Therapeutic Safety Monitoring: What to Look for and When to Look for It

Summary: This review focuses on the safety problems associated with antiepileptic drugs (AEDs) as revealed by laboratory testing and clinical examination. There are two classes of side effects: (a) common and mild and (b) rare and severe. Allergic reactions to AEDs are common and usually mild. However, on rare occasions, they can progress to more severe cutaneous disorders, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Severe allergic reactions to AEDs range from immune responses with fever to multiorgan dysfunction. Allergic rashes may be genetically or immunologically determined. Laboratory abnormalities produced by AEDs are common and mild, and include hepatic enzyme elevation associated with phenytoin and mild elevation in ammonia associated with valproate. Serious, although rare, idiosyncratic side effects, such as aplastic anemia, hepatotoxicity, and thrombocytopenia, have also occurred with AEDs. These reactions are largely confined to the "classic" AEDs. With the exception of felbamate, AEDs approved in the past decade have not been plagued by severe idiosyncratic reactions. Subtle endocrine abnormalities, including variations in thyroid function tests and bone metabolism, and the often subclinical effects on peripheral nerve conduction produced by phenytoin and carbamazepine, are also examined.     

Antiepileptic drugs and the immune system

Data on the effects of antiepileptic drugs on the immune system are frequently inconsistent and sometimes conflicting because the effects of drugs cannot be separated from those of seizures, first-generation drugs have been most intensively investigated, the patient's genetic background, the mechanism of action and the pharmacokinetic profile of AEDs and the concurrent use of immunosuppressant drugs may act as confounders. Valproate, carbamazepine, phenytoin, vigabatrin, levetiracetam, and diazepam have been found to modulate the immune system activity by affecting humoral and cellular immunity. AEDs are associated with pharmacokinetic interactions (most frequently occurring with carbamazepine, phenytoin, phenobarbital and valproate). Hepatic metabolism is the primary site of interaction for both AEDs and immunotherapies (ACTH, dexamethasone, hydrocortisone, methylprednisolone, cyclophosphamide, methotrexate, rituximab), which entail induction or inhibition of drug effects. However, the clinical importance of these drug interactions is still far from defined. An important adverse effect of the action of AEDs on the immune system is antiepileptic hypersensitivity syndrome (AHS), a life-threatening, idiosyncratic cutaneous reaction to aromatic AEDs resulting in end organ damage. Phenytoin, carbamazepine, phenobarbital, lamotrigine, oxcarbazepine, felbamate, and zonisamide have been implicated. The pathogenic mechanisms of AHS are incompletely understood.     

Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy

Antiepileptic drugs, particularly cytochrome P450 enzyme inducers, are associated with disorders of bone metabolism. We studied premenopausal women with epilepsy receiving antiepileptic drug monotherapy (phenytoin, carbamazepine, valproate, and lamotrigine). Subjects completed exercise and nutrition questionnaires and bone mineral density studies. Serum was analyzed for indices of bone metabolism including calcium, 25-hydroxyvitamin D, parathyroid hormone, insulin growth factor I, insulin binding protein III, and bone formation markers, bone-specific alkaline phosphatase, and osteocalcin. Urine was analyzed for cross-linked N-telopeptide of type I collagen, a bone resorption marker. Calcium concentrations were significantly less in subjects receiving carbamazepine, phenytoin, and valproate than in those receiving lamotrigine (p = 0.008). Insulin growth factor-I was significantly reduced in subjects receiving phenytoin compared with those receiving lamotrigine (p = 0.017). Subjects receiving phenytoin had significantly greater levels of bone-specific alkaline phosphatase (p = 0.007). Our results demonstrate that phenytoin is associated with changes in bone metabolism and increased bone turnover. The lower calcium concentrations in subjects taking carbamazepine or valproate compared with those taking other antiepileptic drugs suggest that these antiepileptic drugs may have long-term effects. Subjects receiving lamotrigine had no significant reductions in calcium or increases in markers of bone turnover, suggesting this agent is less likely to have long-term adverse effects on bone.     

