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Antiepileptic Drugs




Efficacy, Dose, Regime, Pharmocokinetics, Adverse Effects & Cost*†

Carbamazepine (Tegretol®, Tegretol XR®, Carbatrol®)
tegretol
Tegretol
tegretol xr
Tegretol XR
carbatrol
Carbatrol

Carbamazepine



Tegretol®, Tegretol XR®, Carbatrol®


Efficacy:

Partial seizures, Secondarily generalized seizures

Dose range:


Adults: 600 to 2,000 mg per day
Children: 10 to 40 mg/kg per day
Comment: Optimal individual maintenance doses will be determined by clinical response; initial doses are lower; pharmacokinetic interactions may affect dosage requirements.

Regimen:

Three to four times per day; two times per day for sustained release preparation, Tegretol XR

Pharmocokinetics:


Hepatic elimination by oxidation, aromatic hydroxylation, and N-glucuronidation
Half-life: 5-20 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Carbamazepine induces the metabolism of cyclosporine A, tricyclic antidepressants, and warfarin (Coumadin).
  • Carbamazepine induces the metabolism of oral contraceptive agents, including ethinyl estradiol and levonorgestrel, with the potential for breakthrough bleeding and contraceptive failure.
  • Carbamazepine levels are increased by the calcium-channel blockers verapamil and diltiazem, erythromycin and other macrolide antibiotics, isoniazid, cimetidine (Tagamet), and propoxyphene (Darvon).
  • Carbamazepine increases phenytoin metabolism to a variable degree.
  • Carbamazepine increases primidone biotransformation to phenobarbital.
  • Carbamazepine increases metabolism of valproate, ethosuximide, and lamotrigine. Carbamazepine metabolism is increased by phenytoin, phenobarbital, primidone, and felbamate.
  • Felbamate increases carbamazepine epoxide levels.
Comment: Steady-state values for the half-life of carbamazepine are reached only after complete hepatic autoinduction, which occurs after approximately one month of carbamazepine administration.

Adverse Effects:


Dose related: Double vision, Dizziness, Nausea, Headache
Idiosyncratic: Rash, Leucopenia
Comment: There is concern about teratogenicity with all antiepileptic medications. An increased incidence of neural tube defects has been shown to occur with carbamazepine.

Cost:


Carbemazepine
(generic)
100 mg/5 ml susp$0.66
200 mg (tablet)$0.11
Carbatrol®
(carbamazepine extended release)
100 mg$1.94
200 mg$1.98
300 mg$2.01
Tegretol®
(carbamazepine)
100 mg/5 ml susp$1.04
200 mg (tablet)$1.44
Tegretol XR®
(carbamazepine extended release)
100 mg$0.75
200 mg$1.47
400 mg$2.90

External Information:


Internet Mental Health
RxList
Clobazam (Frisium®, Urbanol®, Onfi®)

Clobazam



Frisium®, Urbanol®, Onfi®


Efficacy:

Treatment of seizures associated with Lennox-Gastaut Syndrome and adjunctive treatment of epilepsy in patients who have not responded to alternate drugs.

Dose range:


Adults: Initiated at 5–15 mg/day, gradually increasing to a maximum dose of 80 mg/day.
Children: For infants 2 and under, initiated at 0.5–1 mg/kg/day. For children (2-16 years), initiated at 5 mg/day and increased every 5 days to a maximum of 40 mg/day. Note: Patients with impaired renal, liver, or respiratory function may require a reduced dose.

Regimen:

One to two times a day

Pharmocokinetics:


Elimination is renal
Half-life: 10–30 hours
Half-life of active metabolite (N-desmethyl clobazam): 36–46 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Carbamazepine, phenytoin, diphenylhydantoin, phenobarbital, and valproic acid may cause a slight decrease in blood levels of clobazam.
  • Carbamazepine and phenytoin may cause an increase in the metabolic conversion of clobazam to N-desmethyl clobazam.

Adverse Effects:


Dose related: Respiratory Depression, Dizziness, Somnolence, Fatigue, Ataxia, Weight gain, Nervousness, Behavior Disorder, Hostility, Blurred or Double vision, Confusion, Headaches, Dry mouth, Constipation, Loss of appetite, Nausea, Weakness, Disorientation, Tremor, Unsteady gait
Idiosyncratic: Stevens-Johnson Syndrome (SJS), Toxic epidermal necrolysis (TEN), Rashes, Exanthema, Urticaria
Comment: There is concern about teratogenicity with all antiepileptic medications.
Clonazepam (Klonopin®)
klonopin

Clonazepam



Klonopin®


Efficacy:

Myoclonic seizures, Absence seizures, Partial seizures, Secondarily generalized seizures

Dose range:


Adults: 2–4 mg per day
Children: 0.1–0.3 mg/kg per day
Comment: Optimal individual maintenance doses will be determined by clinical response; lower initial doses may reduce somnolence.

