CHAPTER

First-Generation Antiepileptic Drugs

José E. Cavazos

Other Indications for Use

Diazepam is a benzodiazepine and exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant, and amnestic effects. It is used in the management of anxiety disorders, alcohol withdrawal, and several disorders with skeletal muscle spasms. Clonazepam is indicated for the treatment of panic disorders with or without agoraphobia. Lorazepam is indicated as a preanesthetic medication to induce sedation, relieve anxiety, and reduce the ability to remember events related to the day of surgery.

Adverse Effects

Adverse events occur in a dose-dependent manner with drowsiness, sedation, confusion, and amnesia been frequently reported. In some cases, these adverse events may decrease in severity with time.

Toxicity, Overdose, and Contraindications

Benzodiazepines should not be used in patients with a history of sensitivity to this class of drugs or in patients with significant hepatic disease. They are also contraindicated in patients with acute angle glaucoma. Toxic overdose of benzodiazepines is associated with respiratory depression, coma, and even death. Benzodiazepines can worsen seizures, including an increase incidence of generalized tonic–clonic seizures. It is unclear as to whether this is a withdrawal symptom or unrelated to serum concentrations. There is also an increased risk of congenital malformations.

Warning and Precautions

Benzodiazepines interfere with cognitive and motor performance, and patients should avoid the concomitant use of alcohol or other CNS-depressant drugs. Suicidal behaviors and ideation have been reported. Respiratory depression and coma are a concern.

Special Safety Concerns

Benzodiazepines are Schedule IV controlled substances. Gradual discontinuation of these medication is needed, particularly in those patients who have been taking this class of drugs for more than a week.

Teratogenicity Information

Diazepam, lorazepam, and clonazepam are pregnancy category D drugs.

Drug Interaction

The CNS-depressant effects of all benzodiazepines are likely potentiated by alcohol, narcotics, and barbiturates, among other CNS-depressant medications. Cytochrome P-450 inducers induce the metabolism of clonazepam and diazepam by about 30% to 50%, lower than expected for plasma levels. Lorazepam is metabolized by glucuronidation, which can be inhibited by valproic acid in a similar manner as the interaction between valproic acid and lamotrigine. Oral contraceptives increase the hepatic metabolism of lorazepam.

Use in Special Populations

Clearance of benzodiazepines, which tend to be lipophilic molecules, is lower in neonates and the elderly. Metabolism for these drugs also is slower in both special groups. If a benzodiazepine is needed by patients with hepatic or renal insufficiency, lorazepam is the preferred medication due to glucuronidation metabolism. The metabolite of lorazepam is removed by about 40% during a typical hemodialysis.

Pediatric Use

Limited pharmacokinetic data exist in neonates, infants, and children.

CARBAMAZEPINE

Indications

Carbamazepine is recommended as a first-line therapy for patients with newly diagnosed partial seizures and for patients with primary generalized convulsive seizures who are not in an emergent situation.

