CHAPTER

Second-Generation Antiepileptic Drugs

Kathryn Idol Xixis, Roha Khalid, and Mohamad A. Mikati

To establish efficacy of felbamate as adjunctive therapy in partial seizures a double-blind, placebo-controlled crossover trial was conducted. Felbamate (3,600 mg/day) and placebo were then compared in a group of patients who had their standard antiepileptic drugs reduced while undergoing evaluations for surgery of intractable epilepsy. The primary efficacy variable was time to fourth seizure. The median times to fourth seizure were greater than 28 days in the felbamate group and 5 days in the placebo group, which was statistically significant (P = 0.002).

Other Indications for Use

Felbamate is not used in the treatment of psychiatric disorders likely due to the risk of aplastic anemia and hepatotoxicity associated with its use (5).

Adverse Effects

Adverse events occurred at an incidence of 2% or more among 58 adult patients who received felbamate monotherapy at dosages of 3,600 mg/day in double-blind controlled trials. Major side effects were fatigue, insomnia, and anxiety. Minor side effects seen were dyspepsia, vomiting, diarrhea, and constipation.

In add-on controlled trials at dosages up to 3,600 mg/day adverse events also occurred at an incidence of 2% or more among 114 adult patients who received felbamate as an adjunctive therapy. Many of these adverse experiences typically resolved with conversion to monotherapy, or with adjustment of the dosages of other antiepileptic drugs. The most common side effects were headache, somnolence, insomnia, and nervousness. In children, the major side effects were fever, fatigue, somnolence and insomnia, anorexia, and hyperactivity.

The risk of developing aplastic anemia or liver failure is the major factor in restricting the use of felbamate.

Toxicity, Overdose, and Contraindications

Hepatic and aplastic anemia are idiosyncratic side effects. No serious adverse reactions have been reported specifically to overdosing. General supportive measures should be employed if overdosage occurs. It is not known if felbamate is dialyzable. It is contraindicated in patients in whom the risks of using it are not outweighed by the potential benefits (see the following sections, Warning and Precautions; and Special Safety Concerns).

Warning and Precautions

The use of felbamate is associated with an increased incidence of aplastic anemia. Clinical manifestations of aplastic anemia may not be seen for several months after the initiation of use of felbamate. Once the drug is discontinued, the patient remains at a risk for developing aplastic anemia for an unknown amount of time. Patients on felbamate may be at more than a 100-fold greater risk for developing the syndrome than the general population.

There are not enough felbamate-associated cases of aplastic anemia to provide a reliable estimate of incidence or case fatality rate or to assess if there are any factors that place patients at greater or lesser risk. Felbamate has shown a risk of liver failure in about 6 cases per 75,000 patient-years of use. It is uncertain whether the risk of liver failure changes with duration of exposure or the dosage used. Therefore, felbamate should not be used in anyone with hepatic dysfunction. Moreover, felbamate should be discontinued if the liver enzymes are elevated greater than twice the upper limit of normal or if patient develops clinical signs and symptoms of liver failure.

Special Safety Concerns

Aplastic anemia is a potential adverse effect of felbamate. At present there is no way to predict who is likely to get aplastic anemia, nor is there a documented effective means to monitor the patient so as to avoid and/or reduce the risk. Patients with a history of any blood dyscrasia should not receive felbamate. Any signs of infection, bleeding and easy bruising should be reported to the physician.

Another major safety concern is hepatic failure. There is no way to predict who is likely to develop hepatic failure. Patients with a history of hepatic dysfunction should not be started on felbamate. Any patient who is starting on felbamate should undergo liver function testing before using felbamate and at frequent intervals while taking it.

Like most other AEDs, felbamate also increases the risk of suicidal ideation in patients. Therefore, all patients should be monitored for emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Teratogenicity Information

Felbamate is a Pregnancy Category C drug. Animal studies did not show increased incidence of malformations compared to controls in offspring of rats or rabbits when given doses up to 13.9 times (rat) and 4.2 times (rabbit) the human daily dose on an mg/kg basis. However, in rats, there was a decrease in pup weight and an increase in pup deaths during lactation. The cause for these deaths is not known. The no-effect dose for rat pup mortality was 6.9 times the human dose on an mg/kg basis. Placental transfer of felbamate occurs in rat pups. There are, however, no studies in pregnant women.

Felbamate increases the steady-state plasma concentration of phenytoin, valproate, and phenobarbital, while decreasing the steady-state plasma concentration of carbamazepine. Effects of other drugs on felbamate: phenytoin and carbamazepine cause an increase in the clearance of felbamate, thus leading to a 40% to 45% decrease in the steady-state trough concentration. Valproate does not affect felbamate plasma levels, whereas phenobarbital can decrease felbamate levels by 29%. Antacids, erythromycin, and oral contraceptives do not alter its concentration.

Use in Special Populations

The effect of felbamate on labor and delivery in human subjects is unknown. Although felbamate has been detected in human milk its effect on the nursing infant is unknown. No systematic studies in geriatric patients have been conducted. Clinical studies of felbamate did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experiences have not identified differences in responses between the elderly and younger patients. In general, dosage selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pediatric Use

The safety and effectiveness of felbamate in children other than those with Lennox-Gastaut syndrome has not been established. A 70-day double-blind, placebo-controlled trial was done to assess efficacy of felbamate as adjunctive therapy in children with Lennox-Gastaut syndrome. It was concluded that felbamate (45 mg/kg/day) was superior to placebo in controlling the multiple seizure types associated with this condition. Felbamate is started at 15 mg/kg/day in three or four times daily dosing while reducing background AEDs by 20%. Further reductions of the concomitant AEDs dosage may be necessary to minimize side effects due to drug interactions. Felbamate can be increased by 15 mg/kg/day increments at weekly intervals to a maximum of 45 mg/kg/day.

LAMOTRIGINE

Indications

Lamotrigine is approved as an adjunctive therapy for patients aged two years or older in the treatment of partial seizures, primary generalized tonic–clonic seizures, and generalized seizures of Lennox-Gastaut syndrome. For patients 16 years or older, lamotrigine is also approved as a monotherapy alternative in patients who are being treated with carbamazepine, phenytoin, phenobarbital, primidone, or valproate. However, the safety and efficacy of lamotrigine as an initial monotherapy has not been established. Likewise, lamotrigine has not been studied as a monotherapy for patients previously maintained on antiepileptics other than the ones previously listed, and lamotrigine has not been studied as a monotherapy for a patient previously requiring two or more simultaneous antiepileptics (6).

Dosing

Lamotrigine should be initiated slowly to reduce the risk of adverse effects. To determine appropriate dosing of lamotrigine in epilepsy patients, consideration must be made as to the patients’ background antiepileptic regimens and whether or not they contain medications that are inducers or inhibitors of hepatic enzymes. For patients who are not taking carbamazepine, phenytoin, phenobarbital, primidone, or valproate, lamotrigine therapy is initiated at 25 mg orally daily for weeks 1 and 2. This is increased to 50 mg orally daily for weeks 3 and 4. Subsequently, the lamotrigine dose can be safely increased by 50 mg per day every 1 to 2 weeks to a goal maintenance dose of 225 to 375 mg per day, divided into two equal doses. For patients who are taking valproate at the time of lamotrigine initiation, lamotrigine must be titrated more slowly as valproate acts as an inhibitor effectively increasing the dose of lamotrigine. For these patients, initial lamotrigine dose should be started at 25 mg orally every other day for weeks 1 and 2. This can be increased to 25 mg orally every day during weeks 3 and 4. Beginning in week 5, the total lamotrigine dose may be increased by 25 mg to 50 mg per day every 1 to 2 weeks to a goal dose of 100 mg/day to 200 mg/day, in one dose or two divided doses for a patient who will be continuing valproate concurrently with lamotrigine. For patients who will be continuing valproate, an inhibitor, as well as other medications that are inducers, after initiation of lamotrigine, goal maintenance dosing ranges between 100 mg/day and 400 mg/day, in one or two divided doses. Finally, for patients who are continuing carbamazepine, phenytoin, phenobarbital, or primidone, which are all inducing medications that decrease the effective dose of lamotrigine, a different titration is preferable. For these patients, initiation of lamotrigine should be at 50 mg/day for weeks 1 and 2 followed by an increase to 100 mg/day in two divided doses during weeks 3 and 4. From week 5 onward, lamotrigine can be safely increased by 100 mg/day every 1 to 2 weeks to a goal dose of 300 mg/day to 500 mg/day in two divided doses. Caution must be exercised when patients using lamotrigine start or stop estrogen-containing oral contraceptives as these medications have been shown to decrease lamotrigine levels in serum. Lamotrigine should not be abruptly discontinued but instead should be weaned off over an absolute minimum of 2 weeks with approximately 50% reduction per week.