Regimen:

Two to three times per day

Pharmocokinetics:


Hepatic elimination by nitroreduction and acetylation
Half-life: 20–40 hours

Pharmacokinetic drug interactions are uncommon, but administration of hepatic enzyme-inducing agents such as carbamazepine, phenobarbital, and phenytoin may lower clonazepam levels somewhat.

Adverse Effects:


Dose related: Drowsiness, Ataxia, Irritability
Idiosyncratic: Rash, Leucopenia
Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:


Generic Clonazepam
0.5 mg $0.09
1.0 mg $0.12
2.0 mg $0.14
Klonopin®
0.5 mg $2.06
1.0 mg $2.35
2.0 mg $3.24

External Information:


Internet Mental Health
RxList
Ethosuximide (Zarontin®)
zarontin

Ethosuximide



Zarontin®


Efficacy:

Absence seizures

Dose range:


Adults: 500–1250 mg per day
Children: 10-60 mg/kg per day
Comment: Optimal individual maintenance doses will be determined by clinical response.

Regimen:

Two to three times per day

Pharmocokinetics:


Elimination: Hepatic (80%) oxidation; Renal (20%)
Half-life: 30-60 hours
Ethosuximide is not protein bound

Some clinically relevant pharmacokinetic drug interactions:
  • Half-life decreased by concomittant administration of hepatic enzyme-inducing agents such as carbamazepine, phenytoin or phenobarbital.
  • The half-life of ethosuximide may be increased by valproate.
  • Ethosuximide has little or no effect on the pharmacokinetics of other antiepileptic drugs.


Adverse Effects:


Dose related: Nausea, Hiccups, Anorexia
Idiosyncratic: Rash, SLE
Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:


Zarontin®
(ethosuximide)
250 mg $2.04
Ethosuximide
(generic)
250 mg $1.04


External Information:


Internet Mental Health
Ezogabine, Retigabine (Potiga®, Trobalt®)

Ezogabine, Retigabine



Potiga®, Trobalt®


Efficacy:

Adjunctive treatment of partial seizures in adult patients with epilepsy.

Dose range:


Adults: Initiated at 150 mg/day, increased weekly by up to 150mg to a maintenance dose of 600–1200 mg/day.
Children: Not approved for children.

Regimen:

Three times a day

Pharmocokinetics:


Elimination is renal
Half-life: 8 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Phenytoin may reduce ezogabine systemic exposure by 35%.
  • Carbamazepine may reduce ezogabine systemic exposure by 33%.
  • Ezogabine may inhibit renal clearance of digoxin.

Adverse Effects:


Dose related: Dizziness, Somnolence, Vertigo, Fatigue, Confusion, Tremor, Abnormal coordination, Double vision, Inattention, Memory impairment, Weakness, Blurred vision, Disturbed gait, Aphasia, Dysarthria, Balance disorder, Nausea, Constipation, Dyspepsia, Dry mouth, Urinary retention
FDA Safety AlertThe FDA has released an alert that chronic use of ezogabine has been associated with blue pigment deposits in the skin, nail beds, lips, and retina.
Comment: Ezogabine may increase the risk of suicidal thoughts or behaviors.

Cost:


Potiga®
(ezogabine)
50 mg
$3.56
200 mg
$7.16
300 mg
$7.16
400 mg
$7.16
Felbamate (Felbatol®)
felbatol

Felbamate



Felbatol®


Efficacy:

Partial seizures, Secondarily generalized seizures, Generalized seizures, Absence seizures, Myoclonic seizures, Lennox-Gastaut syndrome

Dose range:


Adults: 2400–4600 mg per day
Children: 40–60 mg/kg per day
Comment: Optimal individual maintenance doses will be determined by clinical response; initial doses are lower; pharmacokinetic interactions may affect dosage requirements.

Regimen:

Three times per day

Pharmocokinetics:


Elimination is both renal and hepatic by hydroxylation and glucuronidation.
Half-life: 15–20 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Felbamate increases phenytoin, phenobarbital, and valproate levels.
  • Felbamate decreases carbamazepine concentration but increases the concentration of carbamazepine epoxide.
  • Felbamate levels are decreased by phenytoin and carbamazepine, but valproate has little effect.


Adverse Effects:


Dose related: Anorexia, Weight loss, Headaches, Insomnia
Idiosyncratic: Aplastic anemia, Liver failure
Comment: Use of felbamate is restricted by an FDA advisory because of the risk of idiosyncratic side effects. There is concern about teratogenicity with all antiepileptic medications.

