New anticonvulsants in clinical practice

Epilepsy is a disease that has been known for thousands of years, and many therapeutic approaches and substances have been used to treat it. In recent years, the options for treating epilepsy have multiplied, and a bewildering number of anticonvulsants are now available to physicians. So what to take when?

Epilepsy is a disease that has been known for thousands of years, and many therapeutic approaches and substances have been used to treat it. Modern drug treatment of epilepsy began in the middle of the 19th century with the discovery of the seizure-suppressing effect of bromine, which was then used as a sleeping pill. Since then, several new active ingredients have been discovered and developed. From the second half of the In the 20th century, this development accelerated, with the approval of lamotrigine in 1994 marking the transition from the “old” established substances (such as carbamazepine, phenytoin or valproate) to the “newer” substances. As a result of this development, the options for treating epilepsies have multiplied in recent years, and a bewildering number of anticonvulsants are now available to physicians.

Unfortunately, this still does not solve the basic problem of epilepsy, because all available drugs only suppress seizures symptomatically and do not treat the underlying pathology. Therefore, it is actually not correct to speak of “antiepileptic drugs”, rather they are only “anticonvulsants” or even more accurately, since also only a part of the seizures is “convulsive”, “seizure medication”. The effect on epileptic seizures is about the same with virtually all established drugs, and about 60-70% of patients remain seizure-free with the first drug. Here, the approval of the new preparations has not yet brought any decisive advantage over the older substances.

In order to achieve sufficient protection against the epileptic seizures, which usually occur unpredictably, the corresponding active substance must be taken daily or, in many cases, several times a day. Thus, in addition to the efficacy against the seizures, the tolerability as well as the interaction potential of the active substance used in everyday life are relevant. In this respect, the newer drugs are generally superior to the older preparations.

For medication selection, in addition to the specific circumstances of the individual patient, the type of epilepsy, gender, age, and comorbidities must be considered.

Below, we provide an overview of the most important newer drugs for epileptic seizures.

Lamotrigine

Although lamotrigine is not really a new drug anymore, since it has been on the market since 1994, it should nevertheless be listed here because it is now often the first choice due to its wide range of use in focal and generalized seizures and its good tolerability. Lamotrigine is a sodium channel blocker and also inhibits the release of glutamate. It is 55% bound to protein. The usual initial target dose is 200 mg per day in younger, normal-weight patients; 150 mg may be sufficient in the elderly. Usually the dose is divided into two dosing times, but because of the relatively long half-life of about 25-30 hours, it can be given only once a day in individual cases. Due to the mostly good tolerability, considerably higher daily doses are also used in everyday life.

Lamotrigine has a broad spectrum of action and is well effective in both focal and generalized seizures. However, in myoclonic seizures, it can lead to an increase in myoclonia. Especially in the treatment of young women, its use has increasingly moved to the forefront due to the low risk of malformation in case of pregnancy. Lamotrigine is also popular in elderly patients because of its lack of or minimal cognitive side effects, low sedative effect, and positive psychotropic effect. In disabled patients, however, it can – rarely – lead to increased aggressiveness.

The main disadvantage in clinical practice is the need for very slow up-dosing to avoid allergic skin reactions, which in the worst case can lead to life-threatening dermatological situations. However, the slow dosing regimen significantly reduced the risk of allergy (from about 10% to about 2-3%). It is important to inform patients about this potential risk. Because of the slow dosing, significant seizure protection with lamotrigine is not expected for a few weeks. Therefore, if the seizure frequency is high and the effect is clinically needed, parallel shielding with benzodiazepines can be given, or a drug with faster dosing capability can be used first.

Interactions: Lamotrigine has few but clinically relevant interactions. One of the most important interactions in this regard is with oral contraceptives, more specifically oral contraceptives that have an ethinylestradiol (EE) component. The ethinyl estradiol component may cause a reduction in lamotrigine levels of up to 40-50%, meaning that very low levels may occur while taking the contraceptive, resulting in a lack of seizure protection. Conversely, during the monthly “pill break” of one week that is often observed, this can cause lamotrigine levels to rise enough to cause side effects. In contrast, the progestin component has no effect on lamotrigine levels, whereas conversely, lamotrigine reduces levonorgestrel levels by approximately 20%. It is unclear to date whether this is clinically significant [1,2]. Because of these complex interactions, progestogen-only preparations should therefore be preferred for therapy with lamotrigine (e.g., desogestrel 0.075 mg) or, even better, the use of an IUD (e.g., Mirena, Jaydess).