Dosing

Pharmacology

The mechanism of action of carbamazepine is believed to mainly enhance fast inactivation of voltage-gated sodium channels (ie, sodium channel antagonist). Other effects on ion channels that may contribute to its activity include interaction with voltage-gated calcium and potassium channels. The absorption of carbamazepine from immediate-release tablets (Tegretol) is slow and erratic due to its low water solubility. There is also large variability (up to 40%) in the peak-to-trough concentrations and there is no significant first-pass metabolism through the liver. Food, especially fat, may enhance the bioavailability of carbamazepine. Carbamazepine suspension is absorbed faster than the tablet form. Controlled-release (Tegretol-XR) and sustained-release (Carbatrol) preparations are also available, and are bioequivalent in twice daily (every 12 hours) dosing to immediate-release carbamazepine dosed four times daily (every 6 hours). Compared with immediate-release carbamazepine (Tegretol), both of the extended-release formulations have lower peaks and higher troughs serum levels, which may decrease peak side effects and improve seizure control, respectively. Sustained-released formulations improve overall tolerability and can improve Quality-of-Life (QOL) measurements as compared to the immediate-release formulation. Patients should be told to take Tegretol-XR with food and that the casing will be excreted in the feces, not indicating lack of absorption. Extended-release formulations cannot be broken or crushed. Tegretol-XR and Carbatrol appear to be bioequivalent; however, there is less variability in the absorption of Carbatrol. Carbamazepine is a neutral and highly lipophilic drug that is highly protein bound to α1-acid glycoprotein and albumin. Carbamazepine is metabolized primarily by CYP3A4 and its major metabolite is carbamazepine-10,11-epoxide, which has anticonvulsant activity in animals and humans. The formation of the 10,11-epoxide is influenced by concurrent use of other enzyme-inducing or enzyme-inhibiting drugs; thus, the 10,11-epoxide concentration may change with the administration of other drugs (eg, valproic acid and felbamate) with no change in parent carbamazepine concentration. Carbamazepine induces its own metabolism (autoinduction) within a few weeks, decreasing its half-life after chronic therapy. The presence of other CYP3A4-inducing drugs reduces the half-life of carbamazepine even more. The enzyme-induction effect begins within 3 to 5 days of starting therapy and takes 21 to 28 days to fully induce. Therefore, it is possible to achieve initial concentrations that are within the therapeutic range but have concentrations fall rather quickly despite continued therapy and good compliance. Some patients who respond well to initial therapy may be labeled refractory or noncompliant if the autoinduction phenomenon is not considered. The autoinduction reverses rapidly if carbamazepine is discontinued. Carbamazepine also displays diurnal variation in its serum level with evening levels lower than morning levels. It appears that carbamazepine is cleared significantly faster in females than in males, and in Caucasians compared to African Americans, and therefore variable dosing may be needed. Polymorphisms of CYP3A4 have been described and might account for some of the ethnic and racial differences.

Efficacy Data

Carbamazepine has been well studied in randomized controlled clinical trials. The VA Cooperative Study #118 compared the efficacy and toxicity of four antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, and primidone) for the treatment of partial and secondarily generalized tonic–clonic (GTC) seizures in over 600 adult male Veterans. The study was double-blinded and randomized, following patients for up to 36 months. Carbamazepine was shown to not only have superior tolerability and equal efficacy for secondarily GTC seizures but to also have superior efficacy for all partial seizures as compared to phenobarbital and primidone (1).

Other Indications for Use

Carbamazepine is indicated for the treatment of painful trigeminal neuralgia. It might also be helpful in other painful neuropathies. There is some evidence supporting its use as a mood stabilizer, but does not have an FDA-approved indication.

Adverse Effects

Toxicity, Overdose, and Contraindications

Toxicity after a large ingestion of carbamazepine is typically seen with 1 to 3 hours with a confusional state, ataxia, muscle twitching, rigidity, urinary retention, tachycardia, hypotension, and nausea and vomiting. The patient will require hospital monitoring for supportive treatment of respiratory failure and hypotensive shock. Induction of vomiting and use of activated charcoal might reduce some of the absorption of an overdose. Dialysis might be needed if renal failure occurs.

Carbamazepine is contraindicated in patients with prior bone marrow depression and hypersensitivity reactions to any tricyclic compounds, including antidepressants and carbamazepine. It should not be coadministered with nefazodone. It will reduce the plasma concentrations of many medications metabolized by CYP3A4, including birth control pills, many statins, and antiviral and chemotherapeutic drugs. As with many other anticonvulsants, suicidal behavior and ideation have been observed in a greater frequency in patients using carbamazepine.

Warning and Precautions

Use of carbamazepine is associated with serious dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. There is evidence for an association of these dermatological reactions and the HLA-B*1502 allele, particularly in Oriental populations, where the risk for these reactions is 10 times greater than in Western countries. There is also an association between these dermatological reactions and the HLA-A*3101 allele seen in European, Japanese, Korean, Chinese, Southern Indian, Arabic, African American, and Native American ancestries. There is also evidence of aplastic anemia and agranulocytosis that is 5 to 8 times greater than in the general population (about 2–6 per one million exposures per year).

Special Safety Concerns

Carbamazepine is a tricyclic structure that has some molecular resemblance to tricyclic antidepressants, which might have mild anticholinergic activity. Caution with increased intraocular pressure and urinary retention is needed. Carbamazepine may also precipitate acute attacks in patients with hepatic porphyrias.

