Version May 2024
INTRODUCTION — The overall approach to antiseizure medication therapy and monitoring for patients with epilepsy is reviewed here. Other aspects of epilepsy are discussed separately. (See "Overview of the management of epilepsy in adults" and "Initial treatment of epilepsy in adults" and "Seizures and epilepsy in children: Initial treatment and monitoring" and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)
REFERRAL — It is usually appropriate to refer a patient with seizures to a neurologist when establishing a diagnosis and formulating a course of treatment. Referral to an epilepsy specialist may be necessary if there is doubt about the diagnosis and/or if the patient continues to have seizures.
EDUCATING PATIENTS
Epilepsy counseling — For many patients, being diagnosed with epilepsy brings a time of vulnerability, uncertainty, and confusion as they wait for seizure freedom [1]. Therefore, before starting treatment, the clinician should begin a dialogue with the patient, family, and caregivers to increase their understanding of epilepsy and their ability to report necessary and relevant information. Epilepsy affects each patient in a unique way, and patients differ in their capacity to understand various aspects of the disorder. As a result, clinicians must tailor discussions to clarify the impact of the condition on the specific patient's quality of life and expectations of the treatment plan. These discussions will improve the likelihood that the patient will comply with the plan of treatment.
●SUDEP – Patients with epilepsy have a small but significant risk of sudden unexpected death in epilepsy (SUDEP). Clinicians should inform epilepsy patients, family members, and caregivers about the incidence and risk factors for SUDEP. This can be introduced as part of the rationale for recommending pharmacologic treatment in an individual diagnosed with epilepsy. SUDEP is reviewed in detail separately. (See "Sudden unexpected death in epilepsy".)
●Other comorbidities – The treating clinician should also discuss comorbidities associated with epilepsy. The burden of comorbidity in epilepsy is high and includes several conditions such as depression, anxiety, migraine, and cardiovascular disease [2]. Epilepsy comorbidities are discussed in detail elsewhere. (See "Comorbidities and complications of epilepsy in adults".)
●Alcohol and caffeine intake – Alcohol consumption in small amounts (one to two drinks per day) may not affect seizure frequency or serum levels of antiseizure medications (ASMs) in patients with well-controlled epilepsy [3]. Heavier alcohol intake (three or more drinks per day) increases the risk of seizures, particularly during the withdrawal period (7 to 48 hours after the last drink), and this practice should be strongly discouraged [4].
Coffee or tea consumption is not considered harmful provided consumption of caffeine is less than 400 mg daily (around five cups of coffee) [5].
Explaining the ASM regimen — The clinician should impress upon the patient, family, and caregivers the critical need to follow the prescribed ASM regimen. The consequences of nonadherence to ASM treatment are described in more detail below. (See 'Nonadherence with ASM therapy' below.)
Written instructions on how and when to take the ASMs should be provided and should explain the dosing regimen and any potential adverse effects. The patient must also be warned not to stop taking an ASM and not to allow a prescription to run out or expire.
Patients should be urged not to start any other prescription, over-the-counter medications, dietary supplements, or herbal remedies without first contacting their clinician, because these might affect serum levels of their ASMs [6,7].
ANTISEIZURE MEDICATION TITRATION
ASM selection — Guidance on when to start antiseizure medication (ASM) and the initial selection of an ASM is reviewed separately. (See "Initial treatment of epilepsy in adults".)
"Start low and go slow" principle — We start ASM treatment with a single drug (monotherapy). Approximately 50 percent of patients will obtain seizure freedom with the first monotherapy [8,9]. In general, the strategy is to gradually titrate to identify the lowest effective dose to achieve seizure freedom while minimizing adverse effects. Subsequent dose adjustment is then made based on seizure control and tolerability.
The benefit of slow titration is that there is a lower risk of both dose-dependent and idiosyncratic side effects [10]. Suggested titration schedules for common ASMs are covered separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects" and "Initial treatment of epilepsy in adults".)