Cost:


Felbatol®
(felbamate)
400 mg $5.82
600 mg $6.68
Felbamate
(generic)
400 mg $3.95
600 mg $4.54


External Information:


MedlinePlus
Fosphenytoin (Cerebyx®)

Fosphenytoin



Cerebyx®


This agent been approved for use in the United States. This is a phosphorylated prodrug of phentoin intended for intravenous and intramuscular injection. It is rapidly and completely converted to phenytoin by the body but has significantly fewer IV injection site complications than older preparations of phenytoin (Dilantin) intended for intravenous injection. This is because fosphenytoin is water soluble, whereas phenytoin is provided in a solution of propylene glycol and water with a pH of 12.

Fosphenytoin is dispensed in units of mg phenytoin equivalents, with one mg phenytoin equivalent of fosphenytoin being equivalent to one mg of parenteral phenytoin. The maximum recommended intravenous infusion rate is 150 mg PE/min, with cardiac and blood pressure monitoring being required. This rate of infusion has been shown to be bioequivalent to a phenytoin infusion at a rate of 50 mg/min — that is, "therapeutic" levels of free phenytoin are achieved at approximately the same time after infusion of phenytoin at 50 mg/min and fosphenytoin at 150 mg PE/min.
Gabapentin (Neurontin®)
neurontin

Gabapentin



Neurontin®


Efficacy:

Approved for use as an add-on treatment in adults for partial seizures and secondarily generalized seizures.

Dose range:


Adults: 900–4800 mg per day
Children: 15–30 mg/kg per day
Comment: Optimal individual maintenance doses will be determined by clinical response; lower initial doses may reduce ataxia or somnolence.

Regimen:

Three times per day

Pharmocokinetics:


Renal elimination
Half-life: 5–7 hours

Gabapentin does not have significant pharmacokinetic drug interactions and is not significantly protein bound.

Adverse Effects:


Dose related: Dizziness, Ataxia, Somnolence, Weight gain
Idiosyncratic: Rash
Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:


Generic Gabapentin
100 mg $0.11
300 mg $0.19
400 mg $0.22
600 mg $0.49
800 mg $0.58
Neurontin®
100 mg $1.02
300 mg $2.56
400 mg $3.05
600 mg $4.83
800 mg $5.78

 

Lamotrigine (Lamictal®)
lamictal

Lamotrigine



Lamictal®


Efficacy:

Approved for use in adults as an add-on treatment for partial seizures, absences and atypical absences, Lennox-Gastaut syndrome, and tonic and atonic seizures.
Possible mechanism of action: Blockade of voltage sensitive sodium channels.

Dose range:


Adults and Adolescents:
  • If added to valproate monotherapy: 25 mg daily for two weeks, then 50 mg daily for two weeks, then titrate up to 150 mg twice daily.
  • If added to carbamazepine, phenytoin, phenobarbital, or primidone: initial dose 50 mg twice daily, subsequent increases up to 100–200 mg twice daily.
Children and Infants:
  • If added to valproate monotherapy: initial dose 0.5 mg/kg/day, final maintenance dose of 1–5 mg/kg/day.
  • If added to carbamazepine, phenytoin, phenobarbital, or primidone: initial dose 2 mg/kg/day, with subsequent increases to 5–15 mg/kg/day.
Comment: Optimal individual maintenance doses will be determined by clinical response.

Pharmocokinetics:


Oral bioavailability: 98%
Protein binding: 55%
Elimination by hepatic N-glucuronidation
Half-life: ~26 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Half-life prolonged by valproate
  • Half-life shortened by carbamazepine, phenytoin, phenobarbital, primidone
  • FDA Box Warning: Severe, potentially life-threatening rashes have been reported in association with the use of Lamictal. These reports, occurring in approximately one in every thousand adults, have included Stevens-Johnson syndrome (SJS), and rarely, toxic epidermal necrolysis (TEN). Rare deaths have been reported, but their numbers are too few to permit a a precise estimate of the rate.

    The incidence of severe, potentially life-threatening rash in pediatric patients, however, is very much higher than that reported in adults using Lamictal; specifically, reports for clinical trials suggest as many as 1 in 50 to 1 in 100 pediatric patients develop a potentially life-threatening rash. It bears emphasis, accordingly, that Lamictal is not approved for use in patients below the age of 16. (see indications).

    Other than age, there are as yet no factors identified that are known to predict the risk of occurrence or the severity of rash associated with Lamictal. There are suggestions, yet to be proven, that the risk of rash may also be increased by 1) coadministration of Lamictal with valproic acid (VPA); 2) exceeding the recommended initial dose of Lamictal; or 3) exceeding the recommended dose escalation for Lamictal. However, cases have been reported in the absence of these factors.

    Nearly all cases of life-threatening rashes associated with lamictal have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash.