The mechanism of action of lamotrigine appears to involve blocking voltage-dependent sodium channels, thus decreasing the release of excitatory neurotransmitters.

Lamotrigine has excellent oral bioavailability that is not affected by the presence of food. In studies, lamotrigine’s peak plasma concentration was reached between 1.4 hours and 4.8 hours. Lamotrigine serum levels increase in direct proportion to increases in dosage. The volume of distribution of lamotrigine ranges from 0.9 L/kg to 1.3 L/kg. Lamotrigine is not significantly protein bound. In healthy volunteers, the half-life of single-dose lamotrigine was 32.8 hours and of multiple-dose lamotrigine was 25.4 hours. However, half-life of lamotrigine varies based on other medications that are used concomitantly. Lamotrigine is hepatically metabolized with minimal first-pass effect. This is of clinical significance as the levels of lamotrigine can be decreased or increased by concomitantly administered medications that induce or inhibit hepatic enzymes. A definitive therapeutic plasma concentration range for lamotrigine has not been established. Instead, dosing is best based on therapeutic response.

Efficacy Data

Lamotrigine was established as an adjunctive therapy in adults with partial seizures, as an adjunctive therapy in pediatric patients with partial seizures, as an adjunctive therapy in adult and pediatric patients with primary generalized tonic-clonic seizures, and as an adjunctive therapy in adult and pediatric patients with Lennox-Gastaut Syndrome in a series of studies in which patients were maintained on their current antiepileptic regimens in addition to either lamotrigine or placebo. For patients taking valproate at baseline, lamotrigine target dosing was appropriately lowered. Two of the studies evaluating lamotrigine as adjunctive therapy in adults with partial seizures did not enroll any patients on valproate for ease of lamotrigine dosing. In studies evaluating lamotrigine as adjunctive therapy in adults with partial seizures, in children with partial seizures, and in adults and children with primary generalized tonic–clonic seizures, the seizure frequency of the respective seizure types showed a statistically significant reduction in favor of lamotrigine over placebo. Statistically significant reduction in major motor seizures, drop attacks, and tonic–clonic seizures were seen in the study investigating lamotrigine versus placebo in patients with Lennox-Gaustaut syndrome.

Efficacy in Other Conditions

Lamotrigine is approved for bipolar I disorder in adults who are 18 years or older as a maintenance treatment to prolong the time to occurrence of mood episodes (7). However, lamotrigine is not approved as therapy for the treatment of acute mood episodes as its effectiveness for this indication has not been established. Some studies have also found lamotrigine useful in neuropathic pain syndromes, including trigeminal neuralgia, painful diabetic neuropathy, HIV-associated neuropathy, poststroke pain, postoperative pain, and cold-induced pain; however, additional trials are needed to establish the efficacy of lamotrigine in these conditions (8,9). Small studies have suggested benefit from lamotrigine in unipolar depression, schizophrenia spectrum disorders, borderline personality disorder, and depersonalization disorder as well.

Adverse Effects

Adverse reactions noted in greater than 10% of adult patients in clinical studies include headache, dizziness, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, and rash. Pediatric patients were additionally noted to have vomiting, infection, fever, accidental injury, pharyngitis, abdominal pain, and tremor in more than 10% of the patients in clinical studies.

Toxicity, Overdose, and Contraindications

At extremely high doses and in overdose of lamotrigine, ataxia and nystagmus may occur. In fact, oculogyric crises have been reported in the setting of lamotrigine toxicity (10). In addition, decreased level of consciousness with progression to coma and with accompanying respiratory depression and death, intraventricular conduction delay, and increased seizure activity can be seen. Treatment for overdose is supportive as no specific antidote exists. Given that lamotrigine is metabolized through the liver, dialysis is unhelpful. A systemic allergic-type reaction similar to anticonvulsant hypersensitivity syndrome may also be seen in overdose (11).

Warnings and Precautions

The most well known and one of the most dangerous potential adverse effects associated with lamotrigine is skin rash, which is rare, but for which lamotrigine holds a black box warning; specifically cases of Stevens–Johnson syndrome and toxic epidermal necrolysis have been reported with its use. There is some evidence that patients who are also taking valproate are at higher risk of developing serious adverse skin effects. Multisystem hypersensitivity reactions or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been observed in patients taking lamotrigine, and lamotrigine has a black box warning for these. This typically presents with fever, rash, and lymphadenopathy in association with multiorgan involvement. Isolated liver failure has also occurred. A wide variety of blood dyscrasias and aseptic meningitis have also been seen in patients taking lamotrigine.

Patients taking lamotrigine are at risk for sudden unexpected death in epilepsy (SUDEP) as well; however, studies do not demonstrate that the risk is higher with lamotrigine than with other antiepileptic medications. Lastly, lamotrigine is known to bind with melanin. As such, there is a possibility that lamotrigine could bind melanin-rich tissues and accumulate in those tissues over time. Studies have not proved or disproved the risk of injury after long-term exposure. At this time, there are no recommendations for monitoring this potential side effect, including no specific recommendations for ophthalmologic monitoring.

Teratogenicity

Lamotrigine is Pregnancy Category C drug. No adequate studies regarding the use of lamotrigine in pregnant women exist, but ill effects have been observed in mice and rats. Of note is lamotrigine’s inhibition of dihydrofolate reductase in animal studies that led to a decrease in overall folate levels. Results from the AED pregnancy registry study suggest a lower risk of malformations with lamotrigine than traditional AEDs. In the AED pregnancy registry study, 2% of neonates born to mothers taking lamotrigine were found to have a major congenital malformation. The most common malformation was oral clefting followed by cardiovascular abnormalities and neural tube defects. Furthermore, no apparent dose effect on likelihood of congenital malformation was appreciated (12).

Special Safety Concerns and Monitoring

Special attention should be paid when lamotrigine is used in an antiepileptic regimen concomitantly with valproate, carbamazepine, phenytoin, primidone, phenobarbital, rifampin, and estrogen-containing oral contraceptive pills. This is discussed in more detail in the following. Monitoring of lamotrigine serum levels may be useful in determining levels associated with appropriate clinical response on a patient-by-patient basis, but no standard therapeutic range for lamotrigine has been established. While there are no current monitoring recommendations, blood counts and hepatic function should be checked on an as-needed basis to monitor for blood dyscrasias and hepatotoxicity, respectively (13).

Drug Interactions

Significant drug interactions with lamotrigine involve the risk for increased or decreased active lamotrigine levels in the serum as a result of increased or decreased metabolism of lamotrigine. Concomitant use of lamotrigine and estrogen-containing oral contraceptive pills with ethinylestradiol and levonorgestrel have resulted in an approximate decrease in lamotrigine levels by 50% as well as a decrease in levonorgestrel levels. Additionally, concomitant use of lamotrigine with phenobarbital, primidone, phenytoin, rifampin, carbamazepine decreases lamotrigine serum levels by as much as 40%. It is unclear if the interaction between lamotrigine and carbamazepine also increases the levels of carbamazepine epoxide, the active metabolite of carbamazepine. Lamotrigine and valproate taken together has been shown to almost double lamotrigine levels. The data regarding the effect of this interaction on valproate levels are unclear.

Use in Special Populations

Decreased levels of lamotrigine have been reported during pregnancy with return to prepregnancy levels after delivery. As such, dose adjustment may be necessary in patients who continue on lamotrigine in pregnancy. Lamotrigine is present in human breast milk. Small studies have identified breastfed infants with lamotrigine levels approximately one-half of the level found in the mother. Further consideration must be made for infants of mothers whose lamotrigine dosages required increases during pregnancy as these infants may experience extremely high lamotrigine levels. As the hepatic metabolism of infants is immature, clearance of lamotrigine from the infant may be further delayed. Reported events in breastfed infants of mothers taking lamotrigine include drowsiness, poor sucking, and apnea. These events have not been directly correlated with lamotrigine use but care should be exercised (14).

Use of lamotrigine in patients over the age of 65 has not been sufficiently studied to determine whether or not these patients require a different safety profile from younger patients.

Studies of lamotrigine in patients with hepatic impairment are small and limited. It is generally felt that no dosage adjustment is necessary for mild hepatic impairment. In patients with moderate or severe hepatic impairment, dosing should be reduced by approximately 25%. If patients with severe hepatic impairment exhibit significant ascites, reduction of lamotrigine dosing by approximately 50% should be considered. Specific recommendations for lamotrigine dosage adjustment in renal insufficiency are unavailable.

