,

blurred vision,

weight gain,

ataxia, attention

and concentration

problems;

increased CK level

(uncommon)

Angioedema (face,

mouth, throat,

larynx), rash, hives,

dyspnea, wheezing

Respiratory

depression with

concomitant CNS

depressants

(including opioids)

or with underlying

respiratory

impairment

No DDI with ASMs

Additive cognitive

and gross motor

effects with

opiates,

benzodiazepines,

and ethanol

Weight gain occurs

when taken with

thiazolidinedione

anti-diabetes drugs

primidone

(PRM)

Tablet

Schedule IV

Focal onset and

TCS

Nonspecific

GABA

A

receptor

binding:

affects both

synaptic

(phasic) and

extra-

synaptic

(tonic)

GABA

A

receptors

F = 100%

Protein binding

<5%

PRM and its

metabolites

(PB and PEMA)

are active ASMs

t

1/2

= 12 h

(derived PB is

79 h)

Children:

<8 y =

50 mg qhs

Children &

Adults:

8+ y =

100-125 mg

qhs

Children:

<8 y =

375-750 mg/d

(10-25

mg/kg/d)

Children &

Adults:

8+ y =

750-2000

mg/d

divided tid or

4x/d

6-12

mcg/mL

(plus

derived

PB)

Diplopia,

nystagmus,

drowsiness, ataxia,

vertigo, N/V,

fatigue, irritability,

emotional

disturbance,

impotence

Contraindications:

Porphyria, PB allergy

Rash, RBC

hypoplasia and

aplasia,

agranulocytosis,

megaloblastic

anemia (folate

responsive)

DDIs similar to PB

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

rufinamide

(RUF)

Tablet, oral

suspension

(40 mg/mL)

LGS

Adjunctive Tx

At least 1 y

Enhances

Na

+

channel

rapid

inactivation

F ≥ 85%

PPB = 34%

Absorption is

slow (Tmax = 4-

6 h) and

nonlinear PK

due to low

solubility at

higher doses,

but is helped by

food

Extensively

metabolized by

hydrolysis, then

renal excretion

t

1/2

= 6-10 h

Children:

10 mg/kg/d

(max 400

mg/d) divided

bid

Adults:

400-800 mg/d

divided bid;

lower dose w/

VPA

Children:

Child

maximum =

45 mg/kg/d

(up to 3200

mg/d) divided

bid

Adults:

Adult

maximum =

3200 mg/d

divided bid

Take with food

5-48

mcg/mL

Shortening of QT

interval,

leukopenia

HA, N/V, dizziness,

fatigue, ataxia, gait

disturbances,

somnolence,

coordination

problems

Contraindication:

Familial short QT

syndrome

DRESS, Rash, SE

Caution should be

exercised when

used with drugs

which shorten the

QT interval

Not recommended

in patients with

severe liver failure

Induces CYP3A4, so

decreases estradiol

22% at ≥800 mg bid

and mildly

decreases CBZ and

LTG levels

Mildly increases PB

and PHT levels

VPA increases RUF

level 16%-70%

CBZ, PHT, PB, and

PRM decrease RUF

level 19%-46%

Hemodialysis: RUF

level decreases

30%

stiripentol

(STP)

Capsule,

powder for

suspension,

sachets

Dravet syndrome

Adjunctive Tx

with clobazam

At least 6 months

weighing at least

7 kg

Positive

allosteric

modulator

of GABA

A

receptor at

γ and δ

subunits;

indirect

effect to

raise plasma

level of CLB

and its

metabolite;

inhibits LDH

activity;

inhibits T-

type Ca

currents

Precise F value

unknown but

likely high, as

majority of drug

(parent and

metabolite)

eliminated in

urine

PPB = 99%

Nonlinear;

Metabolized by

CYP1A2,

CYP2C19, and

CYP3A4

t

1/2

= 4.5-13 h

(longer at

higher doses)

