Anticonvulsants General Statement (Monograph)

Drug class: Anticonvulsants
VA class: CN400

Uses for Anticonvulsants General Statement

Seizure Disorders

Anticonvulsant drugs are used principally in the prevention and treatment of seizures, epileptic seizures, and epilepsy syndromes. A seizure is a transient occurrence of signs and symptoms due to abnormal excessive or synchronous neuronal activity in the brain, and epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. While epilepsy is a common cause of seizures, not all seizures are a result of epilepsy. Because a variety of other conditions (e.g., head trauma, hypoglycemia, alcohol or drug withdrawal, high fever) and certain medications also can precipitate seizures, the cause of seizures should be sought in every case and any underlying disorder corrected when possible. It is important to recognize the factors known to lower seizure threshold (e.g., fever, hypoglycemia, hyponatremia) so that corrective measures can be taken.

Seizure Classification

In 1981, the International League Against Epilepsy (ILAE) developed a working classification of seizure types that divided seizures into the following 4 major categories based on EEG and clinical findings: partial seizures (seizures beginning locally in one hemisphere); generalized seizures (seizures that are bilaterally symmetrical without local onset); unilateral seizures (seizures that are predominantly unilateral); and unclassified epileptic seizures. Partial seizures were further subdivided into those with elementary symptomatology (simple partial seizures), those with complex symptomatology (complex partial seizures), and those that were secondarily generalized. Generalized seizures included tonic-clonic (grand mal) seizures, absence (petit mal) seizures, myoclonic seizures, and akinetic seizures. Although the ILAE classification has been revised over the years, the original classification scheme remains in widespread use. The 2017 ILAE classification maintains the basic framework of the 1981 system with some modifications to recognize that some seizure types can have either a focal or generalized onset, allow classification when the onset of seizure is unknown, include new seizure subtypes, and clarify terminology.

The current 2017 ILAE seizure classification continues to categorize seizures based on the type of onset (focal, generalized, or unknown). However, the term “partial” has been replaced with “focal” to better convey a sense of location rather than a part of a seizure. For focal seizures, the next level of classification is based on the individual's level of consciousness (or awareness). If awareness of the event is impaired at any time during the seizure, the seizure is classified as a “focal impaired awareness seizure”, which replaces the previous term “complex partial seizure”. If awareness is not impaired, the seizure is classified as a “focal aware seizure”, which replaces the previous term “simple partial seizure”. Focal seizures may be further characterized by motor or nonmotor onset. Focal seizures that propagate in a bilateral pattern are classified as “focal to bilateral tonic-clonic seizures”, which corresponds to the previous term “secondarily generalized tonic-clonic seizures”. Generalized seizures are further subdivided into motor (e.g., tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, epileptic spasms) or nonmotor (absence) subtypes, which generally have remained the same with the addition of a few new subtypes. Specialized references should be consulted for a more complete discussion of seizure classification.

Status epilepticus has been traditionally defined as more than 30 minutes of either continuous seizure activity or 2 or more seizures that occur sequentially without full recovery of consciousness between the seizures. However, seizures that persist for more than 5 minutes are not likely to stop spontaneously without intervention, and therefore treatment is commonly initiated when the seizure duration reaches 5 minutes. Status epilepticus is further characterized as convulsive or nonconvulsive based on the presence or absence, respectively, of limb stiffness and rhythmic jerking.

Principles of Anticonvulsant Drug Therapy

Initial Evaluation

Patients presenting with a new-onset seizure should undergo a comprehensive diagnostic evaluation (with careful history, physical examination, EEG, and brain imaging) to determine whether the seizure is epileptic or nonepileptic. It is important to differentiate an epileptic seizure, which by definition is a recurring event, from an acute symptomatic seizure provoked by a transient factor (e.g., sleep deprivation, medications, alcohol, illicit drug use) because the management approach can be different. It is also important to rule out other potential causes of the patient's symptoms since other paroxysmal events (e.g., migraines, transient ischemic attacks [TIAs], syncope) can mimic seizures. The risk of seizure recurrence should be considered when determining whether to initiate anticonvulsant drug therapy. Empiric treatment with anticonvulsant drugs may not be warranted in patients with a new-onset seizure.

Choice of Anticonvulsant Therapy

Choice of anticonvulsant therapy should be individualized based primarily on the specific type of seizure and/or epilepsy. In general, broad-spectrum agents (e.g., lamotrigine, levetiracetam, topiramate, valproate, zonisamide) are effective in the management of focal (partial) seizures and most generalized seizures, but have variable efficacy for specific seizure types (e.g., absence or myoclonic seizures). Narrow-spectrum agents (e.g., carbamazepine, oxcarbazepine, phenytoin, lacosamide) are generally effective for all types of focal seizures, but some of the drugs may precipitate or aggravate absence seizures. Anticonvulsant drugs that are effective in absence seizures (e.g., ethosuximide) generally are not useful in generalized tonic-clonic or focal seizures. Although many of the currently available anticonvulsant agents have been used in children and adolescents with seizure disorders, there is generally a lack of well-designed randomized controlled studies to inform selection of anticonvulsant drugs in the pediatric population.

In addition to the seizure type, choice of anticonvulsant therapy should take into account specific patient-related (e.g., age, sex, comorbidities, renal or hepatic impairment, concomitant drugs) and drug-related (e.g., efficacy, adverse effects, cost, route of administration) factors. The older anticonvulsant agents (e.g., carbamazepine, phenobarbital, phenytoin, primidone, valproate) have complex pharmacokinetics and a high potential for drug interactions because of their potent enzyme-inducing or enzyme-inhibiting properties. In patients receiving concomitant medications, use of newer anticonvulsants with more limited drug interaction potential (e.g., gabapentin, levetiracetam, lacosamide, topiramate, zonisamide, tiagabine) may be preferred.

Treatment of epilepsy should begin with a single anticonvulsant agent. If seizures are not controlled, experts generally recommend attempting at least one and sometimes a second alternative anticonvulsant before considering adjunctive therapy. While the majority of patients are able to achieve adequate seizure control with monotherapy (if not with the initial drug, then with an alternative agent), some patients will require a combination of anticonvulsants. Many anticonvulsants, particularly the newer agents, have been evaluated as adjunctive therapy for the treatment of refractory seizures; choice of adjunctive therapy should be individualized based on efficacy, safety, and tolerability of the anticonvulsant; seizure type or epilepsy; patient age; and concomitant medications.

Status Epilepticus

Status epilepticus is a medical emergency that must be treated promptly to reduce substantial morbidity and mortality. Initial treatment should include standard critical care and supportive therapy (e.g., blood pressure and respiratory support, oxygen, IV access, identification and correction of underlying causes), followed by administration of a benzodiazepine. Benzodiazepines are considered the initial drugs of choice for the treatment of status epilepticus because of their rapid onset of action, demonstrated efficacy, safety, and tolerability. Although IV lorazepam is generally preferred because of its longer duration of action, the superiority of one benzodiazepine over another is not clear, and selection of an appropriate agent should be individualized based on local availability, route of administration, pharmacokinetics, cost, and other factors. To achieve a rapid therapeutic effect, IV administration of benzodiazepines is preferred; however, administration via other routes (e.g., IM, rectal, intranasal, buccal) may be considered when IV administration is not possible (e.g., in a prehospital setting).

If seizures continue after initial therapy with a benzodiazepine, a second-line anticonvulsant agent should be administered. There are no evidence-based recommendations to guide selection of second-line therapies; reasonable options include IV fosphenytoin (or phenytoin), IV valproate sodium, IV levetiracetam, and IV phenobarbital. Fosphenytoin is generally better tolerated than phenytoin, and some experts state that fosphenytoin is preferred when both agents are available. If refractory status epilepticus occurs, continuous IV infusion of anticonvulsants, IV barbiturates, or general anesthetics may be necessary.

