THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

24. Seizure Disorders - Stephanie J. Phelps, PharmD, BCPS

24-1. Epilepsy

Introduction

Epilepsy occurs when neurons become depolarized and repetitively fire action potentials. It is involuntary and episodic. The term is applied after two unprovoked seizures. A seizure does not mean a person has epilepsy; however, epilepsy means a person has seizures. Anticonvulsants do not cure epilepsy.

Terminology

• Aura: A subjective sensation or motor phenomenon that marks a seizure onset and is generally associated with sensations that are localized in a particular region of the brain

• Automatisms: Purposeless movements seen with partial seizures

• Postictal: Symptoms and signs seen after a seizure

Types of Epilepsy

There are two main types of epilepsy: partial seizures and generalized seizures.

Partial seizures

Partial seizures begin in one hemisphere of the brain. They are unilateral, asymmetric movements, generally associated with an aura. Complex partial seizures are accompanied by altered consciousness.

Drugs for new-onset seizures

• Monotherapy: Carbamazepine (drug of choice), oxcarbazepine (> 4 years), phenobarbital, phenytoin, topiramate, valproic acid

• Adjunctive therapy: Gabapentin (> 12 years), lacosamide, lamotrigine (> 2 years), levetiracetam (> 4 years), oxcarbazepine (> 2 years), phenobarbital, phenytoin, tiagabine (> 4 years), topiramate (> 10 years), valproic acid, vigabatrin, zonisamide

Drugs for refractory seizures

• Monotherapy: Carbamazepine, felbamate, lamotrigine (conversion > 2 years), phenytoin, phenobarbital, topiramate, valproic acid

• Adjunctive therapy: Gabapentin, lamotrigine, lacosamide, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, zonisamide

Generalized seizures

Generalized seizures begin simultaneously in both brain hemispheres. They are characterized by bilateral movements and have no aura.

Absence seizures

This type of generalized seizure has a sudden onset. It is brief (seconds) and characterized by a blank stare, upward rotation of the eyes, and lip smacking (confused with daydreaming). It has a three per second spike and wave on electroencephalography (EEG) and can be precipitated by hyperventilation.

Drugs

Historically, ethosuximide has been the drug of choice. If a patient has both absence and generalized tonic-clonic seizures and is older than 2 years of age, many consider valproic acid to be the drug of choice. Although not labeled, lamotrigine and topiramate have been used.

Primary generalized tonic-clonic seizure

This type of seizure has two phases:

• Tonic phase: Rigid, violent, sudden muscular contractions (stiff or rigid); crying or moaning; deviation of the eyes and head to one side; rotation of the whole body and distortion of features; suppression of respiration; falling to the ground; loss of consciousness; tongue biting; involuntary urination

• Clonic phase: Repetitive jerks; cyanosis continues; foaming at the mouth; small grunting respirations between seizures, but deep respirations as all muscles relax at the end of the seizure

Drugs of choice

• Monotherapy: Carbamazepine, phenobarbital, phenytoin, topiramate (> 10 years)

• Adjunctive therapy: Lamotrigine (> 2 years), levetiracetam (> 6 years), topiramate (> 2 years), valproic acid

Juvenile myoclonic epilepsy

Myoclonic seizures precede generalized tonic-clonic seizures; they generally occur on awakening. Sleep deprivation and alcohol commonly precipitate them.

Lifelong treatment is required with valproic acid, lamotrigine, levetiracetam, topiramate, or some combination.

Other less common seizure types

Catamenial epilepsy

Catamenial epilepsy is associated with hormonal changes during menstruation. It may be treated with acetazolamide.

Infantile spasms

Infantile spasms begin in the first 6 months of life. They occur in clusters, several times a day. Parents describe symptoms that sound like colic. Infantile spasms have high mortality and morbidity.

Treat this condition with adrenocorticotropic hormone (ACTH) or oral steroids, vigabatrin, or valproic acid (> 2 years). Although not labeled for this purpose, topiramate and zonisamide have been used.

Lennox-Gastaut Syndrome

This difficult-to-treat epilepsy most often appears between 2 and 6 years of age and is often accompanied by mental retardation and behavior problems. It is characterized by frequent and different types of seizures.

Treat this condition with combination anticonvulsants that include felbamate (> 2 years), lamotrigine (> 2 years), rufinamide, and topiramate (> 2 years). Although not labeled by the Food and Drug Administration (FDA) for this purpose, zonisamide has been used.

Post-traumatic epilepsy

These seizures occur after head trauma. Patients may be started on phenytoin or fosphenytoin for a period of 7 days. If no seizures occur, phenytoin should be discontinued.

Etiologies for Epilepsy

• Mechanical: Birth injuries, head trauma, tumors, vascular abnormalities (stroke)

• Metabolic: Electrolyte disturbances (low sodium, elevated calcium); glucose abnormalities (low); inborn errors of metabolism

• Genetic: Benign familial neonatal seizures (chromosome 20), juvenile myoclonic epilepsy (chromosome 6), Baltic myoclonic (chromosome 21)

• Other: Fever; infection

• Drugs: These include the following:

• Recreational drugs such as alcohol, cocaine and crack, ephedra, narcotics, methylphenidate

• Carbapenems (imipenem), lindane, local anesthetics (lidocaine), metoclopramide, theophylline, tricyclic antidepressants

• Meperidine (the metabolite normeperidine can cause seizures in patients with renal failure who receive normal doses)

• Anticonvulsants that are used for treatment of a nonindicated seizure type (

Table 24-1)

Criteria for Treating Epilepsy

Almost no child should be treated after one seizure.

Treat adults who have structural brain damage, a first seizure that was severe, or an occupation that places them at risk of injury should a second seizure occur.

Principles in the treatment of epilepsy

• Monotherapy (one agent): This form of treatment is always preferred.

• Polytherapy (two agents): Add an anticonvulsant with a different mechanism of action, provided serum concentrations (where appropriate)

[Table 24-1. Seizures Caused by Anticonvulsants]

   and doses of the first anticonvulsant have been maximized. Begin to reduce the dose of the first drug slowly. This step is important if the patient has developed side effects or if the patient has not responded to the first anticonvulsant.

• Polytherapy (three or more agents): Although rarely needed, add a third anticonvulsant if (1) a combination of anticonvulsants is tolerated and significantly reduces seizure frequency or severity, but greater control might be achieved, or (2) the two anticonvulsants have been maximized. Reassess response, and discontinue unnecessary anticonvulsants as soon as possible.

Reasons for Treatment Failure

• Incorrect diagnosis

• Wrong anticonvulsant

• Inappropriate dose, route, or formulation

• Altered pharmacokinetics that require a dosage alteration

• Poor patient adherence

• Seizures that are refractory to therapy

Patient Counseling Information Applicable to All Anticonvulsants

• It is important that you keep a diary of your seizures and keep regular appointments with your doctor, so that he or she can determine whether your medication is working properly and whether you are experiencing unwanted side effects.

• The full effects of this medication may not be seen for several weeks. Continue to take the medication unless directed otherwise by your physician.

• Take with food or milk if upset stomach occurs.

• Do not drink alcohol or take central nervous system (CNS) depressants or illegal drugs with this medication.

• If this medication causes blurred vision or drowsiness, do not drive or operate heavy machinery while taking this medication until you have become accustomed to its effects

• Consult with your physician if you anticipate pregnancy, become pregnant, or plan to breast-feed while taking this medication.

• Some medications decrease the effectiveness of birth control pills. You should discuss this with your physician or pharmacist, who may recommend that you use a backup birth control method to prevent pregnancy.

• If you are a woman capable of having children, you should take 1 mg of folic acid a day.

• Do not stop taking this medication unless your doctor advises you to do so; some medicines have to be stopped slowly. Let your doctor or pharmacist know if you stop taking this medication.

• Check with your pharmacist or doctor before taking or starting any new medication (prescription, over-the-counter, or herbal product).

• If you miss a dose, take it as soon as you remember unless it is almost time for the next dose. If it is almost time for the next dose, skip the missed dose and resume your regular schedule. Do not take extra or double doses. If you miss two or more doses, contact your physician for further instructions.

• Contact your physician immediately if skin rash occurs.