During pregnancy, lamotrigine levels usually drop by 50-60% already during the 1st trimester due to hormonal changes – which vary from individual to individual – which is why a lamotrigine level determination is recommended before the onset of pregnancy and every 4 weeks during pregnancy. If lamotrigine levels drop below 65% of baseline and/or clinical seizures occur, an appropriate increase in daily dose should be implemented. Note a rapid postpartum increase in lamotrigine levels within a few days, which is completed after 2-3 weeks [3,4,5]. Accordingly, rapid dose adjustment is required after birth.

Interactions with valproate are also very important. While the elimination half-life of lamotrigine is approximately 25-30 hours in adults and 15 hours in children, it increases up to 60 hours when comedicated with valproate. It is essential to take this into account and the dosing regimen and maintenance dose must be adjusted if valproate is taken at the same time, which means an even twofold slower dosing and a lower maintenance dose! On the other hand, this combination is then often very effective due to the only minor mirror fluctuations. Note: Valproate should be avoided in women of childbearing age if possible due to its high teratogenic potential.

Levetiracetam

Levetiracetam has a very broad range of use and is approved for focal and generalized seizures. Unlike lamotrigine, levetiracetam is very effective against myoclonia and is therefore also popular for posthypoxic myoclonia. Levetiracetam binds the SV2A membrane protein found in synaptic vesicles and also acts through calcium channels and at the AMPA receptor. It is only 10% protein bound and shows no interactions with other drugs. Two-thirds are excreted unchanged by the kidney; in renal insufficiency, the dose must be adjusted.

The advantage, besides the broad spectrum of efficacy, is especially the relatively fast up-dosing (first target dose is 1000 mg per day, in elderly patients 750 mg per day), this is easily achievable in the outpatient setting in 2 weeks. If necessary, it can be dosed even faster, but then there may be more side effects (dizziness, fatigue). Levetiracetam is available as a tablet as well as a juice, solution, and intravenous preparation, which is why it can also be given without difficulty to patients with dysphagia and in status epilepticus [6].

Serious side effects are very rare. As a specific side effect, psychological side effects such as anxiety, aggressiveness and depression occur in at least 10% of cases, about which the patient and especially the relatives must be informed.

In young women, levetiracetam is also popular because it does not interact with oral contraception. In pregnancy, like lamotrigine, it showed a very low risk of malformation. During pregnancy, there may also be a significant 40-60% decrease in the level of effect with levetiracetam. Postpartum, a rapid increase can already be expected within the first week, which is why the dose must then be quickly adjusted again [3,7,8].

Brivaracetam

Brivaracetam is the newest drug on the Swiss market and is currently approved only as add-on therapy for focal seizures. The mechanism of action of levetiracetam already mentioned above via the SV2A membrane protein was further developed with brivaracetam. This binds to it in a different way and with a higher affinity, showing no effect via calcium channels or AMPA receptors. Protein binding is less than 20%, and more than 95% is eliminated renally. It interacts poorly with other anticonvulsants, with only a possible increase in phenytoin levels of up to 20% when co-medicated with phenytoin. Conversely, potent enzyme inducers can decrease brivaracetam levels by up to 30%.

Brivaracetam does not interact with oral contraceptives. Side effects are relatively mild with headache, somnolence and dizziness. Psychiatric side effects have been seen with a frequency only at placebo level, in contrast to levetiracetam. The maintenance dose ranges from 50-200 mg, although day 1 can be started as early as 50 mg or 100 mg. The administration is usually 2× daily.

Add-on therapy of brivaracetam to levetiracetam shows no additional effect because of the similar mechanism of action. In contrast, the above-mentioned typical psychological side effects of levetiracetam may be improved by switching to brivaracetam. This conversion can occur immediately “overnight” at a ratio of approximately 1:10 [9]. The advantage of brivaracetam is also the presence of different modes of administration (tablets, oral solution and intravenous infusion). Studies showed a reduction of focal seizures by >50% in 39% of patients, seizure freedom was observed in 5%. Generalized seizures also appear to be effectively treatable by brivaracetam with a reduction of >50% in 44% of patients [10]. Initial studies also show a good effect in status epilepticus (currently “off-label”).

