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Second-Generation Anti-Epileptic Drugs

Drugs are listed in order of approval in the USA, from oldest to newest.

Felbamate

Felbamate is a broad-spectrum anti-epileptic drug. It is not considered to be a first-line drug because of its potential for serious idiosyncratic side-effects, including potentially fatal aplastic anaemia (incidence of 1 in 3000) and hepatic failure (incidence of 1 in 10000). Recent analyses indicate that aplastic anaemia and liver failure occur almost exclusively within the first year of therapy. During this period, safety monitoring consisting of liver function tests and blood counts is recommended with a frequency of up to twice monthly, despite lack of evidence that early detection of changes will prevent serious health problems, even if the drug is discontinued. Yet, felbamate may still be an important drug in the armamentarium for refractory patients, because it may control seizures when other drugs fail, and tends to be alerting rather than sedating. It has been found to be particularly effective in patients with Lennox-Gastaut syndrome. Felbamate should be started at 300-600 mg twice daily, and increased as necessary over several weeks, up to 3600 mg, or higher in some cases. Drug levels maybe useful, and serum concentrations of 30-80mg/1 are recommended. Three-times-a-day dosing may improve tolerability. Dose-related side-effects include insomnia, decreased appetite and weight loss, ataxia, Gastrointestinal upset and headache. Other serious idiosyncratic adverse events include rash and Stevens-Johnson syndrome. Felbamate has a complex metabolism and elimination, by both the hepatic and renal routes, and inhibits the metabolism of some drugs while inducing others. Adjustments in these medications may be necessary.

Lamotrigine

Lamotrigine is a broad-spectrum anti-epileptic drug that has been widely accepted as a first-line drug for both partial and generalized epilepsy syndromes. Clinical trials have supported its use in partial seizures, primary generalized tonic-clonic seizures, absence seizures and seizures associated with Lennox-Gastaut syndrome. There is some controversy regarding the use of lamotrigine in juvenile myoclonic epilepsy. It is commonly used, but may worsen myoclonus in some patients. Lamotrigine has been the subject of a number of head-to-head studies in newly diagnosed partial and generalized epilepsy. Lamotrigine was equally effective but better tolerated than phenytoin and carbamazepine in several somewhat under-powered studies. Several studies indicated that lamotrigine is better tolerated than carbamazepine in the elderly. A recent very large, randomized open-label study indicated that lamotrigine might be the drug of choice in patients with partial epilepsy, as it was equally effective but better tolerated, but in a companion study it was substantially less effective than valproate in patients with generalized or unclassified epilepsy. Some studies have advocated combining lamotrigine with valproate in refractory patients, to achieve maximum efficacy through a favourable pharmacodynamic interaction. However, side-effects are also enhanced when the drugs are combined. Initiation of lamotrigine is somewhat more complex than for other drugs. Slow titration is mandatory to reduce occurrence of serious rash. In monotherapy, initiation with 25mg/day for 2 weeks, then 50mg/day for another 2 weeks, followed by increases of 25-50 mg/week is appropriate. If the patient is receiving valproate at the time of initiation, starting doses and doses during titration should be cut in half, whereas if they are receiving enzyme-inducing anti-epileptic drugs such as phenytoin, carbamazepine or phenobarbital, doses can be doubled. Doses can then be increased as necessary. Typical doses for patients with newly diagnosed epilepsy are 100-200 mg/day. In refractory patients, doses may be as high as 500-1000 mg/day. There is a great deal of variability in serum concentrations that produce optimal effects. Some patients may do well at serum concentrations of 2mg/l, while others may need levels of up to 20 mg/1. Common dose-related side-effects of lamotrigine include mild tremor, double vision, headache and insomnia. Rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur. Risk is increased for children under 16, and is also more common with concomitant valproate use, and in patients who have experienced rash on other anti-epileptic drugs. Rash almost always occurs within the first 8 weeks of therapy. Other hypersensitivity reactions, although much rarer, may be seen, including lymphadenopathy, fever, hepatic or renal failure, disseminated intravascular coagulation and arthritis. Discontinuation of lamotrigine is recommended in the presence of rash or other indication of hypersensitivity, and it is very important to tell patients to call immediately with such symptoms. Rapid discontinuation can prevent a more severe, potentially life-threatening reaction. In the absence of any clinical symptoms of hypersensitivity, it is unclear that routine monitoring of liver function tests, blood counts or electrolytes is useful. Lamotrigine does not alter the metabolism of other drugs that are given concomitantly. However, other drugs may impact on the metabolism of lamotrigine. One important and common drug interaction that bears noting is that with oral contraceptives, which double the clearance and halve the half-life of lamotrigine. Women on lamotrigine should be told to notify their doctor of any changes in oral contraceptive pill use, something they might not otherwise think to do.