Mechanisms of Action of Anticonvulsants

Anticonvulsants work through a variety of mechanisms including the following:

• Enhancing sodium channel inactivation

• Reducing current through T-type calcium channels

• Enhancing γ-aminobutyric acid (GABA) activity

• Enhancing antiglutamate activity

24-2. Medications Used to Treat Epilepsy

Carbamazepine

Carbamazepine is the most widely used anticonvulsant in adults and children. It is the drug of choice for complex partial seizures. It is effective in most generalized seizures but ineffective in absence seizures and febrile seizures.

Pharmacokinetics

• Bioavailability: Good (75-85%). Dispense in moisture-proof containers because studies show decreased bioavailability with high humidity (as may occur in medicine cabinets).

• Protein binding: 75-90% bound to alpha-1-acid glycoprotein; the 10,11-epoxide metabolite is 50% protein bound.

• Metabolism: Extensively hepatically metabolized to 10,11-epoxide, which is effective as an anticonvulsant and is capable of causing toxicity.

• Renal elimination: Low (1-3%).

• Half-life: About a day if used as monotherapy and about 12 hours if given with more than one anticonvulsant.

• Reference range: 4-12 mg/L (monotherapy, 8-12 mg/L; polytherapy, 4-8 mg/L).

Other aspects

Carbamazepine is one of a few drugs that can induce its own metabolism (i.e., autoinduction). Mean time to onset is 21 days (range: 17-31 days).

Side effects

Upon initiation, side effects are nausea, vomiting, drowsiness, dizziness, and neutropenia. A dose-related, transient, and reversible rash that rarely causes the drug to be discontinued may also occur.

With chronic therapy, the following side effects may occur:

• Syndrome of inappropriate antidiuretic hormone (SIADH) causing hyponatremia and water retention

• Osteomalacia (treat with vitamin D if alkaline phosphatase increase and 25-hydroxycholecalciferol decreases)

• Folate deficiency causing megaloblastic anemia

Some severe or life-threatening side effects are possible:

• FDA black box warning: Potentially fatal, severe dermatologic reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) may occur. Over 90% of patients who experience these reactions do so within the first few months of treatment. Patients of Asian descent are at higher risk for toxic dermatologic reactions and should be screened for the variant HLA-B*1502 allele (genetic marker) prior to initiating therapy.

• FDA black box warning: Aplastic anemia may occur. In such cases, discontinuation of carbamazepine is recommended if white blood count < 2,000-3,000 or neutrophils < 1,000-1,500.

• FDA warning: Direct hepatotoxicity and multiorgan hypersensitivity reactions may occur. These side effects generally present within 1 month. Fever, rash, or fatalities may occur even if carbamazepine is discontinued. Stop carbamazepine if liver function tests increase more than three times above normal.

• FDA warning: Increased risk of suicidal behavior or ideation is possible. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including carbamazepine) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

• Teratogenic concerns: Fetal carbamazepine syndrome is possible. Features include epicanthal folds, short nose, long philtrum, hypoplastic nails, microcephaly, and developmental delay. Carbamazepine is a pregnancy category D drug.

Drug-drug interactions

• Carbamazepine is a CYP3A4, CYP2C9, and CYP2C19 inducer.

• Erythromycin, cimetidine, lithium, and propoxyphene increase the serum concentration or effect of carbamazepine.

• Phenobarbital, primidone, and phenytoin decrease the anticonvulsant effect of carbamazepine.

• Carbamazepine may increase the serum concentration or effect of felbamate; felbamate will increase concentrations of the 10,11-epoxide metabolite carbamazepine and cause toxicity.

Commercially available formulations

Table 24-2 shows the commercially available formulations.

[Table 24-2. Dosage Forms, Normal Maintenance Doses, and Dosing Interval for Older Anticonvulsants]

Patient counseling

See general counseling information. In addition, counsel the patient as follows:

• Shake suspension well.

• Do not store in areas of high humidity (e.g., medicine cabinets).

• Do not use with monoamine oxidase inhibitors.

Ethosuximide

Indications are absence and myoclonic seizures.

Pharmacokinetics

• Bioavailability: Good

• Protein binding: Very low (< 10%)

• Metabolism: 80% hepatically metabolized to three inactive metabolites

• Renal elimination: 50% as metabolites; 10% to 20% as unchanged drug

• Half-life: 30-60 hours

• Reference range: 40-100 mg/L

Side effects

Upon initiation, side effects are nausea, vomiting, dizziness, drowsiness, lethargy, headache, rashes (including Stevens-Johnson syndrome), and urticaria.

With chronic therapy, anorexia and weight loss, as well as gum hypertrophy, could occur.

• FDA warning: Increased risk of suicidal behavior or ideation is possible. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including ethosuximide) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

Drug-drug interactions

• CYP3A3/4 substrate

• Phenytoin, carbamazepine, primidone, and phenobarbital may increase the clearance of ethosuximide.

• Isoniazid may inhibit metabolism and increase ethosuximide serum concentrations.

Commercially available formulations

See Table 24-2 for commercially available formulations.

Felbamate

Felbamate should be used as adjunctive therapy only in severe refractory partial seizures, with or without secondary generalization, in patients older than 14 years of age and in partial or generalized seizures associated with Lennox-Gastaut syndrome.

Pharmacokinetics

• Bioavailability: Complete (> 90%)

• Protein binding: Low (20-25%)

• Metabolism: Hepatic via hydroxylation and conjugation

• Renal elimination: 40-50% excreted unchanged; 40% as inactive metabolites in urine

• Half-life: 20-30 hours; shorter (i.e., 14 hours) with concomitant enzyme-inducing drugs; prolonged (by 9-15 hours) in renal dysfunction

• Reference range: Not necessary to routinely monitor serum drug concentrations, but dose should be titrated to clinical response; therapeutic range not fully determined, but some have proposed 30-100 mg/L

Side effects

Upon initiation, nausea and vomiting, anorexia, headache, insomnia, and dizziness may occur.

With chronic therapy, weight loss significant enough to warrant discontinuing the medication is possible.

Severe or life-threatening side effects are possible:

• FDA black box warning: Direct hepatotoxicity may occur at any time; however, the earliest onset of severe liver dysfunction occurred 3 weeks after starting felbamate. It is not known if dose, duration, or use of concomitant medications affects the risk. Most cases require liver transplantation. Liver enzyme tests and bilirubin should be obtained before initiation and periodically, and felbamate should be immediately withdrawn if liver function tests become elevated.

• FDA black box warning: Aplastic anemia can develop at any point without warning. Risk may be 100-fold greater than the general population. Complete blood count with differential and platelet count should be taken before, during, and for a significant time after discontinuing felbamate therapy. Felbamate should be immediately withdrawn if bone marrow suppression occurs.

• FDA warning: Increased risk of suicidal behavior or ideation may occur. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including felbamate) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

Drug-drug interactions

• Felbamate induces CYP3A4.

• Felbamate inhibits CYP2C19, epoxide hydroxylase, and β-oxidation.

• Carbamazepine, phenobarbital, and phenytoin decrease the anticonvulsant effect of felbamate.

• Phenobarbital, phenytoin, and valproic acid increase the anticonvulsant effect of felbamate.

• Felbamate decreases carbamazepine concentrations but increases the concentration of carbamazepine epoxide (active metabolite), which may result in carbamazepine toxicity.

• Felbamate increases the serum concentrations of phenobarbital, phenytoin, and valproic acid. When felbamate is begun, a 20% reduction in phenytoin dose resulted in phenytoin concentrations comparable to those prior to initiation of felbamate.

Commercially available formulations

See

Table 24-3 for commercially available formulations.

Patient counseling

See general counseling information. In addition, the patient or legal guardian should sign a consent form before taking this medication. A patient information consent form is included as part of the package insert and is available from the local representative or by calling 800-526-3840.

Fosphenytoin

Indications are for short-term parenteral administration for generalized convulsive status epilepticus.

Pharmacokinetics

• Bioavailability: Time for complete conversion to phenytoin is 15 minutes and 30 minutes after intravenous (IV) and intramuscular (IM) administration, respectively.

• Protein binding: Protein binding is high (95-99% primarily to albumin).