Posttraumatic Seizures

The use of anticonvulsant agents for the prevention of posttraumatic seizures is controversial. Most patients suffering traumatic brain injury are not at risk of long-term sequelae; epilepsy appears to occur in 15% or less of civilians with severe head injuries (although the risk may be greater in certain subgroups [e.g., those with prolonged coma]). While some evidence suggests that the risk of developing posttraumatic epilepsy also may be related to the presence of intracranial hematoma, other evidence suggests that it is not. Other patients who have been suggested as being at increased risk include those developing early seizures and those with a depressed skull fracture or dural penetration. In most civilians who develop posttraumatic epilepsy, the disorder becomes evident during the first year after injury. Phenytoin and/or phenobarbital have been used most frequently for prophylactic anticonvulsant therapy in patients with serious head injury; carbamazepine also has been used. However, evidence of the long-term benefit of any anticonvulsant in preventing posttraumatic epilepsy currently is lacking. In one well-designed, placebo-controlled study assessing the potential benefit of phenytoin prophylaxis initiated within 24 hours of hospitalization for serious head trauma, the drug reduced the frequency of seizures during the first week of therapy but not during the second through 52nd week of therapy or after an additional year of posttreatment follow-up. Such therapy was associated with a 73% reduction in the risk of seizures during the first week compared with placebo (seizures occurred in 3.6% of treated patients versus in 14.2% of those receiving placebo). Therefore, some clinicians state that while acute therapy is indicated, routine long-term prophylaxis with phenytoin (and probably other anticonvulsants) after initial stabilization currently does not appear justified, particularly when the potential adverse effects of anticonvulsants are considered. If anticonvulsant prophylaxis is considered necessary, it generally should be limited to patients presumed to be at high risk. There currently is no consensus regarding the optimum duration of anticonvulsant prophylaxis following severe head injury, and additional study is necessary to further define the potential role of anticonvulsant agents for long-term prophylaxis in patients suffering head injuries.

Epilepsy Syndromes

Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome is a rare type of epilepsy that primarily affects young children and is usually refractory to anticonvulsant drugs. Selection of an appropriate anticonvulsant therapy should be guided by the prevalent seizure type. Anticonvulsants that have demonstrated efficacy in the management of seizures associated with Lennox-Gastaut syndrome include cannabidiol, topiramate, rufinamide, lamotrigine, clobazam, clonazepam, and felbamate. Because of serious adverse effects (e.g., aplastic anemia, liver failure), use of felbamate should be reserved for patients who do not respond adequately to other treatments and whose seizure disorder is so severe that the risks of felbamate are deemed acceptable in light of the potential benefits.

Juvenile Myoclonic Epilepsy

Juvenile myoclonic epilepsy is an inherited disorder that generally consists of 3 common seizure types (myoclonic, generalized tonic-clonic, and absence seizures); however, different combinations of these seizure types can occur because of the complex genetics of the disease. Seizures in juvenile myoclonic epilepsy usually can be controlled with the appropriate anticonvulsant drugs, but life-long treatment generally is required because of a high risk of relapse. Valproate is effective in about 90% of patients with this epilepsy syndrome. Levetiracetam also may be used in combination with other anticonvulsants for the management of myoclonic seizures in adults and adolescents with juvenile myoclonic epilepsy.

Infantile Spasms

Infantile spasms (also known as West syndrome) is a severe form of epilepsy that presents with myoclonic-tonic seizures, a characteristic EEG pattern called hypsarryhthmia, and psychomotor retardation. Vigabatrin may be used for the management of infantile spasms in patients for whom the potential benefits outweigh the risk of vision loss, a serious adverse effect of the drug.

Dravet Syndrome

Dravet syndrome (also known as severe myoclonic epilepsy of infancy) is a rare and severe type of epilepsy characterized by early onset of multiple seizure types, frequent episodes of status epilepticus, and developmental delay with cognitive and psychomotor impairment. Up to 85% of patients have mutations in the SCN1A gene encoding the voltage-gated sodium channel. Patients typically present within the first year of life with recurrent generalized tonic-clonic or hemiconvulsive seizures, which are often prolonged and triggered by fever (i.e., febrile seizures). Early mortality is high; the leading causes of death are sudden unexplained death in epilepsy (SUDEP) and status epilepticus. Seizures in patients with Dravet syndrome are generally refractory to current anticonvulsant drug options, and anticonvulsants that inhibit the sodium channel (e.g., carbamazepine, oxcarbazepine, lamotrigine, phenytoin), phenobarbital, or vigabatrin may exacerbate the condition. Because complete seizure freedom is typically not achievable, treatment is generally aimed at reducing the frequency of the most problematic seizures (e.g., convulsive seizures, status epilepticus) while minimizing adverse effects of anticonvulsant therapy.

Although evidence from controlled studies in patients with Dravet syndrome is limited, experts generally recommend initial treatment with either clobazam^{† [off-label]} or valproic acid^{† [off-label]}, followed by a combination of both drugs; however, adequate seizure control is rarely achieved with these drugs alone, and most patients will require additional anticonvulsant agents. Other anticonvulsants that have demonstrated efficacy in patients with Dravet syndrome include cannabidiol, fenfluramine, stiripentol, and topiramate^{† [off-label]}.

Barbiturates

Barbiturate-derivative anticonvulsants (e.g., phenobarbital, primidone) are used in the prophylactic management of various types of seizures. Phenobarbital is used principally in the management of tonic-clonic seizures and partial seizures. Phenobarbital also has been used in the prophylaxis of febrile seizures. The therapeutic uses of primidone are similar to those of phenobarbital and include management of tonic-clonic seizures and various partial seizures. Primidone also may be useful in the management of partial seizures with autonomic symptoms and akinetic seizures. Because of the availability of other anticonvulsant agents, the barbiturate-derived anticonvulsants generally are not recommended as first-line drugs for the treatment of epilepsy; in addition, these drugs are associated with a higher incidence of sedation than other anticonvulsants.

Benzodiazepines

Benzodiazepines are the drugs of choice for initial treatment of status epilepticus. (See Status Epilepticus under Seizure Disorders: Principles of Anticonvulsant Drug Therapy, in Uses.) Benzodiazepine anticonvulsants also have been used in the management of absence seizures, akinetic seizures, and myoclonic seizures. Oral benzodiazepines generally have been used as adjuncts to other anticonvulsants in the management of seizures refractory to other drugs. In general, benzodiazepines are less effective in the prophylactic management of seizures than in the acute treatment of status epilepticus. Tolerance often develops to the anticonvulsant effects of benzodiazepines, which can limit their usefulness in the long-term management of seizure disorders.

Clonazepam is used alone or with other anticonvulsants for the management of absence seizures, especially Lennox-Gastaut syndrome (petit mal variant epilepsy), and of akinetic or myoclonic seizures. Clonazepam also is used in the management of absence seizures that do not respond to succinimides. The drug also has been used with some success in the management of other refractory seizures^{† [off-label]}, including partial seizures with complex symptomatology and some cases of infantile spasms, as well as in the management of some patients with tonic-clonic seizures^{† [off-label]}.

Clobazam, a 1,5-benzodiazepine, is used in combination with other anticonvulsants for the management of seizures associated with Lennox-Gastaut syndrome, and also has been used as adjunctive therapy for the management of other seizure disorders, which have sometimes been refractory, including partial, generalized, and myoclonic seizures^† . Compared with the 1,4-benzodiazepines (e.g., clonazepam, diazepam, lorazepam), clobazam appears to have a broader spectrum of anticonvulsant activity and an improved adverse effect profile (e.g., less sedative effects).

Carboxamides

Carboxamide-derivative anticonvulsants (e.g., carbamazepine, oxcarbazepine, eslicarbazepine) are used principally in the treatment of focal (partial) seizures.

Hydantoins

Hydantoin-derivative anticonvulsants (e.g., ethotoin, phenytoin) are used for control of tonic-clonic seizures and focal (partial) seizures with complex symptomatology. Although efficacy of phenytoin has been well established for the management of seizure disorders, particularly for partial (focal) seizures, use of the drug may be limited because of its complicated pharmacokinetics, adverse effects, and multiple drug interactions. Phenytoin and fosphenytoin (the prodrug of phenytoin) also are used parenterally for the prevention and treatment of seizures occurring during neurosurgery and as second-line drugs of choice for the treatment of status epilepticus. The hydantoins sometimes increase the frequency of absence seizures and therefore should not be used in the treatment of such seizures.

