Seizure and mood stabilizer medications

ACRONYMS AND DEFINITIONS

DRESS - Drug reaction with eosinophilia and systemic symptoms

HLA - Human leukocyte antigen

RCT - Randomized controlled trial

SJS - Stevens-Johnson syndrome

TEN - Toxic epidermal necrolysis

SEIZURE MEDICATIONS

Brivaracetam (Briviact®)

Dosage forms

Tablet

10 mg
25 mg
50 mg
75 mg
100 mg

Solution

10 mg/ml
Comes in 300 ml bottle
Store at room temperature

Dosing

Partial-onset seizures

Recommended dosing for adults and pediatric patients is provided in the table below
When initiating treatment, gradual dose escalation is not required. Dosage should be adjusted based on clinical response and tolerability.
Swallow tablets whole. Do not crush, cut, or chew.
May take without regard to food

Adults	Initial Dosage	Minimum and Maximum Maintenance Dosage
≥ 16 years old and adults	50 mg twice daily	25 mg to 100 mg twice daily
Pediatric (≥ 1 month)	Initial Dosage	Minimum and Maximum Maintenance Dosage
≥ 50 kg	25 mg to 50 mg twice daily	25 mg to 100 mg twice daily
20 kg to <50 kg	0.5 mg/kg to 1 mg/kg twice daily	0.5 mg/kg to 2 mg/kg twice daily
11 kg to <20 kg	0.5 mg/kg to 1.25 mg/kg twice daily	0.5 mg/kg to 2.5 mg/kg twice daily
< 11 kg	0.75 mg/kg to 1.5 mg/kg twice daily	0.75 mg/kg to 3 mg/kg twice daily

Dosing in hepatic impairment

Adults	Initial Dosage	Maximum Maintenance Dosage
≥ 16 years old and adults	25 mg twice daily	75 mg twice daily
Pediatric (≥ 1 month)	Initial Dosage	Minimum and Maximum Maintenance Dosage
≥ 50 kg
20 kg to <50 kg	0.5 mg/kg twice daily	1.5 mg/kg twice daily
11 kg to <20 kg	0.5 mg/kg twice daily	2 mg/kg twice daily
< 11 kg	0.75 mg/kg twice daily	2.25 mg/kg twice daily

Efficacy

Focal seizures

Brivaracetam vs Placebo as Adjunctive Therapy in Adults with Uncontrolled Partial-onset Seizures, Epilepsia (2015) [PubMed abstract]

Generic / Price

- NO/$$$$

Lab monitoring

The value of routine monitoring has not been established
Plasma levels are available from some labs
The recommended steady-state brivaracetam plasma concentration for seizure control is 0.2 to 2.0 mcg/mL [7]

Pharmacokinetics

Half-life: 9 hours [1]

Other

Brivaracetam is a CV controlled substance

Mechanism of action

The precise mechanism by which brivaracetam exerts its anticonvulsant activity is not known. Brivaracetam displays a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain, which may contribute to the anticonvulsant effect.

FDA-approved indications

Treatment of partial-onset seizures in patients 1 month of age and older

Side effects

NOTE: Data is from adjunctive trials in adults

Side effect	Brivaracetam (N=803)	Placebo (N=459)
Somnolence / sedation	16%	8%
Dizziness	12%	7%
Fatigue	9%	4%
Nausea / vomiting	5%	3%
Balance issues	3%	1%
Irritability	3%	1%
Constipation	2%	0%

Drug interactions

Rifampin - rifampin decreases brivaracetam exposure likely through CYP2C19 induction. Brivaracetam doses may need to be increased by up to 100% in patients receiving rifampin.
Carbamazepine - brivaracetam may increase exposure to carbamazepine-epoxide, the active metabolite of carbamazepine. Though available data did not reveal any safety concerns, if tolerability issues arise when co-administered, carbamazepine dose reduction should be considered.
Phenytoin - brivaracetam may increase exposure to phenytoin. Monitor phenytoin levels when combining, particularly when adding or stopping brivaracetam and during dose adjustments.
Levetiracetam - the addition of brivaracetam to levetiracetam provided no added benefit in studies.

Contraindications / Precautions

Pregnancy - there are no adequate data on the developmental risks associated with use of brivaracetam in pregnant women. In animal studies, brivaracetam produced evidence of developmental toxicity (increased embryofetal mortality and decreased fetal body weights in rabbits; decreased growth, delayed sexual maturation, and long-term neurobehavioral changes in rat offspring) at maternal plasma exposures greater than clinical exposures.
Hypersensitivity reactions - hypersensitivity reactions including angioedema and bronchospasm have been reported with brivaracetam. If significant reactions occur, brivaracetam should be discontinued and not restarted.
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Neurological adverse reactions - brivaracetam may increase the risk of adverse neurologic events. In trials, somnolence and fatigue were reported in more brivaracetam-treated patients (20% at 50 mg/day, 26% at 100 mg/day, and 27% at 200 mg/day) than placebo-treated patients (14%). Dizziness and gait disturbances were reported in 16% of brivaracetam-treated patients and 10% of placebo-treated patients. Patients should use caution before engaging in hazardous activities (e.g. driving), especially when initiating therapy.
Psychiatric reactions - in trials, 13% of brivaracetam-treated patients reported adverse psychiatric reactions compared to 8% of placebo-treated patients. The range of reactions was broad and included anxiety, anger, depression, abnormal behavior, and psychosis, to name a few. Drug discontinuations due to psychiatric reactions were 1.7% in brivaracetam-treated patients and 1.3% in placebo-treated patients.
Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
Liver disease - see Dosing above
Kidney disease - no dose adjustment necessary. Not recommended in dialysis.

Dosage forms

Tablet (Tegretol®, Epitol®)

100 mg
200 mg
300 mg
400 mg

Tablet, chewable (Tegretol®, Epitol®)

100 mg

Tablet, extended-release (Tegretol XR®)

100 mg
200 mg
400 mg

Capsule, extended-release (Carbatrol®)

100 mg
200 mg
300 mg

Capsule, extended-release (Equetro®)

100 mg
200 mg
300 mg

Suspension (Tegretol®, Teril®)

100 mg/5ml
Comes in 450 ml bottle

Dosing - Epilepsy

Tegretol® (adults)

Starting: 200 mg twice daily
Maintenance: 800 - 1200 mg/day
Max: 1600 mg/day
Increase dose at intervals of one week by 200 mg/day, given in 3 - 4 divided doses

Tegretol XR®, Carbatrol®, Equetro® (adults)

Starting: 200 mg twice daily
Maintenance: 400 - 800 mg twice daily
Max: 800 mg twice daily
Increase dose at intervals of one week by 200 mg/day, given in 2 divided doses

Dosing - Trigeminal neuralgia

Tegretol®, Tegretol XR®, Carbatrol® (adults)

Starting: 100 mg twice daily
Maintenance: 200 - 400 mg twice daily
Max: 600 mg twice daily
Increase dose by 200 mg/day, given in 2 divided doses

Equetro® (adults)

Starting: 200 mg once daily
Maintenance: 200 - 400 mg twice daily
Max: 1200 mg/day
Increase dose by 200 mg/day, given in 2 divided doses

Dosing - Bipolar

Equetro® (adults)

Starting: 200 mg twice daily
Max: 1600 mg/day
Increase dose by 200 mg/day, given in 2 divided doses

Dosing - Alcohol withdrawal

Tegretol® (off-label)

See carbamazepine for alcohol withdrawal

Generic / Price

Tegretol® (60 tablets) - YES/$
Tegretol® (180 chewable tablets) - YES/$
Tegretol XR® (60 tablets) - YES/$
Carbatrol® (60 capsules) - YES/$
Suspension (450 ml) - YES/$
Equetro® (60 capsules) - NO/$$$$

Lab monitoring

Levels

Routine monitoring is recommended to maintain a therapeutic level and prevent toxicity
Levels should be drawn within an hour of the next dose (trough) [3,4,5]
Therapeutic levels (alone): 4 - 12 mcg/ml [4]
Therapeutic levels (with other antiepileptics): 4 - 8 mcg/ml [3]
Potential Toxic: > 12 mcg/ml [3]

Other labs

Carbamazepine is 75% protein bound. Free (unbound) carbamazepine levels may be useful in cases where protein binding may be altered (e.g. uremia, liver disease). [5]
Carbamazepine-10,11 epoxide is the major active metabolite of carbamazepine. Carbamazepine-10,11 epoxide levels may be helpful when signs of toxicity are present but carbamazepine levels are normal. [5]
Check for HLA-B*1502 allele in at-risk patients (see HLA-B*1502 allele prevalence for more.)
CBC before therapy. Periodically thereafter.
LFTs before therapy. Periodically thereafter.
Thyroid tests periodically.

Pharmacokinetics

Drug half-life is highly variable since it induces its own metabolism. Enzyme induction is usually complete after 3 - 5 weeks of therapy. [1]
Initial half-life: 25 - 65 hours
Half-life after 3 - 5 weeks (adults): 12 - 17 hours [1]
Time to steady state (initial dosing): 5 - 13 days [5]
Time to steady state (chronic dosing): 2 - 5 days [5]

Other

Tegretol®

Take with food

Tegretol XR®

Take with food
Do not crush, cut, or chew tablet
Nonabsorbable tablet coating may be seen in stool. This is normal.
When converting from Tegretol® to Tegretol XR®, the total daily dose remains the same

Equetro®

Equetro® is not rated bioequivalent
May take without regard to food
May open capsule and sprinkle beads on food. Do not chew beads.

Carbatrol®

May take without regard to food

Mechanism of action

Binds to voltage-dependent sodium channels
Inhibits action potentials (nerve-firing)

FDA-approved indications

Tegretol®, Tegretol XR® Carbatrol®, Equetro®

Epilepsy - focal seizures, generalized tonic-clonic seizures, mixed seizure types. Does not appear to be effective for absence seizures.
Trigeminal neuralgia

Equetro®

Bipolar I - acute mania or mixed episodes

Side effects

NOTE: Data is from Equetro® PI

Side effect	Carbamazepine	Placebo
Dizziness	44%	12%
Somnolence	32%	13%
Nausea	29%	10%
Vomiting	18%	3%
Ataxia (Loss of coordination)	15%	0%
Constipation	10%	5%
Itching	8%	2%
Dry mouth	8%	3%
Weakness	8%	4%

Drug interactions

Carbamazepine is a CYP1A2 inducer, a CYP3A4 strong inducer and substrate, and a P-glycoprotein inducer and substrate. Because of this, carbamazepine has a long list of potential drug interactions. See Tegretol PI for more.
Delavirdine (Rescriptor®) - DO NOT COMBINE
Direct-acting oral anticoagulants - direct-acting oral anticoagulants (e.g. rivaroxaban, apixaban, dabigatran, and edoxaban) are P-glycoprotein substrates. Carbamazepine is a P-glycoprotein inducer and it may decrease exposure to these medications. Concomitant use is not recommended.
HIV non-nucleoside reverse transcriptase inhibitors - DO NOT COMBINE
MAO inhibitors - DO NOT COMBINE
Nefazodone - DO NOT COMBINE
CYP3A4 inhibitors and inducers - may affect carbamazepine levels
CYP3A4 substrates - carbamazepine may decrease levels of CYP3A4 substrates
CYP1A2 substrates - carbamazepine may decrease levels of CYP1A2 substrates
P-glycoprotein inducers/inhibitors/substrates - carbamazepine is a P-gp inducer and substrate. P-gp drugs may affect carbamazepine levels and carbamazepine may affect P-gp substrates.
Oral contraceptives - carbamazepine may decrease the effectiveness of oral contraceptives. Consider alternative birth control.
Contraceptive implant (Implanon™) - A study published in 2017 found that carbamazepine reduced levels of etonogestrel below therapeutic levels in patients with contraceptive implants [PMID 28288788]. Alternative birth control should be considered in these patients.
Warfarin - carbamazepine may decrease the effectiveness of warfarin
Clomipramine - carbamazepine may increase blood levels of clomipramine
Lamotrigine - carbamazepine may decrease lamotrigine levels by 40%. Lamotrigine may increase carbamazepine levels. See lamotrigine for details on dosing.
Phenytoin - carbamazepine may increase or decrease phenytoin levels
Valproic acid - carbamazepine may decrease levels of valproic acid by 50%. Valproic acid may affect carbamazepine levels.
Topiramate - carbamazepine may decrease topiramate levels by 40%
Oxcarbazepine - carbamazepine may decrease oxcarbazepine levels by 40%
Primidone - carbamazepine may decrease primidone levels
Lithium - combination may increase neurotoxic effects. Consider lower doses of each drug.
Methotrexate - methotrexate may decrease valproate exposure, increasing the risk of seizures or bipolar symptoms. Monitor valproate levels and clinical response closely when combining.
Cannabidiol - coadministration of cannabidiol and valproate has been associated with liver enzyme elevations. Monitor liver functions closely when combining and reduce or discontinue one or both drugs if necessary.
Chloroquine - may antagonize the activity of carbamazepine
Mefloquine - may antagonize the activity of carbamazepine
Isoniazid (INH) - may increase risk of hepatotoxicity
Neuromuscular blocking agents (vecuronium, etc.) - patients on carbamazepine may be more resistant to effects