    Although benign rashes also occur with Lamictal, it is not possible to predict reliably which rashes will prove to be life-threatening. Accordingly, Lamictal should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuance of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring.


Adverse Effects:


Dose related: Diplopia, Somnolence, Dizziness, Ataxia, Insomnia
Idiosyncratic: Rash. The risk of rash is decreased by lower initial doses.
Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:


Lamictal®
(lamotrigine)
25 mg $6.68
100 mg $9.21
150 mg $8.40
200 mg $9.14
Lamotrigine
(generic)
25 mg $0.15
100 mg $0.22
150 mg $0.24
200 mg $0.25
Levetiracetam (Keppra®)
keppra

Levetiracetam



Keppra®


Efficacy:

Adjunctive therapy of partial and secondarily generalized seizures.

Dose range:


Adults: 1000–3000 mg/day
Children: not established


Regimen:

Twice a day

Pharmocokinetics:


Elimination is primarily renal.
Half-life: 7 hours

No known drug interactions

Adverse Effects:


Dose related: Somnolence, Weakness, Headache, Infection, Behavioral difficulty
Idiosyncratic: none known
Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:


Keppra®
(Levetiracetam)
250 mg $5.10
500 mg $6.27
750 mg $8.46
1000 mg $12.54
Levetiracetam
(generic)
250 mg $0.26
500 mg $0.34
750 mg $0.45
1000 mg $0.82
Oxcarbazepine (Trileptal®)
trileptal

Oxcarbazepine



Trileptal®


Efficacy:

Adjunctive or monotherapy of partial or secondarily generalized seizures.

Dose range:


Adults: 600–2400 mg per day
Children: 10–30 mg/kg per day

Regimen:

Twice a day

Pharmocokinetics:


Hepatic metabolism. Hepatic metabolite MHD is largely responsible for anticonvulsant action.
Half-life: 9 hours (MHD)

Some clinically relevant pharmacokinetic drug interactions:
  • Phenytoin levels increased by doses >1200 mg/d.
  • MHD levels decreased by P450 inducers (phenytoin, carbamazepine, phenobarbital).
  • No autoinduction of MHD, unlike with carbamazepine.
  • Induces metabolism of oral contraceptives and may cause contraceptive failure.
  • Induces metabolism of some dihydropyridine calcium-channel blockers.


Adverse Effects:


Dose related: Dizziness, Double vision, Somnolence, Fatigue, Nausea
Idiosyncratic: Hyponatremia (higher than with carbamazepine), Rash (about 35% of those with carbamazepine rash will get oxcarbazepine rash). No evidence of neutropenia seen with carbamazepine.
Comment: Overall better tolerated than carbamazepine. Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:


Trileptal®
(oxcarbazepine)
150 mg $2.61
300 mg $4.78
600 mg $8.80
Oxcarbazepine
(generic)
150 mg $0.34
300 mg $0.55
600 mg $1.05
Perampanel (Fycompa®)

Perampanel



Fycompa®


Efficacy:

Adjunctive therapy for partial onset seizures in epilepsy patients ages 12 years and older.

Dose range:


Adults: Initial dose of 2 mg/day increased in 2 mg/day increments to a maximum of 12 mg/day.
Children 12 and older: Initial dose of 2 mg/day increased by 2 mg/day increments to 4–8 mg/day. Not approved for children under 12 years of age.
Comment: Patients with impaired liver function should not take more than 8 mg/day.

Regimen:

Once per day

Pharmocokinetics:


Elimination: metabolized in liver via primary oxidation and sequential glucuronidation
Half-life: 105 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, and topiramate may greatly increase clearance, resulting in reduced perampanel plasma concentrations.
  • FDA Box Warning: Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger, homicidal ideation, and threats reported.
    • May occur with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression
    • Advise patients and caregivers to contact a healthcare provider immediately if any reactions or changes in mood, behavior, or personality that are not typical for the patient are observed.
    • Closely monitor patients, particularly during the titration period and at higher doses.

Adverse Effects:


Dose related: Dizziness, Drowsiness, Fatigue, Irritability, Falls, Upper respiratory tract infection, Weight gain, Vertigo, Ataxia, Gait disturbance, Balance disorder, Anxiety, Blurred vision, Dysarthria, Asthenia, Aggression, Hypersomnia
Idiosyncratic: Allergic reaction
Comment: There is concern about teratogenicity with all antiepileptic medications.
Phenobarbital (Luminal®)
phenobarbital

Phenobarbital



Luminal®


Efficacy:

Partial seizures, Secondarily generalized seizures, Myoclonic seizures

Dose range:


Adults: 30–180 mg per day
Children: 2–8 mg/kg per day
Comment: Optimal individual maintenance doses will be determined by clinical response; initial doses are lower; pharmacokinetic interactions may affect dosage requirements.