• Metabolism: Each millimole of fosphenytoin is metabolized to 1 millimole of phenytoin, phosphate, and formaldehyde. Formaldehyde is then converted to formate, which is metabolized by a folate-dependent mechanism. Conversion increases the dose and infusion rate, most likely because of a decrease in fosphenytoin protein binding.

• Renal elimination: None.

• Half-life: See the later discussion of phenytoin for the half-life of the active drug.

• Reference range: 10-20 mg/L (phenytoin).

Side effects

Upon initiation, side effects include hypotension (with rapid IV administration), vasodilation, tachycardia, and bradycardia; burning, pruritus, tingling, and paresthesia (predominately in the groin area); and rash and exfoliative dermatitis.

Chronic therapy does not result in additional side effects.

• FDA warning: Increased risk of suicidal behavior or ideation is possible. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including fosphenytoin) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

• FDA warning: The FDA is investigating the possibility of an increased risk of serious skin reactions (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) in patients given phenytoin who have the human leukocyte antigen allele HLA-B*1502. This allele occurs almost exclusively in individuals with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais. Until the FDA evaluation is finalized, fosphenytoin should be avoided as an alternative for carbamazepine in patients who test positive for HLA-B*1502.

Drug-drug interactions

See the later discussion of phenytoin for drug-drug interactions.

Commercially available formulations

See Table 24-2 for commercially available formulations.

[Table 24-3. Dosage Forms, Normal Maintenance Doses, and Dosing Intervals for the Newer Anticonvulsants]

Gabapentin

Indications are for adjunctive therapy for partial seizures.

Pharmacokinetics

• Bioavailability: Poor (60% with decreasing absorption as age decreases)

• Protein binding: Very low (< 3%)

• Metabolism: None

• Renal elimination: 100%

• Half-life: Short (< 12 hours); increases with decreased renal function (anuric patients: 132 hours; decreased during hemodialysis to about 4 hours)

• Reference range: Routine monitoring of serum concentrations not required; minimum effective concentration thought to be 2 mg/L

Side effects

Upon initiation, somnolence, dizziness, ataxia, fatigue, and nervousness may occur.

With chronic therapy, weight gain may occur. Neuropsychiatric events (i.e., emotional lability, hostility, hyperkinesias) are possible in children, especially those with mental retardation and attention deficit disorders. This problem generally resolves following a reduction in the dose.

• FDA warning: Increased risk of suicidal behavior or ideation is possible. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including gabapentin) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

Drug-drug interactions

• No interactions affect metabolism; aluminum-and magnesium-containing antacids may decrease absorption.

• High protein intake can increase absorption.

• Although it is not a true drug interaction, combination with carbamazepine may cause dizziness. Reduce the dose of carbamazepine.

Commercially available formulations

See Table 24-3 for commercially available formulations.

Patient counseling

See general counseling information. In addition, the patient should be counseled as follows:

• Food may decrease the extent of absorption.

• If you take antacids, wait at least 2 hours before taking gabapentin.

• Refrigerate oral solution.

Lacosamide

Indications are for adjunctive therapy for partial seizures (> 17 years).

Pharmacokinetics

• Bioavailability: Complete

• Protein binding: Very low (< 15%)

• Metabolism: None

• Renal: 95% (40% as unchanged drug, 30% as inactive metabolite, 20% as uncharacterized metabolite)

• Half-life: About 13 hours

Side effects

Upon initiation, nausea and vomiting may occur, as well as dizziness, lack of coordination, and diplopia.

Severe or life-threatening include increased risk of suicidal behavior or ideation. An FDA warning has been issued: The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including lacosamide) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

Drug-drug interactions

Carbamazepine, phenobarbital, and phenytoin may decrease the serum concentration of lacosamide.

Commercially available formulations

See Table 24-3 for commercially available formulations.

Lamotrigine

Lamotrigine is indicated as adjunctive therapy for partial seizures (> 2 years), primary and secondary generalized tonic-clonic seizures (> 2 years), and seizures associated with Lennox-Gastaut syndrome. It is also approved for conversion to monotherapy. Although it is used for absence, atypical absence, atonic, and myoclonic seizures, it is not labeled for these indications.

Pharmacokinetics

• Bioavailability: Complete

• Protein binding: Low (55% to albumin)

• Metabolism: > 75% hepatically metabolized via glucuronidation; autoinduction possible

• Renal: 75-90% excreted as glucuronide metabolites and 10% as unchanged drug

• Half-life: Dependent on patient age and concomitant drug therapy

• Reference range: Proposed serum concentration of 1-5 mg/L, but clinical value of monitoring concentrations has not been established.

Side effects

Upon initiation, nausea and vomiting, dizziness, sedation, somnolence, and diplopia may occur.

No additional side effects are associated with chronic therapy.

Severe or life-threatening side effects are possible:

• FDA black box warning: Although rare, toxic epidermal necrolysis has been reported, and deaths have occurred. The risk of rash may be increased in those receiving valproic acid, large initial doses, or a rapid increase in dosage. The rash usually appears within 2-8 weeks of therapy initiation but has been reported after prolonged treatment (e.g., 6 months). Refer the patient to a physician if signs or symptoms of a rash develop. The physician may suggest holding a single dose until the rash is evaluated.

• FDA warning: Increased risk of suicidal behavior or ideation may occur. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including lamotrigine) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

Drug-drug interactions

• Lamotrigine is a weak uridine diphosphate glucuronosyltransferase inducer.

• Valproic acid may increase the serum concentration or effect of lamotrigine.

• Carbamazepine, phenobarbital, phenytoin, and primidone decrease the serum concentration and effect of lamotrigine.

• Estrogen-containing oral contraceptives may decrease the serum concentration of lamotrigine.

• Lamotrigine may decrease the serum concentration or effect of valproic acid.

• Although not a true drug-drug interaction, the combination with carbamazepine may cause dizziness. Reduce the dose of carbamazepine.

Commercially available formulations

See Table 24-3 for commercially available formulations.

Patient counseling

See general counseling information. In addition, patients should be counseled to notify their physician immediately if a skin rash occurs.

Levetiracetam

Levetiracetam is indicated for adjunct for partial, primary generalized, and myoclonic seizures.

Pharmacokinetics

• Bioavailability: Complete

• Protein binding: Very low (< 10%)

• Metabolism: Not extensive; metabolites not active and renally eliminated

• Renal: Undergoes glomerular filtration and subsequent partial tubular reabsorption; 66% excreted unchanged and 27% as inactive metabolites

• Half-life: Short (4-8 hours)

• Reference range: Not established; clinical value of monitoring concentrations not established

Side effects

Upon initiation, dizziness, fatigue, and sedation may occur.

No additional side effects occur with chronic therapy.

Severe or life-threatening side effects include increased risk of suicidal behavior or ideation. The medication carries an FDA warning: The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including levetiracetam) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

Drug-drug interactions

No significant interactions have been identified.

Commercially available formulations

See Table 24-3 for commercially available formulations.

Oxcarbazepine

Oxcarbazepine is indicated for monotherapy (> 4 years) and adjunct therapy (> 2 years) for partial seizures.

Pharmacokinetics

• Bioavailability: Complete

• Protein binding: 67% (parent compound); 40%, monohydroxy metabolite (MHD) (primarily to albumin)

• Metabolism: Extensive to 10-MHD metabolite, which is active

• Renal: > 95%

• Half-life: 2 hours (oxcarbazepine); 9 hours (MHD)

Side effects

Upon initiation, nausea, vomiting, drowsiness, dizziness, and neutropenia (transient) may occur. On rare instances, a dose-related, transient, and reversible rash causes the drug to be discontinued. The frequency is less than that with carbamazepine, but cross-hypersensitivity reactions with carbamazepine may occur in 25% of patients.

With chronic therapy, the following side effects are possible:

• SIADH: This syndrome, causing hyponatremia and water retention, is more common than with carbamazepine.

• Antiepileptic drug hypersensitivity syndrome: A multiorgan involvement reaction occurs with rash, lymphadenopathy, fever, abnormal liver function tests, hepatitis, nephritis, oliguria, hepatorenal syndrome, hematological abnormalities, pruritus, asthenia, or arthralgia.