Contraindications / Precautions

Known allergy to tricyclic antidepressants - DO NOT USE. Carbamazepine is a tricyclic compound. See tricyclic antidepressants for more.
Pregnancy - DO NOT USE. Carbamazepine has been associated with major congenital malformations, including neural tube defects and malformations involving other body systems (e.g. craniofacial defects and cardiovascular malformations).
Hepatic porphyria - DO NOT USE
Osteoporosis - carbamazepine is a CYP enzyme inducer and this may enhance the metabolism of vitamin D and increase the risk of osteoporosis. Consider checking vitamin D, calcium, and phosphate levels during prolonged therapy. BMD testing may be appropriate in some patients.
Serious skin reactions - SJS, DRESS, and TEN have been reported
HLA-B*1502 allele - carriers of the HLA-B*1502 allele have a higher risk of serious skin reactions. See HLA-B*1502 allele prevalence for more.
HLA-A*3101 allele - carriers of the HLA-A*3101 allele have a higher risk of serious skin reactions. It is more common in Asian, Japanese, Europeans, and others.
Anaphylaxis and angioedema - rare cases of anaphylaxis and angioedema have been reported in patients taking their first or subsequent doses of carbamazepine.
Decreased blood cells - carbamazepine has been associated with aplastic anemia and agranulocytosis. These reactions are rare.
Thyroid tests - carbamazepine may affect thyroid function tests. Incidence is not well-defined.
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Low sodium (hyponatremia) - carbamazepine may cause SIADH
Glaucoma - carbamazepine may cause pupil dilation
Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
Liver disease - consider reducing dose; no specific recommendation given
Kidney disease - effect unknown; no recommendation given

Cenobamate (Xcopri™)

Dosage forms

Tablet (Xcopri™)

50 mg
100 mg
150 mg
200 mg

Titration packs (3 different packs)

12.5 mg X 14 / 25 mg X 14
50 mg X 14 / 100 mg X 14
150 mg X 14 / 200 mg X 14

Maintenance packs

250 mg/day (28 days worth)
350 mg/day (28 days worth)

Dosing

Partial seizures in adults

Starting

Week 1 and 2: 12.5 mg once daily
Week 3 and 4: 25 mg once daily
Week 5 and 6: 50 mg once daily
Week 7 and 8: 100 mg once daily
Week 9 and 10: 150 mg once daily
Week 11 and on: 200 mg once daily

Max: 400 mg once daily
For doses above 200 mg/day, increase dose in increments of 50 mg/day every 2 weeks
May take without regard to food
Do not crush, cut, or chew tablets

Efficacy

Adjunctive Cenobamate vs Placebo in Uncontrolled Focal Seizures, Lancet Neurol (2020) [PubMed abstract]

Other

Cenobamate is a DEA Schedule V (CV) controlled substance

Generic / Price

- NO/$$$$

Lab monitoring

The value of routine monitoring has not been established

Pharmacokinetics

Half-life: 50 - 60 hours
Time to steady state: 2 weeks

Mechanism of action

The precise mechanism by which cenobamate exerts its therapeutic effects in patients with partial-onset seizures is unknown. Cenobamate has been demonstrated to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents. It is also a positive allosteric modulator of the γ-aminobutyric acid (GABA_A) ion channel

FDA-approved indications

Partial-onset seizures in adults (monotherapy and adjunctive therapy)

Side effects

NOTE: Only side effects that occurred at an incidence ≥ 5% are listed

Side effect	Xcopri 200 mg (N=223)	Xcopri 400 mg (N=111)	Placebo (N=216)
Somnolence	22%	37%	11%
Dizziness	22%	33%	15%
Fatigue	14%	24%	7%
Headache	12%	10%	9%
Diplopia	7%	15%	2%
Nausea	6%	9%	3%
Balance Disorder	5%	9%	1%
Gait Disturbance	3%	8%	1%
Constipation	4%	8%	0%
Dysarthria	1%	7%	0%
Nystagmus	7%	6%	0%
Ataxia	3%	6%	2%
Vertigo	1%	6%	1%
Diarrhea	3%	5%	0%
Vomiting	4%	5%	0%
Nasopharyngitis	4%	5%	3%
Decreased Appetite	1%	5%	1%
Back Pain	2%	5%	3%
Urinary Tract Infection	5%	0%	2%

Drug interactions

Lamotrigine - cenobamate may decrease lamotrigine exposure. Increase lamotrigine doses as needed when taken with cenobamate.
Carbamazepine - cenobamate may decrease carbamazepine exposure. Increase carbamazepine doses as needed when taken with cenobamate.
Phenytoin - cenobamate may increase phenytoin exposure. Because of a potential 2-fold increase in phenytoin levels, gradually decrease phenytoin dosage by up to 50% as cenobamate is being titrated.
Phenobarbital - cenobamate may increase phenobarbital exposure. Consider reducing the phenobarbital dose when combining with cenobamate.
Clobazam - cenobamate may increase clobazam exposure. Consider reducing the clobazam dose when combining with cenobamate.
CYP2B6 substrates - cenobamate is a CYP2B6 inducer. Doses of CYP2B6 substrates may need to be increased when combining.
CYP3A4 substrates - cenobamate is a CYP3A4 inducer. Doses of CYP3A4 substrates may need to be increased when combining.
CYP2C19 substrates - cenobamate is a CYP2C19 inhibitor. Doses of CYP2C19 substrates may need to be decreased when combining.
Oral contraceptives - cenobamate may reduce the efficacy of oral contraceptives. Women should use additional or alternative non-hormonal birth control while taking cenobamate.
Drugs that shorten the QT interval - cenobamate can shorten the QT interval. Use caution when combining with other drugs that shorten the QT interval. Patients with symptoms of QT shortening (e.g. prolonged palpitations or fainting) should report them to their physician immediately.
CNS depressants including alcohol - CNS depressants including alcohol may potentiate the sedating effects of cenobamate

Contraindications / Precautions

Pregnancy and nursing - risk is unknown
Familial Short QT syndrome - DO NOT COMBINE. Cenobamate has been shown to shorten the QT interval.
DRESS syndrome - rare cases of DRESS have been reported in patients taking cenobamate. DRESS may present with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present, and systemic symptoms (e.g., fever, lymphadenopathy) may present before a rash is present. Cenobamate should be titrated slowly and any symptoms consistent with DRESS should be evaluated immediately.
QT shortening - in studies, a significant percentage of patients taking cenobamate had QT shortening of > 20 msec (31% at 200 mg and 66% at 500 mg). Familial Short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. These events are believed to occur primarily when the corrected QT interval falls below 300 msec. Symptoms of QT shortening may include prolonged palpitations and/or fainting. Do not use cenobamate in patients with Familial Short QT syndrome, and use caution when combining with other QT shortening drugs.
Elevated liver enzymes - in one study, ALT elevations > 3 X ULN occurred in up to 2.7% of cenobamate-treated patients and no placebo-treated patients
Elevated potassium - in one study, potassium elevations of > 5 meq/L occurred in 17% of cenobamate-treated patients (200 mg) compared to 7% of placebo-treated patients
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Adverse neurological effects - in trials, a significant number of patients taking cenobamate experienced adverse neurological effects including somnolence, fatigue, gait disturbances, cognitive impairment, and visual changes. Patients should be advised that cenobamate may impair their ability to engage in hazardous activities such as driving.
Abrupt discontinuation - abrupt discontinuation of cenobamate can increase the risk of seizures. Gradual withdrawal is recommended.
Liver disease

Child-Pugh A/B: use caution. Dose should not exceed 200 mg once daily.
Child-Pugh C: not recommended

Kidney disease - use caution and consider dose reductions. Do not use in end-stage renal disease or dialysis.

Eslicarbazepine (Aptiom®)

Dosage forms

Tablet (Aptiom®)

200 mg
400 mg
600 mg
800 mg

Dosing

Partial seizures (adults)

Starting: 400 mg once daily
Maintenance: 800 - 1600 mg once daily
Maximum: 1600 mg once daily
Increase dose in increments of 400 - 600 mg at weekly intervals
Treatment may be initiated at 800 mg once daily if need for seizure control outweighs risk for side effects
May take without regard to food
Tablet may be crushed

Partial seizures (4 - 17 years old)

May take without regard to food
Tablet may be crushed

^✝Increase dose at weekly intervals
Body Weight Range	Initial and Maximum Titration Increment Dosage^✝ (mg/day)	Maintenance Dosage (mg/day)
11 - 21 kg	200	400 to 600
22 - 31 kg	300	500 to 800
32 - 38 kg	300	600 to 900
>38 kg	400	800 to 1200

Efficacy

Adjunctive Eslicarbazepine vs Placebo in Uncontrolled Partial Seizures, Epilepsia (2015) [PubMed abstract]

Generic / Price

- NO/$$$$

Lab monitoring

Levels

Eslicarbazepine levels are available at some labs
There is no established therapeutic range
Trough plasma levels following doses of 400 - 2400 mg/day, averaged 2 - 28 mcg/mL
Maximum plasma concentrations following 2400 mg/day dosages averaged 55 mcg/mL [2]

Liver enzymes

Eslicarbazepine has been associated with rare cases of hepatotoxicity
Baseline liver function tests are recommended

Pharmacokinetics

Half-life: 13 - 20 hours
Time to steady state: 4 - 5 days

Mechanism of action

The precise mechanism(s) by which eslicarbazepine exerts anticonvulsant activity is unknown but is thought to involve inhibition of voltage-gated sodium channels

FDA-approved indications

Partial-onset seizures in adults and children ≥ 4 years old (monotherapy and adjunctive therapy)

Side effects

NOTE: Only side effects that occurred at an incidence ≥ 5% are listed

Side effect	Placebo (N=426)	Aptiom 800 mg (N=415)	Aptiom 1200 mg (N=410)
Dizziness	9%	20%	28%
Somnolence	8%	11%	18%
Nausea	5%	10%	16%
Headache	9%	13%	15%
Diplopia	2%	9%	11%
Vomiting	3%	6%	10%
Fatigue	4%	4%	7%
Blurred vision	1%	6%	5%
Ataxia	2%	4%	6%
Vertigo	< 1%	2%	6%

Drug interactions

Oxcarbazepine - DO NOT TAKE eslicarbazepine with oxcarbazepine. Eslicarbazepine is partially metabolized to oxcarbazepine.
Carbamazepine - carbamazepine may reduce exposure to eslicarbazepine. When taken together, higher doses of eslicarbazepine may be needed.
Phenytoin - phenytoin may reduce exposure to eslicarbazepine. When taken together, higher doses of eslicarbazepine may be needed.
Phenobarbital - phenobarbital may reduce exposure to eslicarbazepine. When taken together, higher doses of eslicarbazepine may be needed.
Primidone - primidone may reduce exposure to eslicarbazepine. When taken together, higher doses of eslicarbazepine may be needed.
CYP2C19 substrates - eslicarbazepine is a CYP2C19 moderate inhibitor. Doses of CYP2C19 substrates may need to be decreased when combining.
CYP3A4 substrates - eslicarbazepine is a CYP3A4 inducer. Doses of CYP3A4 substrates may need to be increased when combining.
Oral contraceptives - eslicarbazepine lowers levels of ethinyl estradiol and levonorgestrel which can reduce the efficacy of oral contraceptives. Women should use additional or alternative non-hormonal birth control while taking cenobamate.

Contraindications / Precautions

Pregnancy and nursing - risk is unknown
Oxcarbazepine allergy/hypersensitivity reactions - DO NOT USE. Eslicarbazepine is partially metabolized to oxcarbazepine.
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Serious dermatologic reactions - serious dermatologic reactions including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving eslicarbazepine
DRESS syndrome - rare cases of DRESS have been reported in patients taking eslicarbazepine. DRESS may present with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present, and systemic symptoms (e.g., fever, lymphadenopathy) may present before a rash is present.
Anaphylaxis and angioedema - rare cases of anaphylaxis and angioedema have been reported in patients receiving eslicarbazepine
Hyponatremia - in trials, eslicarbazepine-treated patients had a higher incidence of sodium levels < 125 mEq/L than placebo-treated patients (1% with 800 mg, 1.5% with 1200 mg, 0% with placebo). In addition, 5.1% of eslicarbazepine-treated patients experienced a decrease in sodium levels of > 10 mEq/L compared to 0.7% of placebo-treated patients. Sodium decreases were dose-related and typically occurred within the first 8 weeks of therapy. Concurrent hypochloremia was also present. Measurement of sodium levels should be considered during therapy and if signs of hyponatremia develop (e.g., nausea/vomiting, malaise, headache, lethargy, confusion, irritability, muscle weakness/spasms, obtundation, or increase in seizure frequency or severity). Sodium levels typically normalized within a few days of stopping eslicarbazepine.
Adverse neurological effects - in trials, a significant number of patients taking eslicarbazepine experienced adverse neurological effects including somnolence, fatigue, gait disturbances, cognitive impairment, and visual changes. Patients should be advised that eslicarbazepine may impair their ability to engage in hazardous activities such as driving.
Abrupt discontinuation - abrupt discontinuation of eslicarbazepine can increase the risk of seizures. Gradual withdrawal is recommended.
Hepatic toxicity - cases of hepatotoxicity have been reported with eslicarbazepine. Elevations in ALT/AST and bilirubin without evidence of obstruction are a predictor of severe liver injury. Baseline liver function tests are recommended.
Abnormal thyroid tests - dose-dependent decreases in serum T3 and T4 (free and total) have been observed in patients taking eslicarbazepine. These changes were not associated with increases in TSH levels.
Hematologic adverse reactions - rare cases of pancytopenia, agranulocytosis, and leukopenia have been reported in the postmarketing setting
Liver disease

Child-Pugh A/B: no dose adjustment necessary
Child-Pugh C: has not been studied. Not recommended.

Kidney disease

CrCl ≥ 50 ml/min: no dose adjustment necessary
CrCl < 50 ml/min: decrease dose by 50%. Clearance is decreased.

