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Drug Treatment of Seizures

By

Bola Adamolekun

, MD, University of Tennessee Health Science Center

Last full review/revision Jul 2020| Content last modified Jul 2020
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No single drug controls all types of seizures, and different patients require different drugs. Some patients require multiple drugs. (See also the practice guideline for the treatment of refractory epilepsy from the American Academy of Neurology and the American Epilepsy Society.)

Rarely, an antiseizure drug that is effective for one seizure type may aggravate another seizure type.

Principles of Long-Term Treatment

There are some general principles for using antiseizure drugs (also called antiepileptic or anticonvulsant drugs):

  • A single drug, usually the first or second one tried, controls epileptic seizures in about 60% of patients.

  • If seizures are difficult to control from the outset (in 30 to 40% of patients), 2 drugs may eventually be required.

  • If seizures are intractable (refractory to an adequate trial of 2 drugs), patients should be referred to an epilepsy center to determine whether they are candidates for surgery.

Some drugs (eg, phenytoin, valproate), given IV or orally, reach the targeted therapeutic range very rapidly. Others (eg, lamotrigine, topiramate) must be started at a relatively low dose and gradually increased over several weeks to the standard therapeutic dose, based on the patient’s lean body mass. Dose should be tailored to the patient’s tolerance of the drug. Some patients have symptoms of drug toxicity when blood drug levels are low; others tolerate high levels without symptoms. If seizures continue, the daily dose is increased by small increments.

The appropriate dose of any drug is the lowest dose that stops all seizures and has the fewest adverse effects, regardless of blood drug level. Blood drug levels are only guidelines. Once drug response is known, following the clinical course is more useful than measuring blood levels.

Pearls & Pitfalls

  • Determine the drug dose using clinical criteria (the lowest dose that stops seizures and has the fewest adverse effects), regardless of blood levels.

If toxicity develops before seizures are controlled, the dose is reduced to the pretoxicity dose. Then, another drug is added at a low dose, which is gradually increased until seizures are controlled. Patients should be closely monitored because the 2 drugs can interact, interfering with either drug’s rate of metabolic degradation. The initial drug is then slowly tapered and eventually withdrawn completely.

Use of multiple drugs should be avoided if possible because incidence of adverse effects, poor adherence, and drug interactions increases significantly. Adding a second drug helps about 10% of patients, but incidence of adverse effects more than doubles. The blood level of antiseizure drugs is altered by many other drugs, and vice versa. Physicians should be aware of all potential drug-drug interactions before prescribing a new drug.

Once seizures are controlled, the drug should be continued without interruption until patients have been seizure-free for at least 2 years. At that time, stopping the drug may be considered. Most of these drugs can be tapered by 10% every 2 weeks.

Relapse is more likely in patients who have had any of the following:

  • A seizure disorder since childhood

  • Need for > 1 drug to be seizure-free

  • Previous seizures while taking an antiseizure drug

  • Focal-onset or myoclonic seizures

  • Underlying static encephalopathy

  • Abnormal EEG results within the last year

  • Structural lesions (seen on imaging studies)

Of patients who relapse, about 60% do so within 1 year, and 80% within 2 years. Patients who have a relapse when they are not taking antiseizure drugs should be treated indefinitely.

Antiseizure Drug Choice for Long-Term Treatment

The drugs preferred vary according to type of seizure (see table Choice of Drugs for Seizures). For more detailed drug-specific information, see Specific Antiseizure Drugs.

Traditionally, drugs have been separated into older and newer groups based on when they became available. However, some so-called newer drugs have been available for many years now.

Broad-spectrum antiseizure drugs (which are effective for focal-onset seizures and various types of generalized-onset seizures) include

  • Lamotrigine

  • Levetiracetam

  • Topiramate

  • Valproate

  • Zonisamide

For focal-onset seizures and generalized-onset tonic-clonic seizures, the newer antiseizure drugs (eg, clobazam, clonazepam, felbamate, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, zonisamide) are no more effective than the established drugs. However, the newer drugs tend to have fewer adverse effects and to be better-tolerated.

Epileptic (formerly, infantile) spasms, atonic seizures, and myoclonic seizures are difficult to treat. Valproate or vigabatrin is preferred, followed by clonazepam. For epileptic spasms, corticosteroids for 8 to 10 weeks are often effective. The optimal regimen is controversial. Adrenocorticotropic hormone (ACTH) 20 to 60 units IM once a day may be used. A ketogenic diet (a very high fat diet that induces ketosis) may help but is difficult to maintain.

