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New anti epileptic drugs

Levetiracetam is a broad-spectrum newer antiepileptic drug approved in 1999. It has fewer drug interactions than older AEDs due to simpler pharmacokinetics without enzyme induction. Its unique mechanism of action involves synaptic vesicle protein SV2A. Common adverse effects are mild and reversible. Lacosamide approved in 2008 is indicated as adjunctive therapy for focal seizures. It is initiated at 50mg twice daily and increased weekly by 100mg with a maximum of 400mg daily due to potential CNS and gastrointestinal side effects.

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NEWER ANTI-EPILEPTIC DRUGS IMRAN RIZVI Moderator Dr.H.S.Malhotra, DM Associate Professor, Neurology KGMU
Introduction • Prior to 1993, the choice of an anticonvulsant medication was limited to the “traditional” anticonvulsants [Phenobarbital, Primidone, Phenytoin, Carbamazepine, and Valproate.] • Since 1993, Several new medications have been approved by the US Food and Drug Administration (FDA). • These newer antiepileptic drugs offer the potential advantages of fewer drug interactions, unique mechanisms of action, and a broader spectrum of activity. LaRoche SM et al. JAMA, February 4, 2004—Vol 291, No. 5
ANTIEPILEPTIC DRUG DEVELOPMENT 1840 1860 1880 1900 1920 1940 1960 1980 2000 0 5 10 15 20 Bromide Phenobarbital Phenytoin Primidone Ethosuximide Sodium Valproate Benzodiazepines Carbamazepine Zonisamide Felbamate Gabapentin Topiramate Fosphenytoin OxcarbazepineTiagabine Levetiracetam Rufinamide Lacosamide Brivaracetam Pregabalin Retigabine ? Calendar Year NumberofLicensedAntiepilepticDrugs Lamotrigine
Antiepileptic Drug Year approved Felbamate   1993 Gabapentin   1993 Lamotrigine   1994 Topiramate   1996 Tiagabine   1997 Levetiracetam   1999 Oxcarbazepine   2000 Zonisamide   2000 Pregabalin 2005 Rufinamide 2008 Lacosamide 2009
Advantages of new AEDs • Compared with older agents, many new drugs exhibit simpler pharmacokinetics. (Renal excretion, Lack of interactions.) • Unlike most of the older agents newer AEDs are devoid of significant enzyme inducing or inhibiting properties. • Newer AEDs have a favorable side effect profile when compared to older agents.
Mechanism of action of new AEDs Drug Mechanism Levetiracetam Modifies Synaptic Vesicle Protein (SV2A) Lamotrigine Blocks excitatory sodium channels in a  voltage dependent manner. Lacosamide Modifies sodium channels. Oxcarbazabine Blocks sodium channels, N/P and R type  Calcium channels. Topiramate Modulatory effect on sodium channels,  GABA, AMPA/Kainate receptors. Gabapentin Reduction of Glutamate release at cortical  synapses, reduction of activity dependent  release via interaction with P/Q type  calcium channels.
Mechanism of action of new AEDs Drug Mechanism Vigabatrin Selective irreversible inhibitor of GABA  transaminase Tiagabine Potent, specific GABA uptake inhibitor Rufinamide Limitation of sodium dependent action  potential firing. Zonisamide Sodium channel and T-type calcium  channel blocker.
Adverse events associated with the new AEDs
Adverse events associated with the new AEDs
Levetiracetam • Levetiracetam is a highly effective, broad-spectrum, newer class of AED with a unique mechanism of action. • It was licensed in 1999. • It can be used to treat all focal or generalized, idiopathic or symptomatic epileptic syndromes in all age groups.
Authorized indications • Monotherapy in the treatment of partial onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. • Adjunctive therapy A.In the treatment of partial onset seizures with or without secondary generalization in adults, children and infants from 1 month of age with epilepsy. B.In the treatment of myoclonic seizures in adults and adolescents from 12 years of age with JME. C.In the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with IGE.
Advantages • It is broad spectrum, which is of practical significance, particularly for clinicians who may not have special expertise in differentiating between focal and generalized epileptic seizures. • It has a relatively good safety profile and does not cause significant idiosyncratic reactions or other serious ADRs. • It does not need slow titration, the starting dose is often therapeutic for all forms of seizures and epilepsies. • It is easier to use if polytherapy is necessitated, as it does not cause clinically significant drug–drug interactions
Advantages • 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 metabolized in the liver).
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.
Dosage and titration (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 given in two divided doses.
Main ADRs • Levetiracetam is probably the AED that is most free from ADRs. • The most common ADRs are somnolence, asthenia and dizziness, which are dose dependent and reversible. • Others include headache, common cold or upper respiratory infections, anorexia and behavioral disturbances. • Levetiracetam interferes with rapid motor learning in humans due to suppression of excitatory activity in the motor cortex.
• 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. • All patients who are currently taking or starting on Levetiracetam for any indication should be monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression
Considerations in women • Pregnancy: category C • In the UK Epilepsy and Pregnancy Register of 117 pregnancies exposed to Levetiracetam only three infants (all in the polytherapy group) had a Major Congenital Malformation. Hunt S et al. Neurology 2006;67:1876–9.
Considerations in women • Breastfeeding: There is an extensive transfer of Levetiracetam from mother to fetus and into breast milk. • However, breast-fed infants have very-low Levetiracetam plasma concentrations, suggesting a rapid elimination of Levetiracetam. • Interaction with hormonal contraception: none.
Mechanisms of action • It has a novel mechanism of action that is distinct from that of other AEDs. • It acts by targeting a synaptic vesicle protein in presynaptic terminals. • Its antiepileptic activity does not involve a direct interaction with any of the three main mechanisms of the other AEDs.
Mechanism contd. • Recent experiments have shown that the synaptic vesicle protein 2A (SV2A) is the binding site of Levetiracetam. • Studies in mice lacking SV2A indicate that this protein has a crucial role in the regulation of vesicle formation and fusion. • Mice lacking SV2A develop severe seizures by 1-2 weeks of age. • Thus Levetiracetam’s interaction with SV2A provides a significant contribution to its anti-epileptic activity. Lynch BA et al. Proc Natl Acad Sci USA 2004;101:9861–6.
Pharmacokinetics • Levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED. • it has a high oral bioavailability, which is unaffected by food. (100%) • it is not significantly bound to plasma proteins. • 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.
Pharmacokinetics contd. • It has linear kinetics. • It is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Perucca E et al. Epileptic Disord 2003;5 Suppl 1:S17–26.
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. • Enzyme inducers may decrease Levetiracetam plasma levels by 20–30%. • Other non-AEDs: Levetiracetam has no known interactions with other drugs such as oral contraceptives, warfarin and digoxin. Contin M et al. Ther Drug Monit 2004;26:375–9.
Main disadvantages • There are some reports of increased behavioral and psychiatric abnormalities, particularly in children or patients that may be prone to such problems. White JR et al. Neurology 2003;61:1218–21. Mula M et al. Seizure 2004;13:55–7.
Lacosamide • Lacosamide is a functionalized amino acid (R)-2- acetamido-N-benzyl-3-methoxypropionamide. • It is one of the latest AEDs to be licensed (at the end of 2008) Beydoun A et al. Expert Rev Neurother 2009;9:33-42.
Authorized indications • Tablets are indicated as adjunctive therapy in the treatment of focal seizures in patients with epilepsy aged 17 years and older. • Injection for intravenous use is indicated as adjunctive therapy in the treatment of focal seizures in patients with epilepsy aged 17 years and older when oral administration is temporarily not feasible. Beydoun A et al. Expert Rev Neurother 2009;9:33-42.