Gabapentin | Neurontin® | Horizant® | Gralise®

Dosage forms

Tablet (Neurontin®)

100 mg
300 mg
400 mg
600 mg
800 mg

Capsule (Neurontin®)

100 mg
300 mg
400 mg

Solution (Neurontin®)

250 mg/5 ml
Comes in 470 ml bottle
Store in refrigerator

Tablet (Horizant®)

300 mg
600 mg

Tablet (Gralise®)

300 mg
600 mg

Dosing - Neurontin

Epilepsy (adjunctive therapy for focal seizures)

Starting: 300 mg three times a day
Maintenance: 900 - 1800 mg a day
Max: 3600 mg a day

Postherpetic neuralgia

Starting: 300 mg on day 1, then 300 mg twice a day on day 2, then 300 mg three times a day on day 3
Maintenance: 900 - 1800 mg a day
Max: 1800 mg a day

Diabetic neuropathy (off-label)

Starting: 100 - 300 mg one to three times a day
Target: 900 - 3600 mg/day
See diabetic neuropathy for more

Alcohol use disorder (off-label)

See gabapentin for alcohol withdrawal and gabapentin for chronic alcohol use disorder

Dosing in kidney disease

See Neurontin® PI for specific recommendations
CrCl 30 - 59 ml/min: 400 - 1400 mg/day
CrCl 15 - 29 ml/min: 200 - 700 mg/day
CrCl < 15 ml/min: 100 - 300 mg/day

Dosing - Horizant®

Restless leg syndrome

600 mg once daily at 5PM

Postherpetic neuralgia

Initial: 600 mg a day for 3 days, then 600 mg twice a day
Maintenance: 600 mg twice a day
Kidney disease - see Horizant® PI for specific recommendations

Dosing - Gralise®

Postherpetic neuralgia

Initial: Starter pack (titrates to 1800 mg/day)
Maintenance: 1800 mg once daily with evening meal
Kidney disease - see Gralise® PI for specific recommendations

Efficacy

Sciatica

Gabapentin vs Epidural Steroid Injections for Sciatica, BMJ (2015) [SH review]

Alcohol abuse

Gabapentin vs Placebo for Prevention of Heavy Drinking in Patients with Alcohol Use Disorder, JAMA Intern Med (2020) [SH review]

Chronic pelvic pain

Gabapentin vs Placebo for Chronic Pelvic Pain in Women, Lancet (2020) [PubMed abstract]

Generic / Price

Neurontin® - YES/$ (solution and pills)
Horizant® - NO/$$$$
Gralise® - NO/$$$$

Lab monitoring

The value of routine monitoring has not been established
Levels may be useful to measure compliance and check for toxicity
Ideally, levels should be drawn before the morning dose [4]
Therapeutic level (not well-defined): 4 - 16 mcg/ml [3]

Pharmacokinetics

Half-life: 5 - 7 hours
Time to steady state: 1 - 2 days [2]

Other

Neurontin®

May take without regard to food
May cut or break tablet. Unused half-tablet should be taken at next dose. Half-tablets not used within several days should be discarded.
Solution should be refrigerated
May cause false-positive urine protein test

Horizant®

Take with food
Do not crush, cut, or chew tablet
Not interchangeable with Neurontin®

Gralise®

Take with evening meal
Do not crush, cut, or chew tablet
Not interchangeable with Neurontin®

Mechanism of action

Mechanism not entirely understood
Binds to voltage-activated calcium channels
Inhibits action potentials (nerve-firing)

FDA-approved indications

Neurontin®

Epilepsy - adjunctive therapy in focal seizures with and without secondary generalization
Postherpetic neuralgia

Horizant®

Restless leg syndrome
Postherpetic neuralgia

Gralise®

Postherpetic neuralgia

Side effects

Side effect	Gabapentin	Placebo
Dizziness	28%	8%
Somnolence	21%	5%
Peripheral edema	8%	2%
Diarrhea	6%	3%
Dry mouth	5%	1%

Drug interactions

Antacids - antacids containing aluminum hydroxide and/or magnesium hydroxide may decrease gabapentin absorption when taken concomitantly. Take gabapentin at least 2 hours after antacids.
Naproxen - naproxen may increase gabapentin levels
Opiate medications - respiratory depression and sedation, sometimes resulting in death, have been reported following coadministration of gabapentin with opioids. Use caution when prescribing together.
Hydrocodone - gabapentin may decrease hydrocodone levels, and hydrocodone may increase gabapentin levels
Morphine - morphine may increase gabapentin levels. Monitor for signs of increased sedation when prescribing together.
Cimetidine - cimetidine may increase gabapentin levels

Lab interactions

Urine dipsticks - false-positive urine protein findings have been reported in patients receiving gabapentin when the Ames N-Multistix SG® dipstick is used. More specific measures such as the sulfosalicylic acid precipitation method should be used instead.

Contraindications / Precautions

Anaphylaxis and angioedema - have occurred in patients taking gabapentin. May occur at any time during therapy.
Respiratory depression - cases of serious and sometimes fatal respiratory depression have been reported when gabapentin was taken with other CNS depressants, including opioids, and in patients with underlying respiratory disorders. Use caution when prescribing in these situations.
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
Liver disease - gabapentin does not undergo liver metabolism; no dose adjustment necessary
Kidney disease - see Dosing

Lamotrigine | Lamictal® | Lamictal XR® | Lamictal CD® | Lamictal ODT®

Dosage forms

Tablet (Lamictal®)

25 mg
100 mg
150 mg
200 mg

Tablet, extended-release (Lamictal XR®)

25 mg
50 mg
100 mg
200 mg
250 mg
300 mg

Tablet, chewable (Lamictal CD®)

2 mg
5 mg
25 mg

Tablet, orally disintegrating (Lamictal ODT®)

25 mg
50 mg
100 mg
200 mg

Dosing - Lamictal®

Epilepsy

Typical range: 100 - 500 mg/day given in 2 divided doses
The Lamictal® PI gives specific recommendations for titration and dosing with other anticonvulsants
Lamotrigine should be titrated slowly to decrease the risk for serious skin reactions

Bipolar

Target dose: 200 mg/day
The Lamictal® PI gives specific recommendations for titration and dosing with other anticonvulsants
Lamotrigine should be titrated slowly to decrease the risk for serious skin reactions

Dosing - Lamictal XR®

Epilepsy

Typical range: 200 - 600 mg once daily
The Lamictal XR® PI gives specific recommendations for titration and dosing with other anticonvulsants
Lamotrigine should be titrated slowly to decrease the risk for serious skin reactions

Efficacy

Focal seizures

Lamotrigine vs Zonisamide vs Levetiracetam as Initial Therapy for Focal Seizure Disorder, Lancet (2021) [PubMed abstract]

Generic / Price

Lamictal® - YES/$
Lamictal CD® (60 tablets) - YES/$
Lamictal XR® (30 tablets) - YES/$$
Lamictal ODT® (60 tablets) - YES/$$

Lab monitoring

The value of routine monitoring has not been established
Monitoring levels may be useful in pregnancy (clearance increased by 65%), with concomitant oral contraceptives, and to assess compliance or toxicity
Level should be drawn right before next dose (trough) [5]
Therapeutic trough level: 2 - 20 mcg/ml [3]

Pharmacokinetics

Half-life: 25 - 33 hours [5]
Time to steady state: 2 - 7 days [5]

Other

Lamictal®

May take without regard to food
Orally disintegrating tablet should be placed on the tongue. May swallow with or without water after dissolves.
Chewable tablets may be swallowed whole, chewed, or mixed with water or diluted fruit juice.

Lamictal XR®

May take without regard to food
Do not crush, cut, or chew tablet

Mechanism of action

Mechanism not entirely understood
May inhibit voltage-dependent sodium channels
Inhibits action potentials (nerve-firing)

FDA-approved indication

Lamictal

Epilepsy (adjunctive therapy) - in focal seizures, generalized tonic-clonic seizures, and generalized seizures of Lennox-Gastaut syndrome
Epilepsy (monotherapy) - in patients with focal seizures who are converting to lamotrigine from other seizure therapies
Bipolar I - as maintenance therapy

Lamictal XR

Epilepsy (adjunctive therapy) - in focal seizures, generalized tonic-clonic seizures, and generalized seizures of Lennox-Gastaut syndrome
Epilepsy (monotherapy) - in patients with focal seizures who are converting to lamotrigine from other seizure therapies

Side effects

Bipolar trials
Side effect	Lamotrigine	Placebo
Nausea	14%	11%
Insomnia	10%	6%
Somnolence	9%	7%
Fatigue	8%	5%
Back pain	8%	6%

Adjunctive epilepsy trials (added to other seizure meds)
Side effect	Lamotrigine	Placebo
Dizziness	38%	13%
Headache	29%	19%
Double vision	28%	7%
Loss of coordination	22%	6%
Nausea	19%	10%
Blurred vision	16%	5%
Somnolence	14%	7%
Rash	10%	5%

Drug interactions

NOTE: Below are general guidelines. See Lamictal® PI for specific dosing recommendations

Oral contraceptives

Estrogen-containing oral contraceptives - estrogen-containing oral contraceptives may decrease lamotrigine levels by 50%
Levonorgestrel - lamotrigine may decrease levonorgestrel levels by about 20%

Other seizure medications

Carbamazepine - carbamazepine may decrease lamotrigine levels by 40%. Lamotrigine may increase carbamazepine levels.
Phenobarbital - phenobarbital may decrease lamotrigine levels by 40%
Primidone - primidone may decrease lamotrigine levels by 40%
Phenytoin - phenytoin may decrease lamotrigine levels by 40%
Topiramate - lamotrigine may increase topiramate levels
Valproate - valproate may more than double lamotrigine levels. The effects of lamotrigine on valproate levels are inconsistent.

Other meds

Atazanavir/ritonavir - may decrease lamotrigine levels by 32%
Lopinavir/ritonavir - may decrease lamotrigine levels by 50%
OCT2 substrates - lamotrigine is an inhibitor of OCT2. Exposure to OCT2 substrates may be increased when given with lamotrigine.
Olanzapine - olanzapine may reduce lamotrigine levels
Rifampin - rifampin may decrease lamotrigine levels by 40%
Sodium channel blockers - in vitro studies have shown that lamotrigine has sodium channel blocking activity at relevant concentrations. Concomitant use with other sodium channel blocking drugs (e.g. quinidine, procainamide, lidocaine, mexiletine, phenytoin, flecainide, propafenone, carbamazepine) may increase the risk of arrhythmias.
UGT inhibitors and inducers - UGT is the enzyme that is responsible for the metabolism of lamotrigine. UGT inhibitors and inducers may affect lamotrigine levels. Strong and moderate inducers of CYP3A4 are also known to induce UGT, and these drugs may also decrease lamotrigine levels.

Contraindications / Precautions

Pregnancy - pregnancy category C. The effects of lamotrigine on the developing fetus are unknown. An observational study found no significant link between lamotrigine and orofacial cleft and clubfoot (see pregnancy studies for more).
Serious skin reactions - serious skin reactions including SJS, DRESS, and TEN have been reported in patients taking lamotrigine. In studies, serious skin reactions were seen in up to 0.3% of adults and up to 0.8% of children. The risk may be higher with concomitant valproic acid, higher starting doses, and rapid titration.
Multiorgan hypersensitivity reactions and organ failure - multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred with lamotrigine. DRESS typically presents with fever, rash, eosinophilia, and/or lymphadenopathy in association with other organ involvement (e.g. hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis). Constitutional symptoms (e.g. fever, lymphadenopathy) may present before a rash is present. Patients taking lamotrigine should be aware that a rash or other nonspecific symptoms (e.g. fever) may herald the start of a serious reaction, and they should seek prompt medical attention.
Cardiac rhythm and conduction abnormalities - in vitro studies have shown that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations. Based on this activity, lamotrigine could slow ventricular conduction (widened QRS) and induce arrhythmias in patients with structural heart disease or myocardial ischemia. Lamotrigine should be avoided or used with caution in patients with structural or functional heart disease including heart failure, valvular heart disease, congenital heart disease, conduction system disease, ventricular arrhythmias, cardiac channelopathies (e.g., Brugada syndrome), clinically important ischemic heart disease, or multiple risk factors for ischemic heart disease.
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
Aseptic meningitis - lamotrigine may increase the risk of aseptic meningitis
Hemophagocytic lymphohistiocytosis (HLH) - rare cases of HLH have been reported in patients receiving lamotrigine. HLH is a syndrome that causes an uncontrolled immune response, and it typically presents with persistent fever (> 101°). Other symptoms include rash, enlarged liver and spleen, cytopenias, lymphadenopathy, unusual bleeding, and mental status changes. Untreated HLH can be fatal. Lamotrigine should be stopped immediately in patients with unexplained fever.
Liver disease

Mild (Child-Pugh A) - no dose adjustment necessary
Moderate-to-severe (without ascites) - reduce dose by 25%
Severe (with ascites) - reduce dose by 50%

Kidney disease - use with caution, no specific recommendations given

Levetiracetam | Keppra® | Keppra XR™ | Spritam® | Elepsia XR®

Dosage forms

Tablet (Keppra®)

250 mg
500 mg
750 mg
1000 mg

Extended-release tablet (Keppra XR®)

500 mg
750 mg

Tablet for oral suspension (Spritam®)

250 mg
500 mg
750 mg
1000 mg

Solution (Keppra®)

100 mg/ml
Comes in 480 ml bottle

Extended-release tablet (Elepsia XR®)

1000 mg
1500 mg

Dosing - Keppra® | Spritam®

NOTE: the dosing presented here is general dosing in adults. See the Keppra PI [sec 2] for specific recommendations based on seizure type and age

Seizure disorders (adults and children weighing > 40 kg)

Initial: 500 mg twice a day
Max: 1500 mg twice a day
Increase dose by 1000 mg/day at 2 week intervals to the recommended daily dose of 3000 mg
May take without regard to food
Do not crush, cut, or chew Keppra® tablets
Spritam disintegrates in the mouth when taken with a sip of water. It may also be dissolved with a small amount of water in a cup and swallowed.