Teratogenicity Information

Carbamazepine is a pregnancy category D drug. There is solid epidemiological data demonstrating an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. Folic acid supplementation is important for all women of childbearing age potential taking carbamazepine.

Drug Interaction

Carbamazepine increases the metabolism of many medications because of its potent effect inducing several of the CYP450 isoenzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4. Because of concentration-dependent efficacy and side effects, drug interactions with carbamazepine often are very significant. Drugs that inhibit CYP3A4 potentially may increase carbamazepine serum concentrations, while drugs that induce CYP3A4 may reduce carbamazepine serum concentrations.

Use in Special Populations

Carbamazepine has been studied in children, elderly, and during pregnancy. It also has been used in patients with renal insufficiency. Given its potent hepatic induction properties and very rare association inducing hepatic failure, it is rarely used in patients with severe hepatic insufficiency.

Pediatric Use

In children, between 6 and 12 years of age, the initial dose is 100 mg twice daily and increasing the dose to 400 to 800 mg after the autoinduction of its metabolism. Children over 12 years of age typically use adult dosing. Under 6 years of age, the dose is 10 to 20 mg/kg/day in twice or thrice daily schedule.

ETHOSUXIMIDE

Indications

Ethosuximide is indicated for the treatment of absence epilepsy.

Dosing

Pharmacology

The mechanism of action of ethosuximide is believed to be inhibition of T-type calcium channels, which control the oscillatory behavior of some thalamic neurons. Ethosuximide is metabolized in the liver by hydroxylation, and the metabolites are believed to be inactive. There is some evidence of nonlinear pharmacokinetics at higher concentrations.

Efficacy Data

Ethosuximide was shown to be superior to lamotrigine, and equal to valproic acid, in controlling absence seizures in a one-year double-blind, randomized controlled trial of 453 children with absence epilepsy. Ethosuximide had superior tolerability as compared to valproic acid. Maximal target doses were 60 mg/kg/day or 2,000 mg/day of ethosuximide.

Other Indications for Use

There are no other indications for use.

Adverse Effects

The most frequently reported side effects are nausea and vomiting (up to 40% of patients), which may be minimized by administration of smaller and more frequent doses. Rash is infrequent but has been noted. Other adverse events include sleep disturbances, dizziness, and attention problems.

Toxicity, Overdose, and Contraindications

Patients with a history of hypersensitivity to succinimides should avoid taking ethosuximide. Toxic overdoses may produce not just acute gastrointestinal upset (ie, nausea, vomiting) but also CNS depression including coma with respiratory depression.

Warning and Precautions

Use of ethosuximide has been associated with blood dyscrasias such as aplastic anemia. Abnormal liver and renal function have been reported in rare cases.

Special Safety Concerns

Ethosuximide increases the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Teratogenicity Information

Ethosuximide has not been awarded a Pregnancy category by the FDA. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. Cases of birth defects have been reported with ethosuximide.

Drug Interaction

Ethosuximide has few pharmacokinetic interactions. Ethosuximide is not protein bound, and, thus, displacement interactions do not occur. Valproic acid may inhibit the metabolism of ethosuximide, but only if its metabolism is near saturation. Ethosuximide may elevate phenytoin serum levels. The mechanism of this drug interaction is unclear.

Use in Special Populations

Ethosuximide is primarily used in children and adolescents.

Pediatric Use

A loading dose is not required. Titration over 1 to 2 weeks to maintenance doses of 20 mg/kg per day usually results in therapeutic concentrations. Data suggest that patients can be managed successfully on once-a-day therapy; however, GI distress appears to be dose related, and the total daily dose is usually divided into two equal doses.

PHENOBARBITAL

Indications

Phenobarbital is indicated for the management of tonic–clonic seizures and partial seizures in monotherapy or adjunctive therapy. It is also indicated for the prevention of febrile seizures in infants and young children, and for the prophylactic management of epilepsy. Phenobarbital also indicated as a second-line agent in status epilepticus.

Dosing

Phenobarbital is available in oral and intravenous or intramuscular formulation. For seizure disorders, the typical doses are 15 to 50 mg twice or three times per day. In status epilepticus, the parenteral dose is 15 to 20 mg/kg/day.

Pharmacology

Efficacy Data

Phenobarbital was one of the agents examined in the first VA Cooperative study; it was shown to be comparable in efficacy to carbamazepine, phenytoin, and primidone, but had lower tolerability than carbamazepine and phenytoin.