Dosage and titration • Start with 50 mg twice daily (100 mg/day). • Increase at weekly intervals by 100 mg/day to 200–400 mg/day. • The maximum recommended dose of Lacosamide is 400 mg/day because higher doses may be associated with CNS and gastrointestinal ADRs. • A maximum dose of 300 mg/day is recommended by the FDA for patients with mild or moderate hepatic impairment.
Dosage for I.V Lacosamide • Lacosamide injection (without further dilution or mixed in compatible diluents) should be administered intravenously over 15–60 minutes. • When switching from oral Lacosamide, the initial total daily intravenous dosage should be equivalent to the total daily dosage and frequency of oral Lacosamide.
Main ADRs • Frequent : Dizziness, headache, diplopia, nausea, vomiting and blurred vision. • Serious: A small, asymptomatic, dose-related increase in the PR interval measured on ECG has been observed in clinical studies. • caution is needed in patients with known conduction problems or severe cardiac disease, in the elderly and in co- medication with drugs known to be associated with PR prolongation.
Considerations in women • Pregnancy: category C. • Breastfeeding: unknown but possibly excreted in breast milk (animal data). • Interactions with hormonal contraception: none.
Mechanisms of action • Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyper excitable neuronal membranes and inhibition of repetitive neuronal firing. Curia G et al. Drugs 2009;23:555-68.
Pharmacokinetics • Lacosamide has near-ideal pharmacokinetics. • Oral bioavailability: 100%. • Protein binding: <15% • Metabolism: Primarily eliminated by renal excretion and biotransformation. • Lacosamide showed no potential to induce or inhibit the activity of CYP isoforms. Beydoun A et al. Expert Rev Neurother 2009;9:33-42.
Drug interactions • These are minimal and probably of no clinical significance. • From available evidence, Lacosamide does not affect plasma levels of carbamazepine, gabapentin, lamotrigine, Levetiracetam, oxcarbazepine, phenytoin and valproate. • It does not affects plasma concentration of oral contraceptive levonorgestrel/ ethinylestradiol. • Carbamazepine, phenytoin and phenobarbital may decrease plasma levels of Lacosamide by 15–20%.
Main disadvantages • Not yet exposed to lengthy clinical practice but its use so far has met with favorable results. Halford JJ et al. Epilepsy Curr 2009;9:1-9.
Zonisamide • Zonisamide appears to be an effective broad spectrum AED with extensive clinical use in Japan. • It has been found to be efficacious in focal and generalizes seizures as well as West syndrome, Ohtahara, and Unverricht syndrome. Tosches WA et al. Epilepsy Behav 2006;8:522–6.
Authorized indications • Adjunctive therapy in adult patients with focal seizures with or without secondary generalization. Tosches WA et al. Epilepsy Behav 2006;8:522–6
Dosage and titration • Adults: Start with 100 mg/day in one or two equally divided doses. • After two weeks, the dose may be increased to 200 mg/day. • Evidence from controlled trials suggests that Zonisamide doses of 100–600mg/day are effective. • Children: start with 1–2 mg/kg/day for the first week and titrate in increments of 1–2 mg/kg/day every 2 weeks. • Usual childhood maintenance dose is 4–8 mg/kg/day.
Mechanisms of action • Zonisamide blocks the sustained repetitive firing of voltage-sensitive sodium channels. • Reduces voltage-dependent T-type calcium current without affecting the L-type calcium current. • It has mild carbonic anhydrase inhibitor activity.
ADRs • Cognitive impairment, including word-finding difficulty. • Weight loss and anorexia that may become very severe. • Nephrolithiasis in 4% of patients on prolonged zonisamide therapy. • Oligohidrosis and anhidrosis often accompanied by hyperthermia, especially in children and hot environments.
Rufinamide • Rufinamide is a triazole derivative structurally unrelated to any currently marketed AED. • It is one of the latest AEDs marketed for the treatment of epileptic seizures. • Its licenced indications are for Lennox–Gastaut syndrome, • The next step will probably be for adjunctive treatment of intractable focal epilepsies. Cheng-Hakimian A et al. Int J Clin Pract 2006;60:1497–501.
Authorized indications • Adjunctive treatment of seizures associated with Lennox– Gastaut syndrome in patients 4 years and older. Palhagen S et al. Epilepsy Res 2001;43:115–24.
Dosage and titration Adults and children >30 kg •start treatment with a daily dose of 400 mg. •Dose may be increased by increments of 400 mg/day as frequently as every 2 days. •Maximum recommended dose of 1800 mg/day (in the 30– 50 kg weight range). Palhagen S et al. Epilepsy Res 2001;43:115–24.
Dosage and titration contd. Children <30 kg not receiving valproate •Start with a daily dose of 200 mg. •Dose may be increased by increments of 200 mg/day as frequently as every 2 days. •Maximum recommended dose of 1000 mg/day. Children <30 kg also receiving valproate •Start with a daily dose of 200 mg which after a minimum of 2 days may be increased by 200 mg/day, to the maximum recommended dose of 400 mg/day.
Main ADRs • Frequent and/or important: headache, dizziness, fatigue, somnolence, ataxia and gait disturbances. • Serious: • Status epilepticus has been observed during clinical development studies. • Idiosyncratic reactions and hypersensitivity syndrome (rash and fever with other organ system involvement) • Rufinamide is contraindicated in patients with familial short QT syndrome. • Formal cardiac ECG studies demonstrated shortening of the QT interval (by up to 20 msec) with Rufinamide treatment. Arroyo S. Neurother 2007;4:155–62.
Mechanism of action • Rufinamide reduces the recovery capacity of neuronal sodium channels after inactivation, prolonging their inactive state by limiting neuronal sodium-dependent action potential firing.
Pharmacokinetics • Oral bioavailability: is dose dependent; as the dose increases, the bioavailability decreases. • Food increases the bioavailability of Rufinamide by approximately 34%. • Protein binding: 34%. • Excretion: predominantly renal (85% of the dose). • Elimination half-life: 6–10 hours.
Drug interactions • Rufinamide does not have clinically relevant effects on other AEDs. • But it may decrease phenytoin clearance and increase average steady-state plasma concentrations of co-administered phenytoin. • Rufinamide plasma concentrations are decreased by co- administration with carbamazepine, phenobarbital, primidone, phenytoin or vigabatrin. • Rufinamide plasma concentrations significantly increase with valproate co-administration. • Rufinamide interferes with hormonal contraception.
Main disadvantages • Development of status epilepticus. • Idiosyncratic reactions that may be serious. • Significant interactions with enzyme inducers (they reduce its plasma concentration) and valproate (it increases its plasma concentration).
Topiramate • Topiramate was first introduced into clinical practice in 1995. • It is a highly efficacious new, broad spectrum AED. • In clinical use, Topiramate has been recommended for all types of seizures – focal or generalized, and idiopathic or symptomatic – in adults and children including difficult-to- treat epileptic encephalopathies, such as West and Lennox–Gastaut syndromes.
Authorized indications • Initial monotherapy for focal onset or primary GTCSs in patients ≥10 of age. • Adjunctive therapy for adults and pediatric patients aged 2–16 years with partial onset seizures, or primary generalized tonic-clonic seizures. • In patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.
Dosage and titration • ‘Start very low and go very slow’ is particularly important. • Adults and children over 16 years: start with 25 mg/day for the first week • Titrate in increments of 25 or 50 mg/day in two equally divided doses at 1 or 2 week intervals. • The recommended maintenance dose is 200–400 mg/day. • Children 6–16 years: start treatment with 25 mg or 1–3 mg/kg/day for the first week. • Titrate with increments of 1–3 mg/kg/day in two divided doses at1- or 2-week intervals. • Recommended maintenance dose of 5–9 mg/kg/day in two divided doses.
