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Drug Treatment of Seizures

by Bola Adamolekun, MD

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.)

Principles of Long-Term Treatment

There are some general principles for using anticonvulsants:

  • A single drug, usually the 1st or 2nd 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.

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 The initial, ineffective drug is then slowly tapered and eventually withdrawn completely.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 2nd drug helps about 10% of patients, but incidence of adverse effects more than doubles. The blood level of anticonvulsants 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 yr. At that time, stopping the drug may be considered. Most of these drugs can be tapered by 10% every 2 wk. 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 anticonvulsant

  • Partial 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 yr, and 80% within 2 yr. Patients who have a relapse when they are not taking anticonvulsants should be treated indefinitely.

Drug Choice for Long-Term Treatment

The drugs preferred vary according to type of seizure ( Choice of Drugs for Seizures). For more detailed drug-specific information, see Drug Treatment of Seizures : Specific Anticonvulsants. 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 anticonvulsants (which are effective for partial seizures and various types of generalized seizures) include lamotrigine, levetiracetam, topiramate, valproate, and zonisamide.

For partial seizures and generalized tonic-clonic seizures, the newer anticonvulsants (eg, clobazam, clonazepam, ezogabine, 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.

Infantile spasms, atonic seizures, and myoclonic seizures are difficult to treat. Valproate or vigabatrin is preferred, followed by clonazepam. For infantile spasms, corticosteroids for 8 to 10 wk are often effective. The optimal regimen is controversial. ACTH 20 to 60 units IM once/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.

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 anticonvulsants 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.

Choice of Drugs for Seizures

Type

Drugs

Use

Primary generalized tonic-clonic seizures

Valproate

First-line monotherapy

Lamotrigine

Levetiracetam

Topiramate

2nd-line monotherapy or adjunctive therapy

Zonisamide

Adjunctive therapy

Phenobarbital

Although effective, often considered 2nd-line monotherapy because it is sedating and can cause behavioral and learning problems in children

Partial seizures with or without secondary generalization

Carbamazepine

Lamotrigine

Levetiracetam

Oxcarbazepine

Phenytoin

Topiramate

First-line monotherapy

Gabapentin

Lacosamide

Pregabalin

Valproate

Zonisamide

2nd-line monotherapy or adjunctive therapy

Clobazam

Ezogabine

Felbamate

Tiagabine

Vigabatrin

3rd-line monotherapy or adjunctive therapy

Phenobarbital

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

Typical absence seizures

Ethosuximide

Lamotrigine

Valproate

First-line monotherapy

Clobazam

Levetiracetam

Topiramate

Zonisamide

Also effective

Atypical absence seizures

Absence seizures associated with other seizure types

Felbamate

Lamotrigine

Topiramate

Valproate

First-line monotherapy

Clonazepam

Also effective, but often development of tolerance

Acetazolamide

Reserved for refractory cases

Infantile spasms

Atonic seizures

Myoclonic seizures

Valproate

Vigabatrin

First-line monotherapy; risk of irreversible visual field defects

Clonazepam

2nd-line

Tonic and/or atonic seizures in Lennox-Gastaut syndrome

Lamotrigine

Topiramate

Valproate

First-line monotherapy

Clobazam

Felbamate

Zonisamide

Sometimes alternative or adjunctive therapy for atonic seizures

Juvenile myoclonic epilepsy

Valproate

First-line monotherapy

Lamotrigine

Levetiracetam

Topiramate

Zonisamide

2nd-line monotherapy or adjunctive therapy

Unclassifiable seizures

Valproate

First-line monotherapy

Lamotrigine

2nd-line monotherapy

Levetiracetam

Topiramate

Zonisamide

3rd-line monotherapy or adjunctive therapy

Adverse effects

All anticonvulsants may cause an allergic scarlatiniform or morbilliform rash, and none is completely safe during pregnancy ( Seizure Disorders in Pregnancy). Carbamazepine, phenytoin, and valproate are pregnancy category D drugs (ie, teratogenicity occurs in animal and human pregnancies). Risk of neural tube defects is somewhat greater with valproate than other commonly used anticonvulsants. The newer drugs are category C (ie, teratogenicity occurs in animals, but human risk is unknown).