Pediatric Use

While the guidelines in the previous paragraph are safe, the following recommendations may be more easily applied in small patients. For initiation of therapy in weeks 1 through 4 in a 6.7 kg to 14 kg patient, start with 2 mg every other day in weeks 1 and 2 before transitioning to 2 mg daily in weeks 3 and 4. In a 14.1 kg to 27 kg patient, use 2 mg daily in weeks 1 and 2 before increasing to 4 mg daily in weeks 3 and 4. In a 27.1 kg to 34 kg patient, use 4 mg daily in weeks 1 and 2 before increasing to 8 mg daily in weeks 3 and 4. Lastly, in a 34.1 kg to 40 kg patient, use 5 mg daily for weeks 1 and 2 before increasing to 10 mg daily in weeks 3 and 4. The dosage can then be increased into week 5 and beyond as described earlier until maintenance dosing is reached. As referenced previously, with weight-based dosing in pediatrics tablets may not be available in the exact calculated dosages. Dosages should be rounded down to the nearest available whole tablet size. Tablets should not be split. Additionally, maintenance dosing in patients less than 30 kg may need to be increased by as much as 50% in patients taking carbamazepine, phenytoin, phenobarbital, primidone, valproate, or lamotrigine alone and should be titrated according to clinical response.

GABAPENTIN

Indications

Gabapentin is indicated as an adjunctive therapy in the treatment of partial seizures with and without secondary generalization in patients aged 3 and older (19).

Dosing

Gabapentin is an oral medication. The target dose of gabapentin for use in epilepsy patients aged 12 or older is 900 to 1,800 mg/day administered in three divided doses. Some studies have shown that many patients require and tolerate doses up to 2,400 mg/day. Doses up to 3,600 mg/day have been given. Patients are typically titrated to an initial goal dose of 900 mg/day in three divided doses over the course of a few days.

Pharmacology

The definitive mechanism of action of gabapentin as an anticonvulsant and as an analgesic is unknown. Gabapentin is structurally similar to the neurotransmitter gamma-aminobutyric acid (GABA), but gabapentin is not converted to nor does it interact with the functions of the neurotransmitter GABA. Some studies suggest that at least part of gabapentin’s action may be related to its interaction with voltage-gated calcium channels.

Gabapentin is not metabolized in humans. Observed pharmacological actions are related to the parent compound. Of note, the oral bioavailability of gabapentin decreases as the dose is increased. The bioavailability of gabapentin is not significantly affected by interactions with food. Gabapentin is minimally bound to plasma proteins in distribution. The elimination of gabapentin is via renal excretion, and patients with renal insufficiency will require dose adjustment. The half-life of gabapentin is 5 to 7 hours. The half-life is not affected by differing doses or multiple doses.

Efficacy Data

Efficacy in Other Conditions

In addition to use as an adjunctive therapy for seizures, gabapentin is labeled for use in treatment of postherpetic neuralgia and restless leg syndrome (20). Gabapentin is widely used in and has been shown to be efficacious in a variety of conditions involving neuropathic pain, in addition to postherpetic neuralgia commonly including diabetic neuropathy and trigeminal neuralgia (21). A few studies have found gabapentin useful in the treatment of pain related to fibromyalgia, in the treatment of pain and spasticity associated with multiple sclerosis, and in the treatment of migraines as a prophylactic medication (22,23). A variety of other uses for gabapentin in addition to pain have been evaluated in small studies. These include gabapentin as a treatment for hot flashes, as a treatment for itching related to uremic pruritis, as a treatment for essential tremor, and as a treatment for some forms of acquired and congenital nystagmus (24–26). Gabapentin was investigated as a treatment against the progression of amyotrophic lateral sclerosis, but studies have not shown significant benefit (27). Gabapentin has been used in a variety of psychiatric illnesses, especially in anxiety disorders with mixed results. Gabapentin has also been investigated as a treatment for cocaine cravings.

Adverse Effects

The most commonly noted adverse events in studies of patients older than 12 years taking gabapentin in combination with other antiepileptics, that were not reported at a similar frequency in patients receiving placebo in combination with other antiepileptics, include dizziness, ataxia, nystagmus, fatigue, and somnolence. Likewise, the most commonly noted adverse events in studies of patients aged 3 to 12 years of age taking gabapentin in combination with other antiepileptics, which were not reported at a similar frequency in patients receiving placebo in combination with other antiepileptics, include fever, viral infection, nausea, vomiting, somnolence, and hostility (28). Adverse effects observed in clinical trials were typically mild to moderate in intensity. Adverse effects including sweating, nausea, anxiety, insomnia, and pain have also been reported with abrupt discontinuation of gabapentin.

Toxicity, Overdose, and Contraindications

Animal studies testing doses up to 8000 mg/kg in a single administration have not identified a lethal dose of gabapentin. Signs of acute toxicity as demonstrated by animal studies include ataxia, ptosis, labored breathing, decreased activity, sedation, or excitation. Additional signs of acute toxicity have been reported in human overdoses of up to 49 grams including diplopia, slurred speech, diarrhea, drowsiness, and lethargy. Treatment is largely supportive. Gabapentin can be also removed by hemodialysis in cases where this is deemed necessary.

Warnings and Precautions

Gabapentin, as with all antiepileptic drugs, carries a black box warning for suicidality. However, little specific data regarding gabapentin and suicidal thoughts or behavior are available. Neuropsychiatric adverse events have been noted in some patients between the ages of 3 and 12 taking gabapentin. These include, in order of highest to lowest incidence, emotional lability, hostility, hyperkinesia, and difficulty with concentration and changes in school performance. While recorded events have typically been mild to moderate in severity, one incidence of serious hostility was reported in clinical trials.

Abrupt withdrawal of gabapentin, as with other antiepileptic drugs, can lead to an acute increase in seizure frequency. Gabapentin should be tapered off over a minimum of 1 week. There are insufficient data to conclude whether or not patients treated with gabapentin experience an increased rate of status epilepticus compared to patients not treated with gabapentin.

Preclinical carcinogenicity studies on rats receiving gabapentin showed an increased incidence of pancreatic acinar adenocarcinomas in male rats. This was not found in female rats in the same study. The clinical significance of this is unknown. Clinical studies of epilepsy patients on gabapentin adjunctive therapy followed patients with new tumors and worsening preexisting tumors, but information is scant regarding whether or not populations treated with gabapentin experienced an increased incidence of tumors compared to populations not treated with gabapentin.

Teratogenicity

Gabapentin is classified as a category C medication. In animal studies, gabapentin has been shown to cause delayed bone ossification as well as increased incidence of hydroureter and hydronephrosis. The incidence of other malformations was not increased in animal studies. Of note, some animal studies have demonstrated an increased incidence of fetal loss in animals receiving gabapentin. Adequate studies have not been done on the use of gabapentin in human pregnancies. Gabapentin should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus. Additionally, orally administered gabapentin is secreted into human breast milk. The effect of gabapentin on infants is unknown.

Special Safety Concerns and Monitoring

Laboratory monitoring of gabapentin levels or other parameters is not necessary. Gabapentin may be used in combination with other antiepileptic medications without concern for alteration in plasma levels of either gabapentin or the other antiepileptic medications. If discontinued, gabapentin should be tapered over the course of at least 1 week.

Drug Interactions

Unlike many antiepileptic medications, gabapentin is not significantly metabolized by nor does it interfere with the metabolism of other commonly used antiepileptic drugs including phenytoin, carbamazepine, valproic acid, or phenobarbital. In addition, gabapentin does not significantly inhibit the major cytochrome P450 enzymes. Increases and decreases in gabapentin have been noted with coadministration of gabapentin and certain pain medications. For instance, in studies, coadministration of naproxen and gabapentin led to mild increase in gabapentin absorption. Coadministration of hydrocodone and naproxen led to reduction in hydrocodone levels and to increase in gabapentin levels. Coadministration of morphine and gabapentin led to increase in gabapentin levels. Concomitant use of gabapentin and oral contraceptives were not found to have clinically significant interactions. The bioavailability of gabapentin was decreased when administered with antacids, although this interaction was essentially nonexistent if gabapentin was taken at least 2 hours after the antacid medication.

Use in Special Populations

Studies of gabapentin in epilepsy did not include sufficient numbers of elderly patients to determine whether elderly patients respond differently than younger patients. Notably, however, in studies of gabapentin in postherpetic neuralgia, a larger treatment effect was seen in elderly patients when compared to younger patients who received the same dose. The reason for this is unclear, but is most likely related decreased renal function in the older population.