For some ASMs, such as lamotrigine, a slow titration is mandatory to mitigate the risks of severe skin reactions [11], particularly so when co-administered with valproic acid [12]. In older adult patients, lower initial doses of ASMs and slower titration rates should be used [13].
Factors influencing titration rate — Seizure recurrence in newly diagnosed epilepsy typically occurs after three to six months [14], permitting a slow titration. However, for patients who continue to have frequent or disabling seizures after epilepsy onset, a medication that can be safely titrated rapidly may be preferred over one requiring weeks or months to achieve a therapeutic dose. Such medications include brivaracetam, lacosamide, levetiracetam, valproic acid, and phenytoin [15].
Target dose — There is relatively little evidence to guide which initial ASM dose should be targeted in the absence of dose-dependent side effects, although observations from cohort studies suggest the majority of patients obtaining seizure freedom with a specific medication usually do so at low to medium doses, for example 1500 mg/day for valproic acid, 300 mg/day for lamotrigine, and 400 mg/day for carbamazepine [8]. Details regarding the recommended initial dose for individual ASMs and a potential titration schedule are presented separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)
Risk of seizures during titration phase — If a seizure occurs very soon after the target dose of a specific ASM is reached, a question sometimes arises as to whether this constitutes treatment failure and necessitates a treatment change, whether it be dose escalation or a new ASM.
Addressing this question requires consideration of pharmacokinetic and pharmacodynamic properties of the specific medication chosen (table 1). ASMs with long half-lives require more time to come up to steady state, at which time a seizure would indicate treatment failure. As an example, for levetiracetam, peak serum levels occur 1.3 hours after dosing and steady-state levels within 24 to 48 hours [16], indicating seizures occurring beyond this time frame may be considered a treatment failure. Lamotrigine, by comparison, has a longer half-life of 25 hours [17], and at least four to five days of treatment at the target dose would be expected prior to considering the treatment to be therapeutic. Any decision requires careful consideration of patient-specific factors such as the clinical impact of seizures, urgency to obtain seizure freedom (for example, relating to occupational or driving restrictions), or an expressed desire that the lowest possible efficacious dose be established.
MONITORING
Follow-up visits — We monitor epilepsy treatment regularly: generally every one to three months for patients recently started on treatment or with suboptimal seizure control, and every six to 12 months for patients with chronic stable epilepsy. Follow-up visits should be scheduled to record seizure frequency, inquire about medication side effects, and obtain any needed tests [18].
Laboratory studies (eg, blood counts, hepatic and renal function, and antiseizure medication [ASM] levels) can be obtained when indicated. These visits are also used to address concerns the patient may have about taking the medication and psychosocial aspects of their disorder.
Seizure calendar — Patients and family members should be encouraged to record seizures in a diary or calendar, which can be brought to medical appointments for review. Electronic seizure diaries are also available [19].
●Benefits – There are several benefits to using seizure calendars. They may be used to track the patient's response to ASM therapy, including possible side effects. Seizure calendars can help identify seizure triggers. In one study of 71 patients completing daily seizure diaries, both lack of sleep and higher self-reported stress and anxiety were associated with seizure occurrence [20]. Seizures were also associated with the patients' own prediction of the likelihood of seizure occurrence. Other reported seizure triggers include visual, olfactory, and auditory stimuli; alcohol consumption; missed meals; and hormone fluctuations related to the menstrual cycle [21].
●Accuracy and unawareness of seizures – While information from seizure diaries is vital to guide ASM treatment, all diaries are dependent on accurate recognition and recording of seizures [22]. Studies involving inpatient video-electroencephalography (EEG) monitoring [22] and implanted seizure advisory systems [23] have consistently reported high levels of seizure unawareness, and patients or caregivers also report false-positive events that are not seizures. Other potential problems, such as compliance with diary maintenance, may be partially overcome by the use of electronic seizure diaries [19].