For juvenile myoclonic epilepsy, life-long treatment is usually recommended. Carbamazepine, oxcarbazepine, or gabapentin can exacerbate the seizures. Lamotrigine can be used as second-line monotherapy or adjunctive therapy for juvenile myoclonic epilepsy; however, it can aggravate myoclonic seizures in some patients with juvenile myoclonic epilepsy.

For febrile seizures, drugs are not recommended unless children have a subsequent seizure in the absence of febrile illness. Previously, many physicians gave phenobarbital or other antiseizure drugs to children with complicated febrile seizures to prevent nonfebrile seizures from developing, but this treatment does not appear effective, and long-term use of phenobarbital reduces learning capacity.

For seizures due to alcohol withdrawal, drugs are not recommended. Instead, treating the withdrawal syndrome tends to prevent seizures. Treatment usually includes a benzodiazepine.

Table
icon

Choice of Drugs for Seizures

Type

Drugs

Use

Primarily generalized-onset tonic-clonic seizures

Divalproex

Valproate

First-line monotherapy

Lamotrigine

Levetiracetam

Topiramate

Second-line monotherapy or adjunctive therapy

Perampanel

Zonisamide

Adjunctive therapy

Phenobarbital

Although effective, often considered second-line monotherapy because it is sedating and can cause behavioral and learning problems in children

Various types of focal-onset and focal-to-bilateral tonic-clonic seizures

Carbamazepine

Fosphenytoin

Lamotrigine

Levetiracetam

Oxcarbazepine

Phenytoin

Topiramate

First-line monotherapy

Divalproex

Eslicarbazepine

Gabapentin

Lacosamide

Perampanel

Pregabalin

Valproate

Zonisamide

Second-line monotherapy or adjunctive therapy

Clobazam

Felbamate

Tiagabine

Vigabatrin

Third-line monotherapy or adjunctive therapy

Phenobarbital

Although effective, often considered less desirable because it is sedating and can cause behavioral problems in children

Typical nonmotor (absence) seizures

Divalproex

Ethosuximide

Lamotrigine

Valproate

First-line monotherapy

Clobazam

Levetiracetam

Topiramate

Zonisamide

Also effective

Atypical nonmotor (absence) seizures

Nonmotor seizures associated with other seizure types

Divalproex

Felbamate

Lamotrigine

Topiramate

Valproate

First-line monotherapy

Clonazepam

Also effective, but often development of tolerance

Acetazolamide

Reserved for refractory cases

Epileptic (infantile) spasms

Atonic seizures

Myoclonic seizures

Divalproex

Valproate

First-line monotherapy

Vigabatrin

Risk of irreversible visual field defects

Clonazepam

Second-line

Dravet syndrome

Cannabidiol*

Clobazam

Topiramate

Valproate

Adjunctive therapy.

Tonic and/or atonic seizures in Lennox-Gastaut syndrome

Divalproex

Lamotrigine

Topiramate

Valproate

First-line monotherapy

Cannabidiol

Adjunctive therapy

Clobazam

Felbamate

Zonisamide

Sometimes alternative or adjunctive therapy for atonic seizures

Juvenile myoclonic epilepsy

Divalproex

Valproate

First-line monotherapy

Lamotrigine

Levetiracetam

Topiramate

Zonisamide

Second-line monotherapy or adjunctive therapy

Unclassifiable seizures

Divalproex

Valproate

First-line monotherapy

Lamotrigine

Second-line monotherapy

Levetiracetam

Topiramate

Zonisamide

Third-line monotherapy or adjunctive therapy

Note: Ezogabine has been withdrawn from the market because of limited use; the drug had a boxed warning for retinal abnormalities and potential vision loss.

* Carbamazepine, phenytoin, and lamotrigine can worsen myoclonus and exacerbate seizures in patients with Dravet syndrome.

Lamotrigine can aggravate myoclonic seizures in some patients with juvenile myoclonic epilepsy.

Adverse effects

The different adverse effects of antiseizure drugs may influence the choice of drug for an individual patient. For example, antiseizure drugs that cause weight gain (eg, valproate) may not be the best option for an overweight patient, and topiramate or zonisamide may not be suitable for patients with history of kidney stones.

Some adverse effects of antiseizure drugs can be minimized by increasing the dose gradually.

Overall, the newer antiseizure drugs have advantages, such as better tolerability, less sedation, and fewer drug interactions.

All antiseizure drugs may cause an allergic scarlatiniform or morbilliform rash.

Some types of seizures may be worsened by certain antiseizure drugs. For example, pregabalin and lamotrigine may worsen myoclonic seizures; carbamazepine may worsen absence, myoclonic, and atonic seizures.

