Guide Antiepileptic Drug Interactions: A Clinical Guide

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There are currently several classes of AEDs available for epilepsy management, many of which are also used to treat migraines, bipolar disorder, schizophrenia, depression, and neuropathic pain. Because of their molecular and mechanistic diversity, as well as the potential for drug—drug interactions, AEDs are prescribed and monitored in a highly personalized manner. Content: This review provides a general overview of the use of AEDs with a focus on the role of therapeutic drug monitoring. Discussed topics include mechanisms of action, guidelines on the clinical applications of AEDs, clinical tests available for AED monitoring, and genetic factors known to affect AED efficacy.

Summary: Implementation of AED therapies is highly individualized, with many patient-specific factors considered for drug and dosage selection. Both therapeutic efficacy and target blood concentrations must be established for each patient to achieve seizure mitigation or cessation. The use of an AED with any additional drug, including other AEDs, requires an evaluation of potential drug—drug interactions.

Furthermore, AEDs are commonly used for nonepilepsy indications, often in off-label administration to treat neurological or psychiatric disorders. Understanding the molecular mechanisms of action of antiepileptic drugs, as well as the role of the clinical laboratory in monitoring drug concentrations, can aid in the successful selection and management of epilepsy, in its myriad presentations.

Epilepsies may be generalized affecting both brain hemispheres or focal localized to a single neural network or hemisphere , and these categories vary with respect to their presentation, severity, and response to treatment 1. Because of the multifactorial etiology of the disease, an important consideration in the clinical diagnosis of epilepsy is the ability to differentiate unprovoked seizures from those triggered by head trauma, metabolic disturbances, or drug effects; only the former are used in disease diagnosis 3. The use of antiepileptic drugs AEDs is the primary modality for the mitigation of symptoms and disease management.

AEDs are a diverse group of compounds with a history reaching back to the s. From a historical perspective, potassium bromide was the first compound used therapeutically for recurrent seizures 4. Although potassium bromide is no longer standard of care, many traditional compounds, including phenytoin and phenobarbital, are still used today 2. AEDs may be administered as a monotherapy or combinatorially, with an overall goal of seizure prevention, while minimizing potential side effects on both cognition and mood.

Currently, there are 24 AEDs approved by the U. A summary of antiepileptic agents, including their proposed mechanisms of action, is provided in Table 1. Application of AED therapy can be complex, as a delicate balance must be achieved with respect to efficacy, adverse effects, drug—drug interactions, pharmacogenetics, comorbidities, and patient compliance. Seizures that do not respond to AED therapy are considered refractory and are treated with a ketogenic diet, stimulation of the vagus nerve, deep brain stimulation, or surgery.

AED terminology and drug stratification follows a generational pattern. First-generation AEDs refers to those drugs in use or approved for use before ; second-generation AEDs are those approved between and The most recent AEDs, approved after , are referred to as third-generation agents. While third-generation AEDs elicit their effects via a variety of mechanisms, these compounds exhibit improved bioavailability, lower plasma protein binding with the exception of clobazam, ezogabine, and perampanel , and fewer drug—drug interactions than first- and second-generation compounds 5.

The physiological underpinning of epilepsy is a misfiring of neurons in the brain. Neuronal signaling is based on the propagation of action potentials down a neuronal axon, ultimately resulting in the release of neurotransmitters from the presynaptic neuron into the synaptic junction Fig.

Once released, neurotransmitters bind to receptors on the postsynaptic neuronal membrane, allowing for signal propagation to the postsynaptic cell. Seizures result from either excess neuronal excitation or amelioration of neuronal inhibition. AEDs primarily function by modulating neurotransmitter activity to prevent inappropriate signaling. However, these compounds may also cause sedative effects and pain relief, resulting in AED utilization in clinicopathological states other than epilepsy.

Postsynaptic potentials result from the presynaptic release of neurotransmitters into the synaptic cleft. AEDs can be stratified by their molecular mechanisms of action Table 1. However, there are several AEDs in which the mechanism of action is not established or only partially elucidated. Each drug's mechanism of action can target specific seizure subtypes and other disease states that may benefit from the compound, including the management of pain.

Many of the traditional AEDs, including carbamazepine and phenytoin, elicit their mechanisms of action through the inhibition of voltage-gated sodium channels. These channels serve as critical components for the initiation and propagation of action potentials, facilitating neurotransmitter release and signal transmission to postsynaptic neurons. Voltage-gated channel inhibitors may exert their effects through stabilization of the channel in the inactive state via transient interactions with the core or membrane-bound portions of the channel.