Gabapentin is a renally excreted medication. Therefore, the dosage of gabapentin must be adjusted in patients with renal insufficiency. No studies have been completed on patients younger than 12 years with renal insufficiency. Recommended dosage adjustment for patients aged 12 and older with renal impairment is as follows: for patients with creatinine clearance (CrCl) greater than or equal to 60 mL/min, total daily gabapentin dosing range is 900–3,600 mg/day administered three times a day. For patients with CrCl ranging from greater than 30 to 59 mL/min, total daily gabapentin dosing range is 400–1,400 mg/day administered two times a day. For patients with CrCl ranging from greater than 15 to 29 mL/min, total daily gabapentin dosing range is 200–700 mg/day administered in a single daily dose. For patients with CrCl of 15 mL/min, total daily gabapentin dosing range is 100–300 mg/day administered in a single daily dose. In patients whose CrCl is below 15 mL/min, gabapentin can be used; however, these patients should receive a single daily dose that is decreased in proportion to the decrease in their CrCl below 15 mL/min. For example, a patient with CrCl of 7.5 mL/min should receive a single daily dose of gabapentin that is one-half the amount of the single daily dose of the patient whose CrCl is 15 mL/min. Furthermore, patients on hemodialysis require an additional posthemodialysis supplemental dose ranging between 125 and 350 mg/dose. As gabapentin is not known to be metabolized hepatically, no studies have been performed in patients with hepatic insufficiency.

Pediatric Use

Gabapentin is indicated in children aged 3 or older as adjunctive therapy in the treatment of partial seizures with and without secondary generalization (29,20). Recommended initial dose is 10–15 mg/kg/day in three divided doses. Gabapentin can be quickly titrated up to target dosing over the course of approximately 3 days. Target dosing for patients aged 3 and 4 years is 40 mg/kg/day in three divided doses. Target dosing for patients aged 5 years and older is 25–35 mg/kg/day in three divided doses. Doses up to 50 mg/kg/day have been tolerated in a variety of pediatric age groups. Maximum interval between doses should not be greater than 12 hours.

TOPIRAMATE

Indications

Dosing

When topiramate is used as monotherapy for epilepsy in patients 10 years or older, the recommended dose is 400 mg/day divided in two doses. To reach this target dose, topiramate should be titrated. Typically, topiramate is started at 25 mg twice daily and is increased by 25 mg per dose each week for the first four weeks. Subsequently, the dose may be increased by 50 mg per dose so that the target dose of 400 mg/day is achieved in 6 weeks. When topiramate is used as an adjunctive therapy in patients with partial-onset seizures, the recommended dosing is 200 mg/day to 400 mg/day in two divided doses. In patients being treated for primary generalized tonic–clonic seizures, topiramate is recommended at 400 mg/day in two divided doses for adjunctive therapy. Titration of topiramate is still recommended when topiramate is used as an adjunctive medication. Typical titration includes initiation at 25 to 50 mg/day followed by increases of 25 to 50 mg/day every week. Topiramate is only available in tablets and capsules. A once-a-day oral extended-release preparation has recently become available. Some pharmacies compound topiramate as a 6 mg/ml solution. There is no intravenous form.

Pharmacology

A definitive mechanism of action of topiramate is not known. In studies, topiramate has been noted to block voltage-dependent sodium channels, to antagonize the glutamate receptor at the AMPA-kainate subtype of the receptor, to augment the activity of GABA at some subtypes of the GABA-A receptor, and to inhibit particular isozymes of the carbonic anhydrase enzyme.

Following a 400 mg dose, peak plasma concentrations of topiramate occur in approximately 2 hours. Food does not affect the bioavailability of topiramate. Topiramate has linear pharmacokinetics with increases in medication dosing leading to proportional increases in plasma concentrations. The half-life for elimination of topiramate is 21 hours, meaning that steady state is reached in approximately 4 days in a patient with normal renal function. Interestingly, topiramate is minimally metabolized. It is eliminated in the urine largely unchanged.

Efficacy Data

The efficacy of topiramate as an initial monotherapy for partial seizures or primary generalized tonic–clonic seizures was evaluated in a trial in which enrollees were randomized to receive either 50 mg/day or 400 mg/day of topiramate. The 400 mg/day group had a statistically longer time to first seizure regardless of baseline seizure type than the 50 mg/day group. Topiramate in children age 2 to 10 years as initial monotherapy for partial seizures or primary generalized tonic–clonic seizures has been shown to produce a similar response as in adults. Dosing recommendations in this population were derived from simulations based on pediatric and adult plasma exposure ranges when topiramate is used as initial monotherapy.

Multiple trials have demonstrated the efficacy of topiramate as an adjunctive therapy for partial seizures in adults, for partial seizures in children aged 2 to 16, and for primary generalized tonic–clonic seizures in patients aged 2 and older in trials evaluating frequency of seizures compared to baseline when taking topiramate versus placebo. These trials have shown a statistically significant benefit of topiramate over placebo as an adjunctive antiepileptic medication in partial and generalized tonic–clonic seizures.

The efficacy of topiramate has also been evaluated as an adjunctive medication for seizures in Lennox-Gastaut syndrome and was studied in patients aged 2 and older. Primary efficacy measures were the percent reduction in drop attacks and a parental rating of seizure severity. Using these measures topiramate was found to be effective in the previously mentioned patient population.

Efficacy in Other Conditions

In addition to uses in epilepsy, topiramate is indicated for migraine prophylaxis but not for treatment of acute migraine exacerbation (32). Non-FDA-approved uses in neurology reported in the literature include treatment for idiopathic intracranial hypertension, essential tremor, and neuropathic pain (33–35). Topiramate has been tried in a variety of psychiatric disorders mentioned in the following with mixed results but is not currently FDA approved for use in any psychiatric illness (36). Topiramate has been tried in bipolar disorder for mania, depression, rapid-cycling, and treatment-refractory; in unipolar depression; in schizophrenia, schizoaffective disorders, and other psychosis; in eating disorders; in posttraumatic stress disorder; in alcohol dependence; in borderline personality disorder; and in Tourette’s syndrome (37). Topiramate has also been studied as a weight loss agent (38).

Adverse Effects

The most common adverse reactions reported in clinical trials of topiramate in epilepsy include paresthesias, anorexia and resulting weight loss, fatigue, dizziness, psychomotor slowing, cognitive problems, difficulty with concentration, difficulty with memory, nervousness, confusion, mood problems, infection, fever, and flushing. More severe, but less common, adverse effects are discussed in the following Warnings and Precautions section.

Overdose on topiramate has been reported. While the majority of overdoses were not clinically severe, deaths have been reported when topiramate overdose occurs in combination with overdose on other medications. As expected, topiramate overdose may result in severe metabolic acidosis. Coma, lethargy, status epilepticus, cognitive slowing, changes in speech, diplopia, blurred vision, dizziness, difficulty with coordination, hypotension, abdominal pain, and depression have all been reported in topiramate overdose cases. Topiramate overdose may be managed by gastric lavage or induction of emesis if recent. In laboratory studies, topiramate has been effectively absorbed by activated charcoal. Hemodialysis is effective in removing topiramate, but should be reserved for severe symptoms. Treatment is largely supportive. Bicarbonate may be needed for treatment of severe metabolic acidosis. No specific antidote exists for use in topiramate overdose or toxicity (11). There are no definite contraindications to the use of topiramate; however, caution should be used in patients with certain preexisting conditions as discussed later.

Warnings and Precautions

Topiramate has been associated with the development or exacerbation of several significant medical conditions. A syndrome of acute myopia and secondary angle closure glaucoma has been reported with topiramate in both adult and pediatric patients and is usually seen within the first month after initiation of the medication. Decreased sweating and, rarely, hyperthermia has been cited in patients using topiramate. This has been reported more frequently in the pediatric population and severe hyperthermia has typically been in the setting of concomitantly elevated environmental temperatures (39).

Hyperchloremic metabolic acidosis without an anion gap is a known effect of topiramate and is related to the increase in renal bicarbonate loss that results from topiramate’s inhibition of carbonic anhydrase. Metabolic acidosis related to topiramate typically develops early in treatment and is usually mild to moderate. Manifestations of severe, untreated, acute, or chronic metabolic acidosis include hyperventilation, anorexia, fatigue, cardiac arrhythmias, or stupor. Chronic, untreated severe metabolic acidosis may also increase the risk for nephrocalcinosis or nephrolithiasis and may result in osteomalacia, termed rickets in pediatric populations, or osteoporosis. Consequently, pediatric patients suffering from chronic metabolic acidosis may experience decrease in growth rates that may theoretically lead to decrease in final height. It is also important to note that metabolic acidosis may affect fetuses of pregnant patients taking topiramate.

Topiramate, like all antiepileptic medications, may increase suicidal thought or suicidal behavior. Increase in suicidal thoughts usually occur within 1 week of starting the medication and persist until discontinuation of the antiepileptic drug in question.