Other adverse effects vary by drug (see Specific Antiseizure Drugs).

Antiseizure drug use during pregnancy

Antiseizure drugs are associated with an increased risk of teratogenicity.

Fetal antiepileptic drug syndrome (cleft lip, cleft palate, cardiac defects, microcephaly, growth retardation, developmental delay, abnormal facies, limb or digit hypoplasia) occurs in 4% of children of women who take antiseizure drugs during pregnancy.

Yet, because uncontrolled generalized-onset seizures during pregnancy can lead to fetal injury and death, continued treatment with drugs is generally advisable. Women should be informed of the risks of antiseizure drugs to the fetus, and the risk should be put in perspective: Alcohol is more toxic to the developing fetus than any antiseizure drug. Taking folate supplements before conception helps reduce risk of neural tube defects and should be recommended to all women who are of childbearing age and who take antiseizure drugs.

Many antiseizure drugs decrease folate and B12 serum levels; oral vitamin supplements can prevent this effect.

Risk of teratogenicity is less with monotherapy and varies by drug; none is completely safe during pregnancy (see table Choice of Drugs for Seizures). Risk with carbamazepine, phenytoin, and valproate is relatively high; there is evidence that they have caused congenital malformations in humans (see table Some Drugs With Adverse Effects During Pregnancy). Risk of neural tube defects is somewhat greater with valproate than other commonly used antiseizure drugs. Risk with some of the newer drugs (eg, lamotrigine) seems to be less.

Specific Antiseizure Drugs

Dosing for adults is based on a weight of 70 kg if not specified.

Acetazolamide

Acetazolamide is indicated for refractory absence seizures.

Dosage is

  • Adults: 4 to 15 mg/kg orally 2 times a day (not to exceed 1g/day)

  • Children: 4 to 15 mg/kg orally 2 times a day (not to exceed 1g/day)

Therapeutic and toxic levels are

  • Therapeutic: 8 to 14 mcg/mL (34 to 59 micromole/L)

  • Toxic: > 25 mcg/mL (> 106 micromole/L)

Adverse effects of acetazolamide include renal calculi, dehydration, and metabolic acidosis.

Cannabidiol

A highly purified form of cannabidiol is now available for adjunctive therapy of seizures in Lennox-Gastaut syndrome and Dravet syndrome in patients ≥ 2 years. The mechanism of action is unknown.

Dosage is

  • Initially, 2.5 mg/kg 2 times a day, increased after 1 week to a maintenance dose of 5 mg/kg 2 times a day (maximum recommended dose: 10 mg/kg 2 times a day)

Adverse effects of cannabidiol include somnolence, hepatocellular injury with elevated aminotransferases, anorexia, fatigue, insomnia, and diarrhea.

Carbamazepine

Carbamazepine is indicated for focal-onset, generalized-onset tonic-clonic, and mixed seizures but not absence, myoclonic, or atonic seizures.

Dosage is

  • Adults: 200 to 600 mg orally 2 times a day (starting dose is the same for regular and extended-release tablets)

  • Children < 6 years: 5 to 10 mg/kg orally 2 times a day (tablets) or 2.5 to 5 mg/kg orally 4 times a day (suspension)

  • Children 6 to 12 years: 100 mg orally 2 times a day (tablets) or 2.5 mL (50 mg) orally 4 times a day (suspension)

  • Children > 12 years: 200 mg orally 2 times a day (tablets) or 5 mL (100 mg) orally 4 times a day (suspension)

Therapeutic and toxic levels are

  • Therapeutic: 4 to 12 mcg/mL (17 to 51 micromole/L)

  • Toxic: > 14 mcg/mL (> 59 micromole/L)

Adverse effects of carbamazepine include diplopia, dizziness, nystagmus, gastrointestinal (GI) upset, dysarthria, lethargy, a low white blood cell (WBC) count (3000 to 4000/mcL), and severe rash (in 5%). Idiosyncratic adverse effects include granulocytopenia, thrombocytopenia, liver toxicity, and aplastic anemia.

If people have the HLA (human leukocyte antigen)-B*1502 allele, particularly Asians, risk of severe rash (Stevens-Johnson syndrome or toxic-epidermal necrolysis) is higher than the usual rate of 5%. Thus, before prescribing carbamazepine, clinicians should test for HLAs, at least in Asians.

Complete blood count (CBC) should be monitored routinely for the first year of therapy. Decreases in WBC count and dose-dependent neutropenia (neutrophil count < 1000/mcL) are common. Sometimes, if no other drug can be readily substituted, decreasing the dose can manage these effects. However, if the WBC count decreases rapidly, carbamazepine should be stopped.