• FDA warning: Increased risk of suicidal behavior or ideation is possible. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including oxcarbazepine) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

Drug-drug interactions

• Oxcarbazepine is an inhibitor of CYP2C19.

• Oxcarbazepine is an inducer of CYP3A4 and CYP3A5.

• Oxcarbazepine increases serum concentrations of phenobarbital and phenytoin.

• Oxcarbazepine may decrease serum concentrations of felodipine, lamotrigine, and oral contraceptives (i.e., ethinyl estradiol, levonorgestrel).

• Carbamazepine, phenobarbital, phenytoin, and valproic acid may decrease MHD concentrations.

Commercially available formulations

See Table 24-3 for commercially available formulations.

Patient counseling

This medication decreases the effectiveness of birth control pills. Use a supplemental birth control method to prevent pregnancy while taking oxcarbazepine or contact your physician about a high-estrogen oral contraceptive.

Phenobarbital

Phenobarbital is indicated for neonatal seizures and generalized seizures (except absence). Other anticonvulsants are more effective in complex partial seizures.

Pharmacokinetics

• Bioavailability: Good (70-90%)

• Protein binding: Low (30-50%)

• Metabolism: Hepatic via hydroxylation and glucuronide conjugation

• Renal elimination: 20-50% unchanged in urine; increases with alkalinization of the urine

• Half-life: Long (20-400 hours); increasing half-life with decreasing age

• Reference range: 15-40 mg/L

Side effects

Upon initiation, drowsiness, dizziness, light-headedness, lack of coordination, headaches, or nervousness may occur.

With chronic therapy, the following side effects are possible:

• Hyperactivity occurs, primarily in children; however, it rarely necessitates discontinuation of therapy.

• Lower memory and concentration abilities occur. The medication slightly lowers IQ.

• Folate deficiency may cause megaloblastic anemia.

• Vitamin K-deficient hemorrhagic disease is possible. Administer vitamin K to the mother before delivery and to the newborn.

Severe or life-threatening side effects are possible:

• Hepatic failure: Discontinue phenobarbital if liver function tests increase to more than three times above normal.

• Stevens-Johnson syndrome: Refer the patient to a physician if a rash develops. The physician may suggest holding a single dose until the rash is evaluated.

• FDA warning: Increased risk of suicidal behavior or ideation are possible. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including phenobarbital) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

• Teratogenic effects (phenobarbital syndrome): Effects include developmental delay, short nose, low nasal bridge, low-set ears, wide mouth, protruding lips, and distal digital hypoplasia. The medication is pregnancy category D.

Drug-drug interactions

• Phenobarbital is an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and uridine diphosphate glucuronosyltransferase.

• Chloramphenicol, felbamate, ketoconazole, methylphenidate, and valproic acid increase the serum concentration or effect of phenobarbital.

• Phenytoin decreases the anticonvulsant effect of phenobarbital.

• Phenobarbital may increase the serum concentration or effect of alcohol, caffeine, and monoamine oxidase inhibitors.

• Phenobarbital may decrease the serum concentration or effect of rifampin, birth control pills, corticosteroids, cyclophosphamide, cyclosporine, delavirdine, griseofulvin, haloperidol, lamotrigine, metronidazole, propranolol, quinidine, ritonavir, saquinavir, theophylline, and warfarin.

Other aspects

Phenobarbital is subject to control under the Federal Controlled Substances Act of 1970 as a schedule V (C-V) drug.

Commercially available formulations

See Table 24-2 for commercially available formulations.

Patient counseling

See general counseling information. In addition, this medication decreases the effectiveness of birth control pills. Counsel the patient to use a supplemental birth control method to prevent pregnancy while taking phenobarbital or contact a physician about a high-estrogen oral contraceptive.

Phenytoin

Phenytoin is indicated for all seizure types except absence and febrile seizures. It is also indicated for prevention of seizures following neurosurgery. It is frequently used to prevent post-traumatic epilepsy following head trauma, but is not approved for this indication.

Pharmacokinetics

• Bioavailability: Slow, variable, and formulation dependent; decreased in children

• Protein binding: Very high (90-95%); increased free fraction in neonates

• Metabolism: Hepatic

• Renal elimination: Low (< 5%)

• Half-life: Exhibits capacity-limited or saturable pharmacokinetics (i.e., Michaelis-Menten) and does not technically have a half-life

• Reference range: 10-20 mg/L

Side effects

Upon initiation, nausea, vomiting, drowsiness, and dizziness may occur.

With chronic therapy, the following side effects are possible:

• Peripheral neuropathy may occur.

• Hydantoin facies (thickening of subcutaneous tissues, enlargement of nose and lips) is possible.

• Acne, hirsutism, and gingival hyperplasia may occur. Suggest good oral hygiene.

• Osteomalacia may occur. Treat with vitamin D if alkaline phosphatase increases and 25-hydroxycholecalciferol decreases.

• Vitamin K-deficient hemorrhagic disease is possible. Administer vitamin K to the mother before delivery and to the newborn.

• Folate deficiency may cause megaloblastic anemia.

Severe or life-threatening side effects are as follows:

• Hepatic failure: Discontinue if liver function tests increase more than three times above normal.

• Stevens-Johnson syndrome: Refer the patient to a physician if signs or symptoms of a rash develop. The physician may suggest holding a single dose until the rash is evaluated.

• FDA warning: The FDA is investigating the possibility of an increased risk of serious skin reactions (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) in patients given phenytoin who have the human leukocyte antigen allele HLA-B*1502. This allele occurs almost exclusively in individuals with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais. Until the FDA evaluation is finalized, phenytoin should be avoided as an alternative for carbamazepine in patients who test positive for HLA-B*1502.

• FDA warning: Increased risk of suicidal behavior or ideation may occur. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including phenytoin) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

• Teratogenic effects (fetal hydantoin syndrome): Features include craniofacial anomalies, broad nasal bridges, short upturned noses, low-set and prominent ears, distal digital hypoplasia, and intrauterine growth restriction. The medication is pregnancy category D.

Drug-drug interactions

• Phenytoin induces CYP2C19, UTG.

• Phenytoin inhibits CYP2C9.

• Phenytoin displaces some drugs from albumin binding sites.

• Acute alcohol use; amiodarone; chloramphenicol; chlordiazepoxide; diazepam; disulfiram; estrogens; felbamate; histamine antagonists (e.g., cimetidine); halothane; isoniazid; methylphenidate; phenothiazines; phenylbutazone; salicylates; succinimides; sulfonamides (sulfadiazine, sulfamethoxazole, and sulfisoxazole); tolbutamide; trazodone; warfarin; and zidovudine increase the serum concentration or effect of phenytoin.

• Antacids, bleomycin, cisplatin, nevirapine, rifampin, ritonavir, vinblastine, zidovudine, and some herbals (i.e., shankhapushpi, kava kava, and valerian) decrease the effect of phenytoin.

• Phenytoin may increase the serum concentration or effect of valproic acid.

• Phenytoin may decrease the serum concentration or effect of phenobarbital.

Drug-nutrient interactions

Patients receiving tube feedings and oral phenytoin at the same time may have a significant decrease in absorption of phenytoin. If possible, discontinue feeding 2 hours before and after a dose of phenytoin.

Commercially available formulations

See Table 24-2 for commercially available formulations.

Patient counseling

See general counseling information. In addition, counsel the patient as follows:

• Do not break, crush, or chew capsule before swallowing; swallow whole.

• Shake suspension well.

• This medication may alter your gums. Brush and floss daily, and have regular visits with your dentist.

Pregabalin

Pregabalin is indicated for adjunctive therapy in partial seizures.

Side effects

Upon initiation, nausea, vomiting, dizziness, drowsiness, and lethargy may occur.

With chronic therapy, increased appetite and weight gain are possible.

Severe or life-threatening side effects may occur:

• Angioedema: There is some risk of angioedema (e.g., swelling of the face, tongue, lips, gums, and throat or larynx), with or without life-threatening respiratory compromise.

• FDA warning: Increased risk of suicidal behavior or ideation may occur. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including pregabalin) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

Drug-drug interactions

No known interactions.

Other aspects

Pregabalin is subject to control under the Federal Controlled Substances Act of 1970 as a schedule V (C-V) drug.