Gabapentin

Gabapentin is a narrow-spectrum drug. It is useful only in patients with partial epilepsy, that is those with simple or complex partial seizures, or partial-onset generalized tonic-clonic convulsions. Gabapentin is felt to be more useful in newly diagnosed patients with mild epilepsy and in the elderly, who benefit from the relatively mild side-effect profile and lack of drug interactions, but less useful in patients with refractory epilepsy. Although gabapentin can be initiated at a therapeutic dose of 1200-2400 mg/day, it appears to be better tolerated when titrated. Typically, 300 mg two times a day is well tolerated as a starting dose, but lower starting doses are needed in some patients. Clinical trials have only tested efficacy to 2400 mg/day. However, in clinical experience, higher doses can be useful. However, gabapentin displays dose-dependent, saturable absorption. At higher doses, less may be absorbed across the gut, leading to diminishing returns. The amount of absorption varies from person to person. Determining if serum levels are rising after dose increments can help ascertain whether increasing doses are futile. Gabapentin is not bound to plasma proteins, is eliminated renally and does not interfere with the metabolism of other medications, including anti-epileptic drugs or psychotropic agents. This makes it an ideal drug for the elderly and patients with chronic illness, who are likely to be taking other drugs. Common dose-related side-effects include somnolence, dizziness, ataxia and fatigue. Weight gain is also seen, and appears to be dose related. Peripheral oedema may occur in some patients. Occurrence of myoclonus has been reported, as well as occasional behavioural disturbance in children. There are no reports of serious idiosyncratic side-effects. Therefore, routine monitoring of liver function tests, blood counts and electrolytes is probably not warranted.

Topiramate

Topiramate is another anti-epileptic drug that is felt to be broad spectrum. It has been studied and found effective in patients with partial-onset or primary generalized tonic-clonic seizures, and in patients with seizures associated with Lennox-Gastaut syndrome. Topiramate is felt to be first-line therapy in all these conditions. One head-to-head study in newly diagnosed patients found topiramate to be equal in efficacy with valproate in patients with mostly generalized seizures, and with carbamazepine in patients with mostly partial seizures, although the study was under-powered and has been criticized methodologically. A recent open-label randomized study in newly diagnosed adults and children indicated that topiramate was as efficacious as any other drug for partial and generalized seizures, but was less well tolerated. However, the open-label nature of the study could have produced some bias. Topiramate should be started at a low dose and slowly titrated for best tolerability, although there are no safety concerns related to starting more rapidly. It is best tolerated when initiated at 25 mg/day and increased by 25 mg/week. Typical doses necessary for newly diagnosed patients are in the range of 100-200 mg, while, as is the case for most drugs, refractory patients may require much higher doses. Up to 1000 mg has been tested in clinical trials, although few can tolerate such high doses. As with lamotrigine, serum levels needed to achieve control are variable, from 2 to 20 mg/1. Monitoring serum levels may be useful. Topiramate is well absorbed and has minimal protein binding. Topiramate is partially metabolized by the liver and approximately 60% is excreted unchanged in the urine. The more common dose-related adverse events include somnolence, paraesthesias (especially of fingertips), fatigue, taste perversion, weight loss and dizziness. One of the side-effects that is relatively specific to topiramate is psychomotor slowing, which particularly affects speech. Patients may complain of word-finding difficulty or slowing of speech. Academic performance can be affected. This side-effect is significant in some patients, while others may escape it entirely, even at high doses. Potential, more serious side-effects that occur infrequently include nephrolithiasis, open-angle glaucoma, causing transient and reversible visual loss, and hypohidrosis in children. Rarely, the hypohidrosis has caused heat stroke with serious consequences. Children receiving topiramate have also rarely developed clinically significant metabolic acidosis. Milder forms are common. Topiramate has rarely been associated with hepatic failure, and this seems to happen more commonly when topiramate is combined with valproate. Topiramate does not impact the metabolism of most concomitant drugs, but it does raise phenytoin levels when added to patients with baseline higher phenytoin levels (e.g. above 15 mg/1), which can potentially cause phenytoin toxicity. Therefore, phenytoin levels should be monitored. In addition, the classic hepatic enzyme-inducing antiepileptic drugs, such as phenytoin and carbamazepine, will increase the metabolism of topiramate, and higher doses may be required.