Clobazam

Clobazam is indicated for absence seizures; it is indicated as adjunctive therapy for tonic or atonic seizures in Lennox-Gastaut syndrome and for refractory focal-onset seizures with or without focal-to-bilateral tonic-clonic generalization.

Dosage is

  • Adults: 5 mg to 20 mg orally 2 times a day

  • Children: 5 to 10 mg orally 2 times a day (up to 20 mg orally 2 times a day in children > 30 kg)

Therapeutic levels are not clearly defined.

Adverse effects of clobazam include somnolence, sedation, constipation, ataxia, suicidal thoughts, drug dependency, irritability, and dysphagia.

Clonazepam

Clonazepam is indicated for atypical absence seizures in Lennox-Gastaut syndrome, atonic and myoclonic seizures, epileptic spasms, and possibly absence seizures refractory to ethosuximide.

Dosage is

  • Adults: Initially, 0.5 mg orally 3 times a day, up to 5 to 7 mg orally 3 times a day for maintenance (maximum: 20 mg/day)

  • Children: Initially, 0.01 mg/kg orally 2 to 3 times a day (maximum: 0.05 mg/kg/day), increased by 0.25 to 0.5 mg every 3 days until seizures are controlled or adverse effects occur (usual maintenance dose: 0.03 to 0.06 mg/kg orally 3 times a day)

Therapeutic and toxic levels are

  • Therapeutic: 25 to 30 ng/mL (79 to 95.01 nmol/L)

  • Toxic: > 80 ng/mL (> 253.36 nmol/L)

Adverse effects of clonazepam include drowsiness, ataxia, behavioral abnormalities, and partial or complete tolerance to beneficial effects (usually in 1 to 6 months); serious reactions rare.

Divalproex

Divalproex is a compound composed of sodium valproate and valproic acid and has the same indications as valproate; ie, it is indicated for absence seizures (typical and atypical), focal-onset seizures, tonic-clonic seizures, myoclonic seizures, juvenile myoclonic epilepsy, epileptic spasms, and neonatal or febrile seizures. It is also indicated for tonic or atonic seizures in Lennox-Gastaut syndrome.

Dosage is

  • Children and adults: 10 to 15 mg/kg/day orally in 3-times-a-day doses (eg, 5 mg 3 times a day), increased slowly—eg, by 5 to 10 mg/kg/day (1.67 to 3.33 mg/kg orally 3 times a day) at weekly intervals, especially if other drugs are being taken (maximum: 60 mg/kg/day)

Children may be given delayed (slow)-release tablets for once/day dosing. The total daily dose is 8 to 20% higher than that for the regular tablets. Delayed-release divalproex may have fewer adverse effects, possibly improving adherence.

Therapeutic and toxic levels are

  • Therapeutic levels: 50 to 100 mcg/mL (347 to 693 micromole/L) before the am dose

  • Toxic levels: > 150 mcg/mL (> 1041 micromole/L)

Adverse effects of divalproex include nausea and vomiting, GI intolerance, weight gain, reversible alopecia (in 5%), transient drowsiness, transient neutropenia, and tremor. Hyperammonemic encephalopathy may occur idiosyncratically. Rarely, fatal hepatic necrosis occurs, particularly in young neurologically impaired children treated with multiple antiseizure drugs. Risk of neural tube defects is somewhat greater with divalproex than other commonly used antiseizure drugs.

Because hepatic side effects are possible, patients taking divalproex should have liver function tests every 3 months for 1 year; if serum transaminases or ammonia levels increase significantly (> 2 times the upper limit of normal), the drug should be stopped. An increase in ammonia up to 1.5 times the upper limit of normal can be tolerated safely.

Eslicarbazepine

Eslicarbazepine is indicated for treatment of focal-onset seizures as monotherapy or adjunctive therapy. Unlike carbamazepine and oxcarbazepine, eslicarbazepine is given once a day, possibly improving adherence. Efficacy of eslicarbazepine, carbamazepine, and oxcarbazepine is comparable.

Dosage is

  • Initially, 400 mg orally once a day, increased by 400 mg to 600 mg/day at weekly intervals to a recommended maintenance dose of 800 to 1600 mg once a day

Eslicarbazepine is not indicated for use in patients < 18 years.

Adverse effects of eslicarbazepine include dizziness, diplopia, somnolence, hyponatremia, suicidal ideation, and dermatologic reactions, including Stevens-Johnson syndrome.