Commercially available formulations

See Table 24-3 for commercially available formulations.

Primidone

Primidone is indicated for generalized tonic-clonic, complex partial, and simple partial seizures.

Pharmacokinetics

• Bioavailability: 60-80%

• Protein binding: High (99%)

• Metabolism: Hepatically metabolized to phenobarbital (active) and phenylethylmalonamide (PEMA)

• Renal elimination: Urinary excretion of active metabolites and 15-25% unchanged primidone

• Half-life: Primidone,10-12 hours for primidone; PEMA, 16 hours; phenobarbital, age dependent (20-400 hours)

• Reference range: 5-12 mg/L for primidone; 15-45 mg/L for phenobarbital

Side effects

Upon initiation, nausea, vomiting, dizziness, drowsiness, and lethargy may occur.

With chronic therapy, malignant lymphoma-like syndrome, megaloblastic anemia, and systemic lupus-like syndrome are possible.

• FDA warning: Increased risk of suicidal behavior or ideation is possible. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including primidone and phenobarbital) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

Drug-drug interactions

• Primidone is an inducer of CYP1A2, CYP2B6, CYP2C, CYP2C8, CYP3A3/4, and CYP3A5-7.

• Primidone may decrease serum concentrations of ethosuximide, valproic acid, and griseofulvin.

• Methylphenidate may increase primidone serum concentrations.

• Phenytoin may decrease primidone serum concentrations.

Commercially available formulations

See Table 24-2 for commercially available formulations.

Tiagabine

Tiagabine is indicated for adjunctive therapy in the treatment of partial seizures.

Pharmacokinetics

• Bioavailability: Complete (> 95%)

• Protein binding: High (96%, mainly to albumin and alpha1-acid glycoprotein)

• Metabolism: Hepatic via oxidation and glucuronidation; undergoes enterohepatic recirculation

• Renal: Low (about 2% excreted unchanged in urine)

• Half-life: 5-10 hours

• Reference range: Not established

Side effects

Upon initiation, nausea and vomiting, somnolence, impaired concentration, confusion, ataxia, and speech and language problems may occur.

No additional side effects have been associated with chronic therapy to date.

• FDA warning: Increased risk of suicidal behavior or ideation is possible. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including tiagabine) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

Drug-drug interactions

• Tiagabine is a CYP3A substrate and may also be metabolized by CYP1A2, 2D6, or 2C19.

• Valproic acid may increase the serum concentration or effect of tiagabine.

• Carbamazepine, phenobarbital, primidone, and phenytoin may decrease the anticonvulsant effect of tiagabine.

• Tiagabine may decrease the serum concentration or effect of valproic acid.

Commercially available formulations

See Table 24-3 for commercially available formulations.

Topiramate

Topiramate is indicated for initial monotherapy (> 10 years of age) for partial onset seizures or primary generalized tonic-clonic seizures and for adjunctive therapy for patients (2-16 years) with partial onset seizures or primary generalized tonic-clonic seizures. It is also indicated for seizures associated with Lennox-Gastaut syndrome (> 2 years).

Pharmacokinetics

• Bioavailability: 80%

• Protein binding: 15-41%

• Metabolism: Minor hepatic (via hydroxylation, hydrolysis, and glucuronidation)

• Elimination: 70% excreted unchanged in urine; may undergo renal tubular reabsorption

• Half-life: About 20 hours

• Reference range: Not established; clinical value of monitoring concentrations not established

Side effects

Upon initiation, drowsiness, dizziness, difficulty with concentration, loss of appetite, mood changes, and paresthesias may occur.

With chronic therapy, the following side effects are possible:

• Hyperchloremic metabolic acidosis

• Acute myopia and secondary angle closure glaucoma

• Kidney stones (caution patient that adequate hydration may reduce stone formation)

• Paresthesia

• Word finding difficulties and decreased cognition (dose related)

• Significant weight loss

Severe or life-threatening side effects are as follows:

• Oligohidrosis: Children taking topiramate may not adequately sweat when overheated and could develop hyperthermia and heat stroke. Caution the parent to assess the child's ability to sweat, to be cautious about the child getting overheated, and to have the child drink plenty of water.

• FDA warning: Increased risk of suicidal behavior or ideation may occur. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including topiramate) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

Drug-drug interactions

• Topiramate induces β-oxidation.

• Topiramate inhibits CYP2C19.

• CNS depressants (alcohol, morphine, codeine) and carbonic anhydrase inhibitors (acetazolamide) may increase the serum concentration or effect of topiramate.

• Phenobarbital, phenytoin, and valproic acid may decrease the anticonvulsant effect of topiramate.

• Topiramate may increase the serum concentration or effect of metformin.

• Topiramate may decrease the serum concentration or effect of oral contraceptives and valproic acid.

Commercially available formulations

See Table 24-3 for commercially available formulations.

Patient counseling

See general counseling information. In addition, counsel the patient as follows:

• If using the Topamax sprinkle capsule, sprinkle the contents on a small amount of cool, soft food (e.g., applesauce or yogurt) and swallow immediately without chewing.

• Drink plenty of fluids to avoid kidney stones.

• Confirm that children in hot climates can sweat.

Valproic Acid

Valproic acid is used for all types of generalized and partial seizures; along with ethosuximide, it is the drug of choice for absence seizures. It is rarely used in children < 2 years of age.

Pharmacokinetics

• Bioavailability: Complete

• Protein binding: High (80-90%; dose dependent)

• Metabolism: Extensive via hepatic glucuronide conjugation and oxidation

• Renal: Low (2-3% unchanged in urine)

• Reference range: 50-150 mg/L (curvilinear relationship between serum concentration and protein binding)

Side effects

Upon initiation, nausea and vomiting may occur.

With chronic therapy, the following side effects are possible:

• Weight gain: This side effect is at times significant enough to warrant discontinuing the medication.

• Alopecia: Effects may be partial or total. To prevent or treat alopecia, supplement with zinc and selenium.

• Tremor: This effect is dose dependent. Treat it by decreasing the dose, discontinuing the drug, or adding propranolol.

• Thrombocytopenia: A dose-dependent decrease in platelets may occur.

• Elevation in liver enzymes: This side effect may be transient and responds to discontinuation of valproic acid.

Severe or life-threatening side effects are possible:

• FDA black box warning: Fatal hepatotoxicity is possible. It is most common in children < 2 years of age who have severe epilepsy and are receiving multiple anticonvulsants.

• FDA black box warning: Fatal hemorrhagic pancreatitis may occur.

• FDA black box warning: Fetal valproate syndrome may occur. Features include craniofacial anomalies, small inverted noses, shallow philtrum, flat nasal bridge, long upper lip, congenital liver disease, and spina bifida. This medication is pregnancy category D.

• FDA warning: Increased risk of suicidal behavior or ideation may occur. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including valproic acid) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

Drug-drug interactions

• Valproic acid inhibits CYP2C9, CYP 2C19, uridine diphosphate glucuronosyltransferase, epoxide hydroxylase, and β-oxidation.

• It displaces some drugs from albumin binding sites.

• Felbamate, phenytoin, and salicylates increase the serum concentration or effect of valproic acid.

• Carbamazepine, felbamate, lamotrigine, phenytoin, phenobarbital, and primidone decrease the anticonvulsant effect of valproic acid.

• Valproic acid may increase the serum concentration or effect of amitriptyline, carbamazepine, ethosuximide, felbamate, lamotrigine, phenobarbital, primidone, and zidovudine.

• Valproic acid may decrease the serum concentration or effect of phenytoin.

Commercially available formulations

See Table 24-2 for commercially available formulations.

Patient counseling

See general counseling information. Patients should also be counseled as follows:

• You may take this medication with food or milk to reduce stomach irritation. Do not take with carbonated drinks.

• Swallow valproic acid capsules whole with water only; do not break, chew, or crush.

• Swallow divalproex sodium delayed-released capsules whole or sprinkle the contents on a small amount of cool, soft food (e.g., applesauce or pudding) and swallow without chewing immediately after preparation.

• Swallow divalproex sodium delayed-release tablets whole; do not break, chew, or crush.

• You may mix valproic acid syrup with any liquid or add it to a small amount of food.