ASM levels
Indications for monitoring ASM levels — There are several well-established indications for monitoring serum ASM levels (ie, concentrations), as follows [24]:
●To establish an individual therapeutic concentration (level) that can be used at subsequent times to assess potential causes for a change in drug response (see 'Individual therapeutic concentration' below)
●As an aid in the diagnosis of clinical toxicity
●To assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures (see 'Breakthrough seizures' below)
●To guide dose adjustment in situations associated with increased pharmacokinetic variability (eg, in children, older adults, patients with associated diseases, drug formulation changes)
●When a potentially important pharmacokinetic change is anticipated (eg, in pregnancy, or when an interacting drug is added or removed)
Given the changes in volume of distribution and the increased renal clearance and hepatic metabolism of ASMs associated with pregnancy, serum levels of ASMs should be followed at regular intervals during pregnancy. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Antiseizure medication monitoring and dose adjustment'.)
Trough levels and free levels — Standardized sampling time is important [24]. Ideally, serum levels should be collected immediately before the next dose (a trough level) to measure the lowest ASM concentration in an individual, particularly for ASMs with short half-lives such as valproic acid, carbamazepine, and levetiracetam. Trough levels are used to determine the therapeutic ASM concentration (see 'Individual therapeutic concentration' below) and for guiding dose adjustments.
Measuring free (unbound) levels of ASMs can be clinically useful when treating with ASMs that are highly protein bound, such as phenytoin and valproic acid [25].
Note that clinical treatment decisions should not be made based on ASM levels alone without relevant consideration of patient history and clinical symptoms.
Individual therapeutic concentration — The "individual therapeutic concentration" is defined as the ASM level, or range of levels, empirically associated with an optimum response in an individual patient [24]. Overall, establishing the individual therapeutic concentration is more clinically useful than the laboratory reference range given the considerable interpatient variability in the concentration of a medication that produces a therapeutic response [26]. This concept applies to both older and newer ASMs.
Utility for older versus newer ASMs — As a general principle, the role of measuring levels to guide adjustments of doses is best established for older medications with dose-dependent pharmacokinetics, particularly phenytoin [24]. Newer-generation ASMs may exhibit significant pharmacokinetic variability at any age [27].
Evidence from trials — Randomized trials have failed to demonstrate a benefit of therapeutic drug monitoring with respect to seizure outcomes [28,29]. A randomized trial of therapeutic monitoring for dose adjustment of various newer-generation ASMs (lamotrigine, levetiracetam, oxcarbazepine, topiramate, brivaracetam, zonisamide, and pregabalin) randomly assigned 151 patients in a 1:1 ratio to a systematic drug monitoring group, with ASM levels available at each appointment, or to a rescue drug monitoring group, with ASM levels available for lack of ASM efficacy or adverse events [30]. There was no difference between the two groups for the outcomes of ASM treatment efficacy or tolerability. The authors concluded that systematic level monitoring of newer ASMs was not beneficial due to a poor correlation between clinical effects and drug levels [30]. This is consistent with the results of an observational study, which found that plasma levels of ASMs were lower in seizure-free patients than in those with ongoing seizures, suggesting that efficacy can be reached at the lower part or at times even below the reference ranges in patients with drug-responsive epilepsy [31].
Selected ASMs — The usefulness of measuring levels of specific ASM is discussed for several commonly prescribed ASMs:
●Phenytoin – Therapeutic monitoring of phenytoin is important because of its narrow therapeutic index and the unpredictable relationship between dose and therapeutic level [24], due to a variety of factors including variable absorption, protein binding, and drug interactions [32]. Because of its nonlinear pharmacokinetics, small increments in dose can produce large changes in serum levels. While most patients attain seizure control at levels of 10 to 20 mg/L (40 to 79 micromol/L) some patients may require only very low levels and others will obtain a benefit from levels above 20 mg/L without developing dose-dependent side effects [24].