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 anticonvulsants during pregnancy. Yet, because uncontrolled generalized seizures during pregnancy can lead to fetal injury and death, continued treatment with drugs is generally advisable (see Seizure Disorders in Pregnancy). The risk should be put in perspective: Alcohol is more toxic to the developing fetus than any anticonvulsant. 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 anticonvulsants.

Many anticonvulsants decrease folate and B 12 serum levels; oral vitamin supplements can prevent this effect.

Other adverse effects vary by drug (see Drug Treatment of Seizures : Specific Anticonvulsants).

Specific Anticonvulsants

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

Acetazolamide

This drug is indicated for refractory absence seizures.

Dosage is

  • Adults: 4 to 15 mg/kg po bid (not to exceed 1g/day)

  • Children: 4 to 15 mg/kg po bid (not to exceed 1g/day)

Therapeutic and toxic levels are

  • Therapeutic: 8 to 14 μg/mL (34 to 59 μmol/L)

  • Toxic: > 25 μg/mL (> 106 μmol/L)

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

Carbamazepine

This drug is indicated for partial, generalized, and mixed seizures but not absence or myoclonic seizures.

Dosage is

  • Adults: 200 to 600 mg po bid (starting dose is the same for regular and extended-release tablets)

  • Children < 6 yr: 5 to 10 mg/kg po bid (tablets) or 2.5 to 5 mg/kg po qid (suspension)

  • Children 6 to 12 yr: 100 mg po bid (tablets) or 2.5 mL (50 mg) po qid (suspension)

  • Children > 12 yr: 200 mg po bid (tablets) or 5 mL (100 mg) po qid (suspension)

Therapeutic and toxic levels are

  • Therapeutic: 4 to 12 μg/mL (17 to 51 μmol/L)

  • Toxic: > 14 μg/mL (> 59 μmol/L)

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

If people have the HLA-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.

CBC should be monitored routinely for the first year of therapy. Decreases in WBC count and dose-dependent neutropenia (neutrophil count < 1000/μL) 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

This drug is indicated for absence seizures; it is indicated as adjunctive therapy for tonic or atonic seizures in Lennox-Gastaut syndrome and for refractory partial seizures with or without secondary generalization..

Dosage is

  • Adults: 5 mg to 20 mg po bid

  • Children: 5 to 10 mg po bid (up to 20 mg po bid in children > 30 kg)

Therapeutic levels are not clearly defined.

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

Clonazepam

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

Dosage is

  • Adults: Initially, 0.5 mg po tid, up to 5 to 7 mg po tid for maintenance (maximum: 20 mg/day)

  • Children: Initially, 0.01 mg/kg po bid to tid (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 po tid)

Therapeutic and toxic levels are

  • Therapeutic: 25 to 30 ng/mL

  • Toxic: > 80 ng/mL

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

Divalproex

This drug has the same indications as valproate; ie, it is indicated for absence seizures (typical and atypical), partial seizures, tonic-clonic seizures, myoclonic seizures, juvenile myoclonic epilepsy, infantile spasms, and neonatal or febrile seizures. It is also indicated for tonic or atonic seizures in Lennox-Gastaut syndrome.

Dosage is

  • Adults: 5 mg/kg po tid, increased slowly—eg, by 1.67 to 3.33 mg/kg po tid at weekly intervals, especially if other drugs are being taken (maximum: 20 mg/kg tid)

  • Children: Initially, 5 mg/kg po bid or tid, increased by 5 to 10 mg/kg/day at weekly intervals (usual maintenance dose: 10 to 20 mg/kg po tid)

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 μg/mL (347 to 693 μmol/L) before the am dose

  • Toxic levels: > 150 μg/mL (> 1041 μmol/L)

Adverse effects 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 anticonvulsants. Risk of neural tube defects is somewhat greater with valproate than other commonly used anticonvulsants.