Dosing in kidney disease

CrCl 50 - 80 ml/min: 500 - 1000 mg twice daily
CrCl 30 - 49 ml/min: 250 - 750 mg twice daily
CrCl < 30 ml/min: 250 - 500 mg twice daily

Dosing - Keppra XR®

Partial-onset seizures (adults and adolescents ≥ 12 years old weighing > 50 kg)

Initial: 1000 mg once daily
Max: 3000 mg once daily
Increase dose by 1000 mg/day at 2 week intervals to the recommended daily dose of 3000 mg
May take without regard to food
Do not crush, cut, or chew tablet

Dosing in kidney disease

CrCl 50 - 80 ml/min: 1000 - 2000 mg once daily
CrCl 30 - 49 ml/min: 500 - 1500 mg once daily
CrCl < 30 ml/min: 500 - 1000 mg once daily

Dosing - Elepsia XR®

Partial-onset seizures (≥ 12 years old)

Initial: 1000 mg once daily
Max: 3000 mg once daily
Increase dose by 1000 mg/day at 2 week intervals
May take without regard to food
Do not crush, cut, or chew tablet

Dosing in kidney disease

CrCl > 80 ml/min: no dose adjustment necessary
CrCl 50 - 80 ml/min: 1000 - 2000 mg once daily
CrCl < 50 ml/min: not recommended. Use different levetiracetam product.

Efficacy

Generalized seizures

Levetiracetam vs Valproate as Initial Therapy in Generalized Seizure Disorder, Lancet (2021) [PubMed abstract]

Focal seizures

Levetiracetam vs Lamotrigine vs Zonisamide as Initial Therapy for Focal Seizure Disorder, Lancet (2021) [PubMed abstract]

Generic / Price

Keppra® (60 tablets) - YES/$
Keppra® solution (480 ml) - YES/$
Keppra XR™ (60 tablets) - YES/$
Spritam® (60 tablets) - NO/$$$$
Elepsia XR® (60 tablets) - NO/$$$$

Lab monitoring

The value of routine monitoring has not been established
Monitoring levels may be useful in kidney disease, pregnancy (increased clearance), and to assess compliance or toxicity
Levels should be drawn immediately before the next dose (trough) [4]
Reference interval: 10 - 40 mcg/ml [3]

Pharmacokinetics

Half-life: 6 - 8 hours [1]
Time to steady state: 2 days [1]

Mechanism of action

The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular significance of levetiracetam binding to SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice. These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.

FDA-approved indications

Keppra®

Treatment of partial-onset seizures in patients 1 month of age and older
Adjunctive therapy for partial onset seizures - adults and children ≥ 4 years
Adjunctive therapy for myoclonic seizures - adults and children ≥ 12 years with juvenile myoclonic epilepsy
Adjunctive therapy for generalized tonic-clonic seizures - adults and children ≥ 6 years

Spritam®

Adjunctive therapy for partial onset seizures - adults and children ≥ 4 years weighing more than 20 kg
Adjunctive therapy for myoclonic seizures - adults and children ≥ 12 years with juvenile myoclonic epilepsy
Adjunctive therapy for generalized tonic-clonic seizures - adults and children ≥ 6 years

Keppra XR®

Treatment of partial-onset seizures in patients 12 years of age and older

Elepsia XR®

Adjunctive therapy for the treatment of partial-onset seizures in patients 12 years of age and older

Side effects

NOTE: Data is from adjunctive trials when levetiracetam was added to other seizure meds

Side effect	Keppra	Placebo
Weakness	15%	9%
Somnolence	15%	8%
Headache	14%	13%
Infection	13%	8%
Dizziness	9%	4%

Drug interactions

Levetiracetam is not extensively metabolized
There are no known significant drug interactions

Contraindications / Precautions

Pregnancy - prolonged experience with levetiracetam in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries and reflects experience over two decades. An observational study detailed below found no significant link between prenatal levetiracetam exposure and cognition in children (see pregnancy studies for more). Physiological changes during pregnancy may lower levetiracetam levels, particularly in the third trimester. Dose adjustments may be necessary to maintain clinical response.
Hypersensitivity reactions - levetiracetam may cause hypersensitivity reactions including angioedema and anaphylaxis. Reactions may occur with the first dose or at any time during treatment.
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Behavioral changes - in trials, 13% of adults and 38% of pediatric patients reported behavioral changes when taking levetiracetam compared to 6% and 19% of adult and pediatric patients on placebo. Behavioral changes included aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, and hyperkinesia.
Psychosis - in trials, psychotic symptoms were reported in 1% of adults and 2% of pediatric patients taking levetiracetam
Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
Hematological abnormalities - minor hematologic abnormalities have been seen in patients taking levetiracetam. Abnormalities include decreases in white blood cells, neutrophils, and red blood cells; decreases in hemoglobin and hematocrit; and increases in eosinophil counts. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders.
Serious skin reactions - serious skin reactions including DRESS syndrome have been reported
Liver disease - no dose adjustment necessary
Kidney disease - see Dosing

Lacosamide (Vimpat®)

Dosage forms

Tablet (Vimpat®)

50 mg
100 mg
150 mg
200 mg

Solution (Vimpat®)

10 mg/ml mg
Comes in 200 and 465 ml bottle

Dosing

NOTE: the dosing presented here is general dosing in adults. See the Vimpat PI [sec 2] for pediatric dosing recommendations

Partial onset seizures (adults ≥ 17 years)

Monotherapy

Initial: 100 mg twice daily
Maintenance: 150 - 200 mg twice daily
Max: 200 mg twice daily
Increase by 50 mg twice daily (100 mg per day) every week
May take without regard to food

Adjunctive therapy

Initial: 50 mg twice daily
Maintenance: 100 - 200 mg twice daily
Max: 200 mg twice daily
Increase by 50 mg twice daily (100 mg per day) every week
May take without regard to food

Generic / Price

Vimpat® (60 tablets) - YES/$
Vimpat™ solution (200 ml) - YES/$

Lab monitoring

The value of routine monitoring has not been established
Checking levels may be appropriate to monitor compliance, in patients with renal or hepatic disease, and when drug interactions can affect levels.
Trough levels should be taken
Lacosamide levels of 1 - 10 mcg/ml are generally considered therapeutic
Levels > 20 mcg/ml may be toxic [7]

Pharmacokinetics

Half-life: 15 - 23 hours
Time to steady state: 3 days

Other

Tablets should be swallowed whole. Do not divide tablets.
Lacosamide is a C-V controlled substance

Mechanism of action

The precise mechanism by which lacosamide exerts its antiepileptic effects in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.

FDA-approved indications

Partial-onset seizures - in patients 1 month of age and older
Primary generalized tonic-clonic seizures - as adjunctive therapy in patients 4 years of age and older

Side effects

NOTE: Only side effects that occurred at an incidence ≥ 5% are listed

Side effect	Lacosamide 200 mg/day (N=270)	Lacosamide 400 mg/day (N=471)	Placebo (N=364)
Dizziness	16%	30%	8%
Headache	11%	14%	9%
Nausea	7%	11%	4%
Diplopia	6%	10%	2%
Vomiting	6%	9%	3%
Blurred vision	2%	9%	3%
Somnolence	5%	8%	5%
Ataxia	4%	7%	2%
Fatigue	7%	7%	6%
Tremor	4%	6%	4%
Nystagmus	2%	5%	4%
Diarrhea	3%	5%	3%
Vertigo	5%	3%	1%

Drug interactions

CYP3A4 strong inhibitors - in patients with renal or hepatic impairment, strong CYP3A4 inhibitors may increase exposure to lacosamide. Dose reductions may be necessary. Manufacturer makes no specific recommendation.
CYP2C9 strong inhibitors - in patients with renal or hepatic impairment, strong CYP2C9 inhibitors may increase exposure to lacosamide. Dose reductions may be necessary. Manufacturer makes no specific recommendation.
Medications that affect cardiac conduction - cases of bradycardia, AV block, and ventricular tachyarrhythmia, which have rarely resulted in asystole, cardiac arrest, and death have been reported in patients taking lacosamide. Use caution when giving with other medications that affect cardiac conduction (beta blockers, calcium channel blockers, sodium channel blockers, and potassium channel blockers) including those that prolong the PR interval (e.g. sodium channel blocking antiseizure meds). Obtaining an ECG before and after therapy titration is recommended in susceptible patients.

Contraindications / Precautions

Pregnancy - the risk of birth defects, miscarriage, and other adverse maternal or fetal outcomes in lacosamide-exposed pregnant women is unknown. In rat studies, lacosamide was associated with developmental neurotoxicity.
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Dizziness and ataxia - lacosamide can cause a significant amount of dizziness (up to 30% with 400 mg/day) and ataxia. Symptoms were typically worse during the titration phase. Use caution if performing complex tasks such as driving.
PR interval prolongation - dose-dependent prolongation of the PR interval has been observed with lacosamide. In trials, asymptomatic first-degree atrioventricular (AV) block was observed in 0.4% (4/944) of lacosamide-treated patients and 0% of placebo-treated patients. In the postmarketing setting, there have been reports of bradycardia, AV block, and ventricular tachyarrhythmia, which have rarely resulted in asystole, cardiac arrest, and death. Most cases occurred in patients with underlying proarrhythmic conditions, or in those taking concomitant medications that affect cardiac conduction or prolong the PR interval. Use caution in patients with conduction abnormalities (e.g. marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), severe cardiac disease (such as myocardial ischemia or heart failure, or structural heart disease), and cardiac sodium channelopathies (e.g. Brugada Syndrome). It is recommended that an ECG be performed before therapy and after titration in at-risk patients.
Atrial fibrillation and flutter - atrial fibrillation and atrial flutter have been reported in the postmarketing setting in adults treated with lacosamide. In an exploratory trial for diabetic neuropathy, 0.5% of lacosamide-treated patients developed A fib/flutter compared to 0% of placebo-treated patients.
Syncope - in partial seizure trials, no syncopal events were reported in lacosamide-treated patients. In an exploratory trial for diabetic neuropathy, 1.2% of lacosamide-treated patients reported syncope or loss of consciousness compared to 0% of placebo-treated patients. The cause of syncope was unknown in most cases, however, several were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia. Most cases occurred at doses > 400 mg/day.
Withdrawal of antiepileptic drugs - seizure risk may increase when withdrawing antiepileptic drugs. Discontinue lacosamide gradually over a minimum of 1 week to minimize the risk of rebound seizures.
Serious skin reactions - serious skin reactions including DRESS syndrome have been reported in patients taking antiepileptic drugs. DRESS may present with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present, and systemic symptoms (e.g., fever, lymphadenopathy) may present before a rash is present.
Phenylketonuria - lacosamide oral solution contains aspartame, a source of phenylalanine. A 200 mg dose of lacosamide oral solution (equivalent to 20 mL) contains 0.32 mg of phenylalanine.
Liver disease

Child-Pugh A/B: reduce maximum dose by 25%
Child-Pugh C: has not been studied. Not recommended.

Kidney disease

CrCl ≥ 30 ml/min: no dose adjustment necessary
CrCl < 30 ml/min: reduce maximum dose by 25%

Oxcarbazepine | Trileptal® | Oxtellar XR®

Dosage forms

Tablet (Trileptal®)

150 mg
300 mg
600 mg

Suspension (Trileptal®)

300 mg/5 ml (60 mg/ml)
Comes in 250 ml bottle
Store at room temperature

Tablet, extended-release (Oxtellar XR®)

150 mg
300 mg
600 mg

Dosing - Epilepsy

Trileptal® (Monotherapy)

Initial: 300 mg twice a day
Maintenance: 600 mg twice a day
Max: 1200 mg twice a day
Increase by 300 mg/day every third day

Trileptal® (Adjunctive therapy)

Initial: 300 mg twice a day
Maintenance: 300 - 600 mg twice a day
Max: 600 mg twice a day
Increase by 600 mg/day at weekly intervals

Oxtellar XR® (Adjunctive therapy)

Initial: 600 mg once daily
Maintenance: 1200 - 2400 mg once daily
Max: 2400 mg once daily
Increase by 600 mg/day at weekly intervals
Take on an empty stomach

Pediatric dosing

See Trileptal PI and Oxtellar XR PI for pediatric dosing recommendations

Generic / Price

Trileptal® (60 tablets) - YES/$
Trileptal® suspension (250 ml) - YES/$-$$
Oxtellar XR® (30 tablets) - NO/$$$$

Lab monitoring

Levels

The value of routine monitoring has not been established
Monitoring may be useful in liver disease and to assess compliance or toxicity
Oxcarbazepine is rapidly metabolized to its active metabolite, 10-hydroxy-carbamazepine (MHD). Blood assays measure MHD.
Levels should be drawn immediately before next dose (trough) [5]
Reference interval (MHD): 3 - 35 mcg/ml [4]

Other labs

Monitoring sodium levels may be appropriate in patients at increased risk of hyponatremia

Pharmacokinetics

Half-life (MHD): 9 hours [1]
Time to steady state (MHD): 2 - 3 days [1]

Other

Trileptal®

May take without regard to food
Tablet and suspension are interchangeable on a mg-to-mg basis
Suspension may be mixed with water or swallowed directly from syringe