Clinical Science

Pregabalin Drug Interaction Studies: Lack of Effect on the Pharmacokinetics of Carbamazepine, Phenytoin, Lamotrigine, and Valproate in Patients with Partial Epilepsy Martin J. Brodie, Elaine A. Wilson, David L. Wesche, Christine W. Alvey, Edward J. Randinitis, Edward L. Posvar, Neil J. Hounslow, Nicola J. Bron, G.L. Gibson, and Howard N. Bockbrader Pregabalin (Lyrica) is a new drug that has been approved in the EU as add‐on treatment for partial seizures, and as treatment of peripheral neuropathic pain, in adults. Because many patients with partial seizures require more than one antiepileptic drug (AED) to achieve the best seizure control they can, it is important to determine whether new drugs for treating partial seizures may interact with commonly used AEDs. This paper reports the results of several drug–drug interaction studies of pregabalin and commonly used AEDs. In these studies, pregabalin was given to patients who were each taking one AED, either valproate, phenytoin, lamotrigine, or carbamazepine, to treat their epilepsy. Adding pregabalin to monotherapy with valproate, phenytoin, lamotrigine, or carbamazepine had no effect on the concentrations in the blood of any of these four drugs. Likewise, when concentrations of pregabalin in the blood were measured in these same patients, the concentrations were similar to those seen in the blood of subjects from earlier studies who had received pregabalin by itself. These findings indicate that pregabalin does not interact with any of these four common AEDs. The combinations of pregabalin with either valproate, phenytoin, lamotrigine, or carbamazepine were generally well tolerated by the patients in these studies, and when side effects did occur, they were typically mild to moderate and resolved quickly. Together, these studies demonstrate that pregabalin may be safely added to therapy with valproate, lamotrigine, phenytoin, or carbamazepine without concern for drug–drug interactions.     

Pharmacokinetic interactions between contraceptives and antiepileptic drugs.

The occurrence of bi-directional drug interactions between antiepileptic drugs (AEDs) and combined oral contraceptives (OCs) pose potential risks of un-intended pregnancy and as well as seizure deterioration. It is well established that several of the older AEDs (carbamazepine, phenytoin and phenobarbital), are strong inducers of the hepatic cytochrome P450 (CYP) 3A4 enzyme system, and are associated with increased the risk of contraceptive failure. In addition, it is demonstrated that also some of the newer AEDs, oxcarbazepine and topiramate influence on the pharmacokinetics of OCs, which is thought to be due to a more selective induction of subgroups of the hepatic enzyme system. Estrogens containing OCs induce the glucuronosyltransferase and may reduce the plasma levels and the effect of AEDs cleared by glucuronidation. This has been most intensively studied for lamotrigine but also other AEDs, which undergoes glucuronidation processes, such as valproate and oxcarbazepine, may be affected by OCs. The magnitude of the drug-drug interactions show in general wide inter-individual variability and the change in the elimination rate is often unpredictable and can be influenced by a number of co-variants such as co-medication of other drugs, as well as genetic and environmental factors. It is therefore recommended that change in OC use is assisted by AED monitoring whenever possible.     

Cutaneous drug eruptions by current antiepileptics: case reports and alternative treatment options

Serious cutaneous drug eruptions due to antiepileptics have been defined for many drugs like carbamazepine, diphenylhydantoin, phenytoin and valproate. In recent years, adverse cutaneous reactions due to the current antiepileptic drugs have also been reported. In this paper, two cases are presented: a 48-year-old female receiving gabapentin for postherpetic neuralgia who developed leukocytoclastic vasculitis after 8 weeks and a 23-year-old male receiving lamotrigine for epileptic seizures who developed toxic epidermal necrolysis (TEN) in 15 days. Alternative therapy approaches with practical suggestions are also discussed.     

Serum hormones in male epileptic patients receiving anticonvulsant medication

Circulating sex and thyroid hormones, as well as the pituitary function, were assessed in 63 male patients with epilepsy receiving either a single medication of carbamazepine, phenytoin, or valproate or a combination of carbamazepine plus phenytoin or carbamazepine plus valproate. All therapeutic regimens, including carbamazepine and/or phenytoin were associated with low levels of circulating thyroxine (T4), free thyroxine (FT4), and dehydroepiandrosterone sulfate, and with low values for the free androgen index, and phenytoin and carbamazepine plus phenytoin were associated with high serum concentrations of sex hormone-binding globulin. These hormone parameters were unaffected by valproate monotherapy. It seems probable that accelerated hormone metabolism is responsible for the hormonal changes found in patients treated with carbamazepine and/or phenytoin. However, every drug regimen studied also had depressant and/or stimulatory effects on the function of the hypothalamic-pituitary axis. The diverse endocrine effects of different antiepileptic drug regimens should be considered when starting antiepileptic drug therapy.     