Certain AEDs are postulated to function solely through this mechanism, while several combine this activity with other molecular mechanisms to modulate neurotransmission. The GABA A receptor is a ligand-gated chloride channel that, when activated by GABA or another small molecule, hyperpolarizes the membrane, thereby suppressing action potentials in the postsynaptic neuron. Additionally, gabapentin is structurally similar to GABA, and stimulates GABA release through multiple interactions, one of which may be inhibition of voltage-gated calcium channels 7. Several other molecular mechanisms are used by AEDs that target a diverse set of proteins and processes.

Levetiracetam and its recently approved chemical analog brivaracetam are thought to exert their effects through binding to SV2A, a neurotransmitter reporter found in synaptic vesicles and endocrine granules. Thus, these drugs may be similar to those with GABA-related mechanisms. Notably, both levetiracetam and brivaracetam have improved toxicity profiles compared with earlier generation AEDs.

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AMPA receptors are ligand-gated ion channels that mediate fast excitatory neurotransmission. Further, the primary mechanism of action of third-generation AED perampanel is through the noncompetitive antagonism of the AMPA receptor. NMDA receptor hypofunction and overstimulation have been implicated in a wide range of neurological disorders, including dementia, neuropathic pain, schizophrenia, and epilepsy 9. Major epilepsy groups have published and continue to update clinical guidelines for the diagnosis and treatment of epilepsy.

In , the American Academy of Neurology and American Epilepsy Society published a joint guidance based on a systematic review of 47 qualifying studies on the treatment of adults with a first unprovoked seizure In these studies, the first-generation AEDs carbamazepine, phenytoin, and phenobarbital were most often used. However, no difference in quality of life or rate of long-term 2—5 years seizure remission was found between immediate and delayed AED therapy initiation. These findings suggest that therapeutic drug monitoring TDM may be beneficial to ensure sufficient exposure and minimize toxicities, thereby increasing efficacy and quality of life regardless of when pharmacotherapy is initiated.

Although most clinical trials and guidelines focus on epilepsy in adult populations, children account for roughly one-quarter of all epilepsy cases. The guidelines published in by the American Academy of Neurology and the Practice Committee of the Child Neurology Society provide similar recommendations for children as those provided for adults An important consideration in the initiation of daily pharmacotherapy in a pediatric population is the potential impact of drug administration on the child's psychosocial development.

Although fewer trials have been conducted in pediatric populations, the effects of AED therapy are similar in children as in adults. AED therapy likely reduces the risk of a second seizure, but it does not necessarily improve long-term remission success. A survey of clinical trials evaluating the efficacy of AEDs for various types of epilepsy was first published by the ILAE in 12 and updated in Notably, data were enriched and recommendations made primarily for focal seizures and pediatric absence seizures. For other epilepsy types, such as generalized onset tonic-clonic and juvenile myoclonic epilepsy, only low levels of evidence were available.

Overall, well-designed randomized controlled trials are lacking in epilepsy, and this makes it difficult to determine which AEDs are the most effective for each type of epilepsy. As such, empirical use of AEDs is necessary when recommended first-line drugs are not effective and literature data are limited.

The goals for AED therapy postdiagnosis are to prevent further seizures while minimizing adverse and off-target drug effects. Generally, AED monotherapy is initiated and patient response is monitored. If seizure control is not achieved initially, monotherapy is attempted with a different AED. Transitioning between monotherapies requires vigilant monitoring for efficacy and potential toxicity. Once monotherapy options have been exhausted, combination therapy with an adjunctive AED is commonly pursued for disease management.

Of note, many of the second- and third-generation AEDs were initially approved as adjunctive therapies; however, recent data suggest that many of the third-generation AEDs are also effective as first-line monotherapies 15 , While these drugs may be preferred by patients due to a lower incidence of side effects, most are not currently approved as first-line therapies for epilepsy. Given the large number of drugs and overlapping mechanisms of action within drug classes, AED selection can be a significant challenge. Current guidelines in the US and Europe provide multiple options for first-line, second-line, and adjunctive therapeutic options for each type of seizure, as outlined in Table 2 There are many key factors that must be considered when selecting a therapy, either for initial or combination therapy, all of which are specific to the patient Recommended antiepileptic drugs first-line, adjuvant, and secondary by seizure type.