Oxtellar XR®

Take on an empty stomach, 1 hour before or 2 hours after a meal. Food increases absorption and risk of side effects.
When converting from Trileptal® to Oxtellar XR®, higher doses of Oxtellar XR® may be necessary
Do not crush, cut, or chew tablet

Mechanism of action

Mechanism not entirely understood
Inhibits voltage-sensitive sodium channels
Inhibits action potentials (nerve-firing)

FDA-approved indications

Trileptal®

Epilepsy - monotherapy or adjunctive therapy for partial seizures in adults and children

Oxtellar XR®

Epilepsy - adjunctive therapy for partial seizures in adults and children

Side effects

Side effect	Oxcarbazepine	Placebo
Dizziness	22%	6%
Nausea	16%	12%
Headache	13%	10%
Diarrhea	7%	2%
Upper respiratory infection	7%	0%
Other Fatigue and somnolence were also common at higher doses (20% of patients) Side effects increase with higher doses

Drug interactions

Oxcarbazepine is a CYP2C19 inhibitor and CYP3A inducer
CYP3A4 strong inducers - strong CYP3A4 inducers have been shown to decrease MHD (active oxcarbazepine metabolite) levels. When taken concurrently, monitor MHD levels.
UDP-glucuronosyltransferase (UGT) inducers - UGT inducers have been shown to decrease MHD (active oxcarbazepine metabolite) levels. When taken concurrently, monitor MHD levels.
CYP2C19 substrates - oxcarbazepine may increase levels of CYP2C19 substrates
CYP3A4 substrates - oxcarbazepine may decrease levels of CYP3A4 substrates
Oral contraceptives - oxcarbazepine may decrease ethinyl estradiol and levonorgestrel levels by up to 50%. Use alternative birth control.
Carbamazepine - may decrease oxcarbazepine levels by 40%
Phenobarbital - may increase phenobarbital levels by 14%. Oxcarbazepine levels may decrease by 25%
Phenytoin - may increase phenytoin levels by 40%. Oxcarbazepine levels may decrease by 30%
Valproic acid - oxcarbazepine levels may decrease by 18%
Felodipine - oxcarbazepine may decrease felodipine levels by 28%
Verapamil - verapamil may decrease oxcarbazepine levels by 20%
Cyclosporine - oxcarbazepine may decrease cyclosporine levels

Contraindications / Precautions

Known hypersensitivity to oxcarbazepine or eslicarbazepine (Aptiom) - DO NOT USE
Carbamazepine sensitivity - oxcarbazepine is structurally related to carbamazepine. 25 - 30% of patients with a history of reaction to carbamazepine will have a reaction to oxcarbazepine.
Low sodium (hyponatremia) - oxcarbazepine may cause hyponatremia in up to 2.5% of patients. More common during first 3 months of treatment.
Serious skin reactions - SJS, DRESS, and TEN have been reported. Patients carrying the HLA-B*1502 allele may be at increased risk. See HLA-B*1502 allele prevalence for more.
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
Pregnancy - oxcarbazepine levels may decrease during pregnancy
Angioedema and anaphylaxis - rare
Thyroid hormone - may affect thyroid hormone levels
Seizure exacerbation - oxcarbazepine may exacerbate seizures in some patients, particularly children
Liver disease

Mild to moderate (Child-Pugh A/B) - no dose adjustment necessary
Severe (Child-Pugh C) - has not been studied, use caution

Kidney disease

CrCl < 30 ml/min - initiate at one-half the usual dose (300 mg/day); increase slowly

Phenobarbital

Dosage forms

Tablet

15 mg
16.2 mg
30 mg
32.4 mg

60 mg
64.8 mg
97.2 mg
100 mg

Dosing

Epilepsy

50 - 100 mg two to three times a day

Sedative

30 - 120 mg a day given in 2 or 3 divided doses

Generic / Price

- YES/$

Lab monitoring

Levels

Routine monitoring is recommended to maintain a therapeutic level and prevent toxicity
Levels may be drawn at any time (random) [4]
Therapeutic levels: 15 - 40 mcg/ml [3]
Potentially Toxic: > 40 mcg/ml [3]

Other labs

It may be beneficial to monitor liver function tests periodically

Pharmacokinetics

Half-life: 84 - 108 hours [3]
Time to steady state: 11 - 29 days [5]

Other

Phenobarbital is a C-IV controlled substance

Mechanism of action

Binds to GABA receptors
Causes membrane hyperpolarization
Inhibits action potentials (nerve-firing)

FDA-approved indications

Treatment of seizures
Sedative

Side effects

NOTE: The incidence of side effects with phenobarbital is not well-defined

Drowsiness
Sedation
Nausea
Paradoxical excitement

Drug interactions

Phenobarbital is an enzyme inducer and therefore has many potential drug interactions
CYP3A4 substrates - phenobarbital is a CYP3A4 strong inducer. Phenobarbital may lower blood levels of CYP3A4 substrates.
CYP1A2 substrates - phenobarbital is a CYP1A2 weak inducer. Phenobarbital may lower blood levels of CYP1A2 substrates.
CYP2B6 substrates - phenobarbital is a CYP2B6 inducer (class uncertain). Phenobarbital may lower blood levels of CYP2B6 substrates.
CYP2C9 substrates - phenobarbital is a CYP2C9 weak inducer. Phenobarbital may lower blood levels of CYP2C9 substrates.
P-glycoprotein substrates - phenobarbital is a P-glycoprotein inducer. Phenobarbital may lower blood levels of P-glycoprotein substrates.
Valproic acid - phenobarbital may decrease levels of valproic acid by 50%. Valproic acid may increase phenobarbital levels.
Lamotrigine -phenobarbital may decrease lamotrigine levels by 40%. See lamotrigine for details on dosing.
Oxcarbazepine - may increase phenobarbital levels by 14%. Oxcarbazepine levels may decrease by 25%
Canagliflozin - phenobarbital may decrease canagliflozin levels

Contraindications / Precautions

Porphyria - DO NOT USE
Respiratory distress - DO NOT USE
Osteoporosis - phenobarbital is a CYP enzyme inducer and this may enhance the metabolism of vitamin D and increase the risk of osteoporosis. Consider checking vitamin D, calcium, and phosphate levels during prolonged therapy. BMD testing may be appropriate in some patients.
Serious skin reactions - SJS, DRESS, and TEN have been reported
Abuse and addiction - phenobarbital has abuse and addiction potential
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
Liver disease

Mild-to-moderate disease (Child-Pugh A/B): use caution, no specific dosage recommendations given
Severe (Child-Pugh C): - DO NOT USE

Kidney disease - use caution; no specific recommendations given

Phenytoin | Dilantin® | Phenytek®

Dosage forms

Capsule

30 mg
100 mg
200 mg
300 mg

Tablet, chewable

50 mg

Capsule (Dilantin®)

30 mg
100 mg

Capsule (Phenytek®)

200 mg
300 mg

Suspension

125 mg/5 ml
Comes in 237 ml (8 oz) bottle

Dosing - Epilepsy

Standard dosing

Initial: 100 mg three times a day
Maintenance: 100 mg three to four times a day
Lab monitoring should be used to guide dosing

Once-a-day dosing

Stable patients may wish to change to once-a-day dosing with the entire daily dose taken at bedtime
Once-a-day dosing is only recommended with Dilantin® brand capsules

Loading dose

Three doses (400 mg - 300 mg - 300 mg) administered at 2 hour intervals
Maintenance dosing starts 24 hours after last loading dose

Generic / Price

Phenytoin (generic) - $ (90 capsules)
Dilantin® (brand) - $$$ (90 capsules)
Phenytek® (brand) - $$$$ (90 capsules)
Suspension (generic) - $ (237 ml)

Lab monitoring

Levels

Routine monitoring is recommended to maintain a therapeutic level and prevent toxicity
Phenytoin metabolism is nonlinear. The enzyme responsible for its metabolism can become saturated and blood levels may increase exponentially. After saturation, small increases in dosage can lead to large increases in blood levels.
For most patients, the relation of the blood draw to the last dose will not matter [4]
Frequency of lab monitoring will depend on the patient and their concomitant medical conditions/meds

Total vs Free Phenytoin

Phenytoin is 90% bound to plasma protein
Only free phenytoin is biologically active
Typically, total phenytoin levels are measured
In conditions where binding kinetics may be altered (ex. kidney disease, concurrent protein-bound medications, liver disease, pregnancy, postpartum), free phenytoin levels may be helpful

Phenytoin, Total

Therapeutic level: 10 - 20 mcg/ml [5]

Phenytoin, Free

Therapeutic level: 1 - 2 mcg/ml [5]

Hypoalbuminemia

Because phenytoin is 90% bound to plasma protein, phenytoin levels should be corrected in patients with low albumin levels
Corrected Phenytoin = Total phenytoin (mcg/ml) / (0.2 x Albumin[g/dl] + 0.1)

Pharmacokinetics

Average half-life at steady state: 22 hours (range 7 - 42 hours) [1]
Time to steady state: 7 - 10 days [1]

Other

Phenytoin

Take at the same time each day
Food may alter absorption. Best to take on an empty stomach.

Suspension and tablet

Phenytoin suspension and tablets contain the free acid form of phenytoin where the capsules contain the sodium salt of phenytoin
There is approximately an 8% increase in drug content with the free acid form over that of the sodium salt
Dosage adjustments may be necessary when switching between the capsules and suspension/tablet

Signs of toxicity

Nystagmus
Loss of coordination
Mental status changes

Mechanism of action

Inhibits voltage-dependent sodium channels
Inhibits action potentials (nerve-firing)

FDA-approved indications

Epilepsy - generalized tonic-clonic and psychomotor (temporal lobe) seizures
Prevention of seizures with neurosurgery

Side effects

NOTE: The incidence of phenytoin side effects is not well-defined

Somnolence
Drowsiness
Dizziness
Nystagmus
Nausea
Coarsening of facial features
Gingival hyperplasia - overgrowth of gum tissue
Increased hair growth

Drug interactions

Phenytoin is primarily metabolized by CYP2C9 and to a lesser extent by CYP2C19. It is also a CYP3A4 strong inducer and a CYP1A2 moderate inducer. This, combined with the fact that it has a narrow therapeutic index and is highly protein bound, gives it the potential for a large number of drug interactions. See the Dilantin PI for a comprehensive review.
Delavirdine (Rescriptor®) - DO NOT COMBINE
CYP3A4 substrates - phenytoin may decrease levels of CYP3A4 substrates
CYP1A2 substrates - phenytoin may decrease levels of CYP1A2 substrates
CYP2C19 inhibitors and inducers - CYP2C19 inhibitors and inducers may affect phenytoin levels
CYP2C9 inhibitors and inducers - CYP2C9 inhibitors and inducers may affect phenytoin levels
Highly protein-bound drugs - phenytoin is highly protein-bound. Other highly protein-bound drugs (ex. valproic acid, acetazolamide, aspirin, salicylic acid, phenylbutazone, ceftriaxone, nafcillin, sulfamethoxazole) may displace phenytoin and increase its activity.
P-glycoprotein substrates/inducers/inhibitors - phenytoin is a p-glycoprotein inducer and substrate. Phenytoin may affect other p-glycoprotein drugs, and p-glycoprotein inducers and inhibitors may affect phenytoin
Anticoagulants - phenytoin may decrease levels of anticoagulants (e.g. apixaban, dabigatran, edoxaban, rivaroxaban) through CYP3A4 and/or p-glycoprotein induction. Avoid coadministration if possible.
Antiplatelet drugs - phenytoin may decrease levels of antiplatelet drugs (e.g. ticagrelor) through CYP3A4 and/or p-glycoprotein induction. Avoid coadministration if possible.
Valproic acid - phenytoin may decrease levels of valproic acid by 50%. Valproic acid may affect free phenytoin levels. Concomitant administration of valproate and phenytoin has also been associated with an increased risk of valproate-associated hyperammonemia. Use caution when combining and monitor for symptoms of hyperammonemia.
Lamotrigine - phenytoin may decrease lamotrigine levels by 40%. See lamotrigine for details on dosing.
Carbamazepine - carbamazepine may increase or decrease phenytoin levels
Topiramate - phenytoin may decrease topiramate levels by 48%. Topiramate may increase phenytoin levels.
Oxcarbazepine - may increase phenytoin levels by 40%. Oxcarbazepine levels may decrease by 30%
Digoxin - phenytoin may decrease digoxin levels
Furosemide - phenytoin may decrease the effect of furosemide
Canagliflozin - phenytoin may decrease canagliflozin levels
Antacids and acid-suppressing drugs (famotidine, PPIs, etc.) - Drugs that suppress stomach acid may affect phenytoin levels. In most cases, phenytoin levels will decrease.