Antiepileptic Drugs, Cognitive Function, and Behavior in Children: Evidence from Recent Studies

Summary: The effects of antiepileptic drugs (AEDs) on cognitive function and behavior in children are reviewed on the basis of published studies. Individual AEDs have been shown to differ–the deleterious effects of phenytoin generally contrasting with the relatively minimal effects of valproate and carbamazepine. Some of the differences between results may be attributed to the psychological tests used and to age differences. However, there appears to be a dissociation between AEDs that affect higher cognitive function, e.g., phenytoin, and those mainly affecting motor function, e.g., carbamazepine, which appears to increase speed of performance. AEDs should be prescribed with care in children with epilepsy, taking account of their differing effects on cognitive function and behavior.     

Characterization of glucose homeostasis and lipid profile in adult,seizure‐free,epileptic patients in Asian population

Background and purpose: The most common prescribed antiepileptic drugs (AEDs), phenytoin and valproate, are potent enzyme inducers and inhibitors of the cytochrome P450 system, which interfere with lipid profile and glucose homeostasis. Studies on this topic have suffered from inadequate assessment of confounders and have rarely included glucose homeostasis and lipid profile as well as both enzyme inducers and inhibitors in the same study. We sought to determine whether these drugs had an effect on lipid profile and glucose homeostasis in Thai epileptic patients. Methods: We recruited 98 patients with epilepsy (45 taking phenytoin, 27 taking valproate, and 26 not taking any AED). Fasting blood samples were obtained to measure serum lipid, and glucose homeostasis was evaluated via the oral glucose tolerance test. We calculated the homeostasis model assessment index for each patient. Results: Our study revealed that CYP450 was induced by AEDs, and that patients on phenytoin had an increased mean value of serum total cholesterol, serum total triglycerides, and serum LDL cholesterol when compared with patients with epilepsy taking valproate and those taking no AEDs. No statistical significant difference was observed between patients taking valproate and patients taking no AEDs. In addition, patients with epilepsy taking phenytoin had higher fasting plasma glucose levels at fasting state than both those taking valproate and those taking no AEDs. Thirty percent of the patients taking phenytoin exhibited insulin resistance. We have found a negative correlation between log insulin sensitivity and log TG, but not high‐density lipoprotein (HDL). Conclusion: CYP450‐induced phenytoin produces significant amelioration in several serologic markers of atherosclerosis. These findings suggest that phenytoin may substantially increase the risk of vascular events.     

Seizure type, antiepileptic drugs, and reproductive endocrine dysfunction in Indian women with epilepsy: a cross-sectional study

Background: There is paucity of data regarding occurrence of reproductive endocrine disorders in Asian women with epilepsy (WWE) on antiepileptic drug (AED) therapy. Purpose: To determine the occurrence of reproductive endocrine disorders in Indian WWE, by seizure type and the AED use. Methods: Consecutive 427 reproductive age WWE receiving various AEDs were screened for the occurrence of menstrual abnormalities, weight change, and hirsutism. Of these, 53 WWE with menstrual disturbances and/or hirsutism were further evaluated for ovarian morphology and reproductive hormonal profile. Results: Menstrual abnormalities and/or hirsutism were observed in 83 of 427 (19.4%) WWE irrespective of epileptic seizure type; of these, 50 (60.2%) received valproate, 21 (25.3%) received carbamazepine, 11 (13.3%) received phenytoin, and one (1.2%) received phenobarbitone as the primary AED. Almost half of valproate‐treated women had significant weight gain and obesity. Among 53 of 83 women evaluated further, 23.5% and 63.6% of valproate‐treated women, 25% and 58.3% of carbamazepine‐treated women, and none and 20% of phenytoin‐treated women had polycystic ovaries (PCO) and hyperandrogenemia (HA), respectively. Valproate‐treated women had significantly higher frequency of polycystic ovarian syndrome (PCOS) (11.8% vs. 2.5%, p < 0.0001) and mean serum testrosterone levels (1.78 vs. 1.36 ng/ml, p = 0.03), compared with women treated with other AEDs. Limitations: Limitations include small number of women in antiepileptic subgroups and a high drop out rate in women who underwent ultrasound and endocrinological investigations. Conclusion: Menstrual abnormalities, weight gain, obesity, and PCOS are frequent and significantly higher in WWE receiving valproate, independent of seizure type.     