Addition of an adjunctive AED, or incorporation of an AED into an existing drug regimen, requires an assessment of potential drug—drug interactions. This topic is beyond the scope of this review, and reference texts are available that enumerate the many AED drug—drug interactions that have been established and observed 19 , In brief, most AEDs are at least partially metabolized by liver enzymes, and many AEDs either inhibit or induce hepatic cytochrome P enzyme activity.

Drug doses must be carefully selected and adjusted to achieve desired therapeutic concentrations. The importance of monitoring AED concentrations in blood has been recognized for several decades. AEDs have a narrow therapeutic window and display wide interindividual variability with regard to pharmacokinetics. One challenging aspect of AED therapy is that their clinical efficacy is variable, even among patients with the same serum drug concentrations. Given these considerations and the common use of multiple AEDs, TDM is an important aspect of pharmacological epilepsy treatment.

In particular, they recommended establishing a patient-specific effective range, termed the therapeutic range, after AED therapy is initiated, and assessing drug concentrations every 6—12 months or when changes to the clinical situation warranted. To date, only 2 published randomized trials have compared epilepsy patients with and without routine TDM for guiding AED dosing. Neither trial found an improvement in overall outcome with routine TDM 24 , These results do not, however, address the utility of TDM in selected clinical situations, such as during medication modifications, in which the information provided is likely more impactful.

Further, the need for TDM of third-generation AEDs has not been definitively established and may thus be used in a different context than for first- or second-generation AEDs. Due to short half-lives, many AEDs are associated with a high pill burden to sustain therapeutic concentrations. For some second-generation AEDs, extended-release formulations have been approved and marketed for epilepsy and other indications. These include gabapentin, lamotrigine, levetiracetam, oxcarbazepine, and topiramate.

Reviews of available pharmacokinetic data suggest that the overall PK data for extended-release formulations compares favorably to immediate-release formulations, with reductions in peak-to-trough fluctuations Although small studies have shown that patients rate tolerability and quality of life higher when switched to extended-release formulations, there is no large-scale evidence of increased safety 26 , The potential advantages of once-daily administration include increased compliance, more stable blood concentrations, and patient preference for more convenient dosing.

Although AEDs elicit their mechanisms of action in the non-protein bound, or free, form, laboratory assays typically report total drug concentrations in serum or plasma. Free drug measurements are not indicated or clinically useful for non-highly bound molecules, such as phenobarbital. However, when a molecule is highly protein bound, such as is the case with phenytoin, measurement of free drug concentrations can provide additional information regarding therapeutic efficacy or toxicity. Anemia, hypoalbuminemia, and uremia can all displace drug—protein interactions, thereby increasing free drug concentrations.

Thus, for highly protein-bound AEDs, when plasma protein concentrations are altered, such as during pregnancy, or low, such as in elderly patients, free drug measurements can be clinically useful for drug monitoring 28 , Non-protein bound drug may be separated using methodologies such as ultrafiltration before analysis with downstream laboratory methods. Immunoassays are commonly employed in the measurement of many first-generation AEDs.

While many vendors have automated antibody-based assays available for canonical AEDs like phenytoin and carbamazepine, immunoassay offerings for many second- and third-generation compounds are more limited. Homogeneous immunoassays are available for second-generation AEDs, including lamotrigine 30 , levetiracetam 31 , gabapentin 32 , topiramate 33 , and zonisamide Offerings via third-party vendors, such as the aforementioned assays available through ARK Diagnostics, may be integrated into automated laboratory platforms to streamline laboratory work flows.

Important considerations, however, include potential increased cost per assay and decreased efficiency due to limited reagent stability and laboratory needs. Further, like all immunoassays, they can be subject to interferences and cross-reactivity with similar compounds. In the absence of commercially available methods for all AEDs, mass spectrometry is an alternative approach for AED quantification. Such laboratory tests may be targeted for a single AED or may be multiplexed in design.

In the literature, there are a plethora of methods described for the quantification of individual AEDs in biological matrices, with the majority of these methods utilizing mass spectrometry. Simultaneous quantification of analytes is challenging due to the potential for similar retention times, variable ionization efficiency, and overlapping precursor and product ions.