Contraindications / Precautions

Pregnancy - DO NOT USE
Porphyria - DO NOT USE
Lymphadenopathy - a number of reports have suggested an association between phenytoin and the development of lymphadenopathy (local or generalized), including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. If lymphadenopathy develops, phenytoin should be considered as a possible culprit, and an appropriate workup should be pursued.
Osteoporosis - phenytoin is a CYP enzyme inducer and this may enhance the metabolism of vitamin D and increase the risk of osteoporosis. Consider checking vitamin D, calcium, and phosphate levels during prolonged therapy. BMD testing may be appropriate in some patients.
Carbamazepine sensitivity - phenytoin is structurally related to carbamazepine. Patients sensitive to carbamazepine may cross-react with phenytoin.
Barbiturate sensitivity - phenytoin is structurally related to barbiturates. Patients with barbiturate sensitivity may cross-react with phenytoin.
Serious skin reactions - serious skin reactions including TEN, SJS, acute generalized exanthematous pustulosis (AGEP), and DRESS have been reported in patients taking phenytoin. Reactions can occur at any time during therapy, but they usually occur within the first 28 days. Discontinue phenytoin if a rash occurs, unless it is clearly not drug-related.
CYP2C9 alleles - studies have found that Asian carriers of the CYP2C9*3 allele have a higher risk of serious skin reactions when taking phenytoin. CYP2C9 alleles that are associated with decreased CYP2C9 activity (*1/*3, *2/*2, *3/*3) may also cause higher phenytoin levels when compared to normal metabolizers (*1/*1). Use caution when prescribing phenytoin to these patients. [PMID 25096692].
HLA-B*1502 allele - carriers of the HLA-B*1502 allele have a higher risk of SJS and TEN when taking carbamazepine. There is some evidence that Asian carriers of this allele may also be at greater risk for serious skin reactions when taking phenytoin. Phenytoin should not be used as an alternative to carbamazepine in patients who are positive for HLA-B*1502. See HLA-B*1502 allele prevalence for more.
Hypothyroidism - phenytoin may increase the metabolism of thyroid hormone leading to decreased levels of free T3 and free T4.
Hematopoietic toxicity - cases of thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression have been reported in patients receiving phenytoin. Phenytoin should be considered as a possible culprit if any of these conditions arise.
Cardiac events - cases of cardiac arrest and bradycardia have been reported in patients receiving phenytoin at both therapeutic and toxic levels. Most patients had underlying cardiac disease.
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
Liver disease - because liver disease can affect plasma protein levels, free phenytoin levels should be monitored closely
Kidney disease - because kidney disease can affect protein-binding kinetics, free phenytoin levels should be monitored closely

Pregabalin | Lyrica® | Lyrica® CR

Dosage forms

Capsule (Lyrica®)

25 mg
50 mg
75 mg
100 mg

150 mg
200 mg
225 mg
300 mg

Tablet, extended-release (Lyrica® CR)

82.5 mg
165 mg
330 mg

Solution (Lyrica®)

20 mg/ml
Comes in 16 oz (473 ml) bottle

Dosing - Lyrica®

Neuropathic pain/Postherpetic neuralgia

Starting: 150 mg a day given in two or three divided doses
Maintenance: 150 - 300 mg a day
Max: 300 mg a day

Fibromyalgia

Starting: 75 mg twice a day
Maintenance: 300 - 450 mg a day
Max: 450 mg a day

Epilepsy

Starting: 150 mg a day given in two or three divided doses
Maintenance: 150 - 600 mg a day
Max: 600 mg a day

Dosing in kidney disease

See Lyrica® PI for specific recommendations in kidney disease

Dosing - Lyrica® CR

Diabetic neuropathy

Dosing: Begin with 165 mg once daily and increase to 330 mg once daily within 1 week based on response/tolerability
Max: 330 mg once daily
Take after evening meal

Postherpetic neuralgia

Starting: Begin with 165 mg once daily and increase to 330 mg once daily within 1 week based on response/tolerability
Maintenance: 165 - 660 mg once daily
Max: 660 mg once daily
Patients who do not achieve pain control on 330 mg may increase to 660 mg once daily after 2 - 4 weeks
Take after evening meal

Dosing in kidney disease

CrCL ≥ 60 ml/min: no dose adjustment necessary
CrCL 30 - 60 ml/min: use half the recommended dose
CrCL < 30 ml/min: DO NOT USE

Converting between Lyrica and Lyrica CR

Lyrica total daily dose	Lyrica CR dose
75 mg	82.5 mg
150 mg	165 mg
225 mg	247.5 mg
300 mg	330 mg
450 mg	495 mg
600 mg	660 mg

Efficacy

Sciatica

Pregabalin vs Placebo for Acute and Chronic Sciatica, NEJM (2017) [SH review]

Spinal stenosis

Pregabalin vs Diphenhydramine (active control) for Neurogenic Claudication, Neurology (2015) [SH review]

Generic / Price

Lyrica capsule (60 capsules) - YES/$
Lyrica solution (473 ml) - YES/$$
Lyrica CR (30 tablets) - YES/$$$$

Lab monitoring

The value of routine monitoring has not been established
Monitoring may be useful to assess compliance or toxicity
A normal reference range for pregabalin has not been established [5]

Pharmacokinetics

Lyrica

Half-life: 6 hours
Time to steady state: 1 - 2 days [2]

Lyrica CR

Half-life: 6 hours
Time to steady state: 2 - 3 days

Other

Lyrica

May take without regard to food
Pregabalin is a Schedule-V controlled substance
When discontinuing, taper gradually over a minimum of 1 week

Lyrica CR

Do not crush, cut, or chew tablet
Take following a meal. Food increases absorption.
When discontinuing, taper gradually over a minimum of 1 week

Mechanism of action

Mechanism not completely understood
Binds to alpha₂-delta site on voltage-gated calcium channels
Inhibits action potentials (nerve-firing)

FDA-approved indications

Lyrica

Epilepsy - as adjunctive therapy in partial seizures
Postherpetic neuralgia
Diabetic peripheral neuropathy
Fibromyalgia
Neuropathic pain associated with spinal cord injury

Lyrica CR

Postherpetic neuralgia
Diabetic peripheral neuropathy

Side effects

Side effect	Pregabalin	Placebo
Dizziness	30%	8%
Somnolence	23%	8%
Weight gain	9%	2%
Blurred vision	7%	2%
Peripheral edema	6%	2%
Dry mouth	5%	1%
Weakness	5%	2%

Drug interactions

Pregabalin does not undergo significant liver metabolism
Glitazones (Actos® and Avandia®) - Pregabalin may potentiate the fluid retention that is seen with glitazones

Contraindications / Precautions

Angioedema (swelling of the mouth, face, and tongue) - pregabalin has been associated with rare cases of angioedema during both initial and chronic treatment. Use caution in patients with a history of angioedema.
Hypersensitivity reactions - hypersensitivity reactions including skin redness, blisters, hives, rash, dyspnea, and wheezing have been reported
Peripheral edema - pregabalin may cause peripheral edema. Concomitant glitazones (Actos, Avandia) may increase the risk.
Weight gain - pregabalin may cause weight gain. Concomitant glitazones (Actos, Avandia) may increase the risk.
Heart failure - pregabalin may worsen fluid retention in some patients
Pregnancy - the effects of pregabalin on the developing fetus are unknown. An observational study found a significant link between pregabalin and birth defects (see pregnancy studies for more).
Respiratory depression - cases of serious and sometimes fatal respiratory depression have been reported when pregabalin was taken with other CNS depressants, including opioids, and in patients with underlying respiratory disorders. Use caution when prescribing in these situations.
Driving and operating machinery - pregabalin may cause dizziness and somnolence which can impair a person's ability to drive and operate machinery
Creatine Kinase elevation - pregabalin may cause an increase in CK values in some patients. Significant increases are rare.
Decreased platelet count - pregabalin may cause a decrease in the platelet count. Significant decreases are rare.
PR interval prolongation - pregabalin may prolong the PR interval. An increase in heart block has not been demonstrated.
Abuse potential - pregabalin may have abuse potential
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Abrupt discontinuation - abrupt discontinuation may increase risk of seizure frequency and some patients report insomnia, nausea, headache, anxiety, and diarrhea. Taper Lyrica and Lyrica CR gradually over a minimum of 1 week when discontinuing.
Liver disease - pregabalin does not undergo significant liver metabolism; no dose adjustment necessary
Kidney disease

Lyrica

See Lyrica® PI

Lyrica CR

CrCL ≥ 60 ml/min: no dose adjustment necessary
CrCL 30 - 60 ml/min: use half the recommended dose
CrCL < 30 ml/min: DO NOT USE

Topiramate | Topamax® | Trokendi XR® | Qudexy® XR | Eprontia®

Dosage forms

Capsule (Topamax®)

15 mg
25 mg

Tablet (Topamax®)

25 mg
50 mg
100 mg
200 mg

Capsule, extended-release (Trokendi XR®)

25 mg
50 mg
100 mg
200 mg

Capsule, extended-release (Qudexy® XR)

25 mg
50 mg
100 mg
150 mg
200 mg

Solution (Eprontia®)

25 mg/ml
Comes in 473 ml bottle
Store at room temperature

Dosing - Epilepsy

Topamax® and Eprontia®

See Topamax PI for titration schedules and full dosing recommendations
Topamax and Eprontia are dosed twice daily
In general, dosing for adults and children ≥ 10 years old starts at 25 - 50 mg/day (given in two divided doses) and increases by 50 - 100 mg/day at weekly intervals to a maximum of 400 mg/day
May take without regard to food. Topiramate tablets have a bitter taste and should not be broken. Topamax sprinkle capsules may be opened and sprinkled on food. Do not chew.

Trokendi XR®

See Trokendi PI for titration schedules and full dosing recommendations
Trokendi XR is dosed once daily
In general, dosing for adults and children ≥ 10 years old starts at 50 mg once daily and increases by 50 - 100 mg/day at weekly intervals to a maximum of 400 mg once daily
Do not take Trokendi XR® within 6 hours of alcohol consumption, either before or after. Alcohol affects the release of the drug and may increase blood levels.
May take without regard to food. Swallow capsule whole. Do not open and sprinkle on food.

Qudexy® XR

See Qudexy PI for titration schedules and full dosing recommendations
Qudexy XR is dosed once daily
In general, dosing for adults and children ≥ 10 years old starts at 50 mg once daily and increases by 50 - 100 mg/day at weekly intervals to a maximum of 400 mg once daily
May take without regard to food. Capsules may be opened and sprinkled on soft food. Swallow whole, do not chew food.

Dosing - Migraine prevention

Topamax® and Eprontia® (≥ 12 years old)

Starting: 25 mg in the evening
Target: 50 mg twice a day
Increase daily dose by 25 mg at weekly intervals

Qudexy® XR and Trokendi XR® (≥ 12 years old)

Starting: 25 mg once daily
Target: 100 mg once daily
Increase daily dose by 25 mg at weekly intervals

Dosing - Alcohol use disorder

Topamax® (off-label)

See topiramate for alcohol use disorder

Efficacy

Migraine prevention

Topiramate vs Amitriptyline vs Placebo for Pediatric Migraine Prevention, NEJM (2017) [SH review]

Generic / Price

Topamax® (60 tablets) - YES/$
Trokendi XR® (30 capsules) - NO/$$$$
Qudexy® XR (30 capsules) - YES/$$-$$$
Eprontia® (473 ml) - NO/$$$$

Lab monitoring

Levels

The value of routine monitoring has not been established
Monitoring levels may be useful to assess compliance or toxicity
Levels should be drawn immediately before the next dose (trough) [5]
Therapeutic range: 5 - 20 mcg/ml [4]

Other labs

Baseline and periodic serum bicarbonate levels are recommended
Ammonia levels in patients also taking valproic acid may also be useful
Topiramate may cause decreased phosphorus levels (6% of patients)
Topiramate may cause increased alkaline phosphatase levels (3% of patients)

Pharmacokinetics

Half-life (Topamax/Eprontia): 21 hours
Time to steady state (Topamax/Eprontia): 4 days
Half-life (Trokendi XR): 31 hours
Half-life (Qudexy XR): 56 hours
Time to steady state (Qudexy XR): 5 days [1]

Mechanism of action

The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and the preventive treatment of migraine. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.

FDA-approved indications

Topamax®, Eprontia®, and Qudexy® XR

Partial onset and generalized tonic-clonic seizures (monotherapy) in adults and children ≥ 2 years old
Partial onset and generalized tonic-clonic seizures (adjunctive) in adults and children ≥ 2 years old
Lennox-Gastaut syndrome (adjunctive) in adults and children ≥ 2 years old
Migraine headache prevention in patients 12 years of age and older

Trokendi XR®

Partial onset and generalized tonic-clonic seizures (monotherapy) in adults and children ≥ 6 years old
Partial onset and generalized tonic-clonic seizures (adjunctive) in adults and children ≥ 6 years old
Lennox-Gastaut syndrome (adjunctive) in adults and children ≥ 6 years old
Migraine headache prevention in patients 12 years of age and older

Side effects

Side effect	Topiramate 100 mg/day	Placebo
Paresthesia (typically tingling of the extremities)	51%	6%
Fatigue	15%	11%
Decreased appetite	15%	6%
Nausea	13%	8%
Diarrhea	11%	4%
Change in taste	8%	1%
Diarrhea	11%	4%
Weight loss	9%	1%
Reduced touch sensation	7%	2%
Memory problems	7%	2%
Somnolence	7%	5%
Concentration problems	6%	2%

Drug interactions

Topiramate is a CYP2C19 weak inhibitor and CYP3A4 weak inducer
Phenytoin - in studies, concomitant phenytoin decreased topiramate levels by 48%, while phenytoin concentrations increased by 25% in some patients.
Carbamazepine - in studies, concomitant carbamazepine decreased topiramate levels by 40%
Valproic acid - concomitant valproic acid increases the risk of hyperammonemia, encephalopathy, and hypothermia
Oral contraceptives - topiramate may decrease exposure to the estrogen component of combined oral contraceptives, causing reduced efficacy and breakthrough bleeding. Patients should report changes in menstrual bleeding and be aware that effectiveness may be decreased even in the absence of breakthrough bleeding.
Digoxin - topiramate may decrease digoxin levels
Hydrochlorothiazide (HCTZ) - HCTZ may increase topiramate levels. Combination may increase risk of hypokalemia.
Metformin - topiramate may cause metabolic acidosis in which case metformin would be contraindicated
Pioglitazone (Actos®) - in studies, topiramate decreased pioglitazone exposure. The clinical relevance of this effect is unknown, so patients should increase blood glucose monitoring when combining.
Glyburide - topiramate may decrease glyburide levels
Lithium - topiramate may increase lithium levels
Amitriptyline - topiramate may cause large increases in amitriptyline levels in some patients. Amitriptyline dose adjustments should be based on the patient's clinical response, not serum levels.
Diltiazem - topiramate may decrease diltiazem levels, and diltiazem may increase topiramate levels
Carbonic anhydrase inhibitors - topiramate is a carbonic anhydrase inhibitor, and taking it with other carbonic anhydrase inhibitors (e.g. zonisamide, acetazolamide, and dichlorphenamide) increases the risk of metabolic acidosis, hyperammonemia, and kidney stones.