Oxcarbazepine

Oxcarbazepine, an analogue of carbamazepine, is a narrow-spectrum drug that is considered to be a first-line therapy for the treatment of partial seizures. Although it is similar to carbamazepine, it is effective in some patients for whom carbamazepine has failed and is believed to have additional mechanisms of action. Oxcarbazepine is actually a prodrug for a mono-hydroxylated form, to which it is rapidly converted after oral administration. Several studies have been performed in patients with newly diagnosed epilepsy, comparing oxcarbazepine with older anti-epileptic drugs. In all of these studies, oxcarbazepine was equally efficacious. It was better tolerated than phenytoin and carbamazepine, and as well tolerated as valproate. Oxcarbazepine has been noted to exacerbate myoclonic seizures as well as absence.

Oxcarbazepine should be initiated with titration to avoid side-effects. However, in one inpatient study, 2400 mg/day was started, and caused few dropouts, thus rapid initiation in an emergency is possible. In outpatients, initiation of 300 mg twice daily and titration of 600mg/week is usually well tolerated. Effective doses range from 900 to 2400mg, but higher doses are not well tolerated in combination with other drugs, particularly those with similar side-effect profiles. If side-effects develop as the dose is being increased, spacing out dosing to three times daily, or even four times daily sometimes permits achievement of higher, more efficacious doses. Plasma concentrations of up to 45 mg/1 have been well tolerated. Frequent dose-related adverse events include somnolence, dizziness, headache, ataxia, nausea and vomiting, diplopia, blurred vision, vertigo and tremor. One problematic potential adverse event is hyponatraemia. In a recent study, hyponatraemia was substantially more common for oxcarbazepine (29.9%) than carbamazepine (35.5%), and serum sodium levels of <128mEqA occurred in 12.4%. Risk factors for hyponatraemia include older age and diuretic use. Hypersensitivity syndromes, including rash and Stevens-Johnson syndrome are rare consequences of oxcarbazepine use. Oxcarbazepine does not have the strong enzyme-inducing properties of carbamazepine, and also does not induce its own metabolism. Oxcarbazepine also acts as an inhibitor of phenytoin metabolism, and its own metabolism is induced by the classic inducing anti-epileptic drugs such as phenytoin and carbamazepine.

Tiagabine

Tiagabine is a drug that is considered second-line therapy, and is effective for partial seizures only. Like other drugs that work via y-aminobutyric acid enhancement, tiagabine may exacerbate absence and myoclonic seizures. Tiagabine was compared with carbamazepine in a study of newly diagnosed patients with partial seizures, and was found to be less efficacious. However, it was fairly effective as add-on therapy in patients with refractory epilepsy. Nonetheless, its use has waned in recent years. Of note, some reports of seizures have surfaced when tiagabine has been used off-label for psychiatric indications. Tiagabine is best tolerated when titrated. Initiation of 4 mg once or twice daily is recommended, with dose increments of 4mg/week. A three-four-times-a-day regimen is recommended, due to the short half-life. Doses of up to 64 mg have been used in add-on trials. Patients receiving enzyme inducers will need higher doses than patients taking non-inducing anti-epileptic drugs. Serum levels have not been very clinically useful, due to the short half-life, which results in wide fluctuations in levels from peak to trough. Tiagabine is 96% protein bound, but no protein-binding interactions have been identified clinically. Common dose-related side-effects include tiredness, nervousness, dizziness, headache, tremor and abnormal thinking. An unusual side-effect has been identified, consisting of a stuporous state accompanied by a slow wave or spike-wave pattern on electroencephalogram. This resolves promptly with discontinuation of the drug. Another atypical side-effect is described as weakness or asthenia. No metabolic, hepatic or blood-related adverse events have been identified. Therefore, monitoring of complete blood counts, electrolytes and liver function tests is not clinically warranted. Tiagabine does not impact on the metabolism of other drugs. Other anti-epileptic drugs can impact on the metabolism of tiagabine.