Regimen:

Once per day

Pharmocokinetics:


Elimination is both renal and hepatic by parahydroxylation and conjugation to glucuronic acid.
Half-life: 65-110 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Phenobarbital levels are significantly increased by valproate.
  • Phenobarbital levels may be mildly increased by acetazolamide, phenylethylacetylurea, and methsuximide.
  • Phenobarbital lowers levels of valproate and may cause mild lowering of carbamazepine levels.
  • Interactions between phenobarbital and phenytoin are mild and inconsistent.
  • Chloramphenicol elevates phenobarbital levels.
  • Quinine and phenothiazines lower phenobarbital levels.
  • Phenobarbital decreases levels of theophylline, chloramphenicol, doxycycline, warfarin (Coumadin), cimetidine, cyclosporine, digoxin, and chlorpromazine.
  • Phenobarbital increases metabolism of oral contraceptive agents, potentially leading to breakthrough bleeding and contraceptive failure.


Adverse Effects:


Dose related: Somnolence, Hyperactivity, Depression
Idiosyncratic: Rash, SLE
Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:


Generic Phenobarbital
16.2 mg $0.19
32.4 mg $0.26
64.8 mg $0.38
97.2 mg $0.45
Phenytoin (Dilantin®)
dilantin

Phenytoin



Dilantin®


Efficacy:

Partial seizures, Secondarily generalized seizures

Dose range:


Adults: 200–600 mg per day
Children: 5–10 mg/kg per day
Comment: The half-life of phenytoin is concentration dependent due to nonlinear kinetics.
Optimal individual maintenance doses will be determined by clinical response; lower initial doses may reduce ataxia or somnolence; pharmacokinetic interactions may affect dosage requirements.


Regimen:

Once or twice per day

Pharmocokinetics:


Elimination is nearly entirely hepatic by oxidation, hydroxylation, and glucurinidation.
Half-life: 10-60 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Phenytoin levels are decreased by vigabatrin.
  • Phenytoin levels may be decreased, increased, or unchanged in an unpredictable fashion by phenobarbital or carbamazepine.
  • Phenytoin decreases the levels of carbamazepine, lamotrigine, and valproate, and increases biotransformation of primidone to phenobarbital.
  • Phenytoin increases metabolism of oral contraceptives and dexamethasone (Decadron).
  • Phenytoin decreases levels of theophylline, quinidine, cyclosporine, digitoxin, and chloramphenicol.
  • Phenytoin has variable effects on warfarin (Coumadin).
  • Phenytoin levels are increased by amiodarone, diltiazem, isoniazid, sulfonamides, fluconazole, cimetidine, and phenylbutazone.
  • Total phenytoin levels may be decreased, but free phenytoin levels may be increased by valproate, diazoxide, and high doses of acetylsalicylic acid (Aspirin).


Adverse Effects:


Dose related: Nystagmus, Ataxia, Gingival hyperplasia
Idiosyncratic: Rash, Blood dyscrasia, Dyskinesias
Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:


Dilantin®
(phenytoin)
30 mg $0.51
50 mg
(infatabs)
$0.60
100 mg $0.83

External Information:


Internet Mental Health
RxList
Pregabalin (Lyrica®)




Pregabalin



Lyrica®


Efficacy:

FDA approved as adjunctive treatment of partial seizures in adults.
Comment: Also used for post-herpetic neuralgia and diabetic peripheral neuropathy.
Probable mechanism of action: Blocks voltage-sensitive calcium channels in the CNS, reduces release of neurotransmitters.

Dose range:


Initial: no greater than 50 mg TID or 75 mg BID
Max: 600 mg/d divided BID or TID
Titrate according to individual tolerability and response.

Pharmocokinetics:


Oral bioavailability: 90%+
Protein binding: None
Elimination: Renal
Half-life: 6 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Increased sedative effects with alchohol or benzodiazepine use. No reported interactions with OCPs or other antiepileptic drugs.
  • Must adjust based on creatinine clearance in renal failure:
    Creatinine Clearance (CLcr) (mL/min) Total PregabalinDaily Dose (mg/day) Dose Regimen
    60 or greater 150 300 600 twice or three times daily
    30 to 60 75 150 300 twice or three times daily
    15 to 30 25 to 50 75 150 once or twice daily
    less than 15 25 25 to 50 75 once daily
  • Supplemental dose should be given immediately after 4-hour dialysis treatments:
    Adjusted dose regimen based on CLcr Supplementary dose
    25 milligrams (mg) once daily one supplemental dose of 25 mg or 50 mg
    25 to 50 mg once daily one supplemental dose of 50 mg or 75 mg
    75 mg once daily one supplemental dose of 100 mg or 150 mg