Oxazolidinediones

Oxazolidinedione-derivative anticonvulsants (e.g., trimethadione), formerly drugs of choice in the management of absence seizures, are now used only in the treatment of absence seizures refractory to other anticonvulsants (e.g., ethosuximide). Trimethadione can cause serious adverse effects including rash, blood dyscrasias, renal and ocular dysfunction, lupus and myasthenia-like syndromes, and teratogenicity. As such, the drug was discontinued from the US market in 1995 and is only available on a compassionate-use basis. Oxazolidinedione anticonvulsants are of no benefit in the management of tonic-clonic seizures and may precipitate a patient’s first tonic-clonic seizure or increase the frequency of preexisting tonic-clonic seizures.

Succinimides

Succinimide-derivative anticonvulsants are used mainly in the management of absence seizures. Ethosuximide is considered a drug of choice in controlling absence seizures. Some clinicians have reported good results with ethosuximide in controlling myoclonic seizures or partial seizures with complex symptomatology.

Other Anticonvulsants

In addition to the barbiturates, benzodiazepines, carboxamides, hydantoins, oxazolidinediones, and succinimides, other anticonvulsants used in the management of seizures and epilepsy include cannabidiol, felbamate, fenfluramine, gabapentin/gabapentin enacarbil, lacosamide, lamotrigine, levetiracetam, perampanel, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, valproate, vigabatrin, and zonisamide. for information on these agents, see the individual monographs in 28:12.92.

A wide variety of other drugs are occasionally used in the management of epilepsy. Parenteral magnesium sulfate is used for the prevention or control of seizures in patients with preeclampsia or eclampsia, and also may be useful in controlling seizures associated with epilepsy, glomerulonephritis, or hypothyroidism. Although generally considered obsolete, bromides have been useful in the management of tonic-clonic or myoclonic seizures in some infants and preadolescent children when other drugs were unsuitable. Acetazolamide may be useful in the management of refractory partial, myoclonic, absence, or primary generalized tonic-clonic seizures; however, tolerance develops to the anticonvulsant effect of the drug. Corticotropin and corticosteroids are sometimes used in the management of myoclonic seizures in infants.

Migraine Prophylaxis

Certain anticonvulsants (e.g., topiramate, valproate) may be used for prevention of migraine headaches. The currently available evidence supports the use of topiramate and valproate for migraine prophylaxis in adults. Gabapentin, lamotrigine, and oxcarbazepine also have been evaluated for this use; however, studies with these anticonvulsants either were insufficient or showed no effect of the drug compared with placebo in reducing migraine frequency.

Neuropathic Pain

Certain anticonvulsants (e.g., carbamazepine, clonazepam, gabapentin, lamotrigine, phenytoin, pregabalin, valproate) have been used for the symptomatic treatment of chronic pain arising from peripheral neuropathic syndromes such as trigeminal neuralgia^†, postherpetic neuralgia (PHN)^†, diabetic peripheral neuropathy (DPN)^†, glossopharyngeal neuralgia^†, and posttraumatic neuralgia^† . Gabapentin and pregabalin are recommended by many expert guidelines for use in the treatment of neuropathic pain syndromes. The exact mechanism of action of anticonvulsants in the management of neuropathic pain has not been elucidated; however, it has been suggested that modulation of ion channels (i.e., calcium, sodium), enhanced γ-aminobutyric acid (GABA) inhibition, stabilization of neuronal cell membranes, and/or activation of N-methyl-d-aspartate (NMDA) receptors may be involved.

Some clinicians state that while tricyclic antidepressants traditionally have been used as initial therapy in the symptomatic treatment of neuropathic pain, certain anticonvulsant agents (e.g., carbamazepine, gabapentin, pregabalin) appear to have similar or greater safety and efficacy for this use. Results of clinical studies indicate that gabapentin is effective in the management of PHN and DPN^† . In placebo-controlled studies, pregabalin also has demonstrated efficacy in the treatment of PHN and DPN. Carbamazepine is used for the symptomatic treatment of trigeminal neuralgia. Further comparative studies are needed to evaluate the relative efficacy of anticonvulsants in the symptomatic treatment of neuropathic pain.

Psychiatric Disorders

Certain anticonvulsants have been used in the treatment of psychiatric disorders. Valproate has been used as monotherapy or as an adjunct to antipsychotic agents for the management of acute manic or mixed episodes in patients with bipolar disorder. There is some evidence suggesting greater efficacy of valproate compared with lithium in the treatment of mixed states. Other anticonvulsants, including lamotrigine, oxcarbazepine, and carbamazepine, also have demonstrated efficacy in the management of bipolar disorder, but generally are used when there is an inadequate response to first-line therapies such as lithium, valproate, and antipsychotic agents (e.g., olanzapine).

Valproate and carbamazepine also have been used as an adjunct to antipsychotic agents in the management of schizophrenia. The American Psychiatric Association (APA) states that, with the exception of patients whose illness has strong affective components, these anticonvulsants alone have not been shown to be substantially effective in the long-term treatment of schizophrenia.

Restless Leg Syndrome

Certain anticonvulsants (e.g., gabapentin enacarbil, pregabalin) may be used for the symptomatic treatment of restless legs syndrome.

Anticonvulsants General Statement Dosage and Administration

Administration

Anticonvulsants usually are administered orally. Some anticonvulsants also are available in an IV preparation that may be used when oral administration is temporarily not feasible.

In the treatment of status epilepticus, IV administration of a benzodiazepine is preferred to achieve rapid therapeutic drug concentrations; if IV administration is not possible, some benzodiazepines may be administered by IM, intranasal, buccal, or rectal routes.

In the prevention or control of seizures in patients with preeclampsia or eclampsia, and in the control of seizures associated with epilepsy, glomerulonephritis, or hypothyroidism, magnesium sulfate may be given parenterally (IV or IM).

Patients who are currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior. (See Suicidality under Cautions: CNS Effects and also see Cautions: Precautions and Contraindications.)

Therapeutic Drug Monitoring

Measurement of serum drug concentrations may be necessary with certain anticonvulsants (e.g., carbamazepine, ethosuximide, phenytoin, valproate). Such monitoring can increase the efficacy and safety of anticonvulsant therapy, and can also be useful in assessing patient compliance or in aiding the determination of the cause of toxicity when more than one medication is used.

Dosage

Dosage of anticonvulsants varies from patient to patient. On a weight basis, children require relatively large dosages of phenytoin, phenobarbital, and probably other anticonvulsants.

It is important to begin therapy with a low dosage and proceed slowly when increasing or decreasing the dosage of anticonvulsants as well as when adding, withdrawing, or replacing one anticonvulsant with another. Therapy should begin with a single anticonvulsant; other drugs should be added to the therapeutic regimen only after determining that the maximum tolerated dosage of the initial drug does not control seizures. If the patient continues to have seizures or if toxic effects appear, it is preferable to measure the plasma concentration of the drug before changing the dosage or adding another drug to the regimen. When a single drug is not effective in controlling epileptic seizures, the addition of a second or third drug may be necessary. The usual dosage of an anticonvulsant may vary depending on whether the drug is used alone or in conjunction with other drugs (including other anticonvulsants).

Some anticonvulsants require dosage adjustment for renal or hepatic impairment and other patient factors. When transitioning patients from one anticonvulsant to another, dosage adjustments may be necessary.