• Children 2–6 years: start with 0.5–1 mg/kg/day for the first week and then titrate as for older children. • Renally impaired patients: half of the usual dose is recommended. • Patients with moderate or severe renal impairment may take 10–15 days to reach steady-state plasma concentrations compared with 4–8 days in patients with normal renal function.
Main ADRs • Somnolence, anorexia, fatigue and nervousness. • Abnormal thinking, consisting of mental slowing and word-finding difficulties, has been reported in 31% of patients with titration rates of 100 mg per week. • Difficulty with concentration/attention, memory impairment, psychomotor slowing and speech disorders are often very severe, even when treatment starts with small doses and titration is slow. Ojemann LM et al. Epilepsy Behav 2001;2:579–84.
ADRS contd. • Weight loss (10% of patients) • Treatment-emergent paraesthesiae and abdominal pains. • Metabolic acidosis. • Nephrolithiasis: around 1.5% of adults and 0.6%children in clinical trials of topiramate developed renal stones. • Acute myopia with secondary angle-closure glaucoma • Hyophydrosis
Mechanisms of action • The anti-epileptic effect of topiramate is probably due to multimodal mechanisms of action. a.Blockage of voltage-dependent sodium channels. b.Augmentation of the inhibitory activity of GABA at some subtypes of the GABAA receptor c.Antagonism with the AMPA/kainate subtype of the glutamate receptor. d.Inhibition of the carbonic anhydrase enzyme.
Pharmacokinetics • Oral bioavailability: >80%. • Protein binding: 15–41% over the blood concentration range of 0.5–250 μg/ml. The fraction bound decreases as blood concentration increases. • Metabolism: topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine. • Elimination half life: 21 hours.
Drug interactions • In co-medication, phenytoin plasma levels may increase by 25% and topiramate decrease by 48%. • There is probably no interaction with lamotrigine and Levetiracetam, and interactions with valproate are minimal. • Concomitant use with other carbonic anhydrase inhibitors, such as zonisamide, should probably be avoided.
Lamotrigine • Lamotrigine is an effective broad-spectrum AED for the treatment of all types of seizures except myoclonic jerks. • It was approved for clinical use in the year 1994.
Authorized indications • Adjunctive therapy for focal seizures and primarily GTSC in patients ≥2 years of age. • Adjunctive therapy for the generalized seizures of Lennox–Gastaut syndrome. • Conversion to monotherapy in adults (≥ 16 years of age) with focal seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone or valproate as the single AED.
Dosage and titration Adults and children over 12 years (monotherapy) •Start with 25 mg once daily for 2 weeks. •Followed by 50 mg once daily for 2 weeks. •The usual maintenance dose to achieve optimal response is 100–200 mg/day given once daily or as two divided doses.
Adults and children over 12 years (add-on therapy with valproate) •Start with 25 mg every alternate day for 2 weeks. •Followed by 25 mg once daily for 2 weeks. •Thereafter, the dose should be increased by a maximum of 25–50 mg every 1 or 2 weeks until the optimal response is achieved. Adults and children over 12 years (add-on therapy with enzyme-inducing AEDs) •Start with 50 mg once daily for 2 weeks, followed by 100 mg/day given in two divided doses for 2 weeks. •Thereafter, the dose should be increased by a maximum of 100 mg every 1 or 2 weeks until the optimal response is achieved.
ADRs An allergic skin rash is the most common and probably the most dangerous ADR, prompting withdrawal of lamotrigine. •Skin rash occurs in approximately 10% of patients. • But serious rashes including Stevens–Johnson syndrome occur in approximately 1 out of 300 adults and 1 out of 100 children. •The incidence of skin rash can probably be reduced by starting treatment with a low dose spread over longer intervals.
Mechanism of action and PK • The most likely mechanism is inhibition of voltage gated sodium channels. • Lamotrigine is rapidly and completely absorbed from the gut with no significant first-pass metabolism. • Protein binding: 55%. • Metabolism: lamotrigine is predominantly metabolised in the liver by glucuronic acid conjugation. • Elimination half-life: 29 hours.
Drug interactions • Valproate inhibits the metabolism of lamotrigine, doubling or tripling its half-life. • Enzyme inducers, such as carbamazepine, phenytoin and phenobarbital, accelerate its elimination.
Disadvantages • High incidence of idiosyncratic ADRs, which,exceptionally, may be fatal. • Significant interactions with other AEDs • Pro-myoclonic effect in syndromes with predominant myoclonic jerks, such as JME, Dravet syndrome and progressive myoclonic epilepsies.
Oxcarbazepine Authorized indication: monotherapy or adjunctive therapy in the treatment of focal seizures in adults and as monotherapy in the treatment of focal seizures in children aged 4 years and above with epilepsy. Mechanism of action: Like carbamazepine, blockade of voltage-sensitive sodium channels is its main mechanism of action.
Oxcarbazepine versus carbamazepine • OXC is similar to CBZ in its anti-epileptic efficacy and main mechanism of action. • OXC is better tolerated and has fewer interactions with other drugs because it does not undergo metabolism to epoxide. • OXC does not involve hepatic CYP enzymes for its metabolism. • OXC has a lower incidence of idiosyncratic reactions than CBZ. • Hyponatremia is more common with OXC.
Dose • Adults: start treatment with 150 mg/day and increase by 150 mg/day every second day until a target dose of 900– 1200 mg/day is reached. • In patients with impaired renal function (creatinine clearance <30 ml/min), Oxcarbazepine should be initiated at one-half of the usual starting dose. • Children: start with 10 mg/kg/day in two or three divided doses. The dosage can be increased by 10 mg/kg/day at approximately weekly intervals to a maximum of 30–46
ADRs • The most common CNS adverse events are headache, dizziness, fatigue, nausea, somnolence, ataxia and diplopia. • The reported rate of skin rash with Oxcarbazepine is around 2% (adults) and 5% (children), as opposed to 5– 10% with carbamazepine. • Hyponatremia (serum sodium level <125 mmol/l) occurs in 3% of patients on Oxcarbazepine. • Oxcarbazepine is contraindicated in patients with a history of atrioventricular block.
Disadvantages • Oxcarbazepine is contraindicated in generalized seizures, such as absences or myoclonic jerks in syndromes of IGE. • One out of four patients have cross sensitivity to idiosyncratic reactions with carbamazepine or other AEDs. • Although it is among the first-choice AEDs for monotherapy in focal epilepsies, its use as polytherapy is less satisfactory because of drug–drug interactions.
Gabapentin • Gabapentin was approved for use in 1993. • It is currently indicated as adjunctive therapy for partial seizures with and without secondary generalization in persons 3 years and older. • Although structurally related to GABA, its precise mechanism of action in humans is unknown. • ADRs include included somnolence, dizziness, fatigue, and modest weight gain. • No serious idiosyncratic reactions or organ toxicities have been identified.
• Gabapentin possesses several desirable pharmacokinetic properties: it does not undergo hepatic metabolism and is excreted unchanged in urine. • In addition, gabapentin does not affect plasma concentrations of other antiepileptic drugs and oral contraceptives.
Tiagabine • Tiagabine was FDA approved for use in 1997. • Its authorized indication is adjunctive treatment of partial-onset seizures in persons 12 years or older. • It has a novel mechanism of action, blocking reuptake of GABA into neurons and glial cells. • The most common adverse effects included dizziness, tremor, and impaired concentration. • Tiagabine undergoes extensive hepatic oxidation via the cytochrome P450 system but has not been shown to induce or inhibit hepatic enzyme function and thus has negligible effects on other drugs, including other antiepileptic drugs.