●Levetiracetam – Studies have shown that those taking therapeutic doses of levetiracetam have levels in the order of 12 to 46 mg/L (70 to 270 micromol/L). However, a role for therapeutic monitoring of levetiracetam levels to guide dosing has not been established [33], with the exception of during pregnancy [34].
●Valproate – Several studies have examined the efficacy of valproic acid with reference to drug levels. Collectively, seizure freedom is generally established at levels between 50 and 100 mg/L (346 and 693 micromol/L) [35-38]. A higher level may be maintained if needed for better seizure control, provided dose-related adverse effects are not present. In the absence of adverse effects, the dose can be increased to achieve better seizure control without checking levels.
●Lamotrigine – There does not appear to be a clear relationship between lamotrigine levels and clinical response [39,40]. Adverse effects are more common in levels above 10 mg/L, although much higher levels (above 20 mg/L) are often tolerated and can yield additional benefit in patients with difficult-to-control epilepsy [41].
●Carbamazepine – The optimal effect of carbamazepine treatment is generally achieved at concentrations of 4 to 12 mg/L (17 to 51 micromol/L) [42,43], although symptoms of carbamazepine toxicity can be seen at similar concentrations to those associated with optimal seizure control [44]. Lower concentrations may be associated with symptoms of toxicity in the setting of combination therapy, particularly so with lamotrigine due to the pharmacodynamic interaction [40].
Role of seizure monitoring devices — Existing seizure monitoring devices measure a combination of accelerometry, surface electromyographic (EMG) signals, electrodermal activity (EDA), heart rate, and heart rate variability. More studies are required to explore parameters that do not require motion for seizure detection. Several wearable devices are approved by the US Food and Drug Administration (FDA) and/or have received European CE (conformité européenne) certification for the detection of generalized tonic-clonic seizures [45].
A 2022 systematic review and meta-analysis of automated seizure detection with noninvasive wearable devices found that devices had a high sensitivity for detecting tonic-clonic seizures during recording time in a video-EEG setting but that false alarm rates were relatively high [46]. Wearable devices have also shown promise in their ability to differentiate between epileptic and psychogenic seizures [47].
Ultra-long-term EEG recording via a subcutaneous device may have a role in seizure forecasting and detection [48,49]; however, utilization is mainly restricted to the research setting.
NONADHERENCE WITH ASM THERAPY
Prevalence and consequences — Studies have consistently shown high rates of medication nonadherence among people with epilepsy, ranging from 26 to 79 percent [50-54].
The potential consequences of antiseizure medication (ASM) nonadherence are well established. The RANSOM (Research on Antiepileptic Nonadherence and Serious Outcomes in Medicaid) study of more than 30,000 epilepsy patients found that nonadherence was associated with a more than threefold risk of mortality compared with adherence (hazard ratio [HR] = 3.32) [55]. Other consequences include a higher incidence of attendance to emergency departments, hospital admissions, fractures, head injuries, and increased health care costs [52,53,55]. Another study in which nonadherence was identified by therapeutic drug monitoring with reference to the patient's own control value [56] found that adherence was a factor in 39 percent of patients admitted to hospital with seizures.
Reasons and possible risk factors — A report of 200 people with epilepsy found that female sex and older age were associated with a lower risk of ASM nonadherence, while reduced resilience and symptoms of anxiety and depression were associated with an increased risk [57]. A retrospective cohort study from the United States of people with newly treated epilepsy used Medicare beneficiary data and identified several factors associated with increased risk of nonadherence, including Black race and geographic region [58]. Factors associated with a lower risk of nonadherence included older age, female sex, and neurologist visit.