Because hepatic side effects are possible, patients taking divalproex should have liver function tests every 3 mo for 1 yr; 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.

Ethosuximide

This drug is indicated for absence seizures.

Dosage is

  • Adults: 250 mg po bid, increased in 250-mg increments every 4 to 7 days (usual maximum: 1500 mg/day)

  • Children 3 to 6 yr: 250 mg po once/day (usual maximum: 20 to 40 mg/kg/day)

  • Children > 6 yr: Initially, 250 mg po bid, 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 μg/mL (283 to 708 μmol/L)

  • Toxic: > 100 μg/mL (> 708 μmol/L)

Toxic levels have not been well-established.

Adverse effects include nausea, lethargy, dizziness, and headache. Idiosyncratic adverse effects include leukocytopenia or pancytopenia, dermatitis, and SLE.

Ezogabine

This drug is indicated for partial seizures as 3rd-line monotherapy or adjunctive therapy for patients ≥ 18 yr.

Dosage is

  • Adults: 200 to 400 mg po tid

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

Adverse effects include urinary retention, neuropsychiatric symptoms (eg, confusion, psychosis, hallucinations, suicidal thoughts), QT prolongation, dizziness, and somnolence.

Felbamate

This drug is indicated for refractory partial seizures and atypical absence seizures in Lennox-Gastaut syndrome.

Dosage is

  • Adults: Initially, 400 mg po tid (maximum: 3600 mg/day)

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

Therapeutic and toxic levels are

  • Therapeutic: 30 to 60 μg/mL (125 to 250 μmol/L)

  • Toxic: Not applicable

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

Fosphenytoin

This drug is indicated for status epilepticus. It also has the same indications as IV phenytoin. They include tonic-clonic seizures, complex partial seizures, prevention of seizures secondary to head trauma, and convulsive status epilepticus.

Dosage is

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

  • Children: Same as that for adults

Heart rate and 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 μg/mL (40 to 80 μmol/L)

  • Toxic: > 25 μg/mL (> 99 μmol/L)

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

Gabapentin

This drug is indicated as adjunctive therapy for partial seizures in patients aged 3 to 12 yr and as adjunctive therapy for partial seizures with or without secondarily generalized tonic-clonic seizures in patients aged ≥ 12 yr.

Dosage is

  • Adults: 300 mg po tid (usual maximum: 1200 mg tid)

  • Children 3 to 12 yr: 12.5 to 20 mg/kg po bid (usual maximum: 50 mg/kg bid)

  • Children ≥ 12 yr: 300 mg po tid (usual maximum: 1200 mg tid)

Therapeutic and toxic levels have not been determined.

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

Lacosamide

This drug is indicated as 2nd-line monotherapy or adjunctive therapy for partial seizures in patients ≥ 17 yr.

Dosage is

  • Adults: 100 to 200 mg po bid

Therapeutic and toxic levels are

  • Therapeutic: 5 to 10 ug/mL

  • Toxic: Not well-established

Adverse effects include dizziness, diplopia, and suicidal thoughts.

Lamotrigine

This drug is indicated as adjunctive therapy for partial seizures in patients ≥ 2 yr, generalized seizures in Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures. In patients ≥ 16 yr, lamotrigine is used as substitution monotherapy for partial or secondarily generalized seizures after a concomitantly used enzyme-inducing anticonvulsant (eg, carbamazepine, phenytoin, phenobarbital) or valproate is stopped.