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Chromatographic times varied from 6—12 min 35 , 38 , With an increased number of drugs to separate, analytical run times may exceed 17 min per sample 36 , Most patients on multi-AED therapy are prescribed 2 or 3 AEDs at a time, and these combinations are tailored to the individual patient. If developed for clinical use, a multiplexed assay covering most AEDs could be applied to nearly all patients and reduce the number of separate tests ordered. When potential interferences with an immunoassay are of concern, methodologies that utilize chromatography could be used, as these provide physical separation of serum components.

While AEDs are developed and studied for their ability to address epilepsy, they are also commonly used for other indications. In fact, the majority of AEDs are prescribed to patients without an epilepsy diagnosis, mostly for the treatment of psychiatric disorders 40 , While the use of AEDs in psychiatric disorders is widespread, only 4 AEDs are approved by the FDA for psychiatric indications pregabalin for generalized anxiety disorder and carbamazepine, lamotrigine, and valproic acid for bipolar disorder.

Beyond this small number of drugs and limited indications, the use of AEDs in psychiatric disorders is considered off-label. Support and guidance for how AEDs can be used is derived mainly from open-label studies, small uncontrolled trials, and case reports Additionally, the incidence of psychiatric disorders, particularly depression, among patients with epilepsy is higher than that of the general population and thus appropriate AED therapy may be used to treat both conditions Other common indications for AED use are neuropathic pain and headaches.

Gabapentin and pregabalin are approved for postherpetic neuralgia lingering pain from complications of shingles , while pregabalin is also approved for the treatment of peripheral diabetic neuralgia. Carbamazepine is the first-line treatment for trigeminal neuralgia severe episodic facial pain ; however, the progressive nature of the disease decreases carbamazepine's effectiveness over time The Canadian Pain Society recently recommended gabapentin, pregabalin, and carbamazepine as first-line therapies and other anticonvulsants as fourth-line therapies for neuropathic pain AEDs are used for pain relief from headaches, particularly migraine headaches.

While both topiramate and valproic acid are approved for the treatment of migraines, several other AEDs, such as carbamazepine, clonazepam, levetiracetam, vigabatrin, and zonisamide, are commonly prescribed off-label for this purpose Unfortunately, clinical data for most AEDs for the prevention of migraines are limited. The best clinical evidence is available for topiramate and valproic acid, both of which reduce migraine frequency when compared with placebo in multiple clinical trials Several polymorphisms are known to have pharmacogenetic effects for one or more AEDs.

These effects include alterations to pharmacokinetic parameters and increased risk of serious adverse effects. Within the HLA-B15 serotype, one polymorphism has been identified that increases the risk of certain severe adverse effects of some AEDs. CYP2C9 3 polymorphisms have been demonstrated to decrease the rate of metabolism of phenobarbital, phenytoin, and valproic acid Despite high-quality evidence, prospective CYP2C9 genotyping is not commonly performed, with clinical practice generally relying on monitoring serum drug concentrations and clinical presentation CYP2C19 variants can also impact AED metabolism, with a substantial effect on phenobarbital and to a lesser extent on phenytoin.

Initial studies also suggest that CYP2C19 variants may decrease the rate of zonisamide metabolism Polymorphisms of UGT2B7 significantly decrease serum valproic acid levels in epilepsy patients UGT1A4 is the main enzyme responsible for the glucuronidation of lamotrigine.

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The UGT1A4 L48V variant decreases serum lamotrigine concentrations and affects its overall efficacy in both pediatric and adult patients 49 , Overall, the translation of genotypes of relevant genes to dose adjustments for individual patients remains challenging, partly due to lack of conclusive evidence as well as clear guidelines. Due to their range of neurotransmission-modulating mechanisms, AEDs have been successfully used not only for the treatment of epilepsy but also for various psychiatric conditions and certain types of pain.

Identifying an effective AED for an individual patient involves empirical testing of different drugs, often guided by TDM. Options for adjunctive treatment include carbamazepine , clobazam , gabapentin , lamotrigine , levetiracetam , oxcarbazepine , sodium valproate , or topiramate. If adjunctive treatment is ineffective or not tolerated, a tertiary epilepsy specialist should be consulted who may consider eslicarbazepine acetate , lacosamide , phenobarbital , phenytoin , pregabalin , tiagabine , vigabatrin and zonisamide. Sodium valproate is the first-line treatment for newly diagnosed generalised tonic-clonic seizures except in female patients who are premenopausal, see Valproate below.