Pharmacokinetics and drug interactions with zonisamide

Polypharmacy is a widely employed treatment strategy in epilepsy, particularly for individuals with poorly controlled seizures. Drug combinations should be carefully considered to minimize the potential for unfavorable interactions. Older-generation antiepileptic drugs (AEDs) are well known for their pharmacokinetic interaction potential, which generally results from alterations in the metabolism of concomitant drugs due to effects on the cytochrome P450 (CYP) and uridine glucuronyl transferase enzyme systems. Newer agents, such as zonisamide, are less likely to cause adverse drug interactions. A series of interaction studies has revealed zonisamide to be without effect on the steady-state pharmacokinetics of carbamazepine, phenytoin, sodium valproate, or lamotrigine. However, zonisamide is principally inactivate by CY3A4-dependent reduction. Consequently, carbamazepine, phenytoin, and phenobarbital all increase its clearance, an interaction that may necessitate a dosage increase, but which will also permit more rapid attainment of steady-state zonisamide concentrations. Otherwise, zonisamide is essentially devoid of clinically significant interactions with other AEDs, oral contraceptives and, indeed, all other classes of therapeutic agents investigated to date. As a result, it is reasonable to conclude that zonisamide has a favorable pharmacokinetic profile and that it may be a useful and uncomplicated agent when employed as adjunctive therapy in refractory epilepsy.     

Some common issues in the use of antiepileptic drugs

Since 1993, eight new antiepileptic drugs (AEDs) have become available in the United States for the treatment of epilepsy: felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Of the older AEDs, six continue to be widely used: phenobarbital, phenytoin, primidone, ethosuximide, carbamazepine, and valproate. As a result, there is a relatively large number of alternative AEDs for the treatment of any given type of epilepsy. This has been particularly beneficial for patients with generalized epilepsies, both idiopathic and symptomatic. Given the wide availability of effective agents, the toxicity and pharmacokinetic profile of an AED have become major factors in the selection process. A number of common clinical situations may benefit from the abundance of AEDs. Chronic toxicity observed with some of the older AEDs such as osteoporosis, gingival hyperplasia, or alterations in reproductive endocrine function may be avoided with the use of the newer agents. The obese patient with epilepsy may benefit from the use of AEDs such as topiramate or zonisamide, which have a tendency to produce weight loss. In patients with a history of drug-induced skin rash, AEDs such as valproate, gabapentin, topiramate, tiagabine, and levetiracetam carry a lower risk of cross-reactivity. In patients sensitive to cognitive dysfunction, drugs with a favorable profile include gabapentin, tiagabine, lamotrigine, oxcarbazepine, and levetiracetam. A more favorable pharmacokinetic profile is observed in the majority of the newer AEDs in contraposition to the classic agents. Good absorption, linear kinetics, and low drug-drug interaction potential make these drugs easier to use. The newer AEDs are eliminated through different combinations of liver metabolism and direct renal excretion, thus providing a wider variety of choices in patients with failure of one of these organs. Some specific problems have been found with some of the newer AEDs. Hyponatremia, known to occur rarely with carbamazepine use, appears to be more common with oxcarbazepine. Felbamate has been associated with a high incidence of aplastic anemia and liver failure and should be used exceptionally. Acute angle closure glaucoma has been observed with the use of topiramate. This complication occurs early in the course of therapy and reverses rapidly with discontinuation of the drug, so physician and patient awareness of this problem is very important. In this article several common clinical situations in the management of patients with epilepsy are presented in the form of case studies. These cases illustrate some current aspects of the use of the AEDs and will give some guidelines to help the treating physician in the increasingly complex process of AED selection.     

Seizure-inducing effects of antiepileptic drugs: a review

Seizure-inducing effects can be observed in the treatment of epileptic patients with antiepileptic drugs (AED). This may be a paradoxical reaction (for example the increase of complex focal seizures due to carbamazepine, vigabatrin or phenytoin treatment) or a result of AED-induced encephalopathy (commonly induced by valproate in patients with complex focal seizures). A seizure increase during intoxication with AEDs is a rare phenomenon, thus, it is not directly related to this condition. An incorrect choice of drugs in the treatment of an epileptic syndrome or seizure type may provoke seizures (as for example the provocation of absences due to carbamazepine or phenytoin). The possible seizure-inducing effect of AEDs has to be differentiated from seizure occurrence due to the natural course of epilepsy. This may be especially difficult in patients suffering from West syndrome or Lennox-Gastaut syndrome, in whom seizure frequency may vary even without medication. However, especially in these patients, drug-induced worsening of seizure manifestation is often observed. In general, a seizure-inducing effect of antiepileptic drugs has to be considered when a seizure increase is observed soon after the initiation of therapy, when a stepwise increase of the dosage is followed by a further increase of seizures, a decrease of seizures is seen with tapering of the dosage and a renewed increase of seizures can be observed after this therapy has been reestablished. Finally, one knows that the clinical condition of encephalopathy due to valproate or carbamazepine is accompanied by seizure increase. In spite of these clinical aspects, the underlying mechanisms of seizure increase mostly remain unclear. From animal experiments it is obvious that especially carbamazepine and phenytoin may provoke generalized seizures as absences or myoclonic seizures. A seizure increase during vigabatrin therapy has been attributed to the increase of the cerebral amount of gamma-amino-butyric acid, which is known to possibly exhibit inhibitory or excitatory neuronal effects. The occurrence of tonic seizures in patients with Lennox-Gastaut syndrome has been attributed to the sedative effect of the drugs; however, this conclusion is controversial. From a clinical point of view, one should consider young age of the patient, mental retardation, antiepileptic polytherapy, high frequency of seizures or prominent epileptic activity in the electroencephalogram previous to medication as risk factors for a possible seizure-inducing effect of antiepileptic drugs.     