Other Indications for Use

Phenobarbital is indicated for the relief of anxiety and short-term treatment of insomnia. It can also be used perioperatively to relieve anxiety and induce sedation. Phenobarbital can be used during drug withdrawal from barbiturates or other nonbarbiturate hypnotics. Given its potent hepatic-inducing effect for CYP450 enzymes, it has been indicated for the prevention and treatment of hyperbilirubinemia in neonates and in cholestasis.

Adverse Effects

CNS side effects are the primary factors limiting the use of phenobarbital. Tolerance usually develops to initial complaints of fatigue, drowsiness, sedation, and depression. Phenobarbital has significant side effects, including delayed intellectual development and hyperactivity in children and significant cognitive impairment in adults. It may also cause porphyria and rash, including serious rashes such as Stevens—Johnson syndrome. Rashes are seen in all ages, typically in less than 10% of subjects.

Toxicity, Overdose, and Contraindications

Toxic effects and fatalities have been reported after overdoses with phenobarbital, a potent CNS depressant. Evaluation of respiratory function is needed. Phenobarbital is contraindicated in patients with known hypersensitivity to barbiturates, and in those with severe hepatic impairment or with history of porphyria. Patients with history of addiction to hypnotics and/or sedatives should avoid phenobarbital. If dyspnea or respiratory obstruction is evident, phenobarbital is also contraindicated.

Warning and Precautions

The concomitant use of alcohol, sedatives, tranquilizers, or other CNS depressants with phenobarbital should be discouraged. Phenobarbital might reduce reaction time and impair the performance of potentially hazardous tasks such as driving or operating machinery. Phenobarbital is a potent inducer of CYP450 hepatic enzymes; thus, it potentially has a great number of drug interactions.

Special Safety Concerns

Aplastic anemia, hepatic failure, and severe dermatologic rashes such as Stevens–Johnson syndrome have been reported in patients taking phenobarbital. The effectiveness of many drug therapies metabolized in the liver such as antibiotics, antiviral, anticoagulants, antichemotherapeutic agents, and statins might be significantly reduced. Phenobarbital is a controlled Schedule IV substance.

Teratogenicity Information

Phenobarbital has been assigned to pregnancy category D and is a known teratogen.

Drug Interaction

Phenobarbital is a potent enzyme inducer and can increase the elimination of any drug metabolized by CYP450- or glucuronidation (UGT)-mediated metabolism. Cimetidine and chloramphenicol inhibit phenobarbital metabolism, necessitating a decrease in dose. Ethanol increases the metabolism of phenobarbital.

Use in Special Populations

Phenobarbital may be useful given IV in refractory status epilepticus.

Pediatric Use

Phenobarbital is the drug of choice for neonatal seizures, but in other situations it is reserved for patients who have failed therapy with other AEDs.

Indications

Phenytoin is indicated for the management of tonic–clonic seizures and psychomotor seizures in monotherapy or adjunctive therapy. It is also indicated for the prevention of seizures occurring during or following neurosurgery and the control of generalized tonic–clonic status epilepticus.

Dosing

Phenytoin is available in several oral formulations, including the extended-release form known as phenytoin sodium (ie, Dilantin). There are several intravenous formulations such as phenytoin sodium and a prodrug, fosphenytoin. Fosphenytoin can be used with an intramuscular administration route. Phenytoin sodium can NOT be used in the intramuscular route since the pH of the salt formulation will create severe tissue injury. For seizure disorders, the typical doses are 15 to 50 mg, two or three times per day. Because of saturable absorption, an oral loading dose, such as 20 mg/kg, should be divided into four equal doses and given at 6-hour intervals. Subsequent dosage adjustments should be done cautiously owing to its nonlinear elimination. In status epilepticus, the parenteral loading dose is 15 to 20 mg/kg/day, at a rate not to exceed 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower. Fosphenytoin is dosed in Phenytoin Equivalent (PE) units, which are the unit equivalent of the prodrug that will be converted into phenytoin in serum by phosphatases.