Levetiracetam

Levetiracetam is a broad-spectrum drug that has undergone extensive testing. Therefore, more syndromes have been explored than for some of the other newer anti-epileptic drugs. It is effective in partial seizures. A study of patients with newly diagnosed partial or generalized tonic-clonic seizures showed no differences in efficacy or tolerability between levetiracetam and carbamazepine. Levetiracetam is the only newer anti-epileptic drug approved for use in juvenile myoclonic epilepsy. It was also effective for idiopathic generalized tonic-clonic seizures in an add-on situation. Case series have indicated efficacy in other idiopathic epilepsy syndromes.

One reason levetiracetam has become a very popular choice, for both initial and add-on therapy, is that it is easy to use. It can be started at a therapeutic dose, and data indicate that onset of action is within a day. Patients can be started on either 500mg once daily or 500 mg twice daily. The dose can then be increased gradually as necessary, with maximal dose typically being 3000 mg/day. If necessary, it can be started at a higher dose, although it is not clear if this is clinically necessary. In one study, levetiracetam was started at 4000 mg/ day, and was well tolerated. Serum levels are typically within the range of 10—40mgA, but will vary substantially over the course of a day, because of the short half-life of the drug. Another advantage of levetiracetam is that it is associated with no drug interactions because it is predominantly renally excreted, and shows limited metabolism in humans. As with other renally excreted drugs, lower doses should be used in the elderly, because they have a reduced creatinine clearance .

Side-effects of levetiracetam include irritability, somnolence, dizziness, asthenia and headache. Other uncommon adverse events include behavioural problems, depression and psychosis. Levetiracetam does not often cause rash, and is therefore a reasonable choice in patients with a history of hypersensitivity syndrome. To date, there has been no indication that levetiracetam can cause idiosyncratic safety problems such as aplastic anaemia or hepatic failure. Therefore, routine monitoring of liver function tests, blood counts and electrolytes is not clinically warranted.

Levetiracetam was recently approved in an i.v. formulation. It is being used more frequently for inpatients with other medical conditions who require immediate anti-epileptic drug therapy, and in status epilepticus, but no formal studies have been done.

Zonisamide

Zonisamide is felt to be broad spectrum. Unfortunately, trials in generalized seizure syndromes have not been performed to confirm this clinical impression. The only randomized controlled trials were performed in adults with partial seizures. Randomized trials in patients with newly diagnosed epilepsy have also not been done. Case series and open studies support a role for zonisamide in the treatment of syndromes associated with myoclonus, including juvenile myoclonic epilepsy and progressive myoclonic epilepsies. Zonisamide is better tolerated when it is titrated at initiation. It can be started at 50mg/day or 100 mg/day. The dose should then be titrated by 50mg/week or 100 mg every other week. Doses of 200-300 mg are common, and up to 500 mg can be necessary in difficult-to-treat patients. Serum concentrations of 20-40 mg/1 are considered therapeutic. Since the half-life is long (up to 60 h), serum concentrations can be expected to be steady over the course of the day. Common dose-related adverse events include fatigue, weight loss, dizziness, somnolence, anorexia and abnormal thinking, and decreased sweating. Zonisamide has also been associated with idiosyncratic side-effects. These include hypersensitivity syndromes such as rash and Stevens-Johnson syndrome and renal calculi. Patients living in hot climates, who are on high doses and have a family history of renal calculi may be at higher risk. Patients receiving zonisamide should be advised to drink plenty of fluids. The recurrence rate, even if zonisamide is continued, is not 100%. Hypohidrosis has also been seen, again more common in hot climates, and may infrequently lead to heat stroke in children. Zonisamide is well absorbed and is not extensively bound to plasma proteins. Since enzyme-inducing drugs such as carbamazepine and phenytoin can significantly reduce the half-life of zonisamide, higher doses will be needed in patients taking them in combination. Zonisamide metabolism can also be inhibited by a number of medications as well as by grapefruit juice. Zonisamide has essentially no impact on the pharmacokinetic parameters of other drugs.