Ethosuximide

Ethosuximide is indicated for absence seizures.

Dosage is

  • Adults: 250 mg orally 2 times a day, increased in 250-mg increments every 4 to 7 days (usual maximum: 1500 mg/day)

  • Children 3 to 6 years: 250 mg orally once a day (usual maximum: 20 to 40 mg/kg/day)

  • Children > 6 years: Initially, 250 mg orally 2 times a day, increased by 250 mg/day as needed every 4 to 7 days (usual maximum: 1500 mg/day)

Therapeutic and toxic levels are

  • Therapeutic: 40 to 100 mcg/mL (283 to 708 micromole/L)

  • Toxic: > 100 mcg/mL (> 708 micromole/L)

Toxic levels have not been well-established.

Adverse effects of ethosuximide include nausea, lethargy, dizziness, and headache. Idiosyncratic adverse effects include leukocytopenia or pancytopenia, dermatitis, and systemic lupus erythematosus (SLE).

Felbamate

Felbamate is indicated for refractory focal-onset seizures and atypical absence seizures in Lennox-Gastaut syndrome.

Dosage is

  • Adults: Initially, 400 mg orally 3 times a day (maximum: 3600 mg/day)

  • Children: Initially, 15 mg/kg/day orally (maximum: 45 mg/kg/day)

Therapeutic and toxic levels are

  • Therapeutic: 30 to 60 mcg/mL (125 to 250 micromole/L)

  • Toxic: Not applicable

Adverse effects of felbamate include headache, fatigue, liver failure, and, rarely, aplastic anemia. Written informed consent is required from the patient.

Fosphenytoin

Fosphenytoin is indicated for status epilepticus. It also has the same indications as IV phenytoin. They include tonic-clonic seizures, focal impaired-awareness seizures, prevention of seizures secondary to head trauma, and convulsive status epilepticus.

Dosage is

  • Adults: 10 to 20 phenytoin equivalents (PE) mg/kg IV or IM once (maximum infusion rate: 150 PE/min)

  • Children: Same as that for adults

The dose of fosphenytoin is given in phenytoin equivalents (PE); fosphenytoin 1.5 mg is equivalent to phenytoin 1 mg.

Heart rate and blood pressure (BP) must be monitored if the maximum infusion rate is used, but not at slower rates.

Therapeutic and toxic levels are

  • Therapeutic: 10 to 20 mcg/mL (40 to 80 micromole/L)

  • Toxic: > 25 mcg/mL (> 99 micromole/L)

Adverse effects of fosphenytoin include ataxia, dizziness, somnolence, headache, pruritus, and paresthesias.

Gabapentin

Gabapentin is indicated as adjunctive therapy for focal-onset seizures in patients aged 3 to 12 years and as adjunctive therapy for focal-onset seizures with or without focal-to-bilateral tonic-clonic seizures in patients aged ≥ 12 years.

Dosage is

  • Adults: 300 mg orally 3 times a day (usual maximum: 1200 mg 3 times a day)

  • Children 3 to 12 years: 12.5 to 20 mg/kg orally 2 times a day (usual maximum: 50 mg/kg 2 times a day)

  • Children ≥ 12 years: 300 mg orally 3 times a day (usual maximum: 1200 mg 3 times a day)

Therapeutic and toxic levels have not been determined.

Adverse effects of gabapentin include drowsiness, dizziness, weight gain, and headache and, in patients aged 3 to 12 years, somnolence, aggressive behavior, mood lability, and hyperactivity.

Lacosamide

Lacosamide is indicated as second-line monotherapy or adjunctive therapy for focal-onset seizures in patients ≥ 17 years.

Dosage is

  • Adults: 100 to 200 mg orally 2 times a day

Lacosamide is not indicated for use in children < 17 years.

Therapeutic and toxic levels are

  • Therapeutic: 5 to 10 ug/mL

  • Toxic: Not well-established

Adverse effects of lacosamide include dizziness, diplopia, and suicidal thoughts.

Lamotrigine

Lamotrigine is indicated as adjunctive therapy for focal-onset seizures in patients ≥ 2 years, generalized-onset seizures in Lennox-Gastaut syndrome, and generalized-onset tonic-clonic seizures. In patients ≥ 16 years, lamotrigine is used as substitution monotherapy for focal-onset or focal-to-bilateral tonic-clonic seizures after a concomitantly used enzyme-inducing antiseizure drug (eg, carbamazepine, phenytoin, phenobarbital) or valproate is stopped.