Adverse Effects:


Dose related:Dizziness (placebo: 9%, 600 mg/d: 43%), Somnolence (placebo: 11%, 600mg/d: 28%), Ataxia (placebo: 3%, 600 mg/d: 15%), Blurred vision, Tremor, Incoordination, and Dry mouth (5–10% above placebo), Weight gain in 12.4% (placebo: 0.5kg, 600 mg/d- 2.3 kg), Myoclonus
Teratogenicity unknown.
Likely to be present in breastmilk, effects on infant unknown
Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:


Lyrica®
(pregabalin)
25 mg $3.63
50 mg $3.67
75 mg $3.81
100 mg $3.81
150 mg $3.81
200 mg $3.81
225 mg $3.81
300 mg $3.81
Primidone (Mysoline®)
mysoline

Primidone



Mysoline®


Efficacy:

Partial seizures, Secondarily generalized seizures, Myoclonic seizures

Dose range:


Adults: 500–1250 mg per day
Children: 5–20 mg/kg per day
Comment: Optimal individual maintenance doses will be determined by clinical response; initial doses are lower; pharmacokinetic interactions may affect dosage requirements.

Regimen:

Three times per day

Pharmocokinetics:


Elimination by hepatic transformation by ring scission to phenylethylmalonamide (PEMA) and oxidation to phenobarbital; elimation is then primarily renal.
Half-life: 8-15 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Carbamazepine increases biotransformation to phenobarbital (minor).
  • Carbamazepine levels decreased by primidone.
  • Phenytoin increases phenobarbital levels and decreases primidone levels.
  • Phenytoin levels decreased by primidone.
  • Valproate increases primidone and phenobarbital levels.
  • Clonazepam increases primidone levels.
  • Ethanol and isoniazid increase primidone levels.
  • Primidone decreases warfarin (coumadin), cyclosporine, digitoxin, and theophylline.


Adverse Effects:


Dose related: Somnolence, Ataxia, Depression
Idiosyncratic: Rash, SLE
Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:


Mysoline®
(primidone)
50 mg $2.45
250 mg $8.81
Generic primidone
50 mg $0.18
250 mg $0.33

External Information:


Internet Mental Health
Rufinamide (Banzel®, Inovelon®)

Rufinamide



Banzel®, Inovelon®


Efficacy:

Adjunctive treatment for seizures associated with Lennox-Gastaut syndrome.

Dose range:


Adults: Initiated at a daily dose of 400–800 mg/day, increased by 400–800 mg every other day until a maximum daily dose of 3200 mg/day.
Children: Initiated at a daily dose of approximately 10 mg/kg/day, increased by 10 mg/kg every other day to a target dose of 45 mg/kg/day or 3200 mg/day, whichever is lower.


Regimen:

Twice a day

Pharmocokinetics:


Elimination is hepatic.
Half-life: 6-10 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Valproate increased trough rufinamide concentrations and decreased clearance by 25%.
  • Phenobarbital, phenytoin, and primidone also increased rufinamide clearance by 25%.
  • Carbamazepine, vigabatrin, oxcarbamazepine, and clobazam did not alter the pharmacokinetics of rufinamide. Rufinamide did not in turn alter trough concentrations of phenytoin, carbamazepine, valproate, phenobarbital, primidone, oxcarbamazepine, clonazepam, and clobazam.


Adverse Effects:


Dose related: Fatigue (20%, placebo: 4%), Somnolence (24%, placebo: 13%), Tremor (12%, placebo: 0%), Dizziness (8%, placebo 0%), Vomiting (22%, placebo: 6%), Headache (varies from below placebo to up to 8% above placebo), Diplopia (frequency not reported), Diarrhea (frequency not reported)
Idiosyncratic: Multi-organ hypersensitivity syndrome Comment: Rufinamide may increase the risk of suicidal thoughts or behaviors.
Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:


Banzel®
(rufinamide)
200 mg
$5.03
400 mg
$10.07
Tiagabine (Gabitril®)

Tiagabine



Gabitril®


Efficacy:

This agent was approved for use in the United States on September 30, 1997 as adjunctive therapy for adults and children over 12 with partial onset seizures.

Dose range:


Suggested adult maintanance dose: 32 to 56 mg/day. Dosage titrations of 4–8 mg/day weekly are suggested by the manufacturer.
Comment: Optimal individual maintenance doses will be determined by clinical response; initial doses are lower; pharmacokinetic interactions may affect dosage requirements.

Regimen:

Three to four times per day

Pharmocokinetics:


Elimination is predominantly hepatic by thiophene ring oxidation and glucuronidation.
Half-life: 7-9 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Tiagabine may slightly decrease valproate levels, but does not appear to affect levels of other antiepileptic drugs.
  • Tiagabine levels are significantly decreased by hepatic enzyme-inducing antiepileptic drugs such as carbamazepine, phenytoin, phenobarbital, and primidone.
  • Valproate significantly decreases binding of tiagabine, leading to increased levels of free tiagabine. The significance of this has not been demonstrated.