Anticonvulsants should be discontinued gradually following long-term administration to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus. In long-term anticonvulsant therapy, deciding when to withdraw the drug(s) is as important as the choice of drug(s) at the beginning of therapy. Some clinicians discontinue medication for the management of absence seizures when the patient has been seizure-free for 2 years and the EEG is normal; for febrile seizures when the child is 6 years old or seizure-free for 2 years, or after 30 months in otherwise healthy children who do not experience any complex seizures or sequelae after therapy is started; and for tonic-clonic seizures when the patient is seizure-free for 4 years. Other clinicians continue anticonvulsant administration in all epileptic patients for at least 4 years after the last seizure and then for an additional 1–2 years during which time the drug(s) is gradually withdrawn.

Cautions for Anticonvulsants General Statement

Adverse effects of anticonvulsants are numerous and range from those that are benign and completely reversible (e.g., drowsiness, photophobia, nystagmus) to benign but frequently irreversible (e.g., hypertrichosis) to serious reactions which can be fatal (e.g., hematologic, dermatologic, renal, or hepatic toxicity).

CNS Effects

The most common adverse effects of anticonvulsants are those related to the CNS and these effects can be classified into 3 general categories: somnolence and fatigue; behavioral/psychiatric abnormalities; and impaired psychomotor and cognitive performance. Adverse CNS effects include drowsiness, somnolence, fatigue, ataxia, gait disturbances, headache, restlessness, nystagmus, tremor, dizziness, vertigo, falls, dysarthria, and paresthesia. Adverse CNS effects usually are dose related, occurring more frequently during initial therapy, and can be minimized by starting with low dosages and gradually increasing the dosage.

Other adverse CNS effects include blurred vision, diplopia, and toxic amblyopia (with phenytoin). Polyneuropathies, abducens nerve palsy, and serious periorbital edema and hyperemia have occurred with some anticonvulsants. A few cases of ophthalmoplegia from phenytoin and/or primidone have been reported. In patients receiving phenytoin, ataxia is a frequent early sign of toxicity; with prolonged usage in toxic doses, cerebellar degeneration evidenced by loss of Purkinje cells has been reported.

Adverse neuropsychiatric effects associated with some anticonvulsants include irritability, anger, agitation, anxiety, labile affect, confusional state, psychotic symptoms, hallucinations, belligerence, hostility, and aggression. Serious and potentially life-threatening hostility- and aggression-related behaviors such as homicidal ideation and/or threats and physical assaults have occurred in patients receiving perampanel. In addition, all anticonvulsant drugs have the potential to cause suicidal behavior and ideation. (See Suicidality under Cautions: CNS Effects and also see Cautions: Precautions and Contraindications.)

Phenobarbital and, to a lesser extent, primidone frequently produce paradoxical excitement and hyperactivity in children or exacerbate existing hyperactivity, often requiring replacement of the drug with another barbiturate derivative or another anticonvulsant. Geriatric patients frequently react to barbiturates with excitement, confusion, or depression.

Suicidality

An analysis of suicidality reports from placebo-controlled studies using various anticonvulsants indicated that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%). The analysis included 199 randomized, placebo-controlled studies of 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) involving over 43,000 patients 5 years of age or older; the studies evaluated the effectiveness of the anticonvulsants in epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain). Four of the patients who were receiving one of the anticonvulsant drugs committed suicide whereas none of the patients receiving placebo did. The increased suicidality risk was observed as early as 1 week after beginning therapy and continued through 24 weeks. Because most studies included in the analysis did not extend beyond 24 weeks, the suicidality risk beyond 24 weeks could not be reliably assessed. The results were generally consistent among the 11 drugs studied with varying mechanisms of action and across a range of indications, suggesting that the suicidality risk applies to all anticonvulsants used for any indication. Although patients who were treated for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality compared with placebo, the relative risk was found to be higher in patients with epilepsy compared with those receiving anticonvulsants for other conditions. (See Cautions: Precautions and Contraindications.)

GI Effects

Most anticonvulsants cause GI disturbances such as nausea and vomiting, gastric distress, dysphagia, loss of taste, constipation, diarrhea, and anorexia with or without weight loss. The severity of adverse GI reactions may be minimized by administering the drugs with water or food. The oxazolidinedione and succinimide derivatives frequently cause hiccups.

Cases of life-threatening pancreatitis have been reported in patients receiving valproate.

Dermatologic and Sensitivity Reactions

Dermatologic reactions to nearly all the anticonvulsants have occurred. Adverse dermatologic reactions range from minor erythematous maculopapular rashes to more serious dermatologic reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN]). Carbamazepine, eslicarbazepine acetate, ethosuximide, lamotrigine, oxcarbazepine, phenytoin, and zonisamide have been associated with serious and sometimes fatal dermatologic reactions, including SJS and TEN.

Genetic polymorphism of the human leukocyte antigen (HLA) gene has been implicated in the development of adverse cutaneous reactions to the aromatic anticonvulsants. A strong association has been found between the presence of the HLA-B*1502 allele and an increased risk of SJS or TEN in patients receiving carbamazepine. The allelic distribution pattern for HLA-B*1502 is distinct for specific geographic areas and ethnic groups. The allele is found almost exclusively in patients with ancestry across broad areas of Asia, although marked variation exists in its prevalence among specific Asian populations. Patients with ancestry in genetically at-risk populations should be screened for HLA-B*1502 prior to initiating carbamazepine therapy; screening also should be considered prior to initiating oxcarbazepine. Patients testing positive for HLA-B*1502 should not be initiated on carbamazepine or oxcarbazepine therapy unless the benefits clearly outweigh the risks. Although evidence is more limited, HLA-B*1502 also has been associated with SJS/TEN in patients receiving other structurally similar anticonvulsants (e.g., eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, phenobarbital). Avoidance of these drugs should therefore be considered in HLA-B*1502-positive patients when alternative therapies are otherwise equally acceptable.

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening reaction, has been reported with several anticonvulsants (e.g., carbamazepine, eslicarbazepine, ethosuximide, gabapentin, lacosamide, oxcarbazepine, perampanel, phenytoin, rufinamide, valproate, zonisamide); the clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling in association with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Because DRESS is variable in its expression, other organ systems may be involved. In addition, early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in some cases even when rash is not evident.

Alopecia and a chloasma-like hyperpigmentation of the face and neck (without evidence of endocrinologic abnormality) have been associated with administration of some anticonvulsants. In addition, hypersensitivity reactions, including anaphylaxis and angioedema, have occurred with some anticonvulsants (e.g., fosphenytoin, phenytoin, gabapentin, pregabalin, levetiracetam).

Phenytoin produces gingival hyperplasia, most often in children, and is occasionally so severe that it may require surgical removal. Gingival hyperplasia does not occur in edentulous areas of gums. Gingival hyperplasia has been reported only rarely with other hydantoins. Secondary inflammatory changes which result in edematous enlargement of the primary gingival lesions can be minimized by good oral hygiene and gum massage. Phenytoin also produces hypertrichosis in some patients. Hypertrichosis is usually confined to the extremities but can also occur on the trunk and face and is frequently irreversible. Because of phenytoin’s androgenic effect on hair follicles, the drug also has been implicated in the production of acne.

Hematologic Effects

Most anticonvulsants (e.g., carbamazepine, gabapentin, oxcarbazepine, phenytoin, primidone, valproate, phenobarbital, pregabalin, primidone, topiramate) are associated with reduced serum concentrations of folate and vitamin B₁₂. Some clinicians recommend that prophylactic supplementation with folic acid and cyanocobalamin be considered in patients receiving anticonvulsant therapy.

Hematologic abnormalities have been reported with certain anticonvulsants. Bone marrow depression which can progress to fatal aplastic anemia has occurred with nearly all the drugs. Anticonvulsants have caused anemia, leukopenia, thrombocytopenia, agranulocytosis, and pancytopenia. Aplastic anemia and agranulocytosis have been reported with the use of carbamazepine. Blood dyscrasias, sometimes fatal, have been reported with ethosuximide. Use of felbamate has been associated with a marked increase in the risk of aplastic anemia. The incidence of aplastic anemia in patients receiving felbamate may be more than 100-fold greater than that seen in the general population; although the risk of death varies with severity and etiology, the fatality rate generally ranges from 20 to 30%, but has been reported to be as high as 70%.