10-15 mg/kg/d

divided bid,

then increase

every 1-2 wk

50 mg/kg/d

divided bid or

tid depending

on age and

weight

Maximum

3000 mg/day

divided bid or

tid

Not

establish-

ed

Somnolence,

decreased weight

and appetite,

neutropenia,

thrombocyto-

penia, agitation,

hypotonia, N/V,

tremor, dysarthria,

insomnia

Alcohol and other

CNS depressants

may increase

sedation and

somnolence

Not recommended

for use in patients

with moderate or

severe renal or

hepatic impairment

STP inhibits CYP3A4

and CYP2C19: it

increases CLB level

2-fold, increases

N-desmethyl-CLB

level 5-fold

If somnolence

occurs, consider

CLB dose reduction

of 25%-50%

Powder contains

phenylalanine

PHT, CBZ, and PB

decrease STP levels

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

tiagabine

(TGB)

Tablet

Focal onset

Adjunctive Tx

At least 12 y

Selective

GABA

reuptake

inhibitor

(SGRI):

inhibits

GABA

reuptake

from

synapse into

neurons and

glia

F = 90%

Protein

binding= 96%

Metabolized by

CYP3A4 and

glucuronidation

Metabolites are

excreted in

urine and feces

t

1/2

= 8 h (2-5 h

with EIASMs)

Children &

Adults:

12+ y =

4 mg once

daily (use

lower initial

dose if not

taking EIASMs)

Do not use

loading dose

Children &

Adults:

12+ y = 32-56

mg/d divided

bid (56 mg is

with

concomitant

EIASMs)

5-70

mcg/mL

Dizziness, N/V,

somnolence,

fatigue, tremor,

cognitive slowing,

anxiety, diarrhea,

abdomen pain,

worsened pre-

existing spike-and-

slow-wave

complexes in EEG

Serious rash,

moderately severe

generalized

weakness, may bind

ocular melanin

Worsened

generalized seizures

and SE in people

with epilepsy

Seizure and SE in

patients without

epilepsy

PHT, CBZ, PB, and

PRM decrease TGB

levels

VPA increases free

TGB level 40% due

to high protein

binding

Hepatic failure

increases free TGB

level

Take with food

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

topiramate

(TPM)

Tablet, capsule

(IR and ER),

sprinkle

Focal onset and

GTCS:

At least 2 y

LGS:

Adjunctive Tx

At least 2 y

Inhibits

voltage-

dependent

Na

+

channels,

kainate

glutamate

receptors,

and

carbonic

anhydrase;

enhances

GABA

A

currents

F = 80%

Protein binding

= 15%-41% and

decreases at

higher

concentrations

Not extensively

metabolized.

Urinary

excretion 70%

as unchanged

drug

t

1/2

= 21 h

Children:

2-9 y =

25 mg qpm

Children &

Adults:

10+ y =

25 mg bid

≤11 kg =

75-125 mg bid

12-22 kg =

100-150 mg

bid

23-31 kg =

100-175 mg

bid

32-38 kg =

125-175 mg

bid

>38 kg =

125-200 mg

bid

7-30

mcg/mL

Language and

cognitive

(confusion,

memory, word-

finding, attention,

concentration)

disturbances

Kidney stones,

increased urinary

Ca

2+

, decreased

urinary citrate

Paresthesia,

anorexia, weight

loss, fatigue,

somnolence,

dizziness, anxiety,

depression or

mood problems,

abnormal vision,

fever, taste

perversion,

diarrhea, URI

SJS and TEN.

Acute myopia w/

secondary angle

closure glaucoma

and vision loss,

visual field defects

Oligohydrosis and

hyperthermia (esp.

children)

Hypochloremic MA;

chronic untreated

MA in children may

lead to decreased

growth, increased

alkaline

phosphatase level,

hypophosphatemia,

and osteomalacia

Hyperammonemia

and encephalopathy

+/- VPA

Hypothermia with

VPA

Use cautiously with

CNS depressants

Decreased OC

efficacy (TPM >200

mg/d)

Monitor Li

2+

level

with higher-dose

TPM

Renal impairment:

use ½ dose and

supplement after

hemodialysis

PHT and CBZ lower

TPM level

Use with other

carbonic anhydrase

inhibitors (AZM,

ZNS) increases risk

of MA and kidney

stones

Other DDIs exist

Hydration is

recommended to

reduce kidney

stone formation

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

valproic acid

(VPA) and

divalproex

sodium

Tablet (IR and

ER), capsule,

sprinkle, IV

solution (100

mg/mL)

Focal onset and

absence:

Monotherapy

Multiple seizure

types that include

absence:

Adjunctive Tx

Inhibits

voltage-

dependent

Na

+

and T-

type Ca

2+

channels,

enhances

biosynthesis

and inhibits

degradation

of GABA

F = 90% at

40 mcg/mL and

81.5% at

135 mcg/mL, so

free VPA level is

dose-

dependent,

(ER’s F = 85% of

IR)

Metabolism:

>40% mito-

chondrial β-

oxidation, 30%-

50% glucuron-

idation, <15%-

20% other

oxidation

Nonlinear PK:

total level

increases with

dose to a lesser

extent due to

saturable PPB,

free VPA level

increases

linearly

Elimination PK:

children 3 mo-

10 y have 50%

faster

clearance,

those aged 68+

y have ~40%

lower clearance

t

1/2

= 9-16 h

Children &

Adults:

10+ y =

15 mg/kg/d;

increase

by 5-10

mg/kg/d at

weekly

intervals

<10 y =

dose not

established but

children aged

3 mo-10 y have

50% higher

clearance

expressed on

weight

Children &

Adults:

10+ y =

60 mg/kg/d

divided bid or

tid (IR) or daily

(ER)

50-100+

mcg/mL

Hyperammonemia

+/- encephalopa-

thy (esp. w/ TPM);

decreased platelet

count and

aggregation,

coagulopathy;

hypothermia,

tubulointerstitial

nephritis

Weight gain or

loss, abdominal

pain, anorexia,

N/V, increased

appetite, diarrhea,

constipation

Irregular menses,

polycyctic ovary

syndrome,

potential fertility

problems in males

Tremor, alopecia,

hair texture

change, blurred

vision, ataxia,

amnesia, asthenia,

depression,

diplopia, dizziness,

peripheral edema,

rash, abnormal

thinking, tinnitus

Contraindications:

Women of child-

bearing potential

and in pregnancy

unless other ASMs

fail, and they are

using effective

contra-ception (esp.

true for migraine

prophylaxis); hepatic

disease or significant

dysfunction;

mitochondrial

disorders with POLG

mutation, urea cycle

disorders

Hepatotoxicity (esp.

in children <2 y

receiving multiple

ASMs, and in

patients with

metabolic disorders,

intellectual delay,

organic brain

disease, and

mitochondrial

disorders)

Pancreatitis;

Gestational:

Substantial risk of

major congenital

malformations (esp.

neural tube defects),

intellectual delay,

decreased IQ,

and autism

Monitor periodically:

Platelet count, INR,

PTT, CBC, NH

3

levels,

and LFTs

CBZ, PHT, PB, PRM,

methotrexate and

rifampin decrease

VPA level

FBM increases VPA

level

Monitor VPA levels

with aspirin,

carbapenem, and

estrogen-OCs

VPA may inhibit

metabolism or affect

binding of CZP, DZP,

ESM, LTG, PHT, and

TGB

With RUF, start VPA

at a low dose and

increase to clinical

effect

TPM with VPA

increases risk of

encephalopathy and

increased NH

3

level

Other DDIs: TCAs,

propofol, warfarin,

zidovudine

CBD with VPA

increases risk of

elevated LFTs

Table 1. Antiseizure medications (ASMs) for chronic and subacute treatment of seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA-Approved

Seizure/Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Serum

Level

Range

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions

(DDI)

and Other

Considerations

vigabatrin

(VGB)

Tablet, powder

for oral

solution (500

mg)

Epileptic spasms

(ES):

Monotherapy

1 mo to 2 y

Refractory FIAS:

Adjunctive Tx

At least 2 y

Irreversibly

inhibits

GABA trans-

aminase

(GABA-T)

resulting in

increased

GABA

concentra-

tion in the

CNS

F = 100%

PPB = 40%

Extensive

binding to

RBCs. No

significant

hepatic

metabolism.