Nonadherence can be intentional and/or unintentional (eg, forgetting to take a dose or mistakenly taking an incorrect dose) [59]. In one study of adherence conducted by online survey, 40 percent of people with epilepsy reported unintentional nonadherence and 30 percent intentional nonadherence [59]. In this study, factors associated with unintentional nonadherence included feeling depressed (odds ratio [OR] 1.410), younger age (OR 1.448), and memory problems (OR 1.529). Those with intentional nonadherence cite adverse effects, either experienced or theoretical, and perceived lack of efficacy as the reasons for their decision. Neither intentional nor unintentional nonadherence were associated with polytherapy or seizure freedom.
Discrepancies between prescribed treatment and treatment taken may also be attributable to miscommunication between the treating clinician and patient [60].
Patient-initiated discontinuation may be considered the most extreme form of nonadherence. In a study conducted in Australia, a high-income country, 16 percent of patients with newly diagnosed and treated epilepsy self-discontinued treatment after a median duration of 1.4 years, with a median period of seizure freedom of less than a year [61]. The most common reasons for discontinuation were the presence of adverse effects, belief that treatment was no longer necessary, pregnancy-related concerns, or the culmination of chronic nonadherence. Concerningly, 65 percent experienced further seizures after discontinuation of therapy. Overall, 55 percent restarted treatment, sometimes after a significant seizure-related injury. Those who had stopped treatment due to side effects were most at risk of seizure recurrence. These findings highlight areas for improved discussion with patients, including the chronicity of epilepsy and management strategies for current or potential adverse effects.
Epilepsy classification may also affect adherence, with nonadherence higher in those with generalized seizures compared with focal seizures in one study [56].
Strategies for improving adherence — In addition to patient education, we employ the use of calendars, medication alarms, or dosette boxes to improve medication adherence. Various studies, including randomized trials, have looked at the role of interventions to improve adherence to ASMs. The studied methods include both educational and behavioral interventions [62]. A randomized trial combined the use of motivational interviewing with provision of calendars for participants to self-monitor their medication-taking behavior. Two-hundred-and-seventy-five participants were studied, with several different outcome measures. Compared with the controls, those in the intervention group performed better in measures of medication adherence, therapeutic drug levels, reduced medication concerns, social cognitive variables, seizure severity, and health-related quality of life [63]. Overall, behavioral interventions, such as the use of intensive reminders, have provided more favorable effects on adherence than educational interventions [63-65].
BREAKTHROUGH SEIZURES — For patients with breakthrough seizures or failure of initial antiseizure medication (ASM) monotherapy that is adequately dosed and tolerated, there is only one decision to make, which is to either change to an alternative ASM or to add a second ASM. In practice, ASM addition (combination therapy) is appropriate if the first ASM is well tolerated and improves but does not abolish seizures, whereas ASM substitution is appropriate if the first ASM is poorly tolerated at a lower dose or fails to improve seizure control [66]. The same principles apply to the management of those with established drug-resistant epilepsy.
Although data from randomized trials are limited, several studies have found similar seizure outcomes when switching ASM monotherapy (substitution) was compared with adding a second ASM [9,67,68]. As examples, an open-label randomized trial of 157 patients with focal epilepsy not controlled on a single ASM found that the 12-month probability of seizure freedom was similar for alternative monotherapy versus polytherapy (14 versus 16 percent) [67]. A longitudinal observational study of 489 patients treated between 1982 and 2012 after failure of the initial ASM monotherapy demonstrated that more patients were treated with combination therapy compared with sequential monotherapy (69 versus 31 percent), although seizure-free rates were similar for those with substitution monotherapy versus combination therapy (20 versus 21 percent, risk ratio 1.17) [68].
An earlier prospective study of patients with inadequate seizure control on the first well-tolerated ASM also found that the rates of seizure freedom were similar for the substituted monotherapy and add-on therapy groups (17 versus 26 percent) [9]. A study of 816 ASM changes in 436 adult patients with drug-resistant epilepsy showed no difference between ASM addition or substitution in seizure outcome or tolerability measures [69].