Hepatic Effects

Acute hepatotoxicity, including cases of acute hepatic failure, have been reported with some anticonvulsants (e.g., felbamate, phenytoin, valproate). Children younger than 2 years of age, especially those receiving multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease, are at particularly high risk of valproate-induced hepatotoxicity.

Renal Effects

The oxazolidinedione anticonvulsants have been implicated in renal damage, which has occasionally produced fatal nephrotic syndromes. Renal involvement has been evidenced by edema, urinary frequency and burning, albuminuria, microscopic hematuria, and uremia. Succinimides also have been associated with adverse renal effects. Some patients have recovered from a severe anticonvulsant-induced nephrotic syndrome without therapy following discontinuance of the drug; others recovered following prednisone and cyclophosphamide therapy.

Other Adverse Effects

There is some evidence (mostly from case-control and observational studies) indicating that anticonvulsant agents can cause clinically important reductions in bone mineral density (BMD) and increase the risk of fractures. Some epileptic patients taking anticonvulsants in high dosages over long periods have developed hypocalcemia and, very rarely, rickets or osteomalacia. These effects have been seen predominately with the older anticonvulsant agents, although studies generally are lacking with the newer agents. The enzyme-inducing anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, primidone) can increase metabolism of 25-hydroxyvitamin D, which has been proposed as a possible mechanism of anticonvulsant-induced metabolic bone disease. However, valproate (an enzyme-inhibiting anticonvulsant) also has been associated with adverse bone effects suggesting that this may be a class effect of all anticonvulsants. Clinicians should consider monitoring vitamin D levels and other measures of bone health in patients receiving long-term anticonvulsant therapy. Some clinicians recommend that patients being treated with anticonvulsants (particularly those who may not be receiving adequate nutrition and sunlight) should receive supplemental vitamin D (e.g., 4000 units/week).

Elevations in serum total cholesterol, HDL-cholesterol, and triglycerides have occurred occasionally in patients receiving anticonvulsants.

Adverse ophthalmic effects have been reported with some anticonvulsants, including ezogabine (no longer commercially available in the US) and vigabatrin. Vigabatrin can cause progressive and permanent bilateral visual field defects with a potential risk of vision loss.

Topiramate and zonisamide inhibit carbonic anhydrase and can cause adverse effects similar to those of other carbonic anhydrase inhibitors (e.g., acetazolamide), including metabolic acidosis and kidney stone formation. Oligohidrosis and hyperthermia, characterized by decreased sweating and abnormally high body temperatures, have been reported in patients (particularly pediatric patients) receiving these anticonvulsants.

Severe cardiovascular effects, including cardiovascular collapse and death, have been reported following rapid IV administration of phenytoin or fosphenytoin; hypotension can occur if either drug is administered too rapidly by the IV route. IV phenytoin or diazepam can cause local irritation, swelling, thrombophlebitis, and, rarely, vascular impairment necessitating amputation. Purple glove syndrome (PGS), a delayed soft-tissue injury of the hand and forearm, has been reported in association with IV phenytoin and also may be possible with fosphenytoin.

Precautions and Contraindications

Patients who are currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior. (See Suicidality under Cautions: CNS Effects.) Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality and to pay close attention to any day-to-day changes in mood, behavior, and actions; since changes can happen very quickly, it is important to be alert to any sudden differences. In addition, patients, family members, and caregivers should be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions). If these or any new and worrisome behaviors occur, the responsible clinician should be contacted immediately. Clinicians who prescribe any anticonvulsant should balance the risk for suicidality with the risk of untreated illness. Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician must consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

All anticonvulsants can produce drowsiness, and for this reason patients should be cautioned that these drugs may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Slower dosage escalations or adjustments in the dosage regimen (e.g., giving lower doses, but more frequently) may alleviate such adverse CNS effects of these drugs.

Clinicians should be alert to the signs, including high fever, severe headache, stomatitis, conjunctivitis, rhinitis, urethritis, or balanitis, that may precede the onset of anticonvulsant-induced cutaneous lesions and reactions. Because skin eruptions can precede potentially fatal reactions, the drugs should be discontinued immediately whenever they occur. Adverse cutaneous reactions may proceed to an irreversible stage even though the medication has been discontinued, however, because these drugs are slowly metabolized and excreted.

Some anticonvulsants (e.g., carbamazepine, felbamate) can cause serious adverse hematologic effects and blood counts should be determined prior to and during therapy with these drugs. In addition, patients should be instructed to immediately report symptoms such as sore throat, fever, easy bruising, petechiae, epistaxis, or other signs of infection or bleeding tendency, which may be indications of hematologic toxicity. The drugs should be discontinued if blood dyscrasias occur. Because of the risk of aplastic anemia, felbamate should be used only in patients whose epilepsy is so severe that the risk is deemed acceptable in light of the benefits conferred by its use. Patients generally should not be initiated on felbamate without appropriate expert hematologic consultation.

With some anticonvulsants, patients should have liver function tests before starting therapy and periodically thereafter. Patients should be instructed to report promptly any symptoms of hepatotoxicity such as jaundice, dark urine, anorexia, abdominal discomfort, or other GI symptoms. The drugs should be discontinued if evidence of liver damage occurs. Anticonvulsants generally should be administered with extreme caution in patients with evidence of liver disease or abnormal liver function test values. Felbamate should be used only in patients without active liver disease and with normal baseline serum transaminase concentrations. Patients receiving oxazolidinediones or succinimides should have periodic urinalyses, and the drugs should be discontinued if evidence of renal damage appears.

Appropriate administration procedures and precautions should be followed in patients receiving parenterally administered anticonvulsants (e.g., phenytoin) to minimize the risk of local tissue injury, including purple glove syndrome. (See Cautions: Other Adverse Effects.)

Patients receiving vigabatrin should receive appropriate ophthalmologic assessments prior to initiating therapy and periodically thereafter as recommended. (See Cautions: Other Adverse Effects.)

Specific anticonvulsants are contraindicated in patients who have exhibited hypersensitivity to any derivative of the respective anticonvulsant type. Barbiturate derivatives exacerbate acute intermittent porphyria and porphyria variegata and are contraindicated in patients with a history of porphyria.

Pediatric Precautions

Anticonvulsant therapy may have adverse effects on behavior and cognition in children who have epilepsy. These effects have been shown to occur with therapeutic or supratherapeutic, but not necessarily toxic, serum anticonvulsant concentrations; large doses of virtually all anticonvulsants can affect mental function. Among the older anticonvulsant drugs, phenobarbital is the most likely to affect cognitive function in pediatric patients. Phenobarbital has been associated with hyperactivity, fussiness, lethargy, disturbed sleep, irritability, disobedience, stubbornness, depressive symptom, deficits on neuropsychologic tests, impaired short-term memory, and impaired memory concentration tasks. Cognitive effects of phenytoin have included unsteadiness, involuntary movements, tiredness, alteration of emotional state, deficits on neuropsychologic tests, impaired attention, impaired problem solving, and impaired visuomotor tasks. Carbamazepine has been associated with difficulty sleeping, agitation, irritability, emotional lability, and impaired task performance, and clonazepam has been associated with irritability, aggression, hyperactivity, disobedience, and antisocial activities. Valproate has generally been associated with a lesser effect on cognitive function than the other older anticonvulsant agents; adverse effects associated with the drug have included drowsiness (especially when used in combination with barbiturates) and minimal adverse effects on psychosocial tests. There are less data on the cognitive effects of the newer anticonvulsant agents; studies that have been conducted were performed mostly in the adult population. In general, topiramate appears to be associated with more adverse cognitive effects than most other newer anticonvulsant drugs.