Use of antiepileptic drugs in Estonia: an epidemiologic study of adult epilepsy

An evaluation of general antiepileptic treatment patterns and utilization of particular drugs was carried out based on the prevalence study of adult active epilepsy in a sample of the Estonian population. The antiepileptic drugs (AEDs) used, and their doses were recorded and compared with clinical characteristics. Nineteen per cent of the subjects did not take any AED on the prevalence day; 83% of those on medication were taking a single drug, 15% two, and 2% three AEDs. Localization-related symptomatic epilepsies were most frequently treated with AEDs and were also the largest group receiving polytherapy. The most common agent was carbamazepine (68%), followed by barbiturates. Valproate and phenytoin were used much less. The study design and its impact on the interpretation of results is discussed. The percentage of sodium-channel blockers is generally comparable with that reported from other European countries. The small share of valproate is probably a result of the extensive utilization of barbiturates, and is partially related to the age distribution in the study. The high figure of AED-free cases, and small percentage of polytherapy indicates a tendency for undertreatment. Some points for improvement in AED therapy are discussed.     

Anticonvulsant drugs and hematological disease

Many antiepileptic drugs (AEDs) are associated with hematological disorders that range from mild thrombocytopenia or neutropenia to anemia, red cell aplasia, until bone marrow failure. Fortunately, potentially fatal hematological disorders such as aplastic anemia are very rare. This review investigates hematological effects associated with classic and newer AEDs: a PubMed search indexed for MEDLINE was undertaken to identify studies in adults, children and animals using the name of all anticonvulsant drugs combined with the terms “hematological disease” and “hematological abnormalities” as key words. The most common hematological alterations occur with older AEDs than newer. Indeed, careful hematological monitoring is needed especially using carbamazepine, phenytoin and valproic acid. The pathogenetic mechanisms are still unknown: they seem to be related to an immunological mechanism, but drugs pharmacokinetics and pharmacodynamics interactions may also play an important role. Further research is needed to assess the real pathogenetic mechanism at the basis of hematological complications caused by AEDs.     

Effects of Antiepileptic Drugs on Sperm Motility of Normal Controls and Epileptic Patients with Long-Term Therapy

The in vitro effects of four antiepileptic drugs (AEDs) on human sperm motility were studied with a transmembrane migration method. Sperm motility of epileptic patients receiving chronic AED therapy was also investigated. Sperm motility was measured immediately after semen had been mixed with AED and after a 2-h preincubation at 37 degrees C. Both in vitro and in vivo studies demonstrated that AEDs inhibited sperm motility. When the drug effect was evaluated after the semen-AED mixture had been preincubated for 2 h, sperm motility was inhibited to 50% of control at concentrations of 1.59, 4.23, and 5.00 mM for phenytoin, carbamazepine, and valproate, respectively. Both with and without preincubation, phenobarbital, even up to 12.92 mM, did not inhibit the motility to less than 50% of the control. In the in vivo study, poor sperm motility was noted in epileptic patients with long-term AED therapy despite serum levels within the therapeutic range. Shorter duration of activity of spermatozoa was also observed in these patients. Interference with sperm membrane function by AEDs may be the underlying mechanism.     

53种抗癫癎中成药的成分分析

目的：检测部分抗癫痫中成药中是否含有西药抗癫痫药物的成分。方法：用高效液相色谱法测定53种抗癫痫中成药中是否含有苯巴比妥、苯妥英钠、卡马西平和丙戊酸钠。结果：83.01%中成药中测出含有苯巴比妥、苯妥英钠、卡马西平和丙戊酸。结论：市场上大量未标明含有抗癫痫西药成分的中成药,严重影响癫痫用药安全。