Drug Treatment of Seizures

By Bola Adamolekun, MD, University of Tennessee Health Science Center

Last full review/revision Nov 2018| Content last modified Nov 2018 

 

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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.)

An antiseizure drug that is effective for one seizure type may aggravate another seizure type. This effect is rare.

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 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.

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 2nd 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 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 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 yr, and 80% within 2 yr. 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 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. Lamotrigine can be used as 2nd-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

Choice of Drugs for Seizures

 

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 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 mcg/mL (34 to 59 mcmol/L)
  
• Toxic: > 25 mcg/mL (> 106 mcmol/L)
  

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

 

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 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 mcg/mL (17 to 51 mcmol/L)
  
• Toxic: > 14 mcg/mL (> 59 mcmol/L)
  

Adverse effects of carbamazepine include diplopia, dizziness, nystagmus, GI upset, dysarthria, lethargy, a low 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-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/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 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 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 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 of clonazepam include drowsiness, ataxia, behavioral abnormalities, and partial or complete tolerance to beneficial effects (usually in 1 to 6 mo); 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 po in tid doses (eg, 5 mg tid), increased slowly—eg, by 5 to 10 mg/kg/day (1.67 to 3.33 mg/kg po tid) 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 mcmol/L) before the am dose
  
• Toxic levels: > 150 mcg/mL (> 1041 mcmol/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 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.

 

Eslicarbazepine

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

Dosage is

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

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

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 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 mcg/mL (283 to 708 mcmol/L)
  
  
• Toxic: > 100 mcg/mL (> 708 mcmol/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 SLE.

Felbamate

Felbamate is indicated for refractory focal-onset 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 mcg/mL (125 to 250 mcmol/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)/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 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 mcmol/L)
  
  
• Toxic: > 25 mcg/mL (> 99 mcmol/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 yr and as adjunctive therapy for focal-onset seizures with or without focal-to-bilateral 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 of gabapentin include drowsiness, dizziness, weight gain, and headache and, in patients aged 3 to 12 yr, somnolence, aggressive behavior, mood lability, and hyperactivity.

Lacosamide

Lacosamide is indicated as 2nd-line monotherapy or adjunctive therapy for focal-onset seizures in patients ≥ 17 yr.

Dosage is

• Adults: 100 to 200 mg po bid
  
  

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

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 yr, generalized-onset seizures in Lennox-Gastaut syndrome, and generalized-onset tonic-clonic seizures. In patients ≥ 16 yr, 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 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 antiseizure drugs: 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=""> is

• With enzyme-inducing antiseizure drugs 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 antiseizure drugs 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 antiseizure drugs: 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 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 yr, generalized-onset 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 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 yr as adjunctive therapy and for focal-onset 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 mcg/mL
  

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 yr.

Dosage is

• Initially, 2 mg po once/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/day for focal-onset seizures and 8 mg once/day for primarily generalized seizures
  
  

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

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 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 mcg/mL (43 to 129 mcmol/L)
  
  
• Toxic: > 40 mcg/mL (> 151 mcmol/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 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 to 10 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 mcg/mL (40 to 80 mcmol/L)
  
  
• Toxic: > 25 mcg/mL (> 99 mcmol/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 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)
  
  

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

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 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 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 yr, for atypical absence seizures, and as 2nd-line monotherapy or adjunctive therapy for primarily 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 level is

• 5 to 20 mg/mL (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 yr: 10 to 15 mg/kg/day po in tid doses (eg, 5 mg tid), increased slowly—eg, by 5 to 10 mg/kg/day (1.67 to 3.33 mg/kg tid) 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 mcmol/L) before the am dose
  
  
• Toxic levels: > 150 mcg/mL (> 1041 mcmol/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 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

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

Dosage is

• Adults: Initially, 500 mg po bid, increased by 250 mg bid weekly as needed to usual maintenance dose of 1500 mg po bid
  
  
• 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 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 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)
  
  

Zonisamide is not commonly used in children < 16 yr.

Therapeutic and toxic levels are

• Therapeutic levels: 15 to 40 mcg/mL (at > 30 mcg/mL, 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

• American Academy of Neurology and the American Epilepsy Society: Efficacy and tolerability of the new antiepileptic drugs II: Treatment of refractory epilepsy.
  
  

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