Children receiving anticonvulsant therapy should be under the supervision of clinicians who are knowledgeable about seizure disorders and their management, particularly when to initiate and discontinue anticonvulsant agents. There is generally a lack of well-designed randomized controlled studies of anticonvulsant drugs in the pediatric population. When anticonvulsant therapy is necessary, clinicians should consider the specificity of a drug(s) for the type of seizure, the potential adverse effects of the drug(s), and the relative potential effect of each drug on behavioral and cognitive function. In addition to careful observation of cognitive function, mood, and behavior during follow-up examinations in children receiving anticonvulsant therapy, clinicians should consider the observations of parents and teachers; if significant behavioral or cognitive changes occur and alternative causes are not readily evident, the possibility that anticonvulsant therapy may be responsible and the need for dosage reduction or substitution of an alternative anticonvulsant(s) should be considered.

Pregnancy and Lactation

Pregnancy

Several reports suggest an association between use of anticonvulsants in pregnant, epileptic women and an increased incidence of birth defects in children born to these women. However, the risk from taking anticonvulsants during pregnancy is generally considered to be less than the risk of seizures during pregnancy. Data are most extensive with regard to trimethadione, phenobarbital, phenytoin, and valproate. Major congenital abnormalities also have been demonstrated with prenatal use of topiramate and carbamazepine. Barbiturates can cause fetal harm when administered to pregnant women. Phenytoin has been associated with a fetal hydantoin syndrome consisting of craniofacial abnormalities, nail and digital hypoplasia, prenatal growth deficiency, microcephaly, and mental deficiency. A fetal trimethadione syndrome also has been reported, which may possibly be distinguished from the fetal hydantoin syndrome by the specific anomalies of V-shaped eyebrows, low set ears with anteriorly folded helix, and lack of phalangeal hypoplasia. Other manifestations of the fetal trimethadione syndrome include developmental delay, speech difficulty, palatal anomaly, and irregular teeth. Valproate is associated with the most data to date regarding pregnancy risk. Use of valproate during pregnancy is associated with an increased risk of neural tube defects (e.g., spina bifida) and other major congenital malformations (e.g., craniofacial defects, cardiovascular malformations, malformations involving various body systems). In utero exposure to valproate also can cause decreased IQ scores in children. Exposure to topiramate in utero has been associated with an increased risk of oral clefts (cleft lip and/or palate) and for being small for gestational age.

Some retrospective studies indicate that the risk of having a malformed child is 2–3 times greater in epileptic women who received anticonvulsants in the early stages of pregnancy than in those women without a history of seizure disorders. It is not clear whether these malformations were caused by the drugs, by some manifestation of epilepsy itself, or by other factors. In addition, it is not clear whether the risk applies to all or only some of the anticonvulsant drugs. Most pregnant women receiving anticonvulsants deliver infants without birth defects. If a switch to a less teratogenic anticonvulsant agent is being considered, experts recommend that this be done well before pregnancy to ensure that the new treatment is adequate for seizure control. In most pregnant women with epilepsy, discontinuance of anticonvulsant therapy may not be a reasonable or safe option. Anticonvulsants should not be discontinued in pregnant women in whom the drugs are administered to prevent major seizures, because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases, when the severity and frequency of the seizure disorder are such that discontinuance of therapy does not pose a serious threat to the patient, discontinuance of the drugs may be considered prior to and during pregnancy. The clinician should carefully weigh these considerations in treating or counseling epileptic women of childbearing potential.

Valproate is contraindicated in pregnant women for the prevention of migraine headaches. The drug should not be used in pregnant women with epilepsy or bipolar disorder unless other treatments have failed to provide adequate symptom relief or are otherwise unacceptable; in these cases, the benefits of valproate may continue to outweigh its risks. Other anticonvulsants associated with the greatest risk to the fetus (e.g., trimethadione) should be used during pregnancy only when clearly shown to be essential in the management of the seizure disorder. When such anticonvulsants are used, women of childbearing age should be instructed to use an effective form of contraception during therapy and be informed of the potential hazard to the fetus should they become pregnant during therapy. If such drugs are inadvertently administered during pregnancy or if the patient becomes pregnant while receiving such drugs, the desirability of continuing the pregnancy should be considered. When anticonvulsants are administered during pregnancy, it is advisable to monitor drug concentrations closely and adjust dosage when necessary. Some experts recommend that monitoring of lamotrigine, carbamazepine, and phenytoin concentrations during pregnancy should be considered and that monitoring of levetiracetam and oxcarbazepine may be considered. Results of retrospective studies suggest that combination therapy with anticonvulsants may be associated with a higher prevalence of teratogenic effects than monotherapy with such drugs; therefore, monotherapy is recommended in pregnant women.

The barbiturates and primidone have caused postpartum hemorrhage and hemorrhagic disease of the newborn; coagulation defects have also occurred in neonates whose mothers were receiving phenytoin. The possibility that this may occur with other anticonvulsants (e.g., trimethadione) should be considered. Drug-induced hemorrhagic disease of the newborn is similar to that resulting from vitamin K deficiency and is readily reversed with vitamin K therapy. For this reason, it has been recommended that vitamin K be administered for 1 month prior to and during delivery in pregnant epileptics taking these anticonvulsants. The neonate should also receive vitamin K immediately after birth.

Women who are pregnant while receiving anticonvulsant drugs should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 888-233-2334. Information on the registry also can be found at [Web].

Lactation

Some anticonvulsants probably are distributed into milk (see Pharmacokinetics: Distribution). Because of the potential for serious adverse reactions from most anticonvulsants in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Many drugs have been reported to alter the response to anticonvulsants and/or have their responses altered by the anticonvulsants. Clinically important drug interactions with anticonvulsant agents generally involve inhibition or induction of hepatic drug metabolism, but can also occur as a result of other mechanisms (e.g., GI absorption, protein binding displacement, renal elimination). The first-generation anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin, primidone, valproate) are particularly susceptible to drug interactions because of their potent enzyme-inducing and enzyme-inhibiting properties. Patients should be observed closely for loss of efficacy and clinical signs of toxicity when any drug is added to or deleted from their therapeutic regimen, giving consideration to the possible need for dosage adjustments. Therapeutic drug monitoring may be useful for confirming a suspected drug interaction and for assessing the effect of a particular interaction to determine whether dosage adjustments are needed.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

The older anticonvulsants carbamazepine, phenobarbital, phenytoin, and primidone are potent inducers of various cytochrome P-450 (CYP) isoenzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP3A4); these anticonvulsants can therefore decrease serum concentrations and reduce the pharmacologic effect of many drugs that are metabolized by these isoenzymes. These drugs include, but are not limited to, certain antidepressant agents (e.g., clomipramine, imipramine, nefazodone), antipsychotic agents (e.g., chlorpromazine, haloperidol, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone), antineoplastic agents (e.g., cyclophosphamide, imatinib, lapatinib, irinotecan, methotrexate, tamoxifen), azole antifungal agents, immunosuppressive agents (e.g., cyclosporine, tacrolimus), human immunodeficiency virus (HIV) protease inhibitors, corticosteroids, HMG-CoA reductase inhibitors (statins; e.g., simvastatin, atorvastatin, fluvastatin), selective serotonin-reuptake inhibitors (SSRIs; e.g., citalopram, sertraline), calcium-channel blocking agents (e.g., verapamil, nifedipine), oral contraceptives, rifampin, vitamin D, warfarin, benzodiazepines, and other anticonvulsant agents (e.g., eslicarbazepine, ethosuximide, lamotrigine, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, zonisamide, valproate). Valproate is a potent inhibitor of CYP isoenzymes and can therefore increase serum concentrations of drugs (e.g., carbapenem anti-infectives, cisplatin, etoposide, amitriptyline, nortriptyline, carbamazepine, ethosuximide, lamotrigine, phenobarbital, rufinamide) metabolized by these enzymes, potentially increasing their risk of toxicity.

Among the newer anticonvulsant agents, eslicarbazepine, felbamate, rufinamide, and topiramate have CYP-inducing properties, and felbamate and topiramate have CYP-inhibiting properties; although some of these effects have been shown to be weak to moderate, there is a possibility that clinically important drug interactions may occur when these anticonvulsants are used concomitantly with drugs metabolized by CYP isoenzymes. Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5, although enzyme induction appears to have greater clinical importance. Cannabidiol has the potential to inhibit CYP2C8, CYP2C9, and CYP2C19, and may induce or inhibit CYP1A2 and CYP2B6.