The metabolism of the lamotrigine is increased by enzyme-inducing antiseizure drugs and decreased by enzyme-inhibiting drugs (eg, valproate). Valproate inhibits a broad-spectrum of hepatic enzymes. Lamotrigine may have a special synergistic effect when used with valproate.

Dosage in adults is

  • With enzyme-inducing antiseizure drugs and without valproate: 50 mg orally once a day for 2 weeks, followed by 50 mg orally 2 times a day for 2 weeks, then increased by 100 mg/day every 1 to 2 weeks to the usual maintenance dose (150 to 250 mg orally 2 times a day)

  • With valproate and with or without enzyme-inducing antiseizure drugs: 25 mg orally once every other day for 2 weeks, followed by 25 mg orally once a day for 2 weeks, then increased by 25 to 50 mg/day every 1 to 2 weeks to the usual maintenance dose (100 mg orally once a day to 200 mg orally 2 times a day)

Dosage in patients < 16=""> is

  • With enzyme-inducing antiseizure drugs and without valproate: Initially, 1 mg/kg orally 2 times a day for 2 weeks, followed by 2.5 mg/kg orally 2 times a day for 2 weeks, then 5 mg/kg orally 2 times a day (usual maximum: 15 mg/kg or 250 mg/day)

  • With enzyme-inducing antiseizure drugs and valproate: Initially, 0.1 mg/kg orally 2 times a day for 2 weeks, followed by 0.2 mg/kg orally 2 times a day for 2 weeks, then 0.5 mg/kg orally 2 times a day (usual maximum: 5 mg/kg or 250 mg/day)

  • With valproate and without enzyme-inducing antiseizure drugs: Initially, 0.1 to 0.2 mg/kg orally 2 times a day for 2 weeks, followed by 0.1 to 0.25 mg/kg orally 2 times a day for 2 weeks, then 0.25 to 0.5 mg/kg orally 2 times a day (usual maximum: 2 mg/kg or 150 mg/day)

No significant relationship between blood levels and pharmacologic effect has been observed.

Common adverse effects of lamotrigine include headache, dizziness, drowsiness, insomnia, fatigue, nausea, vomiting, diplopia, ataxia, tremor, menstrual abnormalities, and rash (in 2 to 3%), which sometimes progresses to Stevens-Johnson syndrome (in 1/50 to 100 children and 1/1000 adults). Risk of rash can be reduced by increasing the dosage more slowly, especially if lamotrigine is added to valproate. Lamotrigine may exacerbate myoclonic seizures in adults.

Levetiracetam

Levetiracetam is indicated as adjunctive therapy for focal-onset seizures in patients ≥ 4 years, generalized-onset tonic-clonic seizures in patients > 6 years, myoclonic seizures in patients > 12 years, and juvenile myoclonic epilepsy.

Dosage is

  • Adults: 500 mg orally 2 times a day (maximum: 2000 mg 2 times a day)

  • Children: 250 mg orally 2 times a day (maximum: 1500 mg 2 times a day)

No significant relationship between blood levels and pharmacologic effect has been observed.

Adverse effects of levetiracetam include fatigue, weakness, ataxia, and mood and behavioral changes.

Oxcarbazepine

Oxcarbazepine is indicated for focal-onset seizures in patients aged 4 to 16 years as adjunctive therapy and for focal-onset seizures in adults.

Dosage is

  • Adults: 300 mg orally 2 times a day, increased by 300 mg 2 times a day at weekly intervals as needed to 1200 mg orally 2 times a day

  • Children: Initially, 4 to 15 mg/kg orally 2 times a day, then increased over 2 weeks to 15 mg/kg orally 2 times a day (the usual maintenance dose)

The therapeutic level is

  • 3 to 36 mcg/mL (12 to 140 micromole/L)

Adverse effects of oxcarbazepine include fatigue, nausea, abdominal pain, headache, dizziness, somnolence, leukopenia, diplopia, and hyponatremia (in 2.5%).

Perampanel

Perampanel is indicated as adjunctive therapy for focal-onset seizures and generalized-onset tonic-clonic seizures in people who have epilepsy and are ≥ 12 years.

Dosage is

  • Initially, 2 mg orally once a day, increased by 2 mg/day at weekly intervals, based on clinical response and tolerability, until reaching the recommended maintenance dose of 8 to 12 mg once a day for focal-onset seizures and 8 mg once a day for primarily generalized seizures

Perampanel is not indicated for use in children < 12 years.

Adverse effects of perampanel include aggressiveness, mood and behavioral changes, suicidal ideation, dizziness, somnolence, fatigue. irritability, falls, headache, nausea, vomiting, abdominal pain, weight gain, and gait disturbances.