Contraindications / Precautions

Pregnancy - DO NOT USE. May increase the risk of cleft lip, cleft palate (oral clefts), and being small for gestational age.
Acute myopia and secondary angle closure glaucoma - topiramate has been associated with a syndrome of acute myopia with secondary angle closure glaucoma. Onset typically occurs within the first month of therapy, and cases have been reported in adults and children. Patients who complain of decreased visual acuity and/or ocular pain should be evaluated immediately. The primary treatment is discontinuation of topiramate as rapidly as possible.
Visual field defects - visual field defects independent of elevated intraocular pressure have been reported in patients treated with topiramate. In trials, most defects resolved after discontinuation of topiramate. Consider discontinuing topiramate if vision problems occur at any time during therapy.

Non-anion gap metabolic acidosis - topiramate may cause a non-anion gap metabolic acidosis secondary to renal bicarbonate loss caused by topiramate's inhibition of carbonic anhydrase. Metabolic acidosis (decreased serum bicarbonate in the absence of chronic respiratory alkalosis) may occur at any time during treatment. Bicarbonate decreases are typically mild (average reduction of 4 mEq/L at daily doses of 400 mg in adults and approximately 6 mg/kg/day in pediatric patients), but rare cases of severe loss (≥ 10 mEq/L) have occurred. Other factors that can expose a patient to acidosis (e.g. renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, acetazolamide) may compound the loss. In pediatric trials, the incidence of low serum bicarbonate (< 17 mEq/L) was 11% in topiramate-treated patients and ≤ 2% in placebo-treated patients. Symptoms of metabolic acidosis include hyperventilation, fatigue, anorexia, and in severe cases, cardiac arrhythmias and stupor. Chronic metabolic acidosis may increase the risk of kidney stones and osteomalacia. Baseline and periodic serum bicarbonate measurements are recommended during topiramate therapy. If patients develop metabolic acidosis, decreasing or stopping topiramate should be considered, along with alkali treatment.
Cognitive/neuropsychiatric adverse reactions - topiramate can have negative effects on cognition and mood, including confusion, memory issues, speech or language problems, depression, somnolence, and fatigue.
Decrease in bone mineral density (BMD) - topiramate may cause metabolic acidosis, which can lead to decreases in BMD. In a one-year pediatric trial, 21% of topiramate-treated patients experienced a reduction in BMD (Z score change from baseline of –0.5 or greater) compared to 0% of patients in the control group. Patients aged 6 to 9 years old were most commonly affected.
Suppression of growth - in a one-year pediatric trial, topiramate-treated patients had statistically significant reductions in growth (weight and height velocity) when compared to control patients. Long-term effects on growth are unknown. Monitor growth parameters closely in children receiving topiramate.
Hyperammonemia and encephalopathy - topiramate may raise ammonia levels and cause encephalopathy. The risk may be higher when topiramate is taken with valproic acid or zonisamide. The incidence of hyperammonemia in patients 12 - 17 years of age in migraine trials was 26% (topiramate 100 mg/day), 14% (topiramate 50 mg/day), and 9% (placebo).
Kidney stones - topiramate is a carbonic anhydrase inhibitor, which can promote kidney stone formation by reducing urinary citrate excretion and increasing urinary pH. During adjunctive epilepsy trials, the risk for kidney stones in topiramate-treated adults was 1.5%, which is about 2 to 4 times greater than expected in a similar, untreated population. Patients being treated with topiramate may want to increase fluid intake to help prevent stone formation.
Hypothermia - cases of hypothermia (< 35 °C or 95 °F) have been reported in patients receiving topiramate with valproic acid. Symptoms of hypothermia include lethargy, confusion, and coma. Check an ammonia level and consider stopping topiramate or valproic acid if hypothermia occurs.
Oligohidrosis (decreased sweating) and hyperthermia - Topiramate may cause decreased sweating, leading to hyperthermia. Pediatric patients are at the greatest risk. Use caution in patients exposed to excessive heat and those taking certain medications (e.g. other carbonic anhydrase inhibitors, anticholinergics).
Bleeding - in placebo-controlled trials, topiramate was associated with an increased risk for bleeding (4.5% vs 3% for placebo)
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Serious skin reactions - serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients receiving topiramate. Stop topiramate for rashes that do not have an obvious alternative cause. If symptoms of SJS or TEN occur (e.g. fever, rash, lymphadenopathy, and/or facial swelling in association with other organ system involvement), topiramate should be permanently discontinued.
Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
Liver disease - topiramate levels may be increased. Topiramate may also raise ammonia levels. Use caution.
Kidney disease

CrCl < 70 ml/min: use one-half the usual adult dose

Valproic acid (Depakene®) | Divalproex sodium (Depakote®) (Depakote ER®) | Valproate sodium (Depacon®)

Dosage forms

NOTE: Each form of valproic acid delivers an equivalent amount of valproate ion, the active ingredient

Capsule (Depakene®)

250 mg

Tablet (Depakote®)

125 mg
250 mg
500 mg

Sprinkle capsule (Depakote®)

125 mg

Tablet, extended-release (Depakote ER®)

250 mg
500 mg

Injection (Depacon®)

100 mg/ml

Dosing

General dosing recommendations

Depakote® is dosed twice a day
Depakote ER® is dosed once a day
Depakene® is dosed 2 to 3 times a day

Epilepsy

Initial: 10 - 15 mg/kg/day
Maintenance: based on blood levels and response
Max: 60 mg/kg/day
Increase dose by 5 - 10 mg/kg/week

Migraine

Initial: 500 mg a day
Max: 1000 mg a day

Mania

Initial: 750 mg a day
Maintenance: titrate as needed
Max: 60 mg/kg/day

Specific dosing recommendations

Converting from Depakote® to Depakote ER®

In general, the Depakote ER® dose should be 8 - 20% higher than the total daily dose of Depakote®. See Depakote ER® PI for specific recommendations

Efficacy

Valproate vs Levetiracetam as Initial Therapy in Generalized Seizure Disorder, Lancet (2021) [PubMed abstract]

Generic / Price

Depakote® (60 tablets) - YES/$
Depakote ER® (60 tablets) - YES/$
Depakene® (120 capsules) - YES/$

Lab monitoring

Levels

Routine monitoring is recommended to maintain a therapeutic level and prevent toxicity
Level should be drawn right before the next dose (trough level)
Valproic acid is highly protein bound (> 80%). In conditions where binding kinetics may be altered (ex. kidney disease, concurrent protein-bound medications, liver disease), free valproic acid levels may be helpful [5]

Valproic acid, Total

Therapeutic level (epilepsy): 50 - 100 mcg/ml [1]
Therapeutic level (mania): 50 - 125 mcg/ml [1]
Potential toxicity: > 120 mcg/ml [3]

Valproic acid, Free

Therapeutic level: 6 - 22 mcg/ml [3]

Other labs

Liver enzyme tests should be drawn at baseline and periodically thereafter, particularly in the first 6 months
Platelet counts and coagulation tests should be measured at baseline and periodically (also before surgery)
Valproic acid may cause false-positive urine ketones
Valproic acid may alter thyroid function tests

Pharmacokinetics

Half-life: 9 - 16 hours [1]
Time to steady state: 2 - 4 days [2]

Other

Depakote®

May take without regard to food
Do not cut, crush, or chew tablets
Depakote® sprinkle capsules may be opened and sprinkled on food. Do not chew sprinkles.
Medication residue may be seen in the stool. This is not normal. Check level, consider other therapy.

Depakote ER®

May take without regard to food
Do not cut, crush, or chew tablets
Medication residue may be seen in the stool. This is not normal. Check level, consider other therapy.

Depakene®

May take without regard to food
Swallow capsules whole. Do not open and sprinkle on food.

Mechanism of action

Mechanism not entirely understood
Increases GABA activity in the brain
Inhibits action potentials (nerve-firing)

FDA-approved indications

Epilepsy - monotherapy and adjunctive therapy in complex partial seizures, and simple and complex absence seizures
Bipolar mania
Prevention of migraine headache

Side effects

Side effect	Valproic acid	Placebo
Nausea	31%	10%
Fatigue / Weak	20%	9%
Somnolence	17%	5%
Upset stomach	13%	9%
Dizziness	12%	6%
Diarrhea	12%	7%
Vomiting	11%	1%
Tremor	9%	0%
Abdominal pain	9%	4%
Weight gain	8%	2%
Hair loss	7%	1%

Drug interactions

Lesinurad (Zurampic®) - DO NOT COMBINE. Valproic acid is an epoxide hydrolase inhibitor and it may block the metabolism of lesinurad.
Amitriptyline - valproic acid may increase amitriptyline levels
Aspirin - may increase levels of valproic acid (free and total)
Carbamazepine - carbamazepine may decrease levels of valproic acid by 50%. Valproic acid may affect carbamazepine levels.
Carbapenem antibiotics (imipenem, etc.) - may decrease valproic acid levels to subtherapeutic levels. Monitor levels closely when combining.
Cholestyramine (Depakene only) - cholestyramine may decrease levels of Depakene. Cholestyramine should be given at least 3 hours after Depakene.
Clomipramine - valproic acid may increase clomipramine levels
Clonazepam - may induce absence seizures when combined
Diazepam - valproic acid may increase diazepam levels (free and total)
Estrogen-containing contraceptives - estrogen-containing contraceptives may increase valproic acid clearance and lead to subtherapeutic valproate levels
Ethosuximide - valproic acid may increase ethosuximide levels
Felbamate - felbamate may increase valproic acid levels
Highly protein-bound medications - valproic acid may displace highly protein-bound drugs and increase their levels, and vice-versa
Lamotrigine - valproic acid may increase lamotrigine levels. See lamotrigine for details on dosing
Lorazepam - valproic acid may increase lorazepam levels. Lorazepam dose should be halved when combining.
Nortriptyline - valproic acid may increase nortriptyline levels
Oxcarbazepine - valproic acid may decrease oxcarbazepine levels by 18%
Paliperidone (Invega®) - in a single dose study, divalproex sodium 1000 mg caused an increase of 50% in the Cmax and area under the curve of paliperidone (single 12 mg dose). Consider reducing the dose of paliperidone when prescribing with divalproex.
Phenobarbital - phenobarbital may decrease levels of valproic acid by 50%. Valproic acid may increase phenobarbital levels.
Phenytoin - phenytoin may decrease levels of valproic acid by 50%. Valproic acid may affect free phenytoin levels.
Primidone - valproic acid may increase primidone levels
Propofol - valproic acid may increase propofol levels. Reduce the dose of propofol when combining.
Rifampin - may decrease valproic acid levels
Rufinamide - valproic acid may increase levels of rufinamide by up to 70%. When adding valproate to rufinamide, a low starting dose should be used. When adding rufinamide to valproate, a rufinamide dose of < 400 mg/day should be used.
Tolbutamide - valproic acid may displace tolbutamide from protein-binding
Topiramate - combination may lead to hyperammonemia, encephalopathy, and hypothermia (see precautions)
Warfarin - valproic acid may displace warfarin from protein-binding
Zidovudine - valproic acid may increase zidovudine levels

Lab interactions

Urine ketones - valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test
Thyroid function tests - there have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown.

Contraindications / Precautions

Mitochondrial DNA disorders (POLG, Alpers-Huttenlocher Syndrome) - DO NOT USE. Risk of hepatotoxicity is increased in these patients. Signs of mitochondrial DNA disorders include unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura.
Urea cycle disorders (UCD) - DO NOT USE. Cases of sometimes fatal hyperammonemic encephalopathy have been reported in patients with urea cycle disorders. Urea cycle disorders are rare, but should be considered in patients with with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, history of elevated plasma ammonia or glutamine, cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, protein avoidance, family history of UCD or a family history of unexplained infant deaths (particularly males).
Pregnancy - DO NOT USE. Valproic acid can cause major congenital malformations, particularly neural tube defects. See pregnancy studies for more.
Hepatotoxicity - cases of hepatotoxicity including liver failure have occurred in patients receiving valproate and its derivatives, especially in the first 6 months of treatment. Children under the age of 2 who are on multiple anticonvulsants, have congenital metabolic disorders, have severe seizure disorders accompanied by mental retardation, and/or have organic brain diseases are at greatest risk. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months.
Low platelets - valproic acid may cause a decrease in platelets. In trials of patients with epilepsy who were receiving around 50 mg/kg/day, 27% of patients had at least one platelet count ≤ 75,000 K/µL. After treatment discontinuation, counts returned to normal. The risk appears to be highest at higher blood levels (≥ 110 mcg/ml in females and ≥ 135 mcg/ml in males).
Myelodysplasia - cases of myelodysplasia have been reported
Hyperammonemia and encephalopathy - valproic acid may raise ammonia levels and cause encephalopathy. The risk is higher when taken with topiramate. Most ammonia elevations are asymptomatic. Consider checking an ammonia level in patients with unexplained lethargy, vomiting, changes in mental status, and/or hypothermia.
Hypothermia - hypothermia (temp < 35°C or 95°F) has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. The risk may be greater when taken with topiramate.
Serious skin reactions - serious skin reactions including SJS, DRESS, and TEN have been reported. Symptoms may present as fever, rash, lymphadenopathy, and/or facial swelling in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis.
Virus stimulation - in vitro studies have suggested that valproic acid may stimulate the replication of HIV and CMV virus. The clinical significance of this is unknown.
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Medication residue in stool - there have been rare reports of medication residue in the stool. Patients with shortened bowels (e.g. colostomy) or diarrhea may be at greater risk. If residue is seen, valproate levels should be monitored closely.
Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
Pancreatitis - rare cases of pancreatitis have been reported with valproic acid use. Cases have occurred shortly after starting therapy and after years of use. In trials, 2 cases of pancreatitis without alternative etiology were seen in 1,044 patient-years of use.
Elderly patients - in trials, elderly patients were at greater risk for somnolence. Starting doses should be lower and dose titrations should be slower in elderly patients.
Brain atrophy - rare cases have been reported
Liver disease - DO NOT USE. Valproic acid elimination is greatly reduced in significant liver disease.
Kidney disease - protein-binding may be decreased. Measure free levels.