GENERIC SUBSTITUTION — Most generic medications are much less expensive than brand-name products, which motivates the substitution of generic antiseizure medications (ASMs) for branded ASMs [70,71]. The bioequivalence of generic ASMs and their potential clinical effect are reviewed in the sections that follow.
Bioequivalence — According to the FDA, generic drugs must be "identical, or bioequivalent, to a brand-name drug in terms of dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use" [72].
Measures used to determine bioequivalence include (figure 1):
●The area under the concentration-time curve (AUC) of drug concentration in plasma (plotted on the y-axis) versus time after dose (plotted on the x-axis), which quantifies the exposure to a drug and its clearance rate from the body
●The peak concentration (Cmax) of drug in the blood after a dose is given
For products to be considered bioequivalent according to FDA and European regulations, the geometric means of the AUC and Cmax ratios between the generic and the branded product and their corresponding 90 percent confidence intervals should fall within the 80 to 125 percent range [73-75].
The EQUIGEN (Equivalence Among Antiepileptic Drug Generic and Brand Products in People with Epilepsy) randomized trial demonstrated evidence of bioequivalence of three disparate lamotrigine products [76]. The same conclusion was drawn in a population of so-called "generic-brittle" patients with refractory epilepsy or a history of seizures occurring in the setting of brand switching [77].
Acceptance — Surveys have shown that a significant proportion of people with epilepsy and their caregivers are concerned about adverse effects and/or increased seizure frequency after a generic substitution [78]. A Canadian study showed that the rate of switching back from a generic ASM product to a brand-name product was higher than for comparable medications such as antidepressants [79], possibly reflecting a poor acceptance of generic compounds. There is also retrospective evidence that medication adherence is worse in those taking generic formulations, as they may be perceived by patients to be inferior products [80].
Surveyed neurologists, however, generally accept the use of generic ASMs [81].
In the United States as of 2016, generic medications (including but not limited to ASMs) accounted for 89.5 percent of all dispensed medications but for only 25.8 percent of pharmaceutical expenditures [82].
Effect on seizures and safety — Given the accumulating evidence regarding the safety and efficacy of generic ASM formulations, we agree with a 2016 position statement from the American Epilepsy Society, which notes that "drug formulation substitution with FDA-approved generic products reduces cost without compromising efficacy" [70].
●Seizure control – Although data are limited, the highest-quality evidence comes from a 2010 meta-analysis and systematic review, which included seven randomized trials and 204 patients; there was no difference in the odds of uncontrolled seizure for patients taking generic ASMs compared with those taking brand-name ASMs [83]. A retrospective German study of 678 children and adolescents with epilepsy divided the cohort into a group with seizure recurrence (n = 339) and a group of seizure-free controls (n = 339) [84]. The risk of seizure recurrence was not associated with a switch in brand name or generic ASMs; a switch in treatment occurred for only 11 percent of seizure cases compared with 25 percent of controls [84].
Nevertheless, several case-control studies have shown a possible effect of generic substitution on the risk of requiring emergency or hospital-based treatment for epilepsy [85-87].
●Effect on ASM levels – Variation in ASM serum levels could lead to increased seizures or toxicity in some patients, but data are limited and inconclusive. A study of 50 patients with breakthrough seizures after switching to a generic ASM found lower ASM levels at the time of the breakthrough seizure in 21 of 26 patients with known levels before and after generic substitution [88].
However, a retrospective analysis assessed intrasubject variation in plasma concentration of three ASMs (lamotrigine, levetiracetam, and topiramate) after generic substitution compared with a control group that continued using the brand-name formulation [89]. While both groups exhibited very large day-to-day variability in plasma levels, the proportion of patients exhibiting a change in concentration greater than -20 or +20 percent was similar for the generic substitution compared with the control group for lamotrigine (22 versus 33 percent) and levetiracetam (44 versus 38 percent), and higher in the control (brand-name) group for topiramate (41 versus 6 percent).