Cognitive and neuropsychiatric side effects were one of the most frequently reported adverse events in studies. These included cognitive slowing, difficulty with attention or concentration, difficulty with speech or language, behavioral or psychiatric disturbances, and fatigue or somnolence. The majority of these side effects was mild to moderate in severity and was worse in patients who underwent rapid titration or higher doses of topiramate.

As discussed in detail in the teratogenicity section, topiramate is a Pregnancy Category D medication and should be used in pregnancy only when benefit significantly outweighs risk. Just as topiramate should be titrated for initiation of therapy, it should also be tapered off when discontinuing therapy as abrupt discontinuation may increase the risk for seizures or may increase seizure frequency.

Initial studies of patients taking topiramate did identify SUDEP at a higher incidence than in healthy patients matched for sex and age. However, the incidence of SUDEP in patients taking topiramate was not significantly higher than in patients with epilepsy who were not taking topiramate.

Use of topiramate has been associated with hyperammonemia with and without accompanying encephalopathy. This risk is increased in patients receiving topiramate and valproate concomitantly, and this adverse effect is more common in the pediatric population. In addition, the use of topiramate and valproate together has been associated with hypothermia both in the presence and in the absence of hyperammonemia. Use of topiramate is correlated with an increased risk of nephrolithiasis in the adult and pediatric populations and is likely related to the carbonic anhydrase inhibitory properties of topiramate. Concomitant use of other medications that cause metabolic acidosis and potentially the concomitant use of the ketogenic diet may increase the likelihood of nephrolithiasis. Good hydration should be recommended to minimize this potential complication. Paresthesias, usually consisting of tingling in the extremities, were a commonly reported side effect in studies of topiramate but rarely led to discontinuation of the medication.

Teratogenicity

Special Safety Concerns and Monitoring

Monitoring topiramate levels is usually not necessary. Given the possibility of development of hyperchloremic, nongap, metabolic acidosis while on topiramate therapy, measurement of baseline and periodic bicarbonate levels is recommended. In addition, some studies of patients taking topiramate as an adjunctive therapy for epilepsy have shown a significant decrease in serum phosphorus, a decrease in serum potassium, and a significant increase in serum alkaline phosphatase, although the significance of these findings has not been established. Increase in total protein, increase in creatinine, and increase in BUN have also been observed. As previously discussed, topiramate can produce hyperammonemia both with and without encephalopathy. While no formal recommendations exist regarding the frequency of monitoring for this complication, checking of baseline and periodic ammonia levels should be considered.

Drug Interactions

Topiramate has several possible drug–drug interactions that must be considered, including interactions with other antiepileptic medications. When topiramate is administered concomitantly with carbamazepine or phenytoin in studies, topiramate levels are reduced by up to 40% or 48%, respectively. Coadministration of topiramate and valproic acid has been associated with elevated ammonia levels with and without accompanying encephalopathy as well as hypothermia with and without accompanying hyperammonemia. Coadministration of topiramate with lamotrigine may result in slightly decreased levels of topiramate. The use of topiramate with other CNS depressant medications or alcohol has not been fully studied, but potential interactions between topiramate and these medications are concerning given the association of topiramate use with CNS depression and cognitive difficulties.

Some studies have demonstrated decreased efficacy of oral contraceptives when used concomitantly with topiramate, and patients should be aware of this possibility. Furthermore, lithium levels may be affected by coadministration of high-dose topiramate. While studies have shown no change in lithium levels with topiramate doses of 200 mg/day, lithium levels have been noted to increase when patients were concomitantly taking doses of topiramate up to 600 mg/day. Given the well-known side effect of metabolic acidosis associated with topiramate use, patients taking topiramate should not also be taking metformin, as the use of metformin is contraindicated in the setting of metabolic acidosis. Likewise, topiramate, which causes metabolic acidosis via its mechanism as a carbonic anhydrase inhibitor, should not be prescribed concomitantly with other carbonic anhydrase inhibitors as this may increase the likelihood of developing severe metabolic acidosis and of developing kidney stones.

Use in Special Populations

Topiramate-induced metabolic acidosis may also occur and may be significant for a pregnant or laboring patient and her fetus although the effects of topiramate during labor and delivery have not been studied in detail. Similarly, the use of topiramate in a breast-feeding mother has not been fully studied. Topiramate has been found in the plasma of neonates breast-fed by mothers taking this medication. However, infant plasma levels of topiramate were significantly lower than maternal plasma levels in these cases.

While patients over the age of 60 have been studied in topiramate trials without observation of age-related difference in efficacy or in likelihood of adverse effects, the number of older patients involved in these trials was insufficient to conclude whether or not elderly populations respond differently to topiramate than younger populations.

The clearance of topiramate is decreased in patients with renal impairment. In patients with moderate or severe renal impairment, one-half of the usual starting dose and maintenance dose is recommended. Similarly, patients undergoing dialysis require supplemental doses of topiramate given increased clearance of the medication; however, exact dosage of supplementation depends on details related to the patient and the dialysis. The clearance of topiramate may be decreased in patients with hepatic impairment as well, but the mechanism by which hepatic impairment decreases clearance is not well understood.

Pediatric Use

When topiramate is used as an adjunctive therapy for partial-onset, primary generalized tonic–clonic seizures, or for seizures associated with Lennox-Gastaut syndrome, dosing is weight based for children aged 2 to 16. The recommended total daily dose of topiramate is 5 mg/kg/day to 9 mg/kg/day in two equally divided doses. Topiramate should be initiated with a dose between 1 mg/kg/day and 3 mg/kg/day as a single nightly dose for the first week. The dose can then be safely increased by 1–3 mg/kg/day every 1 to 2 weeks. After the initial week, topiramate should be given in two, equal divided doses. Dosing for patients aged 17 and older for topiramate used as an adjunctive therapy for partial-onset, primary generalized tonic–clonic seizures, or for seizures associated with Lennox-Gastaut syndrome is the same as for adults and is described previously in the section on dosing.

LEVETIRACETAM

Indications

Levetiracetam is indicated as adjunctive treatment of (a) partial-onset seizures in adults and children 4 years of age and older with epilepsy; (b) myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy; and (c) primary generalized tonic–clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy (40). There is also some evidence that levetiracetam may be useful in the treatment of infantile spasms (41).

Dosing

In adults and children older than 16 years treatment is started at 1,000 mg/day and given as twice-daily dosing. Dose can be increased by 1,000 mg/day every 2 weeks to a maximum of 3,000 mg/day. When switching from oral levetiracetam to IV form, the initial total daily intravenous dosage of levetiracetam should be equivalent to the total daily dosage and frequency of oral levetiracetam and vice versa. Levetiracetam is available as 250 mg, 500 mg, 750 mg and 1,000 mg tablets and also in liquid form (100 mg/mL) for oral administration. It is also available in IV form as a single use vial with 500 mg/5mL (100 mg/mL) strength. Extended release tablets, for once/day dosing, are available.

Pharmacology

Levetiracetam binds to the SV2A synaptic vesicle glycoprotein and is thus thought to interfere in neurotransmitter release and synaptic transmission. It is also thought to inhibit presynaptic calcium channels and to enhance GABAergic inhibition.

Levetiracetam is quickly absorbed and has 100% bioavailability when taken orally. The tablets and oral solution are bioequivalent. Pharmacokinetics are linear with no time-variance and low intra- or inter-subject variability. Food does not affect bioavailability of levetiracetam. Only less than 10% of levetiracetam is protein-bound and its volume of distribution is close to the volume of intracellular and extracellular water. Majority of the dose (66%) is renally excreted unchanged. The major metabolic pathway of levetiracetam is an enzymatic hydrolysis of the acetamide group, which is not liver cytochrome P450 dependent. The metabolites do not have known pharmacological activity and are also renally excreted. Peak plasma concentrations occur in an hour and plasma half-life is approximately 6 to 8 hours, but can be increased in the elderly and in patients with renal impairment.

Efficacy

The effectiveness of levetiracetam as adjunctive therapy in adults with refractory partial-onset seizures with or without secondary generalization was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies. All three studies showed statistically significant response (defined as ≥50% reduction from baseline) to levetiracetam when compared to placebo. The efficacy of levetiracetam as adjunctive therapy in patients 12 years of age and older with juvenile myoclonic epilepsy experiencing myoclonic seizures was established in one multicenter, randomized, double-blind, placebo-controlled study that was conducted at 37 different site across 14 countries. The levetiracetam group showed 60.4% response as opposed to 23.7% in the placebo group.