Certain antidepressant agents (e.g., sertraline) and antipsychotic agents (e.g., haloperidol, risperidone, chlorpromazine) can inhibit the metabolism of anticonvulsants (e.g., carbamazepine, valproate, phenytoin), resulting in increased serum concentrations of the anticonvulsant. Macrolide antibiotics that inhibit CYP3A4 (e.g., clarithromycin, erythromycin) can increase serum concentrations of carbamazepine and some clinicians recommend that concomitant use of these drugs be avoided. Rifampin can inhibit the metabolism of lamotrigine, and isoniazid can inhibit the metabolism of carbamazepine, ethosuximide, phenytoin, and valproic acid, resulting in increased serum concentrations of the anticonvulsant. Oral contraceptives can induce the metabolism of lamotrigine and valproic acid, and possibly also oxcarbazepine, resulting in decreased serum concentrations of the anticonvulsant.

Concurrent administration of disulfiram with barbiturates, phenytoin, or ethotoin may result in inhibition of metabolism of the anticonvulsant and an increased incidence of anticonvulsant-induced adverse effects.

Drugs Affected by P-glycoprotein or other Transporters

Some anticonvulsant agents (e.g., carbamazepine, valproate, cannabidiol, stiripentol) can affect the expression of P-glycoprotein (P-gp) or other transporters such as uridine diphosphate glucuronosyltransferase (UGT), potentially altering serum concentrations of drugs affected by these transport proteins. However, additional study is needed to evaluate the role of P-gp and other transporters in anticonvulsant drug interactions.

Protein-bound Drugs

Anticonvulsant drugs that are extensively bound to plasma proteins (e.g., phenytoin, valproate, tiagabine) can displace or be displaced by other highly protein-bound drugs (e.g., salicylates, naproxen, diazepam) when used concomitantly. The resulting interaction can lead to higher free fractions of either drug.

Anticonvulsants

The older anticonvulsants with enzyme-inducing properties (carbamazepine, phenobarbital, phenytoin, and primidone) can increase the metabolism and reduce serum concentrations of most concomitantly administered anticonvulsant drugs, including valproate, tiagabine, ethosuximide, lamotrigine, topiramate, oxcarbazepine, zonisamide, felbamate, and many benzodiazepines. The clinical importance of these interactions is generally modest since the added anticonvulsant can usually compensate for any decrease in anticonvulsant efficacy that may occur. In some cases, however, loss of seizure control can occur and dosage adjustments may be required. Particular caution is advised when withdrawing enzyme-inducing anticonvulsants from concomitant regimens since the consequent increase in serum concentrations of the drug whose metabolism was previously induced may be significant and reach toxic levels.

Phenobarbital may induce the metabolism of phenytoin. In addition, however, phenobarbital may competitively inhibit phenytoin metabolism. Concurrent administration of these drugs may result in an increase, decrease, or no change in blood phenytoin concentrations. The effect of usual therapeutic dosages of phenobarbital on plasma phenytoin concentrations in individual patients is unpredictable and usually not of great clinical importance.

Since valproate also may interact with other anticonvulsant drugs, it is advisable to monitor plasma concentrations of concomitantly administered anticonvulsants during initial valproate therapy and adjust dosages as required. Concomitant administration of valproate and phenobarbital (or primidone which is metabolized to phenobarbital) results in increased plasma phenobarbital concentrations and excessive somnolence. A few patients have become comatose during therapy with valproate and phenobarbital. If valproate is used with a barbiturate, the patient should be closely observed for possible neurologic toxicity, plasma concentrations of the barbiturate should be monitored if possible, and the dosage of the barbiturate decreased if necessary. A reduction in phenobarbital dosage by up to 80% has been required. Valproate can inhibit the metabolism of lamotrigine, which may result in increased serum concentrations and toxicity (e.g., skin rashes, neurotoxic effects) of lamotrigine. Valproate has been associated with both decreased plasma phenytoin concentrations and increased seizure frequency and with increased plasma concentrations of free phenytoin and phenytoin toxicity. Concomitant administration of valproate and clonazepam has produced absence status; therefore, some clinicians recommend that concomitant use of these drugs be avoided.

Since succinimides (e.g., ethosuximide, methsuximide) may interact with other anticonvulsant drugs, it is advisable to monitor plasma concentrations of the drugs during concomitant therapy.

CNS Depressants

Anticonvulsants may be additive with or may potentiate the action of other CNS depressants, including other anticonvulsants and alcohol. Concomitant use of benzodiazepine anticonvulsants with opiate agonists may result in profound sedation, respiratory depression, coma, and death.

Oral Contraceptives

The CYP-inducing anticonvulsants carbamazepine, phenobarbital, phenytoin, and primidone can reduce serum concentrations and decrease efficacy of oral contraceptives. There have been reports of women receiving some of these anticonvulsants (e.g., phenobarbital) who became pregnant while receiving oral contraceptives. Because of the risk of contraceptive failure, some clinicians recommend that concomitant use of oral contraceptives and CYP-inducing anticonvulsants be avoided, and that alternate methods of contraception be used in patients receiving these drugs.

Oral contraceptives can induce the metabolism of lamotrigine and reduce serum concentrations of the anticonvulsant by 50%; because of the possibility that seizure control may be affected, some clinicians recommend that concomitant use of these drugs be avoided. Serum concentrations of valproate also may be reduced by oral contraceptives.

Felbamate, topiramate, oxcarbazepine, eslicarbazepine, rufinamide, clobazam, and perampanel also may decrease serum concentrations of estrogens and/or progestins to a lesser extent, which can also result in contraceptive failure. Drug interactions between oral contraceptives and gabapentin, levetiracetam, pregabalin, tiagabine, vigabatrin, and zonisamide have not been reported to date.

Warfarin

The CYP-inducing anticonvulsants (phenobarbital, phenytoin, carbamazepine, and primidone) may reduce serum concentrations of warfarin and potentially decrease anticoagulant efficacy. Close monitoring of the international normalized ratio (INR) is recommended when warfarin is used concomitantly with these anticonvulsant drugs and dosage adjustments may be required.

Acute Toxicity

The slow rate of elimination of most anticonvulsants should be considered in the treatment of acute toxicity of any anticonvulsant.

Barbiturates

Overdosage of barbiturate derivatives may produce profound CNS depression and shock syndrome and can result in death from respiratory depression and apnea. Treatment of overdosage is mainly supportive and includes maintenance of adequate airway and ventilation and possibly induction of emesis or gastric lavage if the patient is conscious. Oral administration of activated charcoal may be useful. If renal function is normal, forced alkaline diuresis may be of benefit (particularly in the treatment of phenobarbital intoxication) by increasing renal clearance of the drug. Peritoneal dialysis or hemodialysis may be required in severe barbiturate intoxication..

Hydantoins

Hydantoin derivative overdosage produces ataxia, nausea, vomiting, hypotension, motor restlessness, dizziness, fatigue, hallucinations, and insomnia. Deep coma may also occur. Treatment consists of inducing emesis or gastric lavage and general supportive therapy. Peritoneal dialysis or hemodialysis may be beneficial. Forced diuresis is of little or no value in treatment of phenytoin toxicity.

Succinimides

Acute toxicity resulting from succinimide anticonvulsants has only rarely been reported and has produced nausea, vomiting, and profound CNS depression (including coma and respiratory depression). Treatment should include induction of emesis (unless the patient is comatose, obtunded, or convulsing), gastric lavage, activated charcoal, or cathartics, and general supportive measures. Hemodialysis may be beneficial; however, forced diuresis and exchange transfusions are ineffective in removing succinimides.

Oxazolidinediones

Symptoms of oxazolidinedione overdosage include nausea, drowsiness, dizziness, ataxia, and visual disturbances. Coma may occur following massive overdosage. Treatment should include induction of emesis or gastric lavage and general supportive measures. Alkalinization of the urine may enhance elimination of the metabolites of oxazolidinedione derivatives. Following recovery from CNS effects, a careful evaluation of hepatic and renal function should be made.