Phenobarbital

Phenobarbital is indicated for generalized-onset tonic-clonic seizures, focal-onset seizures, status epilepticus, and neonatal seizures.

Dosage is usually once/day, but divided doses may be used. For all indications except status epilepticus, dose is

  • Adults: 1.5 to 4 mg/kg orally at bedtime

  • Neonates: 3 to 4 mg/kg orally once a day, then increased (based on clinical response and blood levels)

  • Infants: 5 to 8 mg/kg orally once a day

  • Children 1 to 5 years: 3 to 5 mg/kg orally once a day

  • Children 6 to 12 years: 4 to 6 mg/kg orally once a day

Dosage for status epilepticus is

  • Adults: 15 to 20 mg/kg IV (maximum infusion rate: 60 mg/minute or 2 mg/kg/minute)

  • Children: 10 to 20 mg/kg IV (maximum infusion rate: 100 mg/minute or 2 mg/kg/minute)

Therapeutic and toxic levels are

  • Therapeutic: 10 to 40 mcg/mL (43 to 129 micromole/L)

  • Toxic: > 40 mcg/mL (> 151 micromole/L)

Adverse effects of phenobarbital include drowsiness, nystagmus, ataxia, and, in children, learning difficulties and paradoxical hyperactivity. Idiosyncratic adverse effects include anemia and rash.

Phenytoin

Phenytoin is indicated for focal-to-bilateral tonic-clonic seizures, focal impaired-awareness seizures, and convulsive status epilepticus. It is also used to prevent seizures secondary to head trauma.

Dosage for all indications except status epilepticus is

  • Adults: 4 to 7 mg/kg orally at bedtime

  • Neonates: Initially, 2.5 mg/kg orally 2 times a day (usual maintenance: 2.5 to 4 mg/kg orally 2 times a day)

Dosage for status epilepticus is

  • Adults: 15 to 20 mg/kg IV

  • Children 6 months to 3 years: 8 to 10 mg/kg IV

  • Children 4 to 6 years: 7.5 to 9 mg/kg IV

  • Children 7 to 9 years: 7 to 8 mg/kg IV

  • Children 10 to 16 years: 6 to 7 mg/kg IV

The maximum infusion rate is 1 to 3 mg/kg/minute for children (up to 16 years) and 50 mg/minute for adults.

Therapeutic and toxic levels are

  • Therapeutic: 10 to 20 mcg/mL (40 to 80 micromole/L)

  • Toxic: > 25 mcg/mL (> 99 micromole/L)

Adverse effects of phenytoin include megaloblastic anemia, gingival hyperplasia, hirsutism, adenopathy, and loss of bone density. Folic acid supplements (0.5 mg/day) can markedly lessen gingival hyperplasia. At high blood levels, phenytoin can cause nystagmus, ataxia, dysarthria, lethargy, irritability, nausea, vomiting, and confusion. Idiosyncratic adverse effects include rash, exfoliative dermatitis, and, rarely, exacerbation of seizures.

Pregabalin

Pregabalin is indicated as adjunctive therapy for focal-onset seizures.

Dosage is

  • Adults: Initially, 50 mg orally 3 times a day or 75 mg orally 2 times a day, increased as needed and tolerated to 200 mg orally 3 times a day or 300 mg orally 2 times a day (maximum: 600 mg/day)

Pregabalin is not indicated for use in children < 18 years.

No significant relationship between blood levels and pharmacologic effect has been observed.

Adverse effects of pregabalin include dizziness, somnolence, ataxia, blurred vision, diplopia, tremor, and weight gain. Pregabalin may exacerbate myoclonic seizures.

Tiagabine

Tiagabine is indicated as adjunctive therapy for focal-onset seizures in patients ≥ 12 years.

Dosage is

  • Adults: 4 mg orally once a day, increased by 4 to 8 mg/day at weekly intervals to 28 mg orally 2 times a day or 14 mg orally 4 times a day (maximum: 56 mg/day)

  • Children ≥ 12 years: 4 mg orally once a day, increased by 4 mg/day as needed at weekly intervals to 16 mg orally 2 times a day or 8 mg orally 4 times a day (maximum: 32 mg/day)

No significant relationship between blood levels and pharmacologic effect has been observed.

Adverse effects of tiagabine include dizziness, light-headedness, confusion, slowed thinking, fatigue, tremor, sedation, nausea, and abdominal pain.

Topiramate

Topiramate is indicated for focal-onset seizures in patients ≥ 2 years, for atypical absence seizures, and as second-line monotherapy or adjunctive therapy for primarily generalized tonic-clonic seizures.