Felbamate • Felbamate was the first new antiepileptic drug to gain FDA approval (in 1993). • It is a broad-spectrum agent approved for both monotherapy and adjunctive treatment of partial-onset seizures in adults as well as partial- and generalized- onset seizures associated with Lennox-Gastaut syndrome (LGS) in children.
• Felbamate acts by potentiation of GABA responses via its interaction with a site on the GABAA receptor and inhibition of N-methyl-D-aspartate (NMDA) receptors via a channel-blocking action. • The most commonly documented adverse effects with Felbamate include gastrointestinal disturbances, anorexia, and insomnia. • Aplastic anemia and hepatic failure are the most serious side effects and are usually seen during the first 6–12 months of therapy.
New versus Old AEDs: Based on evidence
• Comparing the newer generation with the older generation of AEDs is challenging. • One recent large randomized study was performed specifically to compare new and old drugs in terms of both efficacy and tolerability. • It was entitled SANAD, which stands for 'Standard And New Antiepileptic Drugs’. Marson A.G et al. The SANAD trial. Health Technol Assessm 11: 1–154.
• The SANAD trial randomized over 1900 patients with epilepsy into 2 arms ( A & B) • one arm compared new drugs with carbamazepine and the other compared new drugs with valproate. • Arm A evaluated carbamazepine (CBZ) versus gabapentin (GBP) versus lamotrigine (LTG) versus oxcarbazepine (OXC) versus topiramate (TPM) in partial seizures. • Arm B evaluated valproate (VPS) versus LTG versus TPM in generalized seizures.
• Main outcome measures was Time to treatment failure (withdrawal of the randomised drug for reasons of unacceptable adverse events or inadequate seizure control or a combination of the two) and time to achieve a 12-month remission of seizures.
Results of SANAD trial Arm A •LTG had the lowest incidence of treatment failure and was statistically superior to all drugs for this outcome with the exception of OXC. •About 12% fewer patients experienced treatment failure on LTG than CBZ at 1year after randomization. •Health economic analysis supported LTG being preferred to CBZ for both cost per seizure avoided and cost per quality-adjusted life-year gained.
ARM B •VPS was the drug least likely to be associated with treatment failure for inadequate seizure control and was the preferred drug for time to achieving a 12-month remission. •The health economic assessment supported the conclusion that VPS should remain the drug of first choice for idiopathic generalized epilepsies.
Conclusions from SANAD • The study provides evidence that LTG may be a clinical and cost-effective alternative to the existing standard drug treatment, CBZ. • For patients in Arm B with idiopathic generalized epilepsy or difficult to classify epilepsy, VPS remains the clinically most effective drug. • Since the design and start of the trial, three new antiepileptic drugs have been licensed (Levetiracetam, Zonisamide and Pregabalin). It will be important that these drugs are compared in a similarly designed trial.
Substitution Monotherapy With Levetiracetam vs Older Antiepileptic Drugs: A Randomized Comparative Trial. • OBJECTIVE To determine whether patients who fail their first antiepileptic drug (AED) have better neuropsychiatric and quality-of- life (QOL) outcomes if substituted to Levetiracetam monotherapy compared with a second older AED. • Participants with partial epilepsy who had failed monotherapy with phenytoin sodium, carbamazepine, or valproate sodium were randomized to substitution monotherapy with Levetiracetam or a different older AED. • There were no differences between the groups in depression scores at 3 months, but a greater proportion of the older AED group improved on the 89-item Quality of Life in Epilepsy Inventory compared with the Levetiracetam group. Arch Neurol. 2012 Dec;69(12):1563-71
Efficacy and Tolerability of the New Antiepileptic Drugs, I: Treatment of New Onset Epilepsy • Report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society • Published in Neurology 2004
Clinical question • Question : How does the efficacy and tolerability of the new AEDs compare with that of older AEDs in patients with newly diagnosed epilepsy?
Summary of findings Comparison to standard AEDs: • Oxcarbazepine is equivalent to carbamazepine and phenytoin in efficacy, but superior in dose-related tolerability, at individually determined doses. • Oxcarbazepine is equivalent in efficacy and tolerability to valproic acid. • Topiramate at doses of 100 and 200 mg/day was equivalent in efficacy and safety to 600 mg fixed dose carbamazepine and 1250 mg/day valproic acid, both in children aged 6 years and older and adults. • Lamotrigine is equivalent in efficacy to carbamazepine and phenytoin and superior in tolerability to carbamazepine, both in adults and elderly individuals.
Summary of findings Comparison to standard AEDs: • Topiramate at 100mg and 200 mg are equivalent in efficacy and safety to 600 mg of fixed-dose, immediate- release carbamazepine administered in a BID regimen for partial seizures and to 1250 mg of fixed-dose valproic acid for idiopathic generalized seizures. • Gabapentin is effective in monotherapy at 900 and 1800 mg and is equivalent in efficacy to a 600 mg fixed dose of carbamazepine.
• After this review it was concluded that that the new AEDs may be better tolerated than the standard, with equivalent efficacy. • However the new drugs are all substantially more expensive than the old. There is no literature that addresses the cost-benefit.
A Glimpse of the Future • There are several new AEDs that are either in the licensing phase or still undergoing clinical trials. • These include eslicarbazepine acetate, brivaracetam, and retigabine. • Eslicarbazepine acetate, recently licensed as an adjunctive agent in partial epilepsy is structurally linked to carbamazepine and oxcarbazepine. • In phase III clinical trials eslicarbazepine was well tolerated, with the most common AEs reported to include dizziness, headache, and somnolence. Elger C et al. Epilepsia 50:454-63.
• Brivaracetam is a pyrrolidone derivative in the same class as levetiracetam that continues to undergo clinical trials. • Like levetiracetam, brivaracetam binds to the synaptic vesicle protein 2A. • An exploratory, phase IIb, double-blind, randomized, parallel- group, placebo controlled study using brivaracetam doses of 5, 20, or 50 mg/day was performed; tolerability was good, with only 2.6% of patients discontinuing drug due to AEs, compared with 3.7% of patients in the placebo arm. French JA et al. Neurology 75: 519–525
• Retigabine is a structurally novel compound that acts by opening the KCNQ potassium channel, leading to neuronal hyperpolarization. • In a double-blind, randomized, placebo-controlled Phase II clinical trial, retigabine was added to the treatment regimen of 399 participants with partial seizures that were refractory to therapy with other antiepileptic drugs. The frequency with which seizures occurred was significantly reduced (by 23 to 35%) in participants receiving retigabine. Brodie M et al. Epilepsia 49(Suppl. 7): 110.
Conclusion • It is impossible to conclude that 'all old AEDs are bad' or 'all new AEDs are good'. • Some of the newer AEDs such as gabapentin, Levetiracetam, Tiagabine, and Pregabalin are unlikely to cause systemic safety issues, whereas these were associated with all of the older AEDs. • The absence of hepatic enzyme induction/inhibition with most of the newer AEDs provides one major advantage. • In the end, drug selection must be based on individual patient and drug characteristics.

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New anti epileptic drugs

  • 1.
  • 2.
    Introduction • Prior to1993, the choice of an anticonvulsant medication was limited to the “traditional” anticonvulsants [Phenobarbital, Primidone, Phenytoin, Carbamazepine, and Valproate.] • Since 1993, Several new medications have been approved by the US Food and Drug Administration (FDA). • These newer antiepileptic drugs offer the potential advantages of fewer drug interactions, unique mechanisms of action, and a broader spectrum of activity. LaRoche SM et al. JAMA, February 4, 2004—Vol 291, No. 5
  • 3.
