Levetiracetam

Levetiracetam is a single enantiomer, (S)-α-ethyl-2-oxo-pyrrolidine acetamide. Levetiracetam, licensed in 1999, is probably the best of all the newer AEDs^1-7. It is chemically unrelated to any of the other current AEDs.

Authorised indications

EMEA-SmPC: (1) monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy; (2) adjunctive therapy (a) in the treatment of partial onset seizures with or without secondary generalisation in adults, children and infants from 1 month of age with epilepsy (the concentrate for solution for infusion is indicated for adults, adolescents and children from 4 years of age), (b) in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with JME, and (c) in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with IGE.

Levetiracetam concentrate is an alternative for patients when oral administration is temporarily not feasible.

FDA-PI: (1) adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy; (2) adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy; and (3) adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.

Levetiracetam injection is an alternative for adult patients (16 years and older) when oral administration is temporarily not feasible.

Clinical applications

Levetiracetam is probably a major breakthrough in the treatment of epilepsies, similar to that of carbamazepine and valproate in the 1960s. It is a highly effective, broad-spectrum, newer class of AED with a unique mechanism of action, and can be used to treat all focal or generalised, idiopathic or symptomatic epileptic syndromes in all age groups.

Levetiracetam is the first-choice AED in monotherapy and polytherapy of focal epilepsies, where it is the main challenger of carbamazepine. It is also the likely candidate to replace valproate in the treatment of JME and IGEs in general.

The main advantages of levetiracetam include the following:

• it is broad spectrum, which is of practical significance, particularly for clinicians who may not have special expertise in differentiating between focal and generalised epileptic seizures
• it has a relatively good safety profile^9-11 and does not cause significant idiosyncratic reactions or other serious ADRs
• it has superior pharmacokinetics (96% versus 100% of perfect score)⁵
• it does not need slow titration, the starting dose is often therapeutic for all forms of seizures and epilepsies (including the difficult-to-treat myoclonic seizures);¹³ its action starts 2 days after drug initiation¹⁴
• it does not need laboratory tests (such as routine TDM or blood screening for ADRs)
• it is easier to use if polytherapy is necessitated (a lack of clinically significant drug–drug interactions^8,15 and a novel mechanism of action)
• it does not interact with hormonal contraception and is a pregnancy category C drug
• it does not interfere with liver function (a major problem with most other AEDs that are metabolised in the liver).

Levetiracetam has a significant and sustained proven efficacy for newly diagnosed or intractable focal seizures with or without secondarily generalisation.^16-26 Addition of levetiracetam to standard medication seems to have a positive impact on health-related quality of life.⁹

Its effectiveness in generalised epileptic seizures and at any age has been documented in experimental and observational studies, postmarketing experience and RCTs. This includes IGE, JME, myoclonus and photosensitivity (see management sections in relevant chapters).^27–31

Levetiracetam is the only one of the newer AEDs to have been successfully submitted to a prospective RCT in JME and other IGEs with myoclonic jerks. The study concluded that ‘levetiracetam proved to be highly efficacious in the treatment of refractory patients with IGE experiencing myoclonic seizures. Levetiracetam’s outstanding tolerability profile was also confirmed.’³¹

Its efficacy on primarily GTCSs has also been documented with RCTs.²⁵ That levetiracetam is a first-class AED in syndromes of IGEs has also been more recently confirmed.^29-31

Levetiracetam also appears effective in benign childhood focal epilepsies,^32-34 as well as epileptic encephalopathies such as Lennox–Gastaut,^35,36 Landau–Kleffner³⁷ syndrome and myoclonic syndromes.³⁸

As expected by its favourable pharmacokinetic profile, levetiracetam was found to be effective, well tolerated and safe in patients with epilepsy and other concomitant medical conditions, including brain tumours.^39,40 Considering also its relatively safe profile, levetiracetam may be a first-choice AED in the elderly.^41,42

Levetiracetam is available in oral and intra venous formulations. Parenteral formulations are needed when oral administration is temporarily not feasible.⁴³

Dosage and titration

Adults: start treatment with 1000 mg/day (twice-daily dosing), which may be sufficient for seizure control. If needed, levetiracetam can be titrated in steps of 500 mg/ week to a maximum of 3000 mg/day. Panayiotopoulos (2010)⁷² recommends starting with 250 mg twice daily and titrating upwards according to the response.