Lamotrigine is the alternative choice if sodium valproate is not suitable, but may exacerbate myoclonic seizures. In those with established epilepsy with generalised tonic-clonic seizures only, lamotrigine or sodium valproate may be prescribed as the first-line treatment. Carbamazepine and oxcarbazepine may also be considered in newly diagnosed and established tonic-clonic seizures, but may exacerbate myoclonic and absence seizures. Clobazam , lamotrigine , levetiracetam , sodium valproate or topiramate may be used as adjunctive treatment if monotherapy is ineffective or not tolerated.

Ethosuximide , or sodium valproate except in female patients who are premenopausal, see Valproate below , are the drugs of choice in absence seizures and syndromes; lamotrigine is a suitable alternative when ethosuximide and sodium valproate are unsuitable, ineffective or not tolerated. Sodium valproate should be used as the first choice if there is a high risk of generalised tonic-clonic seizures. A combination of any two of these drugs may be used if monotherapy is ineffective.

Clobazam , clonazepam , levetiracetam , topiramate or zonisamide may be considered by a tertiary epilepsy specialist if adjunctive treatment fails. Carbamazepine , gabapentin , oxcarbazepine , phenytoin , pregabalin , tiagabine and vigabatrin are not recommended in absence seizures or syndromes. Myoclonic seizures myoclonic jerks occur in a variety of syndromes, and response to treatment varies considerably.

Sodium valproate is the drug of choice in newly diagnosed myoclonic seizures except in female patients who are premenopausal, see Valproate below ; topiramate and levetiracetam are alternative options if sodium valproate is unsuitable but consideration should be given to the less favourable side-effect profile of topiramate. A combination of two of these drugs may be used if monotherapy is ineffective or not tolerated. If adjunctive treatment fails, a tertiary epilepsy specialist should be consulted and may consider clobazam , clonazepam , zonisamide or piracetam.

Carbamazepine , gabapentin , oxcarbazepine , phenytoin , pregabalin , tiagabine and vigabatrin are not recommended for the treatment of myoclonic seizures. Sodium valproate and levetiracetam are effective in treating the generalised tonic-clonic seizures that coexist with myoclonic seizures in idiopathic generalised epilepsy. Atonic and tonic seizures are usually seen in childhood, in specific epilepsy syndromes, or associated with cerebral damage or mental retardation.

They may respond poorly to the traditional drugs. Sodium valproate is the drug of choice except in female patients who are premenopausal, see Valproate below ; lamotrigine can be added as adjunctive treatment. If adjunctive treatment is ineffective or not tolerated, a tertiary epilepsy specialist should be consulted, and may consider rufinamide or topiramate. Carbamazepine , gabapentin , oxcarbazepine , pregabalin , tiagabine or vigabatrin are not recommended in atonic and tonic seizures.

Some drugs are licensed for use in particular epilepsy syndromes. The epilepsy syndromes are specific types of epilepsy that are characterised according to a number of features including seizure type, age of onset, and EEG characteristics. For more information on epilepsy syndromes in children see BNF for children. A tertiary specialist should be involved in decisions regarding treatment of Dravet syndrome. Sodium valproate except in pregnancy or females of childbearing potential, see Valproate below or topiramate are first-line treatment options in children with Dravet syndrome.

Clobazam or stiripentol may be considered as adjunctive treatment in children and adults if first-line treatments are ineffective or not tolerated. Carbamazepine , gabapentin , lamotrigine , oxcarbazepine , phenytoin , pregabalin, tiagabine , and vigabatrin should not be used as they may exacerbate myoclonic seizures.

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A tertiary specialist should be involved in decisions regarding treatment of Lennox-Gastaut syndrome. Sodium valproate is the first-line drug for treating children with Lennox-Gastaut syndrome except in pregnancy or females of childbearing potential, see Valproate below ; lamotrigine can be used as adjunctive treatment in children and adults if sodium valproate is unsuitable, ineffective or not tolerated.

If adjunctive treatment is ineffective or not tolerated, rufinamide and topiramate may be considered by tertiary specialists. Carbamazepine , gabapentin , oxcarbazepine , pregabalin, tiagabine , and vigabatrin should not be used. Felbamate [unlicensed] may be used in tertiary specialist centres when all other treatment options have failed. Carbamazepine is a drug of choice for simple and complex focal seizures and is a first-line treatment option for generalised tonic-clonic seizures.