Pharmacology

The mechanism of action of phenytoin is a voltage-dependent blockade of repetitive voltage-gated sodium channel activation. The bioavailability of the extended-release formulation is about 90%, and higher for other oral formulations. The bioavailability of phenytoin is almost complete for the intravenous and intramuscular formulations. Phenytoin is highly protein bound. It enters the brain rapidly and is redistributed to other body fluids and tissues, including breast milk and the placenta. Serum concentrations between 10 and 20 mcg/mL are typically associated with therapeutic effect and no clinical signs of toxicity. The half-life of phenytoin in the serum ranges from 10 to 15 hours after an intravenous administration. Its clearance tends to decrease with increasing patient age. Phenytoin is metabolized by the hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19 via a parahydroxylation reaction. The elimination of phenytoin is nonlinear, at least a two-rate kinetics. At low doses, most of the metabolism is due to CYP2C9, but when this isoenzyme is saturated with increasing serum concentrations, CYP2C19 is able to metabolize phenytoin at a slower pace, resulting in a steeper increase in the dose-level curve. The clinical importance of this is that a small change in dose can result in a disproportionally large increase in serum concentrations, potentially leading to toxicity. Phenytoin penetrates the brain at a rate comparable to phenobarbital, and peak concentrations are achieved 3 to 20 minutes after an IV dose. Drugs affecting liver enzymes can alter phenytoin metabolism. It is an enzyme inducer and interacts with many other drugs metabolized by the cytochrome P450 system. Furthermore, there are several polymorphisms for the saturable CYP2C9 metabolism as well as for CYP2C19 metabolism with different degrees of function.

Efficacy data

Phenytoin was one of the agents examined in the first VA Cooperative Study, where it was shown comparable in efficacy to carbamazepine, phenobarbital, and primidone, but had better tolerability than phenobarbital and primidone. Phenytoin was also used as adjunctive serial therapy in a randomized blinded study of convulsive status epilepticus of 518 Veterans.

Other Indications for Use

There are no other approved indications for the use of phenytoin.

Adverse Effects

CNS side effects are the primary factors limiting the use of phenytoin. Phenytoin has significant side effects such as nausea, fatigue, drowsiness, sedation, nystagmus, dizziness, and ataxia. Tolerance usually develops to the neurological adverse events after initial complaints. Some patients develop gingival hyperplasia and hypertrichosis and it can also exacerbate porphyrias. Phenytoin may also cause allergic rash, including serious rashes such as Stevens—Johnson syndrome. Rashes are seen in all ages, typically in less than 10% of subjects.

Toxicity, Overdose, and Contraindications

It is estimated that the lethal dose of phenytoin in adults is about 2 to 5 grams.

Warning and Precautions

There are significant cardiovascular risks, including hypotension and cardiac arrhythmias, associated with rapid infusion of intravenous phenytoin sodium. Careful cardiac monitoring is required. Phenytoin is a potent inducer of CYP450 hepatic enzymes; thus, it has a great number of potential drug interactions.

Special Safety Concerns

Aplastic anemia, hepatic failure, and severe dermatologic rashes such as Stevens–Johnson syndrome have been reported in patients taking phenytoin. The effectiveness of many drug therapies metabolized in the liver such as antibiotics, antiviral, anticoagulants, antichemotherapeutic agents, and statins may be significantly reduced.

Teratogenicity Information

Phenytoin has been assigned to pregnancy category D and is a known teratogen.

Drug Interaction

Phenytoin is associated with many interactions with other drugs involving altered absorption, metabolism, and protein binding that can enhance or reduce its effects. The absorption of phenytoin can be increased or decreased with the administration of food, depending on the composition of the meal. The bioavailability of phenytoin suspension can be decreased in patients receiving continuous enteral nutrient tube feedings. However, a single-dose study of simultaneous administration of enteral feeding found no difference in phenytoin bioavailability, suggesting that the mechanism was something other than physical contact. Phenytoin is a potent inducer of both hepatic CYP450 and glucuronidation (UGT) isoenzymes, and even induces its own CYP2C9 and CYP2C19 metabolism. Drug charts are available online and in the packet insert, but any medication that depends upon hepatic metabolism for its clearance, or if it induces or inhibits CYP2C9 should be considered as a potential target for a drug–phenytoin interaction.