Zonisamide (Zonegran®)

Dosage forms

Capsule (Zonegran®)

25 mg
50 mg
100 mg

Dosing

Partial seizures (adults and children > 16 years)

Starting: 100 mg once daily
Maintenance: 100 - 600 mg/day
Max: 600 mg/day
May be given once or twice daily
Increase dose in increments of 100 mg/day at intervals of no less than 2 weeks
Doses > 400 mg/day have not been shown to increase response
Zonisamide has a long half-life and it takes 2 weeks to achieve steady state
May take without regard to food
Swallow capsules whole

Efficacy

Focal seizures

Zonisamide vs Levetiracetam vs Lamotrigine as Initial Therapy for Focal Seizure Disorder, Lancet (2021) [PubMed abstract]

Generic / Price

- YES/$ (120 capsules)

Lab monitoring

Levels

Trough levels in the range of 10 - 40 mcg/ml are generally considered therapeutic
It takes 2 weeks to achieve steady state after dose adjustments [1,4,7]

Pharmacokinetics

Half-life (plasma): 63 hours
Half-life (red blood cells): 105 hours
Time to steady state: 14 days

Mechanism of action

The precise mechanism(s) by which zonisamide exerts its antiseizure effect is unknown
Zonisamide may work through action at sodium and calcium channels. In vitro pharmacological studies suggest that zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type Ca²⁺ currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization.

FDA-approved indications

Zonisamide is indicated as adjunctive therapy in the treatment of partial seizures in adults (> 16 years) with epilepsy

Side effects

NOTE: Side effects presented below are from trials where zonisamide was added to other seizure medications. Only side effects that occurred at an incidence ≥ 4% are listed.

Side effect	Zonisamide (N=269)	Placebo (N=230)
Somnolence	17%	7%
Anorexia	13%	6%
Dizziness	13%	7%
Headache	10%	8%
Nausea	9%	6%
Agitation / Irritability	9%	4%
Fatigue	8%	6%
Tiredness	7%	5%
Abdominal Pain	6%	3%
Ataxia	6%	1%
Confusion	6%	3%
Difficulty Concentrating	6%	2%
Difficulty with Memory	6%	2%
Depression	6%	3%
Insomnia	6%	3%
Diplopia	6%	3%
Diarrhea	5%	2%
Speech Abnormalities	5%	2%
Flu Syndrome	4%	3%
Nystagmus	4%	2%
Paresthesia	4%	1%
Mental Slowing	4%	2%

Drug interactions

CNS depressants - CNS depressants including alcohol may increase the risk of sedation and other neuropsychiatric adverse events when given with zonisamide. Use caution.
Carbonic anhydrase inhibitors - zonisamide is a carbonic anhydrase inhibitor and it may increase the risk of metabolic acidosis, hyperammonemia, and kidney stones when given with other carbonic anhydrase inhibitors (e.g. topiramate, acetazolamide, and dichlorphenamide)
P-glycoprotein substrates - zonisamide is a weak P-glycoprotein inhibitor. It may increase exposure to P-glycoprotein substrates.
CYP3A4 inducers - zonisamide is a CYP3A4 substrate and exposure may be decreased when taken with CYP3A4 inducers. This effect is unlikely to be significant when zonisamide is added to existing therapy, but it may be necessary to adjust zonisamide if CYP3A4 inducers are withdrawn, added, or adjusted during therapy.
CYP3A4 inhibitors - zonisamide is a CYP3A4 substrate. In pharmacokinetic studies, strong CYP3A4 inhibitors had no significant effect on zonisamide levels so dose adjustments are not recommended.

Contraindications / Precautions

Pregnancy - DO NOT USE. Zonisamide may increase the risk of birth defects.
Sulfa allergy - zonisamide is a sulfonamide. Patients with a history of allergies to sulfa drugs may be at increased risk of having an allergic reaction to zonisamide.
Serious skin reactions - serious skin reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Consider discontinuing zonisamide in patients who develop an otherwise unexplained rash. In trials, serious rash or rash that led to discontinuation occurred in up to 2% of patients. Rash typically occurred within the first 16 weeks of treatment.
Aplastic anemia and agranulocytosis - rare cases of aplastic anemia and agranulocytosis have been reported in patients receiving zonisamide
DRESS syndrome/Multi-Organ Hypersensitivity - rare cases of drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multi-organ hypersensitivity, have been reported in patients receiving zonisamide. DRESS may present with fever, rash, eosinophilia, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.
Decreased sweating and hyperthermia - in the postmarketing setting, decreased sweating and hyperthermia have been reported with an incidence of up to 12 cases per 10,000 patient-years of use. Children appear to be at greater risk. Use caution in patients who are exposed to warm weather and when taken with concomitant carbonic anhydrase inhibitors and anticholinergics.
Acute myopia and angle closure glaucoma - zonisamide has been associated with a syndrome of acute myopia and angle closure glaucoma. Cases have occurred in both children and adults, and onset typically occurs within the first month of therapy. Patients who complain of decreased visual acuity and/or ocular pain should be evaluated immediately.
Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
Non-anion gap metabolic acidosis - zonisamide is a carbonic anhydrase inhibitor and it may cause a non-anion gap, hyperchloremic, metabolic acidosis secondary to renal bicarbonate loss. Zonisamide-induced metabolic acidosis typically occurs early in treatment, but it can develop at any time and at doses as low as 25 mg/day. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate-lowering effects of zonisamide. Symptoms of metabolic acidosis include hyperventilation, fatigue, anorexia, and in severe cases, cardiac arrhythmias and stupor. Baseline and periodic measurement of bicarbonate levels is recommended.
Kidney stones - the chronic metabolic acidosis induced by zonisamide may increase the risk of kidney stones. Use caution in susceptible patients.
Osteomalacia and osteoporosis - the chronic metabolic acidosis induced by zonisamide may increase the risk of osteomalacia and osteoporosis. In trials, zonisamide was associated with reductions in serum phosphorus and increases in serum alkaline phosphatase, changes that may be related to metabolic acidosis and osteomalacia. The effects of zonisamide on growth rates in children and fracture risk in adults is unknown. Use caution in susceptible patients.
Serum bicarbonate loss - zonisamide inhibits carbonic anhydrase which leads to the loss of sodium bicarbonate. In adult trials, average serum bicarbonate levels decreased by 2 mEq/L at doses of 100 mg/day and by 4 mEq/L at doses of 300 mg/day. Serum bicarbonate levels persistently < 20 mEq/L were observed in 21% of subjects at doses of 25 mg - 100 mg/day and in 43% at doses of 300 mg/day.
Abrupt discontinuation - abrupt withdrawal of zonisamide may increase the risk of seizures. Zonisamide should be discontinued gradually.
Depression - zonisamide may increase the risk of depression. In trials, 2.2% of zonisamide-treated patients discontinued zonisamide or were hospitalized for depression compared to 0.4% of placebo-treated patients.
Hyperammonemia and encephalopathy - zonisamide can cause metabolic acidosis which can raise ammonia levels and cause encephalopathy. The risk may be higher when zonisamide is taken with valproic acid or topiramate. Measure serum ammonia concentration if signs or symptoms (e.g., unexplained change in mental status, vomiting, or lethargy) of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued. Hyperammonemia from zonisamide may resolve or decrease in severity with a decrease of the daily dose.
Increase in serum creatinine - in studies, serum creatinine increased an average of 8% in zonisamide-treated patients compared to none in placebo-treated patients. The increase appeared within the first 4 weeks of treatment, and it was persistent but not progressive. In short-term studies, the GFR returned to normal within 2 - 3 weeks of drug discontinuation. No data is available for long-term use.
Liver disease - zonisamide is metabolized by the liver. It has not been studied in liver impairment. Slower titration and more frequent monitoring should be used in liver disease. Manufacturer makes no specific dosage recommendation.
Kidney disease

CrCl < 50 ml/min: not recommended. Has not been studied.

HLA-B*1502 PREVALENCE

Patients with the Human Leukocyte Antigen (HLA) allele B*1502 are at increased risk of developing serious skin reactions from carbamazepine, oxcarbazepine, and phenytoin
Skin reactions typically occur within the first few months of therapy
Screening for the allele before therapy is started may be warranted in certain high-risk populations
The allele is primarily found in Asian populations. Prevalence of the allele in specific populations is listed below.

Reference [6]
Prevalence of HLA-B*1502 allele
Population	Prevalence
Filipino and Malaysian	> 15%
Han Chinese	2 - 12%
Thai	8%
Indian	6%
Korean	2%
European, Japanese, Hispanic, African	< 1%

Pregnancy exposure studies

Prenatal Carbamazepine Exposure and Academic Performance in Adolescents: A Population-Based Cohort Study, Neurology (2023) [PubMed abstract]

Design: Population-based cohort study in all live-born singletons in Denmark between 1996 and 2002 who participated in the national ninth-grade exit examination (N=370,859)
Exposure: In utero exposure to carbamazepine vs None
Primary outcome: Score on ninth-grade exit exam
Findings: In utero exposure to carbamazepine was associated with poorer academic performance in adolescence, as represented by lower scores in ninth-grade exit examination in Danish and mathematics. Additional studies are needed to confirm these findings because of limitations in this study and variable findings in prior studies.

Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study, JAMA Neurology (2021) [PubMed abstract]

Design: Prospective cohort study in children who were born to women with epilepsy vs children born to healthy women
Exposure: Antiseizure drug exposure during gestation vs None
Primary outcome: Language domain score according to the Bayley Scales of Infant and Toddler Development at 2 years of age
Findings: Outcomes of children at 2 years of age did not differ between children of WWE taking ASMs and children of healthy women.

Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child, Cochrane Review (2016) [PubMed abstract]

Design: Meta-analysis of cohort studies and randomized controlled trials (N=31 studies)
Exposure: Antiepileptic drug (AED) during gestation
Primary outcome: Major congenital malformation
Findings: Exposure in the womb to certain AEDs carried an increased risk of malformation in the fetus and may be associated with specific patterns of malformation. Based on current evidence, levetiracetam and lamotrigine exposure carried the lowest risk of overall malformation; however, data pertaining to specific malformations are lacking. Physicians should discuss both the risks and treatment efficacy with the patient prior to commencing treatment.

Pregnancy outcome following maternal exposure to pregabalin may call for concern - Neurology (2016) [PubMed abstract]

Design: Prospective cohort study (N=820 pregnancies)
Exposure: Pregabalin during pregnancy
Primary outcome: Major birth defect rate
Findings: This study demonstrated a signal for increased risk of major birth defects after first trimester exposure to pregabalin. However, several limitations such as the small sample size, differences across groups in maternal conditions, and concomitant medication exposure exclude definitive conclusions, so these results call for confirmation through independent studies.

Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies - Neurology (2016) [PubMed abstract]

Design: Case-control registry study (N=6.3 million births)
Exposure: Lamotrigine during pregnancy
Primary outcome: Orofacial cleft (OC), clubfoot, and other congenital anomalies
Findings: The risk of OC was not significantly raised and we estimate the excess risk of OC to be less than 1 in every 550 exposed babies. We have not found strong independent evidence of a risk of clubfoot subsequent to our original signal. Our study cannot assess the general malformation risk among lamotrigine-exposed pregnancies.

Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate - Neurology (2016) [PMID 27581218]

Design: Cross-sectional observational study (N=171)
Exposure: Prenatal exposure to levetiracetam, topiramate, or valproate
Primary outcome: Cognitive abilities at age 5 - 9 years
Findings: In the adjusted analyses, prenatal exposure to levetiracetam and topiramate were not found to be associated with reductions in child cognitive abilities, and adverse outcomes were not associated with increasing dose. Increasing dose of valproate, however, was associated with poorer full-scale IQ, verbal abilities, nonverbal abilities, and expressive language ability.

PRICE ($) INFO

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$ = 0 - $50
$$ = $51 - $100
$$$ = $101 - $150
$$$$ = > $151

Pricing based on one month of therapy at standard dosing in an adult
Pricing based on information from GoodRX.com®
Pricing may vary by region and availability

BIBLIOGRAPHY

1 - Manufacturer's Package Insert for each drug listed
2 - Quest® diagnostics
3 - LabCorp® website
4 - PMID 18397299 - ILAE drug monitoring GL
5 - CPL website
6 - Trileptal PI
7 - Mayo Clinic Laboratories

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