The effectiveness of levetiracetam as an adjunctive therapy in patients 6 years of age and older with idiopathic generalized epilepsy experiencing primary generalized tonic–clonic (PGTC) seizures was established in one multicenter, randomized, double-blind, placebo-controlled study, conducted at 50 sites in 8 countries. There was a 77.6% reduction in baseline seizure frequency per week in patients treated with Levetiracetam as compared to a 44.6% reduction in the placebo group.

Efficacy in Other Conditions

Levetiracetam has been reported as efficacious in various forms of myoclonus. These include posthypoxic myoclonus, postencephalitic myoclonus, Unverricht-Lundborg disease myoclonus, progressive myoclonic epilepsy, spinal myoclonus, paraneoplastic myoclonus, and myoclonus dystonia (42–46). However, one open-label trial that used levetiracetam for myoclonus of various etiologies that had previously been refractory to at least one treatment showed highly inconsistent responses to levetiracetam. Responses ranged from dramatic improvement to no improvement. The degree of response did not seem to correlate with the etiology of the myoclonus (47).

Adverse Effects

Levetiracetam use has been associated with the occurrence of central nervous system side effects that can be classified into the following categories: (a) somnolence and fatigue, (b) coordination difficulties, and (c) behavioral abnormalities. Behavior abnormalities are described as agitation, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesia, nervousness, neurosis, and personality disorder. Pyridoxine, usually at 100 mg/day, has been reported to help reduce the hyperkinesia and hostility side effects.

Toxicity, Overdose, and Contraindications

During the clinical developmental program, the highest known dose of levetiracetam received was 6,000 mg/day. Drowsiness was the only adverse effect reported in the few cases of overdose in other clinical trials. However, in postmarketing use somnolence, agitation, aggression, depressed level of consciousness, respiratory depression, and coma have been observed with levetiracetam overdoses (48). Levetiracetam does not have a specific antidote. In cases of overdose, the usual precautions to maintain airway should be taken and if required elimination of unabsorbed drug can be attempted with emesis or gastric lavage. General supportive care should also be given to the patient. Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. To date, hemodialysis has not been used in the few known cases of overdose. However, it may be indicated in certain patients due to their clinical state or degree of renal impairment.

Warnings and Precautions

Levetiracetam should not be prescribed to patients who have previously exhibited hypersensitivity to it or to any of its inactive ingredients. Levetiracetam like other AEDs can increase the risk of suicidal thoughts or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs (including levetiracetam) showed that patients taking any one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% CI1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. Therefore, patients should be monitored closely for changes in mood or behavior and emergence of depression.

Teratogencity

Levetiracetam is a Pregnancy Category C drug. There have been no adequate and well-controlled studies conducted in pregnant women. Animal studies have shown evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant patients who took levetiracetam were enrolled in the AED pregnancy registry. As much as 2.4% of the neonates studied were born with congenital anomalies. The most common anomalies were cardiovascular anomalies and neural tube defects that were equally common. Oral clefting and hypospadias were not observed (12).

Special Safety Concerns and Monitoring

Behavioral side effects in children and depression in adults can occur in some patients. Blood levels are mostly useful for checking of compliance and to a lesser extent, if any, for predicting efficacy.

Drug Interactions

Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic for following drugs:

Phenytoin

Levetiracetam (3,000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam was also not affected by phenytoin. Levetiracetam (1,500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate (500 mg twice daily) did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion.

Potential drug interactions between levetiracetam and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, and primidone) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. The data from these studies indicated that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam.

There was about a 22% increase of apparent total body clearance of levetiracetam when it was coadministered with enzyme-inducing AEDs. However, dose adjustment is not recommended. Levetiracetam had no effect on plasma concentrations of carbamazepine, valproate, topiramate, or lamotrigine.

Other Drug Interactions

Oral contraceptives, digoxin, warfarin, and probenacid were studied and none of these drugs was found to alter the pharmacokinetics of levetiracetam. Moreover, coadministration of levetiracetam did not influence the pharmacokinetics or pharmacodynamics of these drugs either.

Use in Special Populations

Pharmacokinetics of levetiracetam was studied in 16 elderly subjects between ages 61 and 88 years whose creatinine clearance ranged from 30 to 74 mL/min. Following oral administration of twice-daily dosing for 10 days, total body clearance decreased by 38% and the half-life was 2.5 hours longer in the elderly compared to healthy adults. This is most likely due to the decrease in renal function in these subjects.

Levetiracetam levels may decrease during pregnancy. The disposition of levetiracetam was studied in adult subjects with varying degrees of renal function. Total body clearance of levetiracetam was reduced in patients with impaired renal function by 40% in the mild group (Creatinine clearance rate or CLcr = 50–80 mL/min), 50% in the moderate group (CLcr = 30–50 mL/min), and 60% in the severe renal impairment group (CLcr <30 mL/min). Clearance of levetiracetam is directly correlated with CLcr. In anuric (end-stage renal disease) patients, the total body clearance decreased 70% compared to normal subjects (CLcr >80 mL/min). About 50% of the pool of levetiracetam in the body can be removed during a standard 4-hour hemodialysis procedure. Dosage should be reduced in patients with impaired renal function receiving levetiracetam, and supplemental doses should be given to patients after dialysis.

In subjects with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment, the pharmacokinetics of levetiracetam were unchanged. In patients with severe hepatic impairment (Child-Pugh C), total body clearance was 50% that of normal subjects, but decreased renal clearance accounted for most of the decrease. Therefore, no dose adjustment is needed for patients with hepatic impairment.

Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions from levetiracetam in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug.

Pediatric Use

Levetiracetam is indicated for adjunctive therapy in the treatment of (a) partial-onset seizures in patients one month of age and older with epilepsy, (b) myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy, and (c) primary generalized tonic–clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy. For children aged 4 to 16 years, levetiracetam is started at 20 mg/kg/day, which is given in two divided doses. The daily dose is increased every 2 weeks by 20 mg/kg/day to the recommended 60 mg/kg/day. Pharmacokinetics of levetiracetam were evaluated in 24 pediatric patients (age 6–12 years) after single dose (20 mg/kg). The body weight-adjusted apparent clearance of levetiracetam was approximately 40% higher than in adults. Following single-dose administration (20 mg/kg) of a 10% oral solution to children with epilepsy (1 month to < 4 years), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. The pharmacokinetic results indicated that half-life was shorter (5.3 h) than for adults (7.2 h) and apparent clearance was faster (1.5 mL/min/kg) than for adults (0.96 mL/min/kg). Population pharmacokinetic analysis showed that body weight was significantly correlated to the clearance of levetiracetam in pediatric patients; clearance increased with an increase in body weight.

OXCARBAZEPINE (OXC)

Indications

Oxcarbazepine is used as monotherapy or adjunctive therapy in the treatment of partial seizures in adults. For children, it is indicated as monotherapy in the treatment of partial seizures in children older than 4 years of age with epilepsy and as an adjunctive therapy in children older than 2 years (49).

When used as adjunctive treatment, oxcarbazepine is initiated with a dose of 600 mg/day, which is given in a twice-daily regimen. If required, the dose can be increased by a maximum of 600 mg/day at 1-week intervals. Per FDA guidelines, the recommended daily dose for adjunctive therapy is 1,200 mg/day. Even though controlled trials have demonstrated greater effectiveness of daily doses above 1,200 mg/day, most patients were unable to tolerate the 2,400 mg/day dose due to side effects of central nervous system and increased interaction with other AEDs.

Patients who are currently receiving other AEDs can be converted to monotherapy by initiating treatment with oxcarbazepine at 600 mg/day (given in a twice-a-day regimen) while simultaneously reducing the dose of the concomitant AEDs. These AEDs should ideally be completely withdrawn over 3 to 6 weeks, while the maximum dose 2,400 mg/day of oxcarbazepine should be achieved in about 2 to 4 weeks. Patients should be closely monitored during the transition.

In patients not receiving other AEDs (monotherapy use), oxcarbazepine is initiated at a dose of 600 mg/day (given in a twice-a-day regimen); the dose is increased by 300 mg/day every third day to a dose of 1,200 mg/day. The maximum dose of 2,400 mg/day is reserved for patients switched to oxcarbazepine from other AEDs. All dosing should be given in a twice-a-day regimen. Oxcarbazepine oral suspension and oxcarbazepine film-coated tablets are interchangeable at equal doses. Oxcarbazepine is available in 150, 300, and 600 mg tablets and 300 mg/5 ml suspension (Trileptal). Similar size extended-release tablets (Oxtellar) for once/day use that need to be given either at least one hour before or two hours after meals are also available.

Pharmacology

The exact mechanism of action is unknown. In vitro electrophysiological studies indicate that oxcarbazepine blocks voltage-sensitive sodium channels causing inhibition of repetitive neuronal firing, decreasing propagation of synaptic impulses, and stabilizing hyper-excited neural membranes.