Renal excretion

t

1/2

= 10 h (10+

y) or 5.7 h

(infants)

ES:

25 mg/kg bid

FIAS:

Children:

2-16 y =

175-250 mg

bid (weight-

based)

Children &

Adults:

>60 kg or 17+ y

= 500 mg bid

ES:

75 mg/kg bid

FIAS:

Children:

2-16 y =

525-1000 mg

bid (weight-

based)

Children &

Adults:

>60 kg or 17+ y

= 1500 mg bid

Not

establish-

ed

Somnolence,

nystagmus,

dizziness, tremor,

blurred vision,

uncoordination,

impaired memory,

weight gain,

arthralgia, ataxia,

tremor, URI,

aggression,

diplopia,

peripheral

neuropathy in

adults, edema

Permanent visual

field constriction,

central retinal

damage with

decreased visual

acuity, abnormal

MRI signal changes

and intramyelinic

edema in infants,

decreased ALT and

AST levels, anemia,

sedation

Adjust dose in renal

impairment

Induces CYP2C9, so

decreases PHT level

18%

Increases CZP level

30%

Stop if no

substantial FIAS

decrease in 3 mo

Complete REMS

follow-up forms

zonisamide

(ZNS)

Capsule

Focal onset

Adjunctive Tx

At least 16 y

Enhances

rapid

inactivation

of Na

+

channels;

decreased

low-

threshold

T-type Ca

2+

currents;

binds GABA

A

BDZ

ionophore;

mild

carbonic

anhydrase-

inhibiting

effects;

facilitates

dopamine

and

serotonin

transmission

F = 100%

Protein

binding= 40% to

albumin

Linear PK up to

800 mg/d but

increases

disproportion-

ally above that

dose due to an

8-fold binding

to RBCs

Partial hepatic

metabolism

Renal excretion

t

1/2

= 69 h,

27-38 h with

EIASM,

46 h with VPA

Children &

Adults:

16+ y =

100 mg/d,

increase by

100 mg every 2

weeks

Children &

Adults:

16+ y =

increase by

100 mg every 2

weeks to 400-

600 mg/d

given once

daily or bid

10-40

mcg/mL

Somnolence,

fatigue, anorexia,

weight loss,

dizziness, ataxia,

agitation,

irritability,

depression,

psychosis, speech

or language

disturbance,

psychomotor

slowing, kidney

stones (risk

increased when

used with TPM or

acetazolamide),

rash,

hyperammonemia

and

encephalopathy

Acute myopia and

secondary angle

closure glaucoma

SJS, TEN, DRESS,

hepatic necrosis,

agranulocytosis,

decreased WBC

counts, aplastic

anemia,

oligohydrosis and

hyperthermia in

children,

hyperchloremic MA

(especially if used

with other carbonic

anhydrase

inhibitors)

Chronic untreated

MA may lead to

decreased growth

rate in children,

increased risk of

kidney stones,

increased alkaline

phosphatase level,

hypophosphatemia,

osteomalacia

Adjust dose in

patients with renal

impairment

ZNS t

1/2

significantly

decreases with CBZ,

PB, and PHT, and

moderately

decreases with VPA

Increased severity

of MA and risk of

kidney stones when

used with other

carbonic anhydrase

inhibitors (AZM,

TPM)

ZNS is a non-

arylamide

sulfonamide- use

with caution in

patients with sulfa

allergy

Table 2. Antiseizure Medications (ASMs) for treatment of acute repetitive seizures. January 2024. (See Abbreviations

.)

Drugs,

Formulations,

and DEA

Scheduling

FDA Approved

Seizure/ Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions (DDI)

and Other

Considerations

diazepam

(DZP)

Intranasal

spray

(individual

spray units =

5 mg, 10 mg,

15 mg, 20 mg)

Schedule IV

Seizure cluster,

acute repetitive

seizures

At least 6 y

GABA

A

receptor

agonist;

binds

between

α and γ

subunits

Data from adults and

children >6 y:

Tmax = 1.5 h

F = 97% compared

with IV; 2- to 4-fold-less

variability in systemic

exposure than rectal gel

Elimination PK same as

rectal DZP

Children:

6-11 y (0.3 mg/kg)

10-18 kg = 5 mg

19-37 kg = 10 mg

38-55 kg = 15 mg

56-74 kg = 20 mg

Children & Adults:

12+ y (0.2 mg/kg)

14-27 kg = 5 mg

28-50 kg = 10 mg

51-75 kg = 15 mg

76+ kg = 20 mg

2nd dose may

be given 4-12 h

later prn

Maximum

dose:

2 doses to

treat a single

episode, and

no more than

1 episode

every 5 days

Not indicated

for chronic

daily therapy

CNS depression,

somnolence, HA,

nasal discomfort,

dysgeusia,

epistaxis

See next entry

(DZP rectal gel) for

complete listing

Use with opioids can

cause respiratory

depression, coma,

and death

Contraindicated in

narrow-angle

glaucoma

With BDZs assess

each patient’s risk

for abuse, misuse,

and addiction

No dose adjustments

required based on

concomitant

medications

See next entry (DZP

rectal gel) for

complete listing

diazepam

(DZP)

Rectal gel

(5 mg/mL)

Schedule IV

Acute repetitive

seizures

At least 2 y

GABA

A

receptor

agonist;

binds

between

α and γ

subunits

F = 90%

Tmax = 1.5 h

Protein binding = 95+%

Metabolism (CYP2C19 and

CYP3A4) principally to

N-desmethylDZP (active)

Clearance is highly variable

likely due to CYP2C19 slow

metabolism in 3%-5% of

Caucasians

Rapid initial distribution

phase (~1 h) is followed by a

prolonged terminal

elimination phase (30-60 h)

Terminal elimination t

1/2

of

active metabolite

N-desmethylDZP is

up to 100 h

Children:

2-5 y = 0.5 mg/kg

6-11 y = 0.3 mg/kg

12+ y = 0.2 mg/kg

Adults:

0.2 mg/kg

Weight-based,

repeat once

prn 4-12 h

after first dose

Give no more

often than

every 5 days or

5x/mo

Not

recommended

for chronic,

daily use due

to tolerance

Sedation,

dizziness,

depression,

fatigue, motor and

cognitive

impairment,

dependence

Tonic SE has

occurred with IV

DZP use for

absence SE

Withdrawal effects

after chronic use

Use with opioids can

cause respiratory

depression, coma,

and death

Contraindicated in

narrow-angle

glaucoma

With BDZs assess

each patient’s risk

for abuse, misuse,

and addiction

May cause absence SE

Clearance is slowed

2- to 5-fold with

alcoholic cirrhosis

CNS-depressant

effects potentiated by

VPA, PB, narcotics,

phenothiazines,

MAOIs, and other

antidepressants

Inhibitors of CYP2C19

(cimetidine) and

CYP3A4 (azoles) may

increase DZP levels

Inducers of CYP2C19

(rifampin) and CYP3A4

(CBZ, PB, PHT) may

increase elimination

Table 2 (continued). Antiseizure Medications (ASMs) for treatment of status epilepticus and acute repetitive seizures. January 2024. (See Abbreviations.)

Drugs,

Formulations,

and DEA

Scheduling

FDA Approved

Seizure/ Syndrome

Type, Mono- or

Adjunctive Therapy,

and Patient Age

Proposed

Mechanism(s)

of Action(s)

Pharmacokinetics

(ADME)

Recommended

Initial Dose and

Patient Age

Minimum and

Maximum

Maintenance

Doses

Selected Possible

Adverse Reactions

Contraindications,

Warnings, and

Precautions

Drug-Drug

Interactions (DDI)

and Other

Considerations

midazolam

(MDZ)

Intramuscular

50 mg/10 mL

multidose vial

IM

autoinjector

(10 mg in 0.7

mL)

Schedule IV

Status epilepticus

Adult

GABA

A

receptor

agonist;

binds

between

α and γ

subunits

F = 44%

Protein binding = 97%

Gut and hepatic metabolism

via CYP3A4 to active

metabolite

1-hydroxymidazolam

t

1/2

of parent and active

metabolite = 2-6 h and

2-7 h, respectively

10 mg IM in mid-

outer thigh

(vastus lateralis

muscle) by

personnel with

adequate training

in recognition and

treatment of SE

and first aid/basic

airway

management

Upper airway

obstruction,

agitation, and

pyrexia

Not recommended

in narrow-angle

glaucoma

Serious

cardiorespiratory

adverse reactions

have occurred,

sometimes resulting

in death or

permanent

neurologic injury

Use with other CNS

depressants may

increase risk of

hypoventilation,

airway obstruction,

desaturation, or

apnea, and may

contribute to

profound or

prolonged drug

effect

Use with caution in

patients receiving

CYP3A4 inhibitors

With BDZs assess each

patient’s risk for

abuse, misuse, and

addiction

midazolam

(MDZ)