●The refilling effect – An important caveat in interpreting the occurrence of seizures in the setting of medication substitution is that refilling of ASM prescriptions is associated with an increased risk of breakthrough seizures, irrespective of whether the refilling occurs with a brand-name or generic product [90]. This is supported by a large population-based case-crossover study of more than 83,000 patients, which found that refilling with the same ASM was associated with an increased risk of breakthrough seizures but that there was no additional risk associated with changing to a different product [91]. This effect may occur because refilling often takes place when patients are running out of medications, leading to missed doses or temporary dose reduction by the patient.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in adults" and "Society guideline links: Seizures and epilepsy in children".)
SUMMARY AND RECOMMENDATIONS
●Education – The diagnosis of epilepsy can be distressing. Before starting treatment, clinicians should begin a dialogue with the patient, family, and caregivers to increase their understanding of epilepsy and their ability to report necessary and relevant information. The discussion should review the incidence and risk factors for sudden unexpected death in epilepsy (SUDEP), other epilepsy comorbidities, and expectations of the treatment plan, including the importance of adherence to antiseizure medication (ASM) therapy. (See 'Educating patients' above.)
●ASM titration – We start treatment with a single ASM (monotherapy). Approximately 50 percent of patients will obtain seizure freedom with the first monotherapy. In general, the strategy is to "start low and go slow" by gradually titrating to the lowest effective dose that achieves seizure freedom while minimizing adverse effects. However, for patients who continue to have frequent or disabling seizures after epilepsy onset, a medication that can be safely titrated rapidly may be preferred. (See 'Antiseizure medication titration' above.)
●Monitoring – We monitor patients with epilepsy with routine follow-up visits to record seizure frequency, inquire about medication side effects, and obtain any needed tests. We encourage the use of a seizure calendar to help track the patient's response to ASM therapy and identify possible side effects and seizure triggers. (See 'Follow-up visits' above and 'Seizure calendar' above.)
●ASM levels – Indications for monitoring serum ASM levels include determining the individual therapeutic concentration (level), diagnosing ASM toxicity, assessing adherence, and guiding dose adjustments in selected clinical situations. ASM serum levels should be collected immediately before the next dose (a trough level) to measure the lowest ASM concentration, which is used to determine the individual therapeutic ASM concentration. (See 'Indications for monitoring ASM levels' above.)
The usefulness of measuring levels for selected ASMs is discussed above for phenytoin, levetiracetam, valproate, lamotrigine, and carbamazepine. (See 'Selected ASMs' above.)
●Nonadherence – Rates of nonadherence are high among people with epilepsy. The potential consequences include an increased risk of seizures, hospitalization, fractures, head injuries, and mortality. Factors associated with an increased risk of nonadherence include younger age, feeling depressed, ASM adverse effects, perceived lack of efficacy, and belief that treatment was no longer needed.
In addition to patient education, the use of calendars, medication alarms, and medication dosette boxes may help improve adherence. (See 'Nonadherence with ASM therapy' above.)
●Breakthrough seizures – For patients with breakthrough seizures or failure of initial ASM monotherapy that is adequately dosed and tolerated, adding a second ASM (combination therapy) is appropriate if the first ASM is well tolerated and improves but does not abolish seizures; ASM substitution is appropriate if the first ASM is poorly tolerated at a lower dose or fails to improve seizure control. Although data from randomized trials are limited, several studies have found similar seizure outcomes when switching ASM monotherapy was compared with adding a second ASM. (See 'Breakthrough seizures' above.)
●Generic substitution – Most generic medications are much less expensive than brand-name products. Bioequivalence of generic medications is defined by regulatory authorities. Although patient acceptance of (and adherence to) generic ASM therapy may be lower compared with brand-name ASMs, accumulating evidence suggests that the use of generic ASMs does not compromise efficacy. (See 'Generic substitution' above.)
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