Perampanel

It is the first approved anticonvulsant with a novel mechanism of action at the glutamate AMPA receptor. It was approved in Switzerland in 2013 initially as an add-on therapy for focal epilepsies and since 2016 also as an add-on for generalized epilepsies, both in patients older than 12 years. It is administered only once a day due to a very long half-life of 60 to 70 (up to 105) hours, if possible initially directly in the evening before bedtime, as it very often causes dizziness. In addition, especially in adolescents, some psychiatric symptoms such as aggressiveness, depressive mood and behavioral changes may occur, so clinical vigilance is necessary in this regard [11]. Perampanel is slowly dosed up (and down, if necessary) by 2mg every 2 weeks, and the usual daily dose is 4 to 8 mg. Tablets of active strength 2, 4, 6, 8, 10 and 12 mg are offered, all of which have the same price (approx. CHF 8 per daily dose). It is bound to plasma proteins to >90% and is metabolized via the CYP system with corresponding interactions, especially with carbamazepine, oxcarbazepine, and phenytoin. The effect of progestogen-containing contraceptives may be reduced [12,13].

Zonisamide

It was not launched on the Swiss market until June 2005; prior to that, it had already been approved in Japan since 1989 and in the USA from 2000. It is approved for monotherapy and add-on therapy of focal epilepsy in adults, and for add-on therapy only in children 6 years of age and older. The mechanism of action is not fully understood, but there appears to be an effect via voltage-gated sodium and calcium channels as well as an inhibitory effect on carbonic anhydrase and modulation of GABAerg-mediated inhibition.

For monotherapy, start with 100 mg once daily and increase by 100 mg daily dose every 2 weeks to the usual maintenance dose of 300-500 mg/day. In combination therapy, the approach is somewhat slower (start with 50 mg/day, divided into two single doses). The half-life is long and is about 60 hours, the steady state is reached only after about 8 weeks. Zonisamide is approximately 50% protein bound and is excreted by the kidney.

The advantages of the substance are the long half-life and the already long experience. Disadvantages include relatively frequent cognitive side effects, the risk of kidney stone formation, and some interaction potential mediated through the CYP3A4 and UGT systems. In addition, similar to topiramate, zonisamide can lead to weight loss [13], although this can of course be a desired side effect in some cases.

Lacosamide

Lacosamide works by enhancing the slow inactivation of voltage-gated sodium channels, making it different from other sodium channel blockers. The market launch took place in Switzerland at the beginning of 2014. It is approved as both monotherapy and add-on therapy for focal epilepsy in adults. Start with 2×50 mg, which can be increased to the usual initial maintenance dose of 2×100 mg after one week. Maximum dose is approximately 400-600 mg/day divided into 2 doses (half-life approximately13 hours). It is only slightly bound to plasma proteins (to about 15%). Lacosamide is available as a tablet as well as a syrup and an intravenous preparation, which favors an increasing use also in status epilepticus [14].

Because of its action through the sodium channel, it should not be combined with other sodium channel blockers, as this may result in a supraadditive increase in side effects. An effect on cardiac conduction may also occur, so special caution should be exercised with concomitant administration of antiarrhythmic drugs [13]. The interaction potential is relatively low and is mediated via CYP2C9 and CYP3A4.

For perampanel, as well as for brivaracetam, lacosamide, and zonisamide, there are not (yet) sufficient data from pregnancy registries to estimate the risk of malformation. However, in animal studies, there is no teratogenicity with lacosamide and perampanel, unlike zonisamide [13].

Summary

In summary, the armamentarium of the clinically active epileptologist continues to expand. The newer substances often show better tolerability and a lower interaction potential than the older substances, but in most cases they are not more effective. The choice of anticonvulsant depends on the individual situation and takes into account the type of epilepsy, age, comorbidities and, in women, any desire to have children. In general, care should be taken in the female gender from childhood onwards to ensure that primarily drugs with low teratogenicity are used. Nevertheless, in some cases of primary generalized epilepsy, valproate, which is particularly effective, cannot be dispensed with. In this case, all precautionary measures and the obligation to provide information with once-a-year written information about the risks under treatment with valproate must be observed (Swissmedic 2020).

Due to the often persistent treatment refractory nature of epilepsies, new compounds are urgently needed and numerous promising compounds are currently in development. Epilepsy surgery is also making great progress, so that it is recommended that after the unsuccessful use of two anticonvulsants correctly selected in the indication in adequate dosage, also think about this often very successful option, which can ideally lead to freedom from seizures and thus even cure from epilepsy, and refer patients to an appropriate center.

Take-Home Messages

• New substances are usually well tolerated.
• Interactions of lamotrigine with oral contraception should be noted.
• In pregnancy, lamotrigine and levetiracetam are the first choice. Mirror checks during and after pregnancy are important.
• Consider epilepsy surgery early in refractory course.

Literature:

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InFo NEUROLOGY & PSYCHIATRY 2020; 18(2): 6-19.