• Report any sore throat, fever, fatigue, bleeding, or bruising that is severe or persists to your physician.

• Your doctor may monitor your liver function with blood tests every 1-2 weeks initially and periodically thereafter.

Vigabatrin

Vigabatrin is indicated for infantile spasms; it is adjunctive therapy for complex partial seizures.

Pharmacokinetics

• Bioavailability: Complete

• Protein binding: Low

• Metabolism: Minimal

• Renal: 80% (unchanged)

• Half-life: 5-13 hours

Side effects

Upon initiation, fatigue, headache, drowsiness, dizziness, tremor, or agitation. Hyperactivity (e.g., hyperkinesia, agitation, excitation, or restlessness) has been reported in children.

With chronic therapy, permanent decrease in peripheral vision may occur. However, there is no effect on central vision or color.

• FDA warning: Increased risk of suicidal behavior or ideation is possible. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including vigabitrin) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

• FDA black box warning: Medication may cause permanent vision loss in infants, children, and adults. Due to the risk of vision loss and because vigabatrin provides an observable symptomatic benefit when it is effective, the patient who fails to show substantial benefit within a short period of time after initiation of treatment (2-4 weeks for infantile spasms; < 3 months in adults) should be withdrawn from therapy. If in the clinical judgment of the prescriber evidence of treatment failure becomes obvious earlier in treatment, vigabatrin should be discontinued at that time.

Commercially available formulations

See Table 24-3 for commercially available formulations.

Patient counseling

See general counseling information. In addition, counsel patients to notify their physician of any change in vision.

Zonisamide

Zonisamide is indicated for partial seizures.

Pharmacokinetics

• Bioavailability: Complete

• Protein binding: Low (40%)

• Metabolism: Undergoes acetylation and subsequent conjugation with glucuronide in the liver

• Renal elimination: 62% (35% as unchanged)

• Half-life: 50-70 hours

• Reference range: proposed therapeutic range, 10-20 mg/L; concentrations > 30 mg/L associated with adverse effects

Side effects

With chronic therapy, side effects are very similar to those of topiramate:

• Kidney stones (contraindicated in patients with a history of kidney stones; should be adequately hydrated)

• Weight loss

• Reversible or irreversible psychosis (rare)

Severe or life-threatening side effects may occur:

• Oligohidrosis: The medication carries an FDA warning. Children taking zonisamide may not sweat as needed and could develop hyperthermia. Warn parents of the need to be aware of children getting overheated and to have them drink plenty of water.

• FDA warning: Zonisamide may cause a dose-dependent metabolic acidosis, which has occurred at doses as small as 25 mg/d. Metabolic acidosis is usually asymptomatic; however, chronic untreated metabolic acidosis may result in decreased growth rates in children, as well as decreased fetal growth and fetal death following exposure during pregnancy. The FDA is now recommending a serum bicarbonate level prior to initiation and periodically during therapy. If metabolic acidosis develops, consider decreasing the dose or discontinuing use with appropriate dose tapering.

• FDA warning: Increased risk of suicidal behavior or ideation may occur. The FDA has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants (including zonisamide) and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) of patients receiving placebo (0.22%).

• Other: Zonisamide is a sulfonamide. Life-threatening sulfonamide reactions may occur (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, aplastic anemia, agranulocytosis, and fulminant hepatic necrosis).

Drug-drug interactions

• Zonisamide is a CYP3A4 substrate.

• Carbamazepine, phenobarbital, phenytoin, and valproic acid decrease the effect of zonisamide.

• Lamotrigine may inhibit the clearance of zonisamide and increase zonisamide serum concentrations.

Commercially available formulations

See Table 24-3 for commercially available formulations.

Patient counseling

See general counseling information. In addition, counsel the patient as follows:

• Notify your pharmacist or physician if you are allergic to sulfa medications.

• Drink plenty of fluids to help prevent kidney stones.

• Contact your doctor if your child is not sweating as usual.

24-3. Other Issues

Nondrug Treatment of Epilepsy

Nondrug treatments are as follows:

• Ketogenic diet

• Vagal nerve stimulator

• Surgical correction

Withdrawal of Anticonvulsants

Over half of patients who remain seizure free for 2 years can have their anticonvulsant successfully withdrawn. Most who are seizure free for 4 years can be successfully withdrawn from anticonvulsants.

Unless the patient is experiencing a severe or life-threatening adverse effect, never abruptly discontinue an anticonvulsant; taper slowly over 2-6 months.

Status Epilepticus

Status epilepticus is defined as a seizure that lasts longer than 5 minutes or two or more discrete seizures between which there is incomplete recovery of consciousness. It is a medical emergency. See

Table 24-4 for suggested order of therapies.

Benzodiazepines

Benzodiazepines are first-line agents. Diazepam or lorazepam are preferred.

Hydantoin (phenytoin or fosphenytoin)

Phenytoin (intravenous)

Phenytoin can only be mixed with normal saline.

If an individual is not already receiving phenytoin, give a loading dose of 15-20 mg/kg. Because phenytoin contains propylene glycol and is in itself cardiotoxic, do not infuse faster than 50 mg/minute.

If the maintenance dose is to be given every 12 hours, give the first dose 12 hours after the end of the loading dose. If the maintenance dose is to be given every 24 hours, give the first dose 24 hours after the end of the loading dose.

The alkaline pH of phenytoin precludes IM administration.

Fosphenytoin

Fosphenytoin is a phenytoin prodrug that is converted to phenytoin within minutes after infusion. It can be admixed with any IV solution.

Fosphenytoin must be dosed in PE (phenytoin equivalents): 1 mg of phenytoin = 1.5 mg of fosphenytoin. It can be given at a rate of 150 mg/min (three times faster than phenytoin).

Phenobarbital

Phenobarbital may cause respiratory depression or arrest. The likelihood of such an effect may be increased if benzodiazepines have been given.

Phenobarbital-induced sedation may eliminate the ability to perform an accurate neurologic assessment.

[Table 24-4. Treatment of Status Epilepticus]

Because phenobarbital contains propylene glycol and is cardiotoxic, do not infuse faster than 60 mg/min in adults and 30 mg/min in children.

Midazolam

Because of midazolam's very short half-life, the loading dose should be followed by continuous infusion.

Medically induced coma

Medically induced coma is used for severe refractory status epilepticus. It is usually achieved with pentobarbital.

Give a loading dose (20-40 mg/kg) over 1-2 hours, followed by continuous infusion (1-4 mg/kg/hr).

If hypotension occurs, begin dopamine or slow the rate of infusion.

Titrate to burst suppression (isoelectric) on EEG.

Other therapies used for refractory status epilepticus

• Propofol

• Newer anticonvulsants (IV: levetiracetam; oral: topiramate)

• Magnesium

• Lidocaine

• IV immune globulin

Febrile Seizures

A febrile seizure is a benign seizure that occurs in the absence of CNS infection in a child with fever. It is the most common seizure disorder in childhood. The age of onset is 4 months to 5 years (peaks at 14-18 months).

A child is at risk if he or she has two of the following risk factors:

• A first- or second-degree relative with a history of a febrile seizure

• Developmental delay

• Delayed discharge (> 28 days) from a newborn center

• Day care attendance

Overall, the development of epilepsy in children who have experienced such seizures is rare (1-2%). However, about 15% of children who have complex febrile seizures (as defined below) will go on to develop epilepsy.

There are two types of febrile seizures:

• Simple febrile seizure:

• Benign

• A primary generalized seizure

• Less than 15 minutes in duration

• Does not recur within 24 hours

• Complex febrile seizure:

• Focal (involves an arm, leg, or face on one side only or eye deviation toward one side)

• Prolonged (> 15 minutes) or recurring within 24 hours of the initial seizure

Acute treatment of a simple or complex febrile seizure

Drugs of choice for prolonged febrile seizure are rectally administered benzodiazepines (rectal diazepam or lorazepam). Diastat is a commercially available gel of diazepam to be given rectally.

Prophylaxis for a simple or complex febrile seizure

If temperature is > 38C°, give the patient a nonaspirin antipyretic.

Daily anticonvulsants are not indicated for the prevention of recurrent febrile seizures.