Pharmacology

The principal pharmacologic actions of the anticonvulsants are elevation of the seizure threshold of the motor cortex to electrical or chemical stimuli and/or limitation of propagation of the seizure discharge from its origin (focus) to the effector organ(s). Limitation of spread of the seizure discharge from its focus may be accomplished by depression of synaptic transmission, limiting post-tetanic potentiation (PTP) of synaptic transmission, or reducing nerve conductance. When drugs are screened in the laboratory for anticonvulsant activity, some of the simpler screening tests include ability to block pentylenetetrazol-induced and other chemically induced seizures and electrically induced seizures. These tests have been widely used and, in general, drugs that protect animals against pentylenetetrazol-induced seizures are effective in the management of absence (petit mal) seizures and drugs that protect animals against seizures produced by electrical stimulation are useful in the management of tonic-clonic (grand mal) seizures and partial seizures. Although all anticonvulsants may produce some CNS depression, the degree differs with the individual agents.

The precise mechanism(s) of action of anticonvulsants has not been confirmed at the molecular level. The basic mechanism is probably stabilization of the cell membrane secondary to modification of cation (sodium, potassium, calcium) transport either by increasing sodium efflux or inhibiting sodium influx.

The exact mechanisms of action of anticonvulsants in the management of neuropathic pain have not been elucidated; however, it has been suggested that modulation of ion channels (i.e., calcium, sodium), enhanced γ-aminobutyric acid (GABA) inhibition, stabilization of neuronal cell membranes, and/or activation of N-methyl-D-aspartate (NMDA) receptors may be involved.

Barbiturates

Anticonvulsant effects of barbiturate derivatives are multiple and rather nonselective. The principal mechanism of action is believed to be reduction of monosynaptic and polysynaptic transmission resulting in decreased excitability of the entire nerve cell; depression of PTP is negligible. Barbiturates also increase the threshold for electrical stimulation of the motor cortex.

Benzodiazepines

The exact mechanism by which benzodiazepines exert their anticonvulsant effects is unknown, but is thought to be related to their ability to potentiate the activity of GABA. In animals, benzodiazepines protect against seizures induced by electrical stimulation and by pentylenetetrazol; benzodiazepines appear to act, at least partly, by augmenting presynaptic inhibition. The drugs suppress the spread of seizure activity but do not abolish the abnormal discharge from a focus in experimental models of epilepsy. In usual doses, benzodiazepines appear to have very little effect on the autonomic nervous system, respiration, or the cardiovascular system.

Hydantoins

Most authorities agree that the principal mechanism of action of the hydantoin anticonvulsants, particularly phenytoin, is limitation of seizure propagation by reduction of PTP, possibly by reducing the passive influx of sodium ions or by increasing the efficiency of the sodium pump so that excess accumulation of intracellular sodium does not occur during tetanic stimulation. Loss of PTP also prevents cortical seizure foci from detonating adjacent cortical areas.

Oxazolidinediones and Succinimides

Oxazolidinedione and succinimide derivatives elevate seizure threshold in the cortex and basal ganglia and reduce synaptic response to low frequency repetitive stimulation. They have no appreciable effect on PTP. Oxazolidinedione and succinimide derivatives suppress the paroxysmal spike and wave pattern of the EEG, which is common in absence seizures.

Anticonvulsants General Statement Pharmacokinetics

Absorption

Precise information on the rate and degree of absorption from the GI tract is lacking for most anticonvulsants. Onset and duration of action vary with each drug and frequently among patients receiving the same drug. Most anticonvulsants have a relatively long plasma half-life, and several days to several weeks of therapy may be required to achieve steady-state plasma concentrations.

Distribution

Anticonvulsants are widely distributed in the body. High concentrations of barbiturates are present in brain and liver. Hydantoins, especially phenytoin, reach highest concentrations in brain, liver, and salivary glands. Succinimides are freely distributed throughout body water. Some anticonvulsants (e.g., carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproate) may cross the placental barrier. Whether or not other anticonvulsants cross the placenta is unknown. Phenobarbital, phenytoin, carbamazepine, eslicarbazepine acetate, gabapentin, oxcarbazepine, lamotrigine, levetiracetam, primidone, topiramate, valproate, and vigabatrin are distributed into milk of nursing women. However, in some cases, the amount of drug distributed into breast milk may not be clinically important.

Elimination

Most anticonvulsants are metabolized by microsomal enzyme systems in the liver. Some anticonvulsants may inhibit or induce cytochrome P-450 (CYP) isoenzymes and thus inhibit or induce metabolism of other concomitantly administered drugs metabolized by these enzymes. (See Drug Interactions.)

Anticonvulsants that are eliminated renally include gabapentin, levetiracetam, pregabalin, and vigabatrin.

Chemistry

Anticonvulsants are used to reduce the number and/or severity of seizures in patients with epilepsy; many of the principal anticonvulsants used in the management of epilepsy are derivatives of barbiturates, benzodiazepines, hydantoins, or succinimides.

Barbiturates and Analogs

• mephobarbital (no longer commercially available)

• metharbital (no longer commercially available)

• phenobarbital

• primidone

All barbiturates are useful in the management of convulsive states; however, only phenobarbital and primidone (the structure of which is closely related to that of the barbiturates) currently are used in the management of epilepsy because they are effective anticonvulsants in subhypnotic doses. Other barbiturates (e.g., secobarbital or amobarbital) are occasionally used parenterally to terminate an acute seizure episode. and individual monographs in 28:24.04.) Primidone is a structural analog of phenobarbital in which the carbonyl group at position 2 has been replaced by a methylene group.

Benzodiazepines

• clobazam

• clonazepam

• clorazepate

• diazepam

• lorazepam

• midazolam

The benzodiazepines contain a benzene ring structure fused to a 7-membered diazepine ring. The classic benzodiazepines (e.g., clonazepam, diazepam, lorazepam) are referred to as 1,4-benzodiazepines because they contain nitrogen atoms at positions 1 and 4 on the diazepine ring. Clobazam, a 1,5-benzodiazepine, differs structurally from the traditional benzodiazepines in that its nitrogen atoms are at positions 1 and 5 on the diazepine ring; clobazam is the only 1,5-benzodiazepine that is currently used in clinical practice. Commercially available 1,4-benzodiazepines used as anticonvulsants, except chlordiazepoxide and midazolam, have the same characteristic structure but differ in the substitutions at the R¹, R³, R⁷, and R^2- positions. In chlordiazepoxide, a 1,4-benzodiazepine-4-oxide, a methylamino group replaces the ketone at the 2 position and a chlorine atom is at R⁷. In midazolam, an imidazobenzodiazepine, an imidazole ring fused at positions 1 and 2 of the benzodiazepine nucleus replaces the ketone at position 2 of the nucleus.

Hydantoins

• ethotoin

• fosphenytoin

• mephenytoin (no longer commercially available)

• phenacemide (no longer commercially available)

• phenytoin

The hydantoins have a 5-membered ring structure containing 2 nitrogens in an ureide configuration. Phenytoin is the prototype of the hydantoin derivatives. Ethotoin differs from phenytoin in that one phenyl substituent at position 5 is replaced by hydrogen, and the hydrogen substituent at position 3 is replaced by an ethyl group. Fosphenytoin is a phosphate ester prodrug of phenytoin.

Succinimides

• ethosuximide

• methsuximide

Succinimide derivatives also have a 5-membered ring structure similar to the hydantoins; however, the imino nitrogen at position 3 in the hydantoin structure is replaced with a methylene group which is mono- or di-substituted with methyl, ethyl, or phenyl group(s).

Oxazolidinediones

• trimethadione

Oxazolidinedione derivatives have a 5-membered ring structure like the hydantoins, but these drugs have oxygen instead of nitrogen at position 1. The only available oxazolidinedione anticonvulsant in the US is trimethadione, but only on a limited basis.

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