    ANTIEPILEPTIC DRUG DEVELOPMENT 1840 18601880 1900 1920 1940 1960 1980 2000 0 5 10 15 20 Bromide Phenobarbital Phenytoin Primidone Ethosuximide Sodium Valproate Benzodiazepines Carbamazepine Zonisamide Felbamate Gabapentin Topiramate Fosphenytoin OxcarbazepineTiagabine Levetiracetam Rufinamide Lacosamide Brivaracetam Pregabalin Retigabine ? Calendar Year NumberofLicensedAntiepilepticDrugs Lamotrigine
  • 4.
    Antiepileptic Drug Yearapproved Felbamate   1993 Gabapentin   1993 Lamotrigine   1994 Topiramate   1996 Tiagabine   1997 Levetiracetam   1999 Oxcarbazepine   2000 Zonisamide   2000 Pregabalin 2005 Rufinamide 2008 Lacosamide 2009
  • 5.
    Advantages of newAEDs • Compared with older agents, many new drugs exhibit simpler pharmacokinetics. (Renal excretion, Lack of interactions.) • Unlike most of the older agents newer AEDs are devoid of significant enzyme inducing or inhibiting properties. • Newer AEDs have a favorable side effect profile when compared to older agents.
  • 6.
    Mechanism of actionof new AEDs Drug Mechanism Levetiracetam Modifies Synaptic Vesicle Protein (SV2A) Lamotrigine Blocks excitatory sodium channels in a  voltage dependent manner. Lacosamide Modifies sodium channels. Oxcarbazabine Blocks sodium channels, N/P and R type  Calcium channels. Topiramate Modulatory effect on sodium channels,  GABA, AMPA/Kainate receptors. Gabapentin Reduction of Glutamate release at cortical  synapses, reduction of activity dependent  release via interaction with P/Q type  calcium channels.
  • 7.
    Mechanism of actionof new AEDs Drug Mechanism Vigabatrin Selective irreversible inhibitor of GABA  transaminase Tiagabine Potent, specific GABA uptake inhibitor Rufinamide Limitation of sodium dependent action  potential firing. Zonisamide Sodium channel and T-type calcium  channel blocker.
  • 8.
    Adverse events associatedwith the new AEDs
  • 9.
    Adverse events associatedwith the new AEDs
  • 10.
    Levetiracetam • Levetiracetam isa highly effective, broad-spectrum, newer class of AED with a unique mechanism of action. • It was licensed in 1999. • It can be used to treat all focal or generalized, idiopathic or symptomatic epileptic syndromes in all age groups.
  • 11.
    Authorized indications • Monotherapyin the treatment of partial onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. • Adjunctive therapy A.In the treatment of partial onset seizures with or without secondary generalization in adults, children and infants from 1 month of age with epilepsy. B.In the treatment of myoclonic seizures in adults and adolescents from 12 years of age with JME. C.In the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with IGE.
  • 12.
    Advantages • It isbroad spectrum, which is of practical significance, particularly for clinicians who may not have special expertise in differentiating between focal and generalized epileptic seizures. • It has a relatively good safety profile and does not cause significant idiosyncratic reactions or other serious ADRs. • It does not need slow titration, the starting dose is often therapeutic for all forms of seizures and epilepsies. • It is easier to use if polytherapy is necessitated, as it does not cause clinically significant drug–drug interactions
  • 13.
    Advantages • It doesnot 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 metabolized in the liver).
  • 14.
    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.
  • 15.
    Dosage and titration(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 given in two divided doses.
  • 16.
    Main ADRs • Levetiracetamis probably the AED that is most free from ADRs. • The most common ADRs are somnolence, asthenia and dizziness, which are dose dependent and reversible. • Others include headache, common cold or upper respiratory infections, anorexia and behavioral disturbances. • Levetiracetam interferes with rapid motor learning in humans due to suppression of excitatory activity in the motor cortex.
  • 17.
    • In anuncontrolled 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. • All patients who are currently taking or starting on Levetiracetam for any indication should be monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression
  • 18.
    Considerations in women •Pregnancy: category C • In the UK Epilepsy and Pregnancy Register of 117 pregnancies exposed to Levetiracetam only three infants (all in the polytherapy group) had a Major Congenital Malformation. Hunt S et al. Neurology 2006;67:1876–9.
  • 19.
    Considerations in women •Breastfeeding: There is an extensive transfer of Levetiracetam from mother to fetus and into breast milk. • However, breast-fed infants have very-low Levetiracetam plasma concentrations, suggesting a rapid elimination of Levetiracetam. • Interaction with hormonal contraception: none.
  • 20.
    Mechanisms of action •It has a novel mechanism of action that is distinct from that of other AEDs. • It acts by targeting a synaptic vesicle protein in presynaptic terminals. • Its antiepileptic activity does not involve a direct interaction with any of the three main mechanisms of the other AEDs.
  • 21.
    Mechanism contd. • Recentexperiments have shown that the synaptic vesicle protein 2A (SV2A) is the binding site of Levetiracetam. • Studies in mice lacking SV2A indicate that this protein has a crucial role in the regulation of vesicle formation and fusion. • Mice lacking SV2A develop severe seizures by 1-2 weeks of age. • Thus Levetiracetam’s interaction with SV2A provides a significant contribution to its anti-epileptic activity. Lynch BA et al. Proc Natl Acad Sci USA 2004;101:9861–6.
  • 22.
    Pharmacokinetics • Levetiracetam, comesespecially close to fulfilling the desirable pharmacokinetic characteristics for an AED. • it has a high oral bioavailability, which is unaffected by food. (100%) • it is not significantly bound to plasma proteins. • 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.
  • 23.
    Pharmacokinetics contd. • Ithas linear kinetics. • It is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Perucca E et al. Epileptic Disord 2003;5 Suppl 1:S17–26.
  • 24.
    Drug interactions • Unlikethe majority of other AEDs, Levetiracetam has no clinically meaningful drug–drug interactions. • Other AEDs: Levetiracetam does not influence the plasma concentration of existing AEDs. • Enzyme inducers may decrease Levetiracetam plasma levels by 20–30%. • Other non-AEDs: Levetiracetam has no known interactions with other drugs such as oral contraceptives, warfarin and digoxin. Contin M et al. Ther Drug Monit 2004;26:375–9.
  • 25.
    Main disadvantages • Thereare some reports of increased behavioral and psychiatric abnormalities, particularly in children or patients that may be prone to such problems. White JR et al. Neurology 2003;61:1218–21. Mula M et al. Seizure 2004;13:55–7.
  • 26.
    Lacosamide • Lacosamide isa functionalized amino acid (R)-2- acetamido-N-benzyl-3-methoxypropionamide. • It is one of the latest AEDs to be licensed (at the end of 2008) Beydoun A et al. Expert Rev Neurother 2009;9:33-42.
  • 27.
    Authorized indications • Tabletsare indicated as adjunctive therapy in the treatment of focal seizures in patients with epilepsy aged 17 years and older. • Injection for intravenous use is indicated as adjunctive therapy in the treatment of focal seizures in patients with epilepsy aged 17 years and older when oral administration is temporarily not feasible. Beydoun A et al. Expert Rev Neurother 2009;9:33-42.
  • 28.
    Dosage and titration •Start with 50 mg twice daily (100 mg/day). • Increase at weekly intervals by 100 mg/day to 200–400 mg/day. • The maximum recommended dose of Lacosamide is 400 mg/day because higher doses may be associated with CNS and gastrointestinal ADRs. • A maximum dose of 300 mg/day is recommended by the FDA for patients with mild or moderate hepatic impairment.
  • 29.
    Dosage for I.VLacosamide • Lacosamide injection (without further dilution or mixed in compatible diluents) should be administered intravenously over 15–60 minutes. • When switching from oral Lacosamide, the initial total daily intravenous dosage should be equivalent to the total daily dosage and frequency of oral Lacosamide.