Adverse Effects:


Dose related: Tremor, Dizziness, Nervousness, Difficulty concentrating, Sleepiness
Comment: There is concern about teratogenicity with all antiepileptic medications. Specific data on risk of teratogenesis with tiagabine is unknown (Pregnancy category C).

Cost:


Gabitril®
(tiagabine)
2 mg $4.50
4 mg $4.95
12 mg $5.76
16 mg $13.53
Topiramate (Topamax®)


Topiramate



Topamax®


Efficacy:

Topiramate is approved for use for partial seizures, primary general seizures, and Lennox-Gastaut syndrome.

Dose range:


Adults: 400 mg per day. An initiation schedule in which the medication dose is increased by 50 mg/day each week is recommended to reduce adverse effects; slower rates of initiation are used by some physicians.
Comment: Optimal individual maintenance doses will be determined by clinical response; initial doses are lower; pharmacokinetic interactions may affect dosage requirements.

Regimen:

Twice per day

Pharmocokinetics:


Elimination is primarily (approximately 70%) renal in patients not receiving hepatic enzyme-inducing medications. A small proportion is metabolized by hydroxylation, hydrolysis and glucuronidation. At typical concentrations, 13–17% binding to plasma proteins occurs. Hepatic elimination is significant in patients also taking carbamazepine, phenytoin, or barbiturates.
Half-life: 21 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Topiramate may decrease valproate levels.
  • Topiramate may increase phenytoin levels in some patients.
  • Topiramate levels are decreased by carbamazepine, phenytoin and valproate.


Adverse Effects:


Dose related: Psychomotor slowing, Fatigue, Nausea, Parasthesias, Weight loss. In clinical trials of this agent, 1.5% of patients reported the occurrence of kidney stones.
Comment: There is concern about teratogenicity with all antiepileptic medications. Topiramate is associated with an increased risk of cleft palate. (Pregnancy category D).

Cost:


Topamax®
(topiramate)
25 mg $3.73
50 mg $7.44
100 mg $10.15
200 mg $11.92
Topiramate
(generic)
25 mg $0.11
50 mg $0.17
100 mg $0.22
200 mg $0.29
Valproate, Sodium divalproex (Depakene®, Depakote®)

Valproate, Sodium divalproex



Depakene®, Depakote®


Efficacy:

Partial seizures, Secondarily generalized seizures, Generalized seizures, Absence seizures, Myoclonic seizures, Lennox-Gastaut syndrome

Dose range:


Adults: 750–4000 mg per day
Children: 15–70 mg/kg per day
Comment: Optimal individual maintenance doses will be determined by clinical response; initial doses are lower; pharmacokinetic interactions may affect dosage requirements.

Regimen:

Three to four times per day

Pharmocokinetics:


Elimination is almost entirely hepatic by several conjugation and oxidative reactions.
Half-life: 5-15 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Valproate increases phenobarbital, lamotrigine, felbamate, and ethosuximide levels.
  • Valproate decreases total phenytoin levels but increases free phenytoin levels.
  • When valproate is administered with primidone, both primidone and phenobarbital levels may increase.
  • Valproate levels are decreased by carbamazepine, phenobarbital, and phenytoin.
  • Valproate levels are increased by felbamate.
  • Valproate does not increase clearance of oral contraceptive agents.

Adverse Effects:


Dose related: Weight gain, Hair loss, Tremor
Idiosyncratic: Liver failure, Pancreatitis, Thrombocytopenia
Comment: There is concern about teratogenicity with all antiepileptic medications. An increased incidence of neural tube defects and a number of other birth defects has been shown to occur in offspring of mothers who took valproate during pregnancy. A reduction in IQ of the offspring has also been described.

Cost:


Depakote DR®
(divalproex sodium)
125 mg $1.33
250 mg $2.61
500 mg $4.78
Divalproex Sodium
(generic)
125 mg $0.13
250 mg $0.18
500 mg $0.30
Depakote ER®
(divalproex sodium
extended release)
250 mg $2.38
500 mg $4.16
Divalproex Sodium ER
(generic)
250 mg $0.46
500 mg $0.64

External Information:


Internet Mental Health
RxList
Vigabatrin (Sabril®)

Vigabatrin



Sabril®


Efficacy:

Approved as adjunctive therapy for adults with refractory complex partial seizures who have responded inadequately to several alternative treatments. Also approved as monotherapy for infants with infantile spasms.