Dosage is

  • Adults: 50 mg orally once a day, increased by 25 to 50 mg/day every 1 to 2 weeks (usual maximum: 200 mg 2 times a day)

  • Children 2 to 16 years: 0.5 to 1.5 mg/kg orally 2 times a day (maximum: 25 mg/day)

Therapeutic level is

  • 5 to 20 mg/mL (15 to 59 micromole/L) probably

Adverse effects of topiramate include decreased concentration, paresthesias, fatigue, speech dysfunction, confusion, anorexia, weight loss, reduced sweating, metabolic acidosis, nephrolithiasis (in 1 to 5%), and psychosis (in 1%).

Valproate

Valproate is indicated for absence seizures (typical and atypical), focal-onset seizures, tonic-clonic seizures, myoclonic seizures, juvenile myoclonic epilepsy, epileptic spasms, and neonatal or febrile seizures. It is also indicated for tonic or atonic seizures in Lennox-Gastaut syndrome. Valproate inhibits a broad-spectrum of hepatic enzymes.

Dosage is

  • Children and adults ≥ 10 years: 10 to 15 mg/kg/day orally in 3-times-a-day doses (eg, 5 mg 3 times a day), increased slowly—eg, by 5 to 10 mg/kg/day (1.67 to 3.33 mg/kg 3 times a day ) at weekly intervals, especially if other drugs are being taken (maximum: 60 mg/kg/day)

Therapeutic and toxic levels are

  • Therapeutic levels: 50 to 100 mcg/mL (347 to 693 micromole/L) before the am dose

  • Toxic levels: > 150 mcg/mL (> 1041 micromole/L)

Adverse effects of valproate include nausea and vomiting, GI intolerance, weight gain, reversible alopecia (in 5%), transient drowsiness, transient neutropenia, and tremor. Hyperammonemic encephalopathy may occur idiosyncratically. Rarely, fatal hepatic necrosis occurs, particularly in young neurologically impaired children treated with multiple antiseizure drugs. Risk of neural tube defects is somewhat greater with valproate than other commonly used antiseizure drugs.

Because hepatic adverse effects are possible, patients taking valproate should have liver function tests every 3 months for 1 years; if serum transaminases or ammonia levels increase significantly (> 2 times the upper limit of normal), the drug should be stopped. An increase in ammonia up to 1.5 times the upper limit of normal can be tolerated safely.

Vigabatrin

Vigabatrin is indicated as adjunctive therapy for focal-onset seizures; it is also indicated for epileptic spasms.

Dosage is

  • Adults: Initially, 500 mg orally 2 times a day, increased by 250 mg 2 times a day weekly as needed to usual maintenance dose of 1500 mg orally 2 times a day

  • Children: Titrated up to 100 mg/kg/day orally in 1 week, then usual maintenance dose of 100 to150 mg/kg/day

No significant relationship between blood levels and pharmacologic effect has been observed.

Adverse effects of vigabatrin include drowsiness, dizziness, headache, fatigue, and irreversible visual field defects (requires regular visual field evaluations).

Zonisamide

Zonisamide is indicated as adjunctive therapy for focal-onset seizures in patients ≥ 16 years; it is also indicated as alternative or adjunctive therapy for tonic or atonic seizures in Lennox-Gastaut syndrome.

Dosage is

  • Adults: 100 mg orally once a day, increased up to 100 mg/day every 2 weeks (maximum: 300 mg 2 times a day)

Zonisamide is not commonly used in children < 16 years.

Therapeutic and toxic levels are

  • Therapeutic levels: 10 to 40 mcg/mL (45 to 180 micromole/L; at > 30 mcg/mL,central nervous system [CNS] adverse effects are possibly increased)

  • Toxic levels: > 40 mcg/mL

Adverse effects of zonisamide include sedation, fatigue, dizziness, ataxia, confusion, cognitive impairment (eg, impaired word finding), weight loss, anorexia, and nausea. Less commonly, zonisamide causes depression, psychosis, urinary calculi, and oligohidrosis.

More Information

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

Drugs Mentioned In This Article

Drug Name Select Trade
APTIOM
KEPPRA
TRILEPTAL
DIAMOX
TEGRETOL
No US brand name
CEREBYX
ZARONTIN
LAMICTAL
ZONEGRAN
VIMPAT
TOPAMAX
SABRIL
KLONOPIN
LYRICA
NEURONTIN
FELBATOL
DILANTIN
POTIGA
GABITRIL
ONFI
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