Maintenance therapy

Maintenance therapy is not generally used. However, an anticonvulsant (i.e., phenobarbital) may be considered after a complex febrile seizure if epilepsy is suspected.

Carbamazepine and phenytoin are not effective in the prevention of recurrent febrile seizures.

24-4. Key Points

• Phenytoin can be mixed only with normal saline and should not be given faster than 50 mg/min.

• Gabapentin and levetiracetam are not associated with any significant drug interactions.

• As of September 2009, the following anticonvulsants carry a U.S. black box warning: carbamazepine (aplastic anemia, dermatologic reactions); valproic acid (liver failure, teratogenicity, pancreatitis); felbamate (aplastic anemia, hepatic failure); and lamotrigine (serious rash). FDA warnings have been given for Zonisamide and topiramate, which have been reported to cause oligohidrosis and hyperthermia. The FDA has found that 11 of the anticonvulsants are associated with an increased risk of suicidal behavior or ideation.

• Although absence seizures are frequently treated with ethosuximide or valproic acid (if ≥ 2 years of age), lamotrigine and topiramate are also used.

• Carbapenems (e.g., imipenem) and normeperidine (a metabolite of meperidine that accumulates in renal failure) may cause seizures.

• Carbamazepine undergoes autoinduction (i.e., it induces its own metabolism), and phenytoin has capacity-limited or saturable (i.e., Michaelis-Menten) pharmacokinetics.

• Because of the potential for severe life-threatening liver toxicity, valproic acid is generally not used in a patient < 2 years of age.

• There may be an association between folic acid deficiency and spina bifida; hence, all women with epilepsy who are of childbearing age should be on daily folic acid (1 mg).

• Unless a patient is experiencing a life-threatening adverse effect, an anticonvulsant should not be abruptly discontinued.

• Topiramate may cause significant weight loss, and valproic acid may cause significant weight gain.

• Topiramate and zonisamide may cause kidney stones.

• Patients with an allergy to sulfa medications should not be given zonisamide.

24-5. Questions

1.

Which of the following is true regarding phenytoin?

A. The maximum rate of intravenous administration is 50 mg/min.

B. If intravenous access cannot be established, phenytoin can be given IM.

C. Because phenytoin contains propylene glycol, it is soluble as any IV fluid.

D. It is an inhibitor of the cytochrome P450 system.

E. A major limitation to the use of the product in pediatric patients is the lack of a commercially available liquid formulation.

 

2.

A 50 kg patient with no history of epilepsy presents in status epilepticus. The patient is given an adequate dose of lorazepam and is about to be given a loading dose of intravenous phenytoin. Assuming a phenytoin Vd of 0.6 L/kg, what dose of phenytoin should be given to achieve a serum phenytoin concentration of ~ 16-18 mg/L?

A. 18 mg/kg

B. 500 mg

C. 30 mg/kg

D. 50 mg

E. 5 g

 

3.

Which of the following is true regarding a patient with refractory status epilepticus who is placed in a medically induced coma with a barbiturate?

A. If the patient is mechanically ventilated, the barbiturates will induce respiratory arrest.

B. The goal of a coma that is medically induced with a barbiturate is to induce burst suppression (isoelectric) on EEG.

C. If hypotension develops, the patient should be given nitroprusside.

D. The barbiturates are not associated with drug interactions.

E. A major problem with this type of therapy is kidney failure.

 

4.

Which of the following is associated with autoinduction?

A. Phenobarbital

B. Phenytoin

C. Carbamazepine

D. Gabapentin

E. Levetiracetam

 

5.

Which of these agents reduces the likelihood of congenital malformations in epileptic women receiving valproate?

A. Folic acid

B. Vitamin B12

C. Ginkgo biloba

D. Iron

E. Selenium

 

6.

A 33-year-old woman is being started on an anticonvulsant. She is already slightly overweight and is very concerned about the effects of the various medications on her weight. Which of the following is (are) true regarding anticonvulsants and their effect on weight?

I. Valproic acid increases weight.

II. Topiramate decreases weight.

III. Phenytoin increases weight.

A. I

B. I and II

C. II

D. III

E. I, II, and III

 

7.

A 24-year-old woman has complex partial seizures that are currently controlled with valproic acid, gabapentin, and topiramate. She calls your pharmacy to ask if any of her medications can cause nosebleeds since she has had one or two in the past week. You refer her to her local medical doctor, where her platelet count is reported to be 95,132/mm3. Which of the following is true?

A. None of her anticonvulsants cause thrombocytopenia.

B. Valproate can cause a dose-related thrombocytopenia.

C. Gabapentin has inhibited the metabolism of topiramate, and the elevated concentration of topiramate is responsible for the thrombocytopenia.

D. Gabapentin can cause idiosyncratic thrombocytopenia.

E. Topiramate can cause thrombocytopenia.

 

8.

A patient has hypertension, diabetes mellitus, and chronic renal failure (serum Cr = 6.8), and has developed seizures. Which of the following anticonvulsants would require dosage adjustment in this patient?

A. Gabapentin, topiramate

B. Lamotrigine, felbamate

C. Phenobarbital, gabapentin

D. Phenytoin, valproic acid

E. Phenobarbital, levetiracetam

 

9.

Which of the following anticonvulsants is metabolized to phenobarbital?

A. Ethosuximide

B. Primidone

C. Zonisamide

D. Levetiracetam

E. Carbamazepine

 

10.

A 7-year-old boy on valproic acid for partial complex seizures with secondary generalization that are refractory to phenobarbital, phenytoin, carbamazepine, and gabapentin continued to have seizures and was started on lamotrigine 2 weeks ago. Today he presents with a diffuse maculopapular erythematous rash with lesions on the lips. Which of the following is correct?

A. A rash associated with lamotrigine generally occurs within the first few days; hence, the rash is not associated with an anticonvulsant.

B. The patient should be given diphenhydramine, and lamotrigine should be continued.

C. Lamotrigine should be discontinued.

D. The rash is secondary to a drug interaction between gabapentin and carbamazepine.

E. All of the anticonvulsants are associated with life-threatening rash. To prevent status epilepticus associated with abrupt discontinuation of the anticonvulsants, the medications should be slowly discontinued.

 

11.

A new anticonvulsant has just been approved by the FDA. Its bioavailability is > 95%, and it is highly protein bound to α1-acid glycoprotein. It undergoes extensive hepatic metabolism by CYP450 2C9. Less than 5% is excreted unchanged in the urine. It is known to inhibit CYP450 3A4. A patient on this anticonvulsant has developed significant depression and is being started on an antidepressant that is 93% bound to albumin and is a potent inhibitor of CYP450 2C19. The antidepressant is metabolized by CYP450 3A4 to an active metabolite that is hepatically cleared by CYP450 2C9. The neurologist wants to know if any drug interactions may occur that would necessitate a reduction in drug dosage.

A. No drug interactions should occur in this patient.

B. The dose of the anticonvulsant should be reduced because of a potential protein binding interaction that would increase the serum concentration of the anticonvulsant.

C. The dose of the anticonvulsant should be increased.

D. The dose of the antidepressant should be reduced.

E. Because of an interaction in the gut that decreases bioavailability, the dose should be increased.

 

12.

Which of the following is (are) not associated with any drug-drug interactions?

I. Gabapentin

II. Carbamazepine

III. Levetiracetam

A. I

B. II

C. I and III

D. II and III

E. I and II

F. III

 

13.

A 42-year-old woman has been successfully treated with valproic acid for years, but she has experienced some undesirable side effects. She is slowly titrated onto a new anticonvulsant, and the valproic acid is slowly discontinued. She presents to the emergency department with severe flank pain and is diagnosed with a kidney stone. Which of the following may have precipitated her current situation?

A. Gabapentin

B. Lamotrigine

C. Levetiracetam

D. Topiramate

E. Phenytoin

 

14.

Which of the following drugs carries (carry) a black box warning?

I. Carbamazepine

II. Felbamate

III. Levetiracetam

A. II

B. III

C. I

D. I and II

E. II and III

 

15.

Which of the following carries a black box warning for pancreatitis?

A. Carbamazepine

B. Felbamate

C. Zonisamide

D. Valproic acid

E. Phenytoin

 

16.