Dose range:


Adults:Initiate therapy at 500 mg twice daily, increasing total daily dose per instructions. The recommended dose is 1.5 g twice daily.
Infants: Initiate therapy at 50 mg/kg/day twice daily increasing total daily dose per instructions to a maximum of 150 mg/kg/day.

Regimen:

Two times per day

Pharmocokinetics:


Elimination: Renal
Half-life: ~7.5 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Decreased phenytoin plasma levels have been reported.
  • Must adjust based on creatinine clearance in renal failure:
    Creatinine Clearance (CLcr) (mL/min) Dose Reduction
    >50 to 80 mL/min 25%
    >30 to 50 mL/min 50%
    >10 to 30 mL/min 75%

  • FDA Box Warning: WARNING: VISION LOSS
    • SABRIL causes permanent vision loss in infants, children and adults. Because assessing vision loss is difficult in children, the frequency and extent of vision loss in infants and children is poorly characterized. For this reason, the data described below is primarily based on the adult experience.
    • In adults, SABRIL causes permanent bilateral concentric visual field constriction in 30 percent or more of patients that ranges in severity from mild to severe, including tunnel vision to within 10 degrees of visual fixation, and can result in disability. In some cases, SABRIL also can damage the central retina and may decrease visual acuity.
    • The onset of vision loss from SABRIL is unpredictable, and can occur within weeks of starting treatment or sooner, or at any time during treatment, even after months or years.
    • The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss.
    • It is possible that vision loss can worsen despite discontinuing SABRIL.
    • Because of the risk of vision loss, SABRIL should be withdrawn from patients with infantile spasms who fail to show substantial clinical benefit within 2 to 4 weeks of initiation, or sooner if treatment failure becomes obvious. Patient response to and continued need for SABRIL should be periodically reassessed.
    • In infants and children, vision loss may not be detected until it is severe. Nonetheless, unless a patient is formally exempted from periodic ophthalmologic assessment as documented in the SHARE program, vision should be assessed to the extent possible at baseline (no later than 4 weeks after starting SABRIL) and at least every 3 months during therapy. Once detected, vision loss due to SABRIL is not reversible. Vision assessment is also required about 3 to 6 months after the discontinuation of SABRIL therapy.
    • Drug discontinuation should be considered, balancing benefit and risk, if visual loss is documented.

Adverse Effects:


Dose related: Neurotoxicity, Anemia, Somnolence and fatigue, Peripheral neuropathy, Weight gain, Edema, Increased risk of suicidal thoughts or behavior.
Idiosyncratic: Abnormal MRI signal changes have been reported in some infants with infantile spasms.
Note: Sabril causes permanent vision loss (see box warning).
Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:



Sabril®
(vigabatrin)
500 mg $60.62

Zonisamide (Zonegran®)

Zonisamide



Zonegran®


Efficacy:

Adjunctive therapy of partial and secondarily generalized seizures. May be useful in primarily generalized seizures as well.

Dose range:


Adults: 100–400 mg / day
Children: not established


Regimen:

Once or twice a day

Pharmocokinetics:


Elimination is renal.
Half-life: 60-100 hours

Some clinically relevant pharmacokinetic drug interactions:
  • Half-life of zonisamide decreased to 26–46 hours by coadministration with phenytoin, carbamazepine, or valproate. Zonisamide does not affect the metabolism of these other drugs.


Adverse Effects:


Dose related: Somnolence, Difficulty concentrating, Dizziness, Anorexia, Agitation or irritability
Idiosyncratic: Renal stones
Comment: Patients with sensitivity to sulfa drugs should avoid zonisamide.
Comment: There is concern about teratogenicity with all antiepileptic medications.

Cost:


Zonegran®
(zonisamide)
25 mg
$1.37
100 mg
$5.48
Zonisamide
(generic)
25 mg
$0.20
100 mg
$0.37

*Disclaimer: We make no claims for the accuracy of the information on this page and will not be held legally responsible for its contents. Discussion of specific antiepileptic medications does not constitute an endorsement of those agents or of the pharmaceutical companies that manufacture them.

The FDA has required that manufacturers of antiepileptic drugs update product labeling to include a warning about an increased risk of suicidal thoughts or actions with their use, and have a Medication Guide to help patients understand this risk. These requirements affect all approved AEDs except those indicated only for short-term use.

Estimated prices are per pill and are based on the purchase of a 30-day supply at UW-affiliated pharmacies. Purchasing drugs in larger or smaller quantities may affect pricing.

†References: The most comprehensive reference on the properties of antiepileptic drugs is:
Levy, RH, Mattson, RH, and Meldrum, BS.Antiepileptic Drugs. 5th Ed. New York: Raven Press, 1995. Some of the information on this page comes from this source.

Prices are based on HealthTrans 2013 estimates.
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