  • 30.
    Main ADRs • Frequent: Dizziness, headache, diplopia, nausea, vomiting and blurred vision. • Serious: A small, asymptomatic, dose-related increase in the PR interval measured on ECG has been observed in clinical studies. • caution is needed in patients with known conduction problems or severe cardiac disease, in the elderly and in co- medication with drugs known to be associated with PR prolongation.
  • 31.
    Considerations in women •Pregnancy: category C. • Breastfeeding: unknown but possibly excreted in breast milk (animal data). • Interactions with hormonal contraception: none.
  • 32.
    Mechanisms of action •Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyper excitable neuronal membranes and inhibition of repetitive neuronal firing. Curia G et al. Drugs 2009;23:555-68.
  • 33.
    Pharmacokinetics • Lacosamide hasnear-ideal pharmacokinetics. • Oral bioavailability: 100%. • Protein binding: <15% • Metabolism: Primarily eliminated by renal excretion and biotransformation. • Lacosamide showed no potential to induce or inhibit the activity of CYP isoforms. Beydoun A et al. Expert Rev Neurother 2009;9:33-42.
  • 34.
    Drug interactions • Theseare minimal and probably of no clinical significance. • From available evidence, Lacosamide does not affect plasma levels of carbamazepine, gabapentin, lamotrigine, Levetiracetam, oxcarbazepine, phenytoin and valproate. • It does not affects plasma concentration of oral contraceptive levonorgestrel/ ethinylestradiol. • Carbamazepine, phenytoin and phenobarbital may decrease plasma levels of Lacosamide by 15–20%.
  • 35.
    Main disadvantages • Notyet exposed to lengthy clinical practice but its use so far has met with favorable results. Halford JJ et al. Epilepsy Curr 2009;9:1-9.
  • 36.
    Zonisamide • Zonisamide appearsto be an effective broad spectrum AED with extensive clinical use in Japan. • It has been found to be efficacious in focal and generalizes seizures as well as West syndrome, Ohtahara, and Unverricht syndrome. Tosches WA et al. Epilepsy Behav 2006;8:522–6.
  • 37.
    Authorized indications • Adjunctivetherapy in adult patients with focal seizures with or without secondary generalization. Tosches WA et al. Epilepsy Behav 2006;8:522–6
  • 38.
    Dosage and titration •Adults: Start with 100 mg/day in one or two equally divided doses. • After two weeks, the dose may be increased to 200 mg/day. • Evidence from controlled trials suggests that Zonisamide doses of 100–600mg/day are effective. • Children: start with 1–2 mg/kg/day for the first week and titrate in increments of 1–2 mg/kg/day every 2 weeks. • Usual childhood maintenance dose is 4–8 mg/kg/day.
  • 39.
    Mechanisms of action •Zonisamide blocks the sustained repetitive firing of voltage-sensitive sodium channels. • Reduces voltage-dependent T-type calcium current without affecting the L-type calcium current. • It has mild carbonic anhydrase inhibitor activity.
  • 40.
    ADRs • Cognitive impairment,including word-finding difficulty. • Weight loss and anorexia that may become very severe. • Nephrolithiasis in 4% of patients on prolonged zonisamide therapy. • Oligohidrosis and anhidrosis often accompanied by hyperthermia, especially in children and hot environments.
  • 41.
    Rufinamide • Rufinamide isa triazole derivative structurally unrelated to any currently marketed AED. • It is one of the latest AEDs marketed for the treatment of epileptic seizures. • Its licenced indications are for Lennox–Gastaut syndrome, • The next step will probably be for adjunctive treatment of intractable focal epilepsies. Cheng-Hakimian A et al. Int J Clin Pract 2006;60:1497–501.
  • 42.
    Authorized indications • Adjunctivetreatment of seizures associated with Lennox– Gastaut syndrome in patients 4 years and older. Palhagen S et al. Epilepsy Res 2001;43:115–24.
  • 43.
    Dosage and titration Adultsand children >30 kg •start treatment with a daily dose of 400 mg. •Dose may be increased by increments of 400 mg/day as frequently as every 2 days. •Maximum recommended dose of 1800 mg/day (in the 30– 50 kg weight range). Palhagen S et al. Epilepsy Res 2001;43:115–24.
  • 44.
    Dosage and titrationcontd. Children <30 kg not receiving valproate •Start with a daily dose of 200 mg. •Dose may be increased by increments of 200 mg/day as frequently as every 2 days. •Maximum recommended dose of 1000 mg/day. Children <30 kg also receiving valproate •Start with a daily dose of 200 mg which after a minimum of 2 days may be increased by 200 mg/day, to the maximum recommended dose of 400 mg/day.
  • 45.
    Main ADRs • Frequentand/or important: headache, dizziness, fatigue, somnolence, ataxia and gait disturbances. • Serious: • Status epilepticus has been observed during clinical development studies. • Idiosyncratic reactions and hypersensitivity syndrome (rash and fever with other organ system involvement) • Rufinamide is contraindicated in patients with familial short QT syndrome. • Formal cardiac ECG studies demonstrated shortening of the QT interval (by up to 20 msec) with Rufinamide treatment. Arroyo S. Neurother 2007;4:155–62.
  • 46.
    Mechanism of action •Rufinamide reduces the recovery capacity of neuronal sodium channels after inactivation, prolonging their inactive state by limiting neuronal sodium-dependent action potential firing.
  • 47.
    Pharmacokinetics • Oral bioavailability:is dose dependent; as the dose increases, the bioavailability decreases. • Food increases the bioavailability of Rufinamide by approximately 34%. • Protein binding: 34%. • Excretion: predominantly renal (85% of the dose). • Elimination half-life: 6–10 hours.
  • 48.
    Drug interactions • Rufinamidedoes not have clinically relevant effects on other AEDs. • But it may decrease phenytoin clearance and increase average steady-state plasma concentrations of co-administered phenytoin. • Rufinamide plasma concentrations are decreased by co- administration with carbamazepine, phenobarbital, primidone, phenytoin or vigabatrin. • Rufinamide plasma concentrations significantly increase with valproate co-administration. • Rufinamide interferes with hormonal contraception.
  • 49.
    Main disadvantages • Developmentof status epilepticus. • Idiosyncratic reactions that may be serious. • Significant interactions with enzyme inducers (they reduce its plasma concentration) and valproate (it increases its plasma concentration).
  • 50.
    Topiramate • Topiramate wasfirst introduced into clinical practice in 1995. • It is a highly efficacious new, broad spectrum AED. • In clinical use, Topiramate has been recommended for all types of seizures – focal or generalized, and idiopathic or symptomatic – in adults and children including difficult-to- treat epileptic encephalopathies, such as West and Lennox–Gastaut syndromes.
  • 51.
    Authorized indications • Initialmonotherapy for focal onset or primary GTCSs in patients ≥10 of age. • Adjunctive therapy for adults and pediatric patients aged 2–16 years with partial onset seizures, or primary generalized tonic-clonic seizures. • In patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.
  • 52.
    Dosage and titration •‘Start very low and go very slow’ is particularly important. • Adults and children over 16 years: start with 25 mg/day for the first week • Titrate in increments of 25 or 50 mg/day in two equally divided doses at 1 or 2 week intervals. • The recommended maintenance dose is 200–400 mg/day. • Children 6–16 years: start treatment with 25 mg or 1–3 mg/kg/day for the first week. • Titrate with increments of 1–3 mg/kg/day in two divided doses at1- or 2-week intervals. • Recommended maintenance dose of 5–9 mg/kg/day in two divided doses.
  • 53.