Children: start with 5–10 mg/kg/day, which may be sufficient for seizure control. If needed, levetiracetam can be titrated in steps of 5–10 mg/kg/week to a usual maintenance dose of 20–40 mg/kg/day (a maximum of 60 mg/kg/day has been used) given in two equally divided doses.^44-47

Based on weight, the maintenance dose for children should be 30–40% higher than that for adults. The reason for this is that levetiracetam clearance in children is 30–40% higher than in adults.^48,49 The increase, compared with adults, is even higher in infants.^50,51

Levetiracetam administered by intravenous infusion at dosages and/or infusion rates higher than those proposed are well tolerated in healthy subjects, and the pharmacokinetic profile is consistent with that for oral levetiracetam.^52,53

Dosing: twice daily. Dose adjustment is required for patients with renal dysfunction, but not for patients with liver disease.

TDM: usually not needed and can be efficacious from the starting dose. However, pregnancy appears to enhance the elimination of levetiracetam, resulting in a marked decline in plasma concentration, which suggests that TDM may be of value.⁵⁴

Reference range: 6–20 mg/l (35–120 μmol/l).

Main ADRs

Levetiracetam is probably the AED that is most free from ADRs. Few major ADRs were reported in the clinical trials and, overall, their incidence in the levetiracetam-treated groups was little higher than that in the placebo groups.⁵⁵

Frequent and/or important: the most common ADRs are somnolence, asthenia and dizziness, which are dosedependent and reversible. Others include headache, infection (common cold or upper respiratory infections, which were not preceded by low neutrophil counts that might suggest impaired immunological status), anorexia, behavioural disturbances, pharyngitis and pain. No withdrawal-related behavioural ADRs were reported during the cross-titration period.^136,137 Levetiracetam interferes with rapid motor learning in humans due to suppression of excitatory activity in the motor cortex.⁵⁶

Caution should be exercised when administering levetiracetam to individuals who may be prone to psychotic or psychiatric reactions.

In an uncontrolled study, add-on levetiracetam was associated with a paradoxical increase in seizure frequency, particularly in mentally retarded patients and those with difficult-to-treat focal-onset seizures treated with high doses of levetiracetam.⁵⁷ This may be avoided by using a lower initial dose and a slower dose escalation than recommended.

FDA warning: All patients who are currently taking or starting on levetiracetam for any indication should be monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression.

Considerations in women

Pregnancy: category C. Recently, in the UK Epilepsy and Pregnancy Register of 117 pregnancies exposed to levetiracetam (39 in monotherapy and 78 in combination with at least one other AED), only three infants (all in the polytherapy group) had a MCM (2.7%; 95% confidence interval [CI], 0.9–7.7%) .⁵⁸

Breastfeeding: there is an extensive transfer of levetiracetam from mother to foetus and into breast milk. However, breast-fed infants have very-low levetiracetam plasma concentrations, suggesting a rapid elimination of levetiracetam^47,57

Interaction with hormonal contraception: none.

Main mechanisms of action

It has a novel mechanism of action that is distinct from that of other AEDs by targeting a synaptic vesicle protein in presynaptic terminals.^58-60 Its antiepileptic activity does not involve a direct interaction with any of the three main mechanisms of the other AEDs. Thus, levetiracetam does not modulate Na⁺ and low voltage-gated (T-type) Ca2⁺ currents, and does not induce any conventional facilitation of the GABAergic system. In contrast, levetiracetam has been observed to exert several atypical electrophysiological actions, including a moderate inhibition of high voltage-gated N-type Ca2⁺ currents, reduction of intracellular Ca2⁺ release from the endoplasmic reticulum, as well as suppression of the inhibitory effect of zinc and other negative allosteric modulators of both GABA- and glycine-gated currents.