Pregabalin

Pregabalin has a similar efficacy profile to gabapentin, that is to say its use is restricted to partial seizures. No formal monotherapy studies have been completed, in either newly diagnosed or refractory patients. An advantage of pregabalin when compared to gabapentin, is that it is highly bioavailable, and does not require active dose-dependent transport in the Gastrointestinal tract. Pregabalin is better tolerated when titrated. A recent study indicated that starting at the highest dose of 600 mg, while safe, led to 32% dropouts. Pregabalin can be initiated at 50-75 mg twice daily, and titrated by 50-75 mg every week or two weeks. There are very few clinical data available regarding the safety and tolerability of doses above 600mg/day. Twice-daily dosing is commonly used, despite the short half-life of the drug. A study comparing efficacy and tolerability of the same total daily dose, given as twice daily or thrice daily showed no statistically significant difference, but there was a trend to both better efficacy and tolerability when thrice daily was used. Therefore, it is reasonable to start off with a twice-daily regimen, and switch to thrice daily only if side-effects are present and/or breakthrough seizures are occurring. Pregabalin levels have only recently become available, and their clinical utility is unknown. Common dose-related side-effects predominantly affecting the central nervous system include dizziness, somnolence and ataxia. Weight gain and peripheral oedema are also seen. Weight gain is also dose related. To date, no idiosyncratic side-effects have been identified. Need for routine monitoring of liver functions, electrolytes and blood counts is therefore not established. Pregabalin is almost exclusively excreted unchanged in the urine, and does not undergo metabolic changes. To date, no drug-drug interactions have been uncovered, and none are expected.

Vigabatrin (not approved in the usa)

Vigabatrin, like felbamate, is an anti-epileptic drug that has been associated with a significant adverse drug effect (irreversible visual field restriction) that limits its use to those patients who have severe epilepsy which has not responded to other anti-epileptic drugs. In adults, vigabatrin appears to have a narrow spectrum of action, and its use is primarily restricted to those patients with refractory partial epilepsy. It has been found inferior in efficacy to carbamazepine in trials of newly diagnosed patients. It has also been known to worsen myoclonus. In infants, however, vigabatrin was found to be highly effective in the devastating childhood epilepsy known as infantile spasms, or West syndrome [99]. In a randomized trial, there was a 78% reduction in seizures on vigabatrin, compared with 26% on placebo. Moreover, in the open-label phase, 38% of children were completely spasm free. Vigabatrin is particularly effective in patients with spasms associated with tuberous sclerosis. Vigabatrin can be initiated at 500-1000mg, given once or twice a day. The dose can be increased in 500-1000 mg weekly increments, up to 3000 mg. Some patients worsen at higher doses. Vigabatrin has unique pharmacokinetic properties, in that its mechanism of action involves changes in brain chemistry that far outlast its presence in the bloodstream. Therefore, vigabatrin levels are not useful for therapeutic monitoring.

As noted, the main safety concern relates to irreversible peripheral visual field defects. This problem is estimated to occur in 30-50% of patients receiving the drug. Often, this will be picked up on screening visual field testing, but the patients will not spontaneously report any problem. Since early development of this problem has not been seen in controlled studies, there may be a 3-month ‘window of opportunity’ to see if the drug works before there is a risk of the visual field defect. However, once it occurs, it is not reversible.

Other side-effects of vigabatrin include drowsiness, depression, weight gain, dizziness and rare psychosis .

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