Oxcarbazepine is completely absorbed after oral administration and is metabolized to its pharmacologically active form 10-monohydroxy metabolite (MHD). The half-life of oxcarbazepine is about two hours, while the half-life of MHD is about nine hours, so MHD is responsible for most antiepileptic activity. Food does not affect rate and extent of absorption of oxcarbazepine. Therefore, the tablets and suspension can be taken with or without food. Twice-a-day dosing of oxcarbazepine allows steady-state plasma concentrations of MHD to be reached within 2 to 3 days. It is excreted by the kidneys and greater than 95% of the dose appears in the urine.

Efficacy Data

Four randomized, controlled, double-blind, multicenter trials were conducted in the adult population to prove the efficacy of oxcarbazepine as monotherapy. All studies showed statistically significant results in favor of oxcarbazepine compared with placebo. To establish the effectiveness of oxcarbazepine, as an adjunctive therapy for partial seizures, two multicenter, randomized, double-blind, placebo-controlled trials were conducted. One study had 692 patients (15–66 years of age) and the other 264 pediatric patients (3–17 years of age). The comparison was statistically significant in favor of oxcarbazepine at all doses tested in both trials. However, over 65% of patients in the high-dose (2400 mg/day) treatment group discontinued treatment because of adverse effects on cognition that was not seen in the monotherapy studies. Another rater-blind, randomized, age-stratified, parallel-group study was done comparing two doses of oxcarbazepine in 128 pediatric patients (1 month to < 4 years of age). The comparison was statistically significant in favor of oxcarbazepine (60 mg/kg/day) compared with placebo. However, in this study, there was no evidence that oxcarbazepine was effective in patients below the age of 2 years. The efficacy of oxcarbazepine and carbamazepine has been compared as well and is similar (50).

Efficacy in Other Conditions

Uses for oxcarbazepine reported in the literature but not FDA approved include bipolar disorder, panic disorder, and agitation (51). Recent studies have not substantiated oxcarbazepine as more efficacious than placebo in the treatment of bipolar disease in children however (52). In addition, no significant effect of oxcarbazepine on agitation and aggression in severe dementia has been substantiated (53). There is some evidence that oxcarbazepine can be efficacious in the treatment of neuropathic pain (54).

Adverse Effects

The most commonly observed (≥5%) adverse experiences seen in association with oxcarbazepine were dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, and abnormal gait. Pediatric patients also reported similar adverse effects as the adult population. About 11% of 456 pediatric discontinued treatment because of somnolence (2.4%), vomiting (2.0%), ataxia (1.8%), diplopia (1.3%), dizziness (1.3%), fatigue (1.1%), and nystagmus (1.1%).

Toxicity, Overdose, and Contraindications

Warnings and Precautions

Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelids have been reported in patients after taking the first or subsequent doses of oxcarbazepine. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with oxcarbazepine, the drug should be discontinued and an alternative treatment started. Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with oxcarbazepine use. The median time of onset for reported cases was 19 days. Like other antiepileptic drugs, oxcarbazepine increases the risk of suicidal thoughts or behavior in patients. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Lastly, patients who have had hypersensitivity reactions to carbamazepine should be informed that approximately 25% to 30% of them might experience hypersensitivity reactions with oxcarbazepine. One case has been reported that raised concern that oxcarbazepine therapy may induce infantile spasms and West syndrome (55). Likewise, worsening of myoclonus in juvenile myoclonic epilepsy and myoclonic status epilepticus, concerns traditionally raised with administration of carbamazepine, have been reported with oxcarbazepine (56).

Teratogenicity

While small numbers of neonates born to patients taking oxcarbazepine were enrolled in the AED pregnancy registry, the numbers were not sufficient to draw conclusions as to the possible congenital anomalies related to this drug. It is a Pregnancy Category C drug as increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity were observed in the offspring of animals treated with either oxcarbazepine or MHD during pregnancy at doses similar to the maximum recommended human dose (12).

Special Safety Concern and Monitoring

Clinically significant hyponatremia (sodium <125 mmol/L) can develop during oxcarbazepine use. Measurement of serum sodium levels should be considered for patients during maintenance treatment with oxcarbazepine, particularly if the patient is receiving other medications known to decrease serum sodium levels or if symptoms possibly indicating hyponatremia develop such as nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity.

Drug Interactions

Carbamazepine, phenytoin, and phenobarbital are strong inducers of cytochrome P450 and have been shown to decrease the plasma levels of MHD up to 29% to 40%. Concurrent use of oxcarbazepine with hormonal contraceptives may render contraceptives less effective as oxcarbazepine decreases levels of ethinylestradiol and levonorgestrel. Verapamil has been shown to decrease plasma levels of MHD by 20%. Oxcarbazepine appears to increase concentrations of phenytoin and to decrease trough concentrations of lamotrigine and topiramate, because oxcarbazepine has absent or lower enzyme-inducing effects, switching from carbamazepine to oxcarbazepine can result in increased serum concentrations of background medications.

Use in Special Populations

Mild-to moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD. No dose adjustment for oxcarbazepine is recommended in patients with mild-to-moderate hepatic impairment. The pharmacokinetics of oxcarbazepine has not been evaluated in severe hepatic impairment, and, therefore, caution should be exercised when dosing severely impaired patients.

There is a linear correlation between creatinine clearance and the renal clearance of MHD. When oxcarbazepine is administered as a single 300-mg dose in renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a two-fold increase in area under the curve (AUC). Dose adjustment for oxcarbazepine is recommended in these patients.

Oxcarbazepine and its active metabolite are excreted in breast milk. Therefore, the risks and benefits of the use of this medication in nursing mothers should be carefully considered.

Pediatric Use

Children aged 4 to 16 years receiving concomitant antiepileptic drugs may be converted to monotherapy of oxcarbazepine by initiating treatment at approximately 8 to 10 mg/kg/day given in a twice-a-day regimen, while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drugs. The concomitant antiepileptic drugs can be completely withdrawn over 3 to 6 weeks, while oxcarbazepine may be increased as clinically indicated by a maximum increment of 10 mg/kg/day at approximately weekly intervals to achieve the recommended daily dose. Patients should be observed closely during this transition phase

TIAGABINE

Indications

Tiagabine is approved as adjunctive therapy in the treatment of partial seizures in patients aged 12 and older (57,58).

Dosing

Tiagabine is an oral medication that should be administered with food. The initiation of tiagabine requires titration over several weeks. As the plasma concentration of tiagabine is significantly affected by hepatic enzyme-inducing medications, the dosing of tiagabine is dependent upon whether or not a patient is taking inducing medications concomitantly. In patients aged 12 and older who are taking enzyme-inducing antiepileptic medications at the time of initiation of tiagabine, a starting dose of 4 mg once daily should be used for 1 week. Following this, dose increases can be made once weekly according to the following titration. Increase tiagabine dose by 4 mg to a dose of 8 mg/day given in two divided doses in week 2. Increase tiagabine dose by 4 mg to a dose of 12 mg/day given in three divided doses in week 3. Increase tiagabine dose by 4 mg to a dose of 16 mg/day given in two to four divided doses in week 4. Increase tiagabine dose by 4 to 8 mg for a total dose of 20 to 24 mg/day given in two to four divided doses in week 5. Increase tiagabine dose by 4 to 8 mg for a total dose of 24 to 32 mg/day given in two to four divided doses in week 6. The dose of tiagabine should continue to be increased until clinical response is seen or until dose reaches 32 mg/day. For 12- to 18-year-olds, 32 mg/day given in two to four divided doses is considered maximum dosing although a few adolescents have tolerated higher doses. For patients over the age of 18, maintenance dosing can continue to be increased up to 56 mg/day given in two to four divided doses if needed. It is important to note that in patients who are not taking enzyme-inducing AEDs the plasma concentration of tiagabine is estimated to be more than twice that of the concentration in patients who are taking enzyme-inducing AEDs. Therefore, patients who are not taking enzyme-inducing AEDs at the time of initiation of tiagabine require lower doses and may require slower titration of tiagabine. At this time, tiagabine has been administered primarily to induced populations, and there are limited data on dosing in noninduced populations such that no official recommendations for titration exist.

Pharmacology

The mechanism of action of tiagabine is not fully understood, but it is known that tiagabine enhances the activity of GABA. In vitro studies have shown that tiagabine blocks GABA uptake into presynaptic neurons by binding to sites associated with the GABA uptake carrier. This effectively increases the amount of GABA available for binding at sites on postsynaptic neurons (59).