Use in Special Populations

Patients with hypoalbuminemia, renal, and/or hepatic insufficiency typically have an increased fraction of unbound phenytoin. The active fraction of phenytoin is only about 10% of the total serum level, which is what is typically measured clinically. In these patient populations, carefulness in dosing is critical as the point of clinical toxicity might be achieved at lower total serum concentrations. The clearance of phenytoin is primarily based upon the metabolism of the hepatic isoenzyme, CY2C9. The serum concentration necessary to saturate CY2C9 activity appears to decrease in elderly patients. The intravenous formulation are likely useful in refractory status epilepticus.

Pediatric Use

In pediatric populations, a typical loading dose would be 15 to 20 mg/kg of phenytoin or fosphenytoin PE.

VALPROIC ACID

Indications

Valproic acid (Depakene) and its derivates, including valproate sodium (Depacon) and divalproex sodium (Depakote), are indicated for the treatment of simple and complex absence seizures and for the therapy of complex partial seizures. This is in monotherapy and/or in adjunctive therapy. Valproic acid is also indicated as adjunctive therapy for the treatment of multiple seizure types. Guidelines from several professional organizations (American Academy of Neurology, American Epilepsy Society, International League Against Epilepsy, National Institute for Health and Care Excellence) recommend these compounds as the first-line therapy for primary generalized seizures, including myoclonic, atonic, and absence seizures. These compounds will be discussed further under the term valproic acid, as it is the active compound at the site of the presumed mechanism of action. The compounds of the valproic acid family are available in several oral formulations for immediate release (tablets, sprinkles, syrup, enteric-coated) and in several extended-release presentations. In addition, intravenous formulation of valproate sodium can be used in the patients in whom the oral administration of valproic acid is indicated but temporarily not feasible.

Dosing

Pharmacology

The mechanism of action of valproic acid is not entirely understood, and there are several lines of investigation suggesting multiple mechanisms of action. There are alterations in the synthesis and degradation of GABA, but these do not fully explain the antiseizure activity. Valproic acid may potentiate postsynaptic GABA responses, may have a direct membrane-stabilizing effect, and may affect potassium channels. It appears to be absorbed completely from available oral dosage forms when administered on an empty stomach. However, the rate of absorption differs among preparations. Peak concentrations occur in 0.5 to 1 hour with the syrup, 1 to 3 hours with the capsule, and 2 to 6 hours with the enteric-coated tablet. The extended-release formulation (Depakote-ER) is FDA approved for patients with migraine headache and epilepsy. The bioavailability of this formulation is approximately 15% less than that of enteric-coated divalproex sodium (Depakote). Valproic acid is extensively bound to albumin, and this binding is saturable. Accordingly, the valproic acid free fraction will increase as the total serum concentration increases. Because of this saturable binding, measurement of unbound serum concentrations may be a better monitoring parameter than the total valproic acid serum concentration, especially at higher concentrations or in patients with hypoalbuminemia. The primary route of valproic acid metabolism is β-oxidation, although up to 40% of a dose may be excreted as glucuronide. At least 10 metabolites of valproic acid have been identified. Some of these may have weak anticonvulsant activity, and at least one metabolite may be responsible for the hepatotoxicity reported. One of the lesser oxidative metabolites, 2-propyl-4-pentenoic acid (4-ene-VPA), causes hepatotoxicity in rats. The formation of this metabolite is increased when valproic acid is given with enzyme-inducing drugs. Valproic acid displays diurnal elimination with lower evening serum levels occurring than morning levels. It crosses into the placenta, and concentrations may be up to five times higher in cord serum blood than in the mother due to higher binding in the fetal compartment.

Efficacy Data

Formulations of valproic acid have been used as the primary comparator drug in patients with primary generalized epilepsies when other medications such as lamotrigine, levetiracetam, topiramate, and zonisamide were added in adjunctive therapy. In complex partial seizures, divalproex sodium was compared in blinded controlled trials to carbamazepine and found to have equal efficacy.

Other Indications for Use

Valproic acid formulations have been indicated for the treatment of mania and the prophylaxis of migraine headaches in adults.