The apparent absence of any direct interaction with conventional mechanisms involved in the action of other AEDs parallels the discovery of a specific binding site for levetiracetam. Recent experiments have shown that the synaptic vesicle protein 2A (SV2A) is the binding site of levetiracetam.^63,64

Studies in mice lacking SV2A indicate that this protein has a crucial role in the regulation of vesicle function, probably involving a modulation of vesicle fusion. These mice seem normal at birth, but develop unusually severe seizures by 1 or 2 weeks of age and die within 3 weeks after birth.⁵⁶ Brain membranes and purified synaptic vesicles from mice lacking SV2A did not bind a tritiated derivative of levetiracetam, indicating that SV2A is necessary for levetiracetam binding. Levetiracetam and related derivatives bind to SV2A, but not to the related isoforms SV2B and SV2C expressed in fibroblasts, indicating that SV2A is sufficient for levetiracetam binding. In contrast, none of the other AEDs tested revealed any binding to SV2A.⁶³

The severe seizures observed in mice lacking SV2A support the interpretation that this protein influences mechanisms of seizure generation or propagation. Furthermore, there is a strong correlation between the binding affinity of a series of levetiracetam derivatives such as brivaracetam and their anticonvulsant potency in the audiogenic seizure mice model. These results suggest that levetiracetam’s interaction with SV2A provides a significant contribution to its anti-epileptic activity.

Pharmacokinetics

The pharmacokinetic profile of levetiracetam closely approximates the ideal characteristics expected of an AED, with good bioavailability, rapid achievement of steady-state concentrations, linear and time-invariant kinetics, minimal protein binding, and minimal metabolism.⁶⁵

Levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED: (1) it has a high oral bioavailability, which is unaffected by food; (2) it is not significantly bound to plasma proteins; (3) it is eliminated partly in unchanged form by the kidneys and partly by hydrolysis to an inactive metabolite, without involvement of oxidative and conjugative enzymes; (4) it has linear kinetics; and (5) it is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Although its halflife is relatively short (6–8 hours), its duration of action is longer than anticipated from its pharmacokinetics in plasma, and a twice-daily dosing regimen is adequate to produce the desired response.¹⁵

Oral bioavailability: 100% and it is unaffected by food. Levetiracetam is rapidly and almost completely absorbed after oral administration with peak plasma concentrations occurring in about 1 hour. The pharmacokinetics are linear and time-invariant, with low intra- and inter-subject variability.

Protein binding: <10%. Levetiracetam is not appreciably protein-bound nor does it affect the protein binding of other drugs. Its volume of distribution is close to the volume of intracellular and extracellular water.

Metabolism/elimination: the major metabolic path way of levetiracetam (24% of dose) is an enzymatic hydrolysis of the acetamide group. This is not dependent on the hepatic CYP system. Further, levetiracetam does not inhibit or induce hepatic enzymes to produce clinically relevant interactions. Levetiracetam is eliminated from the systemic circulation by renal excretion as an unchanged drug, which represents 66% of the administered dose. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolites have no known pharmacological activity and are also renally excreted.

Elimination half-life: 6–8 hours. It is shorter in children and longer in the elderly and subjects with renal impairment.

Drug interactions

Unlike the majority of other AEDs, levetiracetam has no clinically meaningful drug–drug interactions.

Other AEDs: levetiracetam does not influence the plasma concentration of existing AEDs. In addition, levetiracetam does not affect the in vitro glucuronidation of valproate. Enzyme inducers may decrease levetiracetam plasma levels by 20–30%.⁶⁶

Other non-AEDs: levetiracetam has no known interactions with other drugs such as oral contraceptives, warfarin and digoxin. It does not reduce the effectiveness of oral contraceptives.

Main disadvantages

There are some reports of increased behavioural and psychiatric abnormalities, particularly in children or patients that may be prone to such problems.^67-70 An explanation for this may be the fast titration recommended by the manufacturers. A recent short-term study found that add-on levetiracetam in patients with intractable focal epilepsies has a favourable neuropsychological and psychiatric impact.⁷¹

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