Tiagabine is rapidly and nearly completely absorbed. Food does slow absorption rate but does not significantly alter the degree of absorption. Peak plasma concentration is reached in approximately 45 minutes when administered without food and in approximately 150 minutes when administered with food. Tiagabine was administered with food in all clinical trials. It exhibits linear pharmacokinetics. Notably, tiagabine is 96% bound to human plasma proteins. The metabolism of tiagabine is through the hepatic cytochrome P450 pathway. The half-life of tiagabine in healthy volunteers is 7 to 9 hours; however, tiagabine elimination is significantly affected in patients who are also receiving hepatic enzyme-inducing medications such that the clearance of tiagabine in induced patients is approximately 60% greater than in noninduced patients. The half-life of tiagabine in induced patients is 2 to 5 hours. Interestingly, studies on the steady-state values of tiagabine have shown diurnal variation with values being lower after the evening dose than after the morning dose.

Efficacy Data

Study 2 demonstrated that in patients taking tiagabine, the proportion of patients achieving any particular level of reduction in the rate of all partial seizures was greater than in those taking placebo. However, only the patients in the group taking tiagabine four times a day were found to have a statistically significant median reduction and only in the frequency of complex partial seizures. Study 3 showed a statistically significant improvement in all partial and complex partial seizure rates in patients taking tiagabine compared to placebo. The two cross-over studies that assessed efficacy of tiagabine both showed statistically significant reductions in seizure rates in patients taking tiagabine over placebo.

Efficacy in Other Conditions

Some open-label reports have suggested that the anticonvulsant tiagabine may be efficacious in bipolar disorder. There is a need to clarify the evidence available, in the form of randomized controlled trials, for its use in the treatment of acute affective episodes in bipolar disorder (60). Tiagabine has been used for anxiety and panic disorders. It did not show beneficial effects on clinical symptoms in panic disorder compared to placebo, but results of challenge experiments suggest that patients on tiagabine had decreased sensitivity to experimentally induced panic (61,62).

Tiagabine has been used for treatment of primary insomnia. One study showed that tiagabine increased slow-wave sleep and reduced wake after sleep onset in a dose-dependent manner. Tiagabine dosages up to 8 mg did not compromise next-morning alertness and psychomotor performance in adult patients with primary insomnia (63).

Adverse Effects

Several side effects have been reported. The more frequent ones are classified according to type of system affected.

General: Allergic reaction, chest pain, chills, cyst, neck pain, and malaise. Cardiovascular System: Hypertension, palpitation, syncope, and tachycardia. Digestive System: Gingivitis and stomatitis. Heme and Lymphatic System: Lymphadenopathy. Metabolic and Nutritional: Edema, peripheral edema, weight gain, and weight loss. Musculoskeletal System: Arthralgia. Nervous System: Depersonalization, dysarthria, euphoria, hallucination, hyperkinesia, hypertonia, hyperesthesia, hypokinesia, hypotonia, migraine, myoclonus, paranoid reaction, personality disorder, hyporeflexia, stupor, twitching, and vertigo. Respiratory System: Bronchitis, dyspnea, epistaxis, and pneumonia. Skin and Appendages: Alopecia, dry skin, and sweating. Senses: Abnormal vision, ear pain, otitis media, and tinnitus. Urogenital System: Dysmenorrhea, dysuria, metrorrhagia, urinary incontinence, and vaginitis. The use of tiagabine has been reported with new onset of nonconvulsive status that can present as a confusional state (64). It also can result in myoclonic seizures as an adverse effect.

Toxicity, Overdose, and Contraindications

Tiagabine is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

Human experience of acute overdose with tiagabine is limited. Eleven patients in clinical trials took single overdoses of tiagabine up to 800 mg. All patients fully recovered, usually within 1 day. The most common symptoms reported after overdose included somnolence, impaired consciousness, agitation, confusion, speech difficulty, hostility, depression, weakness, and myoclonus. One patient who ingested a single dose of 400 mg experienced generalized tonic–clonic status epilepticus, which responded to intravenous phenobarbital. From postmarketing experience, there have been no reports of fatal overdoses involving tiagabine alone (doses up to 720 mg). However, overdoses involving multiple drugs, including tiagabine, have often resulted in fatal outcomes. Symptoms most often accompanying tiagabine overdose, alone or in combination with other drugs, have included: seizures including status epilepticus in patients with and without underlying seizure disorders, nonconvulsive status epilepticus, coma, ataxia, confusion, somnolence, impaired speech, drowsiness, agitation, lethargy, myoclonus, tremors, spike wave stupor, disorientation, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the context of seizures. Management of Overdose: There is no specific antidote for overdose with tiagabine. Emesis or gastric lavage can be attempted to remove unabsorbed drug. Airway precautions should be taken and supportive care provided to the patient. Since tiagabine is mostly metabolized by the liver and is highly protein bound, dialysis is not useful.

Warnings and Precautions

Postmarketing reports have shown that tiagabine use has been associated with new-onset seizures and status epilepticus in patients without epilepsy. Dose may be an important predisposing factor in the development of seizures, although seizures have been reported in patients taking daily doses of tiagabine as low as 4 mg/day. In most cases, patients were using concomitant medications (antidepressants, antipsychotics, stimulants, narcotics) that are thought to lower the seizure threshold. Some seizures occurred near the time of a dose increase, even after periods of prior stable dosing. In nonepileptic patients who develop seizures while on tiagabine treatment, tiagabine should be discontinued and patients should be evaluated for an underlying seizure disorder.

Teratogenicity

Special Safety Concern and Monitoring

A therapeutic range for tiagabine plasma concentrations has not been established. In controlled trials, trough plasma concentrations observed among patients randomized to doses of tiagabine that were statistically significantly more effective than placebo ranged from less than 1 ng/mL to 234 ng/mL (median, 10th, and 90th percentiles are 23.7 ng/mL, 5.4 ng/mL, and 69.8 ng/mL, respectively). Because of the potential for pharmacokinetic interactions between tiagabine and drugs that induce or inhibit hepatic metabolizing enzymes, it may be useful to obtain plasma levels of tiagabine before and after changes are made in the therapeutic regimen.

Drug Interactions

Tiagabine is a nonenzyme-inducing medication. Studies of tiagabine administered concomitantly with other antiepileptic medications showed no effect on the concentrations of phenytoin or carbamazepine, showed a slight decrease in the concentration of valproate, and showed no significant change in the concentrations of phenobarbital or primidone, although further studies are needed. Studies investigating the effect of concomitantly administered antiepileptic medications on tiagabine showed an increase in tiagabine clearance of 60% in patients taking carbamazepine, phenytoin, phenobarbital, and/or primidone in combination with tiagabine. While no significant change was noted in the clearance or concentration of tiagabine when concomitantly administered with valproate in human subjects, in vitro studies have reported an increase of 40% in the free tiagabine concentration when valproate is administered with tiagabine. The clinical significance of this finding is unknown. The interactions of various other medications and tiagabine have been studied. No significant interactions were noted in the coadministration of tiagabine and cimetidine, theophylline, warfarin, digoxin, ethanol, triazolam, oral contraceptives, and antipyrine. Of note, in vitro studies have demonstrated that tiagabine is 96% bound to human plasma protein. Therefore, the potential for interaction of tiagabine with other highly protein bound medications exists.

Use in Special Populations

Tiagabine administered in studies to geriatric patients showed similar pharmacokinetics as when administered to younger adults. Nonetheless, it is important to note that few geriatric patients were included in studies on tiagabine, and it is difficult to draw conclusions about the safety or efficacy of tiagabine in the geriatric population. As discussed previously, tiagabine is highly protein bound. Studies have shown that clearance of unbound tiagabine is significantly reduced in patients with moderate hepatic impairment. Thus, when compared to patients with normal hepatic function, patient with impaired hepatic function may require lower initial and maintenance doses and may require longer dosing intervals. Studies of tiagabine in patients with renal insufficiency have shown that the pharmacokinetics of bound and unbound tiagabine is not significantly affected in renal impairment even in renal failure necessitating hemodialysis. Therefore, no adjustment is needed to the dosing of tiagabine in patients with renal insufficiency.

Pediatric Use

Tiagabine hydrochloride is indicated as adjunctive therapy in children 12 years and older in the treatment of partial seizures. Tiagabine has not been investigated adequately in well-controlled clinical trials in patients younger than 12 years of age. In adolescents 12 to 18 years old, tiagabine should be initiated at 4 mg once daily. Concomitant AEDs do not have to be modified, unless clinically indicated. The total daily dose of tiagabine may be increased by 4 mg at the beginning of week 2. Thereafter, the total daily dose may be increased by 4 to 8 mg at weekly intervals until clinical response is achieved or up to 32 mg/day. The total daily dose should be given in divided doses two to four times daily.