Adverse Effects

The most frequently reported side effects are gastrointestinal, or GI (up to 20%), including nausea, vomiting, anorexia, as well as weight gain. Pancreatitis is rare. GI complaints may be minimized, but not totally alleviated, with the enteric-coated formulation or by giving the drug with food. Alopecia and hair changes are temporary, and hair growth returns even with continued dosing. Weight gain can be significant for many patients and is associated with an increase in fasting insulin and leptin serum levels. The increase in serum insulin is believed to be caused by the inhibition of metabolism of insulin by the liver. This has led to the development of insulin resistance in obese male and female subjects. Valproic acid causes minimal cognitive impairment.

Multiple AEDs can alter the metabolism of valproic acid, leading to increased formation of the potentially liver-toxic 4-ene-VPA. Valproic acid has been shown to alter carnitine metabolism, and it has been postulated that a deficiency of carnitine alters fatty acid oxidation that could lead to both liver toxicity and hyperammonemia. However, valproic acid hepatotoxicity has occurred in a patient taking supplemental carnitine, and a prospective study demonstrated no effect on well-being when carnitine was added. Although carnitine can ameliorate hyperammonemia in part, it is expensive, and there are only limited data to support routine supplemental use in patients taking valproic acid. Thrombocytopenia and alterations in platelet aggregation occur in patients receiving valproic acid, and these phenomena are related to serum concentration. These blood coagulopathies may occur more frequently in children than in adults.

Toxicity, Overdose, and Contraindications

As in the case of other anticonvulsants, a history of known hypersensitivity to valproic acid or any of the closely related compounds is a contraindication for their use as medications in the future. In addition, known mitochondrial disorders, urea cycle disorders, and significant hepatic dysfunction are also contraindications for the use of compounds in the valproic acid family.

Warning and Precautions

Suicidal ideation or similar behaviors should be monitored in patients taking these anticonvulsants. Thrombocytopenia is not an uncommon side effect of chronic therapy with these agents, but severe thrombocytopenia leading to severe bleeding is uncommon. Hepatotoxicity can be fatal, and the risk is greater in neonates, infants, and children. Pancreatitis, hyperammonemia, and multiorgan hypersensitivity reactions have been observed rarely.

Special Safety Concerns

Other alternatives to the use of valproic acid compounds should be examined in all women of childbearing potential. If therapy with these compounds is necessary, folic acid supplementation should be given. The physician should aim at the lowest possible daily dosage that controls the epileptic seizures in these clinical scenarios.

Teratogenicity Information

Valproic acid is a known teratogen with documented increases in spina bifida and decreased cognitive development (decreased intelligence quotient (IQ)) for the child after in utero exposure. The FDA has assigned a pregnancy category D for the indications of epilepsy and for manic episodes associated with bipolar disorder but a pregnancy category X for prophylaxis of migraine headaches.

Drug Interaction

Because it is highly protein bound, other highly protein-bound drugs (eg, free fatty acids and aspirin) can displace valproic acid. However, adding valproic acid to a patient taking phenytoin will transitorily result in an increased free-fraction of phenytoin as valproic acid has a tighter binding to serum proteins, displacing some of the bounded phenytoin. Many of the hepatic inducers of CYP450 will increase the clearance of valproic acid, resulting in lower serum concentrations than otherwise expected. Felbamate increases valproic acid serum concentrations. Valproic acid can inhibit specific CYP450 isozymes, epoxide hydrolase, and glucuronidation (UGT) isozymes. The latter is an important source of valproic acid–drug interaction by inhibiting the metabolism of lamotrigine, easily tripling the half-life of lamotrigine. The addition of valproic acid to phenobarbital results in a 30% to 50% decrease in phenobarbital clearance and significant toxicity if the dose of phenobarbital is not reduced. Data also suggest that combination oral contraceptives may increase the clearance of valproic acid and lower serum levels by 20% (2). In addition, carbapenems, especially merepenem, can lower valproic acid levels. As a hepatic CYP450 enzyme inhibitor, it is involved in multiple drug–drug interactions.

Use in Special Populations

In the elderly, the initial and target doses of valproic acid are lower than in adults by at least 20% to 25%. Children under the age of 2 have a significantly higher incidence of severe hepatotoxicity and these compounds should be avoided, if possible.

Pediatric Use

The safety and tolerability of valproic acid formulations in pediatric patients is comparable to that in adults. However, the incidence of severe hepatotoxicity is significantly higher in neonates and children as compared to adults.