    • Children 2–6years: start with 0.5–1 mg/kg/day for the first week and then titrate as for older children. • Renally impaired patients: half of the usual dose is recommended. • Patients with moderate or severe renal impairment may take 10–15 days to reach steady-state plasma concentrations compared with 4–8 days in patients with normal renal function.
  • 54.
    Main ADRs • Somnolence,anorexia, fatigue and nervousness. • Abnormal thinking, consisting of mental slowing and word-finding difficulties, has been reported in 31% of patients with titration rates of 100 mg per week. • Difficulty with concentration/attention, memory impairment, psychomotor slowing and speech disorders are often very severe, even when treatment starts with small doses and titration is slow. Ojemann LM et al. Epilepsy Behav 2001;2:579–84.
  • 55.
    ADRS contd. • Weightloss (10% of patients) • Treatment-emergent paraesthesiae and abdominal pains. • Metabolic acidosis. • Nephrolithiasis: around 1.5% of adults and 0.6%children in clinical trials of topiramate developed renal stones. • Acute myopia with secondary angle-closure glaucoma • Hyophydrosis
  • 56.
    Mechanisms of action •The anti-epileptic effect of topiramate is probably due to multimodal mechanisms of action. a.Blockage of voltage-dependent sodium channels. b.Augmentation of the inhibitory activity of GABA at some subtypes of the GABAA receptor c.Antagonism with the AMPA/kainate subtype of the glutamate receptor. d.Inhibition of the carbonic anhydrase enzyme.
  • 57.
    Pharmacokinetics • Oral bioavailability:>80%. • Protein binding: 15–41% over the blood concentration range of 0.5–250 μg/ml. The fraction bound decreases as blood concentration increases. • Metabolism: topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine. • Elimination half life: 21 hours.
  • 58.
    Drug interactions • Inco-medication, phenytoin plasma levels may increase by 25% and topiramate decrease by 48%. • There is probably no interaction with lamotrigine and Levetiracetam, and interactions with valproate are minimal. • Concomitant use with other carbonic anhydrase inhibitors, such as zonisamide, should probably be avoided.
  • 59.
    Lamotrigine • Lamotrigine isan effective broad-spectrum AED for the treatment of all types of seizures except myoclonic jerks. • It was approved for clinical use in the year 1994.
  • 60.
    Authorized indications • Adjunctivetherapy for focal seizures and primarily GTSC in patients ≥2 years of age. • Adjunctive therapy for the generalized seizures of Lennox–Gastaut syndrome. • Conversion to monotherapy in adults (≥ 16 years of age) with focal seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone or valproate as the single AED.
  • 61.
    Dosage and titration Adultsand children over 12 years (monotherapy) •Start with 25 mg once daily for 2 weeks. •Followed by 50 mg once daily for 2 weeks. •The usual maintenance dose to achieve optimal response is 100–200 mg/day given once daily or as two divided doses.
  • 62.
    Adults and childrenover 12 years (add-on therapy with valproate) •Start with 25 mg every alternate day for 2 weeks. •Followed by 25 mg once daily for 2 weeks. •Thereafter, the dose should be increased by a maximum of 25–50 mg every 1 or 2 weeks until the optimal response is achieved. Adults and children over 12 years (add-on therapy with enzyme-inducing AEDs) •Start with 50 mg once daily for 2 weeks, followed by 100 mg/day given in two divided doses for 2 weeks. •Thereafter, the dose should be increased by a maximum of 100 mg every 1 or 2 weeks until the optimal response is achieved.
  • 63.
    ADRs An allergic skinrash is the most common and probably the most dangerous ADR, prompting withdrawal of lamotrigine. •Skin rash occurs in approximately 10% of patients. • But serious rashes including Stevens–Johnson syndrome occur in approximately 1 out of 300 adults and 1 out of 100 children. •The incidence of skin rash can probably be reduced by starting treatment with a low dose spread over longer intervals.
  • 64.
    Mechanism of actionand PK • The most likely mechanism is inhibition of voltage gated sodium channels. • Lamotrigine is rapidly and completely absorbed from the gut with no significant first-pass metabolism. • Protein binding: 55%. • Metabolism: lamotrigine is predominantly metabolised in the liver by glucuronic acid conjugation. • Elimination half-life: 29 hours.
  • 65.
    Drug interactions • Valproateinhibits the metabolism of lamotrigine, doubling or tripling its half-life. • Enzyme inducers, such as carbamazepine, phenytoin and phenobarbital, accelerate its elimination.
  • 66.
    Disadvantages • High incidenceof idiosyncratic ADRs, which,exceptionally, may be fatal. • Significant interactions with other AEDs • Pro-myoclonic effect in syndromes with predominant myoclonic jerks, such as JME, Dravet syndrome and progressive myoclonic epilepsies.
  • 67.
    Oxcarbazepine Authorized indication: monotherapyor adjunctive therapy in the treatment of focal seizures in adults and as monotherapy in the treatment of focal seizures in children aged 4 years and above with epilepsy. Mechanism of action: Like carbamazepine, blockade of voltage-sensitive sodium channels is its main mechanism of action.
  • 68.
    Oxcarbazepine versus carbamazepine •OXC is similar to CBZ in its anti-epileptic efficacy and main mechanism of action. • OXC is better tolerated and has fewer interactions with other drugs because it does not undergo metabolism to epoxide. • OXC does not involve hepatic CYP enzymes for its metabolism. • OXC has a lower incidence of idiosyncratic reactions than CBZ. • Hyponatremia is more common with OXC.
  • 69.
    Dose • Adults: starttreatment with 150 mg/day and increase by 150 mg/day every second day until a target dose of 900– 1200 mg/day is reached. • In patients with impaired renal function (creatinine clearance <30 ml/min), Oxcarbazepine should be initiated at one-half of the usual starting dose. • Children: start with 10 mg/kg/day in two or three divided doses. The dosage can be increased by 10 mg/kg/day at approximately weekly intervals to a maximum of 30–46
  • 70.
    ADRs • The mostcommon CNS adverse events are headache, dizziness, fatigue, nausea, somnolence, ataxia and diplopia. • The reported rate of skin rash with Oxcarbazepine is around 2% (adults) and 5% (children), as opposed to 5– 10% with carbamazepine. • Hyponatremia (serum sodium level <125 mmol/l) occurs in 3% of patients on Oxcarbazepine. • Oxcarbazepine is contraindicated in patients with a history of atrioventricular block.
  • 71.
    Disadvantages • Oxcarbazepine iscontraindicated in generalized seizures, such as absences or myoclonic jerks in syndromes of IGE. • One out of four patients have cross sensitivity to idiosyncratic reactions with carbamazepine or other AEDs. • Although it is among the first-choice AEDs for monotherapy in focal epilepsies, its use as polytherapy is less satisfactory because of drug–drug interactions.
  • 72.
    Gabapentin • Gabapentin wasapproved for use in 1993. • It is currently indicated as adjunctive therapy for partial seizures with and without secondary generalization in persons 3 years and older. • Although structurally related to GABA, its precise mechanism of action in humans is unknown. • ADRs include included somnolence, dizziness, fatigue, and modest weight gain. • No serious idiosyncratic reactions or organ toxicities have been identified.
  • 73.
    • Gabapentin possessesseveral desirable pharmacokinetic properties: it does not undergo hepatic metabolism and is excreted unchanged in urine. • In addition, gabapentin does not affect plasma concentrations of other antiepileptic drugs and oral contraceptives.
  • 74.