What is the drug of choice for absence seizures in a child < 2 years of age?

A. Phenytoin

B. Phenobarbital

C. Ethosuximide

D. Valproic acid

E. Primidone

 

17.

Diastat is given by which of the following routes?

A. Rectally

B. Intramuscularly

C. Intravenously

D. Intranasally

E. Subcutaneously

 

18.

Which of the following is true?

A. Febrile seizures must be accompanied by a CNS infection.

B. Complex febrile seizures last > 15 minutes.

C. Most children who have a febrile seizure go on to develop epilepsy.

D. The drug of choice for a simple febrile seizure is carbamazepine.

E. Simple febrile seizures should never be treated.

 

19.

Which of the following anticonvulsants is (are) available in a liquid, chewable tablet, and intravenous formulation?

I. Carbamazepine

II. Phenytoin

III. Valproic acid

A. II

B. III

C. I

D. I and II

E. I, II, and III

 

20.

Patients should be told to drink plenty of fluid when taking which of the following?

A. Carbamazepine

B. Topiramate

C. Levetiracetam

D. Gabapentin

E. Phenytoin

 

21.

Which of the following medications may cause seizures in an adult patient with renal failure?

A. Meperidine

B. Phenobarbital

C. Carbamazepine

D. Lamotrigine

E. Theophylline

 

22.

Which of the following is associated with Michaelis-Menten pharmacokinetics?

A. Carbamazepine

B. Valproic acid

C. Topiramate

D. Phenytoin

E. Phenobarbital

 

23.

A patient on which of the following medications should be made aware of the importance of good oral hygiene?

A. Felbamate

B. Phenytoin

C. Zonisamide

D. Phenobarbital

E. Levetiracetam

 

24-6. Answers

1.

A. Because phenytoin contains propylene glycol and is itself cardiotoxic, the IV formulation should not be infused faster than 50 mg/min. Phenytoin is extremely alkaline (pH ~ 13). Not only is IM administration associated with tissue damage, it is erratically absorbed. Phenytoin can be admixed only with normal saline, is an inducer, and is also available as a suspension and a chewable tablet.

 

2.

B. The equation for calculation of a loading dose is as follows: Dose = Cp (serum concentration) desired × Vd (volume of distribution). So Cp desired is ~ 17 × (0.6 L/kg × 50 kg) ≈ 510 mg.

 

3.

B. The goal is to produce a "flat" EEG. If the patient is mechanically ventilated, the effect of a medication on respiration is not a factor in its administration. Although pentobarbital may cause hypotension if given too rapidly, nitroprusside is a vasodilator used to treat hypertension. The barbiturates are known inducers. Coma that is medically induced with a barbiturate does not cause kidney failure.

 

4.

C. Carbamazepine induces its own metabolism, with peak effects seen about 21 days after beginning the medication or following an increase in dosage. Phenobarbital and phenytoin are inducers. Gabapentin and levetiracetam are not cleared hepatically.

 

5.

A. Many of the anticonvulsants can cause folic acid deficiency. An association exists between folic acid deficiency and spina bifida; hence, all women with epilepsy who are of childbearing age should receive supplemental folic acid every day (1 mg).

 

6.

B. Topiramate can cause significant weight loss, and valproate can cause significant weight gain. Phenytoin does not significantly affect weight.

 

7.

B. Valproic acid can cause clinically significant thrombocytopenia. Gabapentin is not associated with any drug interaction that affects metabolism, and it does not cause a decrease in platelets. Topiramate does not cause thrombocytopenia.

 

8.

A. Gabapentin and topiramate would require dosage adjustment because they are renally eliminated.

 

9.

B. Primidone (Mysoline) is an active anticonvulsant, but it is also metabolized to phenobarbital.

 

10.

C. Lamotrigine has a black box warning for severe rash. Because this patient has a diffuse rash and lesions on the lips, lamotrigine should be discontinued. Because the incidence of severe rash may be higher in children than in adults, current practice would be to discontinue lamotrigine and not "treat through" the rash with diphenhydramine. Gabapentin does not interact with lamotrigine. However, the combination of valproic acid and lamotrigine is associated with a higher incidence of rash. Although abrupt discontinuation of an anticonvulsant may induce status epilepticus, an anticonvulsant may be abruptly discontinued in the face of a life-threatening event.

 

11.

D is correct because the new anticonvulsant inhibits CYP450 3A4 and the antidepressant is metabolized by this enzyme.

 

12.

C. At this time, neither gabapentin nor levetiracetam is associated with significant drug-drug interactions. The absorption of gabapentin may be reduced by concurrent administration of aluminum- or magnesium-containing antacids; hence, antacids should be given 2 hours before or after a dose of gabapentin. Carbamazepine is an inducer that is associated with numerous drug-drug interactions.

 

13.

D. Both topiramate and zonisamide may cause kidney stones. Although neither agent is contraindicated in an individual with a history of kidney stones, these drugs should be used cautiously in such patients. Patients should be counseled to remain adequately hydrated because doing so may decrease the risk of stone formation.

 

14.

D. Both carbamazepine and felbamate are associated with aplastic anemia and hepatic failure. Levetiracetam has no black box warning.

 

15.

D. Valproic acid may cause fatal hemorrhagic pancreatitis.

 

16.

C. Although valproic acid is extremely effective and is frequently used as monotherapy for absence seizures, it should not be given to a patient < 2 years of age.

 

17.

A. Diastat is a commercially available gel form of diazepam that is given rectally.

 

18.

B. Unlike simple febrile seizures, which last a brief period, complex febrile seizures are prolonged (> 15 minutes) or recur within 24 hours of the initial seizure. Febrile seizures must occur in the absence of CNS infection in a child with fever. Most febrile seizures are benign, and children do not go on to develop epilepsy. Carbamazepine is ineffective in febrile seizures.

 

19.

A. Only phenytoin is available as a liquid (125 mg/5 mL), as a chewable tablet (50 mg), and in an intravenous dosage form. Carbamazepine is not available in an IV dosage form, and valproic acid is not available as a chewable tablet.

 

20.

B. Because topiramate may cause kidney stones, patients should be encouraged to drink plenty of fluids. This would also be true for zonisamide.

 

21.

A. Normeperidine, a metabolite of meperidine, can accumulate in patients with renal failure who receive normal doses and cause seizures. The other agents listed are not eliminated renally in adults.

 

22.

D. Phenytoin has capacity-limited or saturable (i.e., Michaelis-Menten) pharmacokinetics.

 

23.

B. Phenytoin may cause gingival hyperplasia (i.e., overgrowth of the gums). Hence, patients should be instructed to brush and floss daily and to have regular visits with the dentist.

 

24-7. References

American Academy of Neurology, Quality Standards Subcommittee. Practice parameter: A guideline for discontinuing antiepileptic drugs in seizure-free patients—summary statement. Neurology. 1996;47:600-2.

Anderson GD. A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998;32: 554-63.

Baumann RJ, Duffner PK. Treatment of children with simple febrile seizures: The AAP practice parameter. Pediatr Neurol. 2000;23:11-17.

Brunbech L, Sabers A. Effect of antiepileptic drugs on cognitive function in individuals with epilepsy: A comparative review of newer versus older agents. Drugs. 2002;62:593-604.

Carroll MC, Yueng-Yue KA, Esterly NB, et al. Drug-induced hypersensitivity syndrome in pediatric patients. Pediatrics. 2001;108:485-92.

Commission on Antiepileptic Drugs, International League against Epilepsy. Guidelines for therapeutic monitoring on antiepileptic drugs. Epilepsia. 1993;34:585-87.

Deckers CL, Knoester PD, de Haan GJ, et al. Selection criteria for the clinical use of the newer antiepileptic drugs. CNS Drugs. 2003;17:405-21.

Johannessen SI, Battino D, Berry DJ, et al. Therapeutic drug monitoring of the newer antiepileptic drugs. Ther Drug Monit. 2003;25:347-463.

Perucca E. The clinical pharmacokinetics of the new antiepileptic drugs. Epilepsia. 1999;40(suppl 9): S7-13.

Working Group on Status Epilepticus. Treatment of convulsive status epilepticus: Recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus. JAMA. 1993;270: 854-59.