The metabolism of the lamotrigine is increased by enzyme-inducing anticonvulsants and decreased by enzyme-inhibiting anticonvulsants (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 anticonvulsants and without valproate: 50 mg po once/day for 2 wk, followed by 50 mg po bid for 2 wk, then increased by 100 mg/day every 1 to 2 wk to the usual maintenance dose (150 to 250 mg po bid)

  • With valproate and with or without enzyme-inducing anticonvulsants: 25 mg po once every other day for 2 wk, followed by 25 mg po once/day for 2 wk, then increased by 25 to 50 mg/day every 1 to 2 wk to the usual maintenance dose (100 mg po once/day to 200 mg po bid)

Dosage in patients < 16 yr is

  • With enzyme-inducing anticonvulsants and without valproate: Initially, 1 mg/kg po bid for 2 wk, followed by 2.5 mg/kg po bid for 2 wk, then 5 mg/kg po bid (usual maximum: 15 mg/kg or 250 mg/day)

  • With enzyme-inducing anticonvulsants and valproate: Initially, 0.1 mg/kg po bid for 2 wk, followed by 0.2 mg/kg po bid for 2 wk, then 0.5 mg/kg po bid (usual maximum: 5 mg/kg or 250 mg/day)

  • With valproate and without enzyme-inducing anticonvulsants: Initially, 0.1 to 0.2 mg/kg po bid for 2 wk, followed by 0.1 to 0.25 mg/kg po bid for 2 wk, then 0.25 to 0.5 mg/kg po bid (usual maximum: 2 mg/kg or 150 mg/day)

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

Common adverse effects 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.

Levetiracetam

This drug is indicated as adjunctive therapy for the following: partial seizures in patients ≥ 4 yr, primary generalized tonic-clonic seizures in patients > 6 yr, myoclonic seizures in patients > 12 yr, and juvenile myoclonic epilepsy.

Dosage is

  • Adults: 500 mg po bid (maximum: 2000 mg bid)

  • Children: 250 mg po bid (maximum: 1500 mg bid)

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

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

Oxcarbazepine

This drug is indicated for partial seizures in patients aged 4 to 16 yr as adjunctive therapy and for partial seizures in adults.

Dosage is

  • Adults: 300 mg po bid, increased by 300 mg bid at weekly intervals as needed to 1200 mg po bid

  • Children: Initially, 4 to 15 mg/kg po bid, then increased over 2 wk to 15 mg/kg po bid (the usual maintenance dose)

The therapeutic level is

  • 15 to 25 μg/mL

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

Phenobarbital

This drug is indicated for generalized tonic-clonic seizures, partial 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 po at bedtime

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

  • Infants: 5 to 8 mg/kg po once/day

  • Children 1 to 5 yr: 3 to 5 mg/kg po once/day

  • Children 6 to 12 yr: 4 to 6 mg/kg po once/day

Dosage for status epilepticus is

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

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

Therapeutic and toxic levels are

  • Therapeutic: 10 to 40 μg/mL (43 to 129 μmol/L)

  • Toxic: > 40 μg/mL (> 151 μmol/L)

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

Phenytoin

This drug is indicated for secondarily generalized tonic-clonic seizures, complex partial 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 po at bedtime

  • Neonates: Initially, 2.5 mg/kg po bid (usual maintenance: 2.5 to 4 mg/kg po bid)

Dosage for status epilepticus is

  • Adults: 15 to 20 mg/kg IV

  • Children 6 mo to 3 yr: 8 to10 mg/kg IV

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

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

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

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

Therapeutic and toxic levels are

  • Therapeutic: 10 to 20 μg/mL (40 to 80 μmol/L)

  • Toxic: > 25 μg/mL (> 99 μmol/L)

Adverse effects 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

This drug is indicated as adjunctive therapy for partial seizures.

Dosage is

  • Adults: Initially, 50 mg po tid or 75 mg po bid, increased as needed and tolerated to 200 mg po tid or 300 mg po bid (maximum: 600 mg/day)

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

Adverse effects include dizziness, somnolence, ataxia, blurred vision, diplopia, tremor, and weight gain.