    Tiagabine • Tiagabine wasFDA approved for use in 1997. • Its authorized indication is adjunctive treatment of partial-onset seizures in persons 12 years or older. • It has a novel mechanism of action, blocking reuptake of GABA into neurons and glial cells. • The most common adverse effects included dizziness, tremor, and impaired concentration. • Tiagabine undergoes extensive hepatic oxidation via the cytochrome P450 system but has not been shown to induce or inhibit hepatic enzyme function and thus has negligible effects on other drugs, including other antiepileptic drugs.
  • 75.
    Felbamate • Felbamate wasthe first new antiepileptic drug to gain FDA approval (in 1993). • It is a broad-spectrum agent approved for both monotherapy and adjunctive treatment of partial-onset seizures in adults as well as partial- and generalized- onset seizures associated with Lennox-Gastaut syndrome (LGS) in children.
  • 76.
    • Felbamate actsby potentiation of GABA responses via its interaction with a site on the GABAA receptor and inhibition of N-methyl-D-aspartate (NMDA) receptors via a channel-blocking action. • The most commonly documented adverse effects with Felbamate include gastrointestinal disturbances, anorexia, and insomnia. • Aplastic anemia and hepatic failure are the most serious side effects and are usually seen during the first 6–12 months of therapy.
  • 77.
    New versus OldAEDs: Based on evidence
  • 78.
    • Comparing thenewer generation with the older generation of AEDs is challenging. • One recent large randomized study was performed specifically to compare new and old drugs in terms of both efficacy and tolerability. • It was entitled SANAD, which stands for 'Standard And New Antiepileptic Drugs’. Marson A.G et al. The SANAD trial. Health Technol Assessm 11: 1–154.
  • 79.
    • The SANADtrial randomized over 1900 patients with epilepsy into 2 arms ( A & B) • one arm compared new drugs with carbamazepine and the other compared new drugs with valproate. • Arm A evaluated carbamazepine (CBZ) versus gabapentin (GBP) versus lamotrigine (LTG) versus oxcarbazepine (OXC) versus topiramate (TPM) in partial seizures. • Arm B evaluated valproate (VPS) versus LTG versus TPM in generalized seizures.
  • 80.
    • Main outcomemeasures was Time to treatment failure (withdrawal of the randomised drug for reasons of unacceptable adverse events or inadequate seizure control or a combination of the two) and time to achieve a 12-month remission of seizures.
  • 81.
    Results of SANADtrial Arm A •LTG had the lowest incidence of treatment failure and was statistically superior to all drugs for this outcome with the exception of OXC. •About 12% fewer patients experienced treatment failure on LTG than CBZ at 1year after randomization. •Health economic analysis supported LTG being preferred to CBZ for both cost per seizure avoided and cost per quality-adjusted life-year gained.
  • 82.
    ARM B •VPS wasthe drug least likely to be associated with treatment failure for inadequate seizure control and was the preferred drug for time to achieving a 12-month remission. •The health economic assessment supported the conclusion that VPS should remain the drug of first choice for idiopathic generalized epilepsies.
  • 83.
    Conclusions from SANAD •The study provides evidence that LTG may be a clinical and cost-effective alternative to the existing standard drug treatment, CBZ. • For patients in Arm B with idiopathic generalized epilepsy or difficult to classify epilepsy, VPS remains the clinically most effective drug. • Since the design and start of the trial, three new antiepileptic drugs have been licensed (Levetiracetam, Zonisamide and Pregabalin). It will be important that these drugs are compared in a similarly designed trial.
  • 84.
    Substitution Monotherapy WithLevetiracetam vs Older Antiepileptic Drugs: A Randomized Comparative Trial. • OBJECTIVE To determine whether patients who fail their first antiepileptic drug (AED) have better neuropsychiatric and quality-of- life (QOL) outcomes if substituted to Levetiracetam monotherapy compared with a second older AED. • Participants with partial epilepsy who had failed monotherapy with phenytoin sodium, carbamazepine, or valproate sodium were randomized to substitution monotherapy with Levetiracetam or a different older AED. • There were no differences between the groups in depression scores at 3 months, but a greater proportion of the older AED group improved on the 89-item Quality of Life in Epilepsy Inventory compared with the Levetiracetam group. Arch Neurol. 2012 Dec;69(12):1563-71
  • 85.
    Efficacy and Tolerabilityof the New Antiepileptic Drugs, I: Treatment of New Onset Epilepsy • Report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society • Published in Neurology 2004
  • 86.
    Clinical question • Question: How does the efficacy and tolerability of the new AEDs compare with that of older AEDs in patients with newly diagnosed epilepsy?
  • 87.
    Summary of findings Comparisonto standard AEDs: • Oxcarbazepine is equivalent to carbamazepine and phenytoin in efficacy, but superior in dose-related tolerability, at individually determined doses. • Oxcarbazepine is equivalent in efficacy and tolerability to valproic acid. • Topiramate at doses of 100 and 200 mg/day was equivalent in efficacy and safety to 600 mg fixed dose carbamazepine and 1250 mg/day valproic acid, both in children aged 6 years and older and adults. • Lamotrigine is equivalent in efficacy to carbamazepine and phenytoin and superior in tolerability to carbamazepine, both in adults and elderly individuals.
  • 88.
    Summary of findings Comparisonto standard AEDs: • Topiramate at 100mg and 200 mg are equivalent in efficacy and safety to 600 mg of fixed-dose, immediate- release carbamazepine administered in a BID regimen for partial seizures and to 1250 mg of fixed-dose valproic acid for idiopathic generalized seizures. • Gabapentin is effective in monotherapy at 900 and 1800 mg and is equivalent in efficacy to a 600 mg fixed dose of carbamazepine.
  • 89.
    • After thisreview it was concluded that that the new AEDs may be better tolerated than the standard, with equivalent efficacy. • However the new drugs are all substantially more expensive than the old. There is no literature that addresses the cost-benefit.
  • 90.
    A Glimpse ofthe Future • There are several new AEDs that are either in the licensing phase or still undergoing clinical trials. • These include eslicarbazepine acetate, brivaracetam, and retigabine. • Eslicarbazepine acetate, recently licensed as an adjunctive agent in partial epilepsy is structurally linked to carbamazepine and oxcarbazepine. • In phase III clinical trials eslicarbazepine was well tolerated, with the most common AEs reported to include dizziness, headache, and somnolence. Elger C et al. Epilepsia 50:454-63.
  • 91.
    • Brivaracetam isa pyrrolidone derivative in the same class as levetiracetam that continues to undergo clinical trials. • Like levetiracetam, brivaracetam binds to the synaptic vesicle protein 2A. • An exploratory, phase IIb, double-blind, randomized, parallel- group, placebo controlled study using brivaracetam doses of 5, 20, or 50 mg/day was performed; tolerability was good, with only 2.6% of patients discontinuing drug due to AEs, compared with 3.7% of patients in the placebo arm. French JA et al. Neurology 75: 519–525
  • 92.
    • Retigabine isa structurally novel compound that acts by opening the KCNQ potassium channel, leading to neuronal hyperpolarization. • In a double-blind, randomized, placebo-controlled Phase II clinical trial, retigabine was added to the treatment regimen of 399 participants with partial seizures that were refractory to therapy with other antiepileptic drugs. The frequency with which seizures occurred was significantly reduced (by 23 to 35%) in participants receiving retigabine. Brodie M et al. Epilepsia 49(Suppl. 7): 110.
  • 93.
    Conclusion • It isimpossible to conclude that 'all old AEDs are bad' or 'all new AEDs are good'. • Some of the newer AEDs such as gabapentin, Levetiracetam, Tiagabine, and Pregabalin are unlikely to cause systemic safety issues, whereas these were associated with all of the older AEDs. • The absence of hepatic enzyme induction/inhibition with most of the newer AEDs provides one major advantage. • In the end, drug selection must be based on individual patient and drug characteristics.