It can be used as adjunctive treatment for focal seizures when monotherapy has been ineffective. It is essential to initiate carbamazepine therapy at a low dose and build this up slowly. Carbamazepine may exacerbate tonic, atonic, myoclonic and absence seizures and is therefore not recommended if these seizures are present. Oxcarbazepine is licensed as monotherapy or adjunctive therapy for the treatment of focal seizures with or without secondary generalised tonic-clonic seizures. It can also be considered for the treatment of primary generalised tonic-clonic seizures [unlicensed].

Oxcarbazepine is not recommended in tonic, atonic, absence or myoclonic seizures due to the risk of seizure exacerbation. Eslicarbazepine acetate is licensed for adjunctive treatment in adults with focal seizures with or without secondary generalisation. Ethosuximide is a first-line treatment option for absence seizures. It may also be prescribed as adjunctive treatment for absence seizures when monotherapy is ineffective. Ethosuximide is also licensed for myoclonic seizures.

Gabapentin and pregabalin are used for the treatment of focal seizures with or without secondary generalisation. They are not recommended if tonic, atonic, absence or myoclonic seizures are present. Both are also licensed for the treatment of neuropathic pain. Pregabalin is licensed for the treatment of generalised anxiety disorder. Lamotrigine is an antiepileptic drug recommended as a first-line treatment for focal seizures and primary and secondary generalised tonic-clonic seizures. It is also licensed for typical absence seizures in children but efficacy may not be maintained in all children and is an unlicensed treatment option in adults if first-line treatments have been unsuccessful.

Lamotrigine can also be used as adjunctive treatment in atonic or tonic seizures if first-line treatment has failed [unlicensed]. Myoclonic seizures may be exacerbated by lamotrigine and it can cause serious rashes especially in children; dose recommendations should be adhered to closely.

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Lamotrigine is used either as sole treatment or as an adjunct to treatment with other antiepileptic drugs. Valproate increases plasma-lamotrigine concentration, whereas the enzyme-inducing antiepileptics reduce it; care is therefore required in choosing the appropriate initial dose and subsequent titration.

When the potential for interaction is not known, treatment should be initiated with lower doses, such as those used with valproate.

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  • Levetiracetam is used for monotherapy and adjunctive treatment of focal seizures with or without secondary generalisation, and for adjunctive treatment of myoclonic seizures in patients with juvenile myoclonic epilepsy and primary generalised tonic-clonic seizures. Levetiracetam may be prescribed alone and in combination for the treatment of myoclonic seizures, and under specialist supervision for absence seizures [both unlicensed]. Brivaracetam is used as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation. Phenobarbital is effective for tonic-clonic and focal seizures but may be sedative in adults.

    It may be tried for atypical absence, atonic, and tonic seizures. Rebound seizures may be a problem on withdrawal. Primidone is largely converted to phenobarbital and this is probably responsible for its antiepileptic action. A low initial dose of primidone is essential. Phenytoin is licensed for tonic-clonic and focal seizures but may exacerbate absence or myoclonic seizures and should be avoided if these seizures are present.

    It has a narrow therapeutic index and the relationship between dose and plasma-drug concentration is non-linear; small dosage increases in some patients may produce large increases in plasma concentration with acute toxic side-effects. Similarly, a few missed doses or a small change in drug absorption may result in a marked change in plasma-drug concentration. Monitoring of plasma-drug concentration improves dosage adjustment.

    When only parenteral administration is possible, fosphenytoin sodium , a pro-drug of phenytoin , may be convenient to give. Unlike phenytoin which should only be given intravenously , fosphenytoin sodium may also be given by intramuscular injection. Rufinamide is licensed for the adjunctive treatment of seizures in Lennox-Gastaut syndrome.

    It may be considered by a tertiary specialist for the treatment of refractory tonic or atonic seizures [unlicensed]. Topiramate can be given alone or as adjunctive treatment in generalised tonic-clonic seizures or focal seizures with or without secondary generalisation. It can be used as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome and for absence, tonic and atonic seizures under specialist supervision [unlicensed]. It can also be considered as an option in myoclonic seizures [unlicensed].

    Female patients should be fully informed of the risks related to the use of topiramate during pregnancy and the need to use effective contraception—for further information, see Conception and contraception and Pregnancy in the topiramate drug monograph. Sodium valproate is effective in controlling tonic-clonic seizures, particularly in primary generalised epilepsy.

    It is a drug of choice in primary generalised tonic-clonic seizures, focal seizures, generalised absences and myoclonic seizures, and can be tried in atypical absence seizures. It is recommended as a first-line option in atonic and tonic seizures. Sodium valproate has widespread metabolic effects and monitoring of liver function tests and full blood count is essential.