Intranasal

spray

(individual

spray unit =

5 mg)

Schedule IV

Seizure clusters,

acute repetitive

seizures

At least 12 y

GABA

A

receptor

agonist;

binds

between

α and γ

subunits

Data from adults:

F = 44%

Protein binding = 97%

Tmax (5-mg dose) = 17 min

Cmax = 54.7 ng/mL

Less variability in absorption

compared with IV MDZ

Gut and hepatic metabolism

via CYP3A4 to active

metabolite

1-hydroxymidazolam

t

1/2

of parent and active

metabolite = 2-6 h and

2-7 h, respectively

First dose:

5 mg (1 spray)

into 1 nostril

Second dose

(if needed):

10 min following

the first dose =

5 mg (1 spray)

into opposite

nostril

Maximum

dose:

No more than

2 intranasal

doses to treat

1 episode

Should not be

used to treat

more than 1

episode every

3 days

Not for chronic

daily therapy

CNS depression,

somnolence,

impaired

cognition, HA,

nasal discomfort,

runny nose, throat

irritation

Use with opioids can

cause respiratory

depression, coma,

and death

Contraindicated in

narrow-angle

glaucoma

With BDZs assess

each patient’s risk

for abuse, misuse,

and addiction

Use with caution in

patients receiving

CYP3A4 inhibitors

Table 3. Medications for Initial Treatment of Convulsive Status Epilepticus.

6,1414

January 2024. (See Abbreviations.)

Drug - Generic Name

Route/Dose

lorazepam

IV:

0.1 mg/kg

Maximum dose = 4 mg

May repeat once

midazolam

IM:

5 mg (patient weight 13-40 kg)

10 mg (patient weight > 40 kg )

diazepam

IV:

0.15-0.2 mg/kg

Maximum dose = 10 mg

May repeat once

Table 4. Antiseizure Medications (ASMs) Enzymatic Considerations

Enzyme

Substrates

Enzyme Inhibitors

Enzyme Inducers

CYP3A4

cannabidiol, carbamazepine, clobazam, clonazepam,

diazepam, ethosuximide, everolimus, felbamate,

lacosamide, midazolam, oxcarbazepine, perampanel,

stiripentol, tiagabine, zonisamide,

carbamazepine, eslicarbazepine, felbamate,

oxcarbazepine, perampanel, phenobarbital phenytoin,

primidone, rufinamide, stiripentol, topiramate,

cenobamate

CYP2C19

brivaracetam, cannabidiol, clobazam, diazepam,

lacosamide, phenobarbital, phenytoin, primidone,

stiripentol, valproate, zonisamide

cannabidiol, eslicarbazepine, felbamate,

topiramate, valproate, cenobamate

carbamazepine, phenobarbital, phenytoin, primidone,

stiripentol

CYP2C9

carbamazepine, lacosamide, phenobarbital, primidone,

valproate

perampanel, stiripentol, valproate,

cannabidiol

carbamazepine, phenobarbital, primidone

CYP2B6

clobazam, perampanel, valproate

carbamazepine, perampanel

CYP1A2

stiripentol

cannabidiol, stiripentol

UGT

cannabidiol, diazepam, lamotrigine, oxcarbazepine

valproate

lamotrigine, phenobarbital, primidone

Epoxide hydrolase

carbamazepine 10,11 epoxide

valproate, brivaracetam

Abbreviations

ACTH = adrenocorticotropic hormone

ADME = absorption, distribution,

metabolism, and excretion

AE = adverse event

ALT = alanine aminotransferase

AST = aspartate aminotransferase

BDZ = benzodiazepine

bid = twice a day

BP = blood pressure

BRV = brivaracetam

CBC = complete blood cell count

CBD = cannabidiol

CBZ = carbamazepine

CK = creatine kinase

CLB = clobazam

Cmax = maximum plasma concentration

CMP = comprehensive metabolic panel

CNB = cenobamate

CNS = central nervous system

CrCl = creatinine clearance

CYP = cytochrome P

CZP = clonazepam

d = day

DDI = drug-drug interaction

DEA = Drug Enforcement Administration

DRESS = drug reaction with eosinophilia

and systemic symptoms (formerly

known as multiorgan hypersensitivity)