Primidone

This drug is indicated for partial and generalized tonic-clonic seizures.

Dosage is

  • Adults and children > 8 yr: Initially, 100 to 125 mg po at bedtime, followed by 100 to 125 mg po bid on days 4 to 6 and 100 to 125 mg po tid on days 7 to 9, then 250 mg po tid

  • Children < 8 yr: Initially, 50 to 125 mg po at bedtime, increased by 50 to 125 mg/day every 3 to 7 days (usual maintenance dose: 3 to 8 mg/kg tid)

Therapeutic and toxic levels are

  • Therapeutic: 5 to 12 μg/mL (23 to 55 μmol/L)

  • Toxic: > 15 μg/mL (> 69 μmol/L)

Adverse effects are the same as those for phenobarbital: drowsiness, nystagmus, ataxia, and learning difficulties and, in children, paradoxical hyperactivity. Idiosyncratic adverse effects include anemia and rash.

Tiagabine

This drug is indicated as adjunctive therapy for partial seizures in patients ≥ 12 yr.

Dosage is

  • Adults: 4 mg once/day po, increased by 4 to 8 mg/day at weekly intervals to 28 mg po bid or 14 mg po qid (maximum: 56 mg/day)

  • Children ≥ 12 yr: 4 mg po once/day, increased by 4 mg/day as needed at weekly intervals to 16 mg po bid or 8 mg po qid (maximum: 32 mg/day)

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

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

Topiramate

This drug is indicated for partial seizures in patients ≥ 2 yr, for atypical absence seizures, and as 2nd-line monotherapy or adjunctive therapy for primary generalized tonic-clonic seizures.

Dosage is

  • Adults: 50 mg po once/day, increased by 25 to 50 mg/day every 1 to 2 wk (usual maximum: 200 mg bid)

  • Children 2 to 16 yr: 0.5 to 1.5 mg/kg po bid (maximum: 25 mg/day)

Therapeutic levels is

  • 5 to 20 mg/mL (probably)

Adverse effects 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

This drug is indicated for absence seizures (typical and atypical), partial seizures, tonic-clonic seizures, myoclonic seizures, juvenile myoclonic epilepsy, infantile 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

  • Adults: 5 mg/kg po tid, increased slowly—eg, by 1.67 to 3.33 mg/kg tid at weekly intervals, especially if other drugs are being taken (maximum: 20 mg/kg tid)

  • Children: Initially, 5 mg/kg po bid or tid, increased by 5 to 10 mg/kg/day at weekly intervals (usual maintenance: 10 to 20 mg/kg tid)

Therapeutic and toxic levels are

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

  • Toxic levels: > 150 μg/mL (> 1041 μmol/L)

Adverse effects 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 anticonvulsants. Risk of neural tube defects is somewhat greater with valproate than other commonly used anticonvulsants.

Because hepatic adverse effects are possible, patients taking valproate should have liver function tests every 3 mo for 1 yr; 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

This drug is indicated as adjunctive therapy for partial seizures; it is also indicated for infantile spasms.

Dosage is

  • Adults: Initially, 0.5 to 1.0 g/day po, increased by 0.5 to 1.0 g every 1 to 2 wk to usual maintenance dose of 2 to 4 g/day

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

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

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

Zonisamide

This drug is indicated as adjunctive therapy for partial seizures in patients ≥ 16 yr; it is also indicated as alternative or adjunctive therapy for tonic or atonic seizures in Lennox-Gastaut syndrome.

Dosage is

  • Adults: 100 mg po once/day, increased up to 100 mg/day every 2 wk (maximum: 300 mg bid)

Therapeutic and toxic levels are

  • Therapeutic levels: 15 to 40 μg/mL (at > 30 μg/mL, CNS adverse effects are possibly increased)

  • Toxic levels: > 40 μg/mL

Adverse effects 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.

Resources In This Article

Drugs Mentioned In This Article

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

* This is a professional Version *