    The Importance of Drug Interactions in Epilepsy Therapy

    Because of its high teratogenic potential, valproate must not be used in females of childbearing potential unless the conditions of the Pregnancy Prevention Programme are met and alternative treatments are ineffective or not tolerated. During pregnancy, it must not be used for epilepsy unless it is the only possible treatment. For further information see Important safety information , Conception and contraception , and Pregnancy in the sodium valproate and valproic acid drug monographs.

    Valproic acid as semisodium valproate is licensed for acute mania associated with bipolar disorder. Zonisamide can be used alone for the treatment of focal seizures with or without secondary generalisation in adults with newly diagnosed epilepsy, and as adjunctive treatment for refractory focal seizures with or without secondary generalisation in adults and children aged 6 years and above. It can also be used under the supervision of a specialist for refractory absence and myoclonic seizures [unlicensed indications]. Clobazam may be used as adjunctive therapy in the treatment of generalised tonic-clonic and refractory focal seizures.

    It may be prescribed under the care of a specialist for refractory absence and myoclonic seizures. Clonazepam may be prescribed by a specialist for refractory absence and myoclonic seizures, but its sedative side-effects may be prominent. Acetazolamide , a carbonic anhydrase inhibitor, has a specific role in treating epilepsy associated with menstruation. Piracetam is used as adjunctive treatment for cortical myoclonus. Immediate measures to manage status epilepticus include positioning the patient to avoid injury, supporting respiration including the provision of oxygen, maintaining blood pressure, and the correction of any hypoglycaemia.

    Parenteral thiamine should be considered if alcohol abuse is suspected; pyridoxine hydrochloride should be given if the status epilepticus is caused by pyridoxine hydrochloride deficiency. Seizures lasting longer than 5 minutes should be treated urgently with intravenous lorazepam repeated once after 10 minutes if seizures recur or fail to respond. Intravenous diazepam is effective but it carries a high risk of thrombophlebitis reduced by using an emulsion formulation.

    Absorption of diazepam from intramuscular injection or from suppositories is too slow for treatment of status epilepticus. Patients should be monitored for respiratory depression and hypotension. Where facilities for resuscitation are not immediately available, diazepam can be administered as a rectal solution or midazolam oromucosal solution can be given into the buccal cavity. If, after initial treatment with benzodiazepines, seizures recur or fail to respond 25 minutes after onset, phenytoin sodium, fosphenytoin sodium , or phenobarbital sodium should be used; contact intensive care unit if seizures continue.

    If these measures fail to control seizures 45 minutes after onset, anaesthesia with thiopental sodium , midazolam , or a non-barbiturate anaesthetic such as propofol [unlicensed indication], should be instituted with full intensive care support. Phenytoin sodium can be given by slow intravenous injection, followed by the maintenance dosage if appropriate.

    Alternatively, fosphenytoin sodium a pro-drug of phenytoin , can be given more rapidly and when given intravenously causes fewer injection-site reactions than phenytoin sodium. Although it can also be given intramuscularly, absorption is too slow by this route for treatment of status epilepticus. Doses of fosphenytoin sodium should be expressed in terms of phenytoin sodium.

    If there is incomplete loss of awareness, usual oral antiepileptic therapy should be continued or restarted. Patients who fail to respond to oral antiepileptic therapy or have complete lack of awareness can be treated in the same way as for convulsive status epilepticus, although anaesthesia is rarely needed. Brief febrile convulsions need no specific treatment; antipyretic medication e. Prolonged febrile convulsions those lasting 5 minutes or longer , or recurrent febrile convulsions without recovery must be treated actively as for convulsive status epilepticus.

    Long-term anticonvulsant prophylaxis for febrile convulsions is rarely indicated. Home Treatment summary Epilepsy. Epilepsy control The object of treatment is to prevent the occurrence of seizures by maintaining an effective dose of one or more antiepileptic drugs. Management When monotherapy with a first-line antiepileptic drug has failed, monotherapy with a second drug should be tried; the diagnosis should be checked before starting an alternative drug if the first drug showed lack of efficacy.

    If the prescribed product is unavailable, it may be necessary to dispense a product from a different manufacturer to maintain continuity of treatment of that antiepileptic drug. Such cases should be discussed and agreed with both the prescriber and patient or carer ; Usual dispensing practice can be followed when a specific product is not stated.