DZP = diazepam

EIASM = enzyme-inducing antiseizure

medication (e.g., CBZ, PHT, PB, PRM)

EKG = electrocardiogram

ER = extended release

ES = epileptic spasms

ESL = eslicarbazepine acetate

ESM = ethosuximide

EtOH = ethyl alcohol

EVL = everolimus

F = bioavailability

FBM = felbamate

FFA = fenfluramine

FIAS = focal impaired awareness seizure

focal onset = focal-onset seizures with or without

progression to bilateral tonic-clonic convulsions

(formerly known as partial-onset seizures)

FOS = fosphenytoin

GABA = γ-aminobutyric acid

GBP = gabapentin

GGT = γ-glutamyl transferase

GI = gastrointestinal

GTCS = generalized-onset tonic-clonic seizure

h = hour

HA = headache

HCN = hyperpolarization-activated, cyclic

nucleotide-gated

IM = intramuscular

INR = international normalized ratio

IQ = intelligence quotient

IR = immediate release

IV = intravenous

LCM = lacosamide

LEV = levetiracetam

LFT = liver function test

LGS = Lennox-Gastaut syndrome

LTG = lamotrigine

mo = month

MA = metabolic acidosis

MAOI = monoamine oxidase inhibitor

MDZ = midazolam

MHD = monohydroxy derivative of OXC (R- and S-

licarbazepine)

mTOR = mammalian target of rapamycin

N/A = not applicable

Na+ = sodium

N-desmethyl-CLB = N-desmethylclobazam

NE = norepinephrine

NMDA =

N-methyl-D-aspartate

nor-FEN = norfenfluramine

N/V = nausea and vomiting

OC = oral contraceptive

OXC = oxcarbazepine

PB = phenobarbital

PE = phenytoin sodium equivalent

PEMA = phenylethylmalonamide

PER = perampanel

PGB = pregabalin

PHT = phenytoin

PI = FDA-approved prescribing information

PK = pharmacokinetics

PRM = primidone

prn = as needed

PTT = partial thromboplastin time

q6h = every 6 hours

qhs = every night at bedtime

qpm = every afternoon or evening

RBC = red blood cell

REMS = risk evaluation and mitigation strategies

RUF = rufinamide

SGPT = serum glutamic-pyruvic transaminase

SJS = Stevens-Johnson syndrome

SE = status epilepticus

STP = stiripentol

t

1/2

= half-life

TCA = tricyclic antidepressant

TEN = toxic epidermal necrolysis

TGB = tiagabine

tid = three times a day

Tmax = time at which Cmax is observed

TPM = topiramate

Tx = therapy

URI = upper respiratory infection

VGB = vigabatrin

VPA = valproic acid

WBC = white blood cell

wk = week

y = year

ZNS = zonisamide

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Acknowledgements

This document has been reviewed and approved by the American Epilepsy Society Treatments Committee, Council on Clinical Activities, and

Board of Directors. The authors thank Aatif Husain, MD, Chair of the AES Council of Clinical Activities, and the members of the AES Treatments

Committee for their thoughtful review of this document. They also thank Lauren Orciuoli, MBA, MPH, Joy Keller MS, RD, MSLIS, and Shawna

Strickland, PhD, CAE, RRT, FAARC for editorial review and support.

American Epilepsy Society Treatments Committee, 2024

John Stern, MD, MA, FAES, Chair

Sasha Alick-Lindstrom, MD, FAES, FACNS, FAAN

Ali Asadi-Pooya, MD

David Auerbach, PhD

Ausaf Bari, MD, PhD

Marjorie Bunch, MD, FAES

Kamil Detyniecki, MD, FAES

Sara Eyal, PhD

Jessica Falco-Walter, MD

Jim Herbst, PharmD

Wesley Kerr, MD, PhD

Shilpa Klocke, PharmD

W. Curt LaFrance, MD, MPH, FAPA, FAAN

Alain Zingraff Lekoubou Looti, MD, MS

Adrian Rabinowicz, MD, FAAN

Maralena Taube, PharmD