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Recent advances in the pharmacotherapy of epilepsy
CLINICAL THERAPEUTICSVVOL.19, NO. 3, 1997
Recent Advances in the Pharmacotherapy of Epilepsy Michelle K. Bazil, RPh, PhD,I and Carl W. Bazil, MD, Ph@ ‘Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, and 2The Neurological Institute, Columbia Presbyterian Medical Center, New York, New York
ABSTRACT The therapeutic options for the treatment of epilepsy have expanded during the 1990s. Since 1993, four novel agents (felbamate, gabapentin, lamotrigine, and topiramate) have been approved by the US Food and Drug Administration, primarily for adjunctive treatment of partial seizures. In addition, a water-soluble pro-drug of phenytoin, fosphenytoin, and a sustainedrelease preparation of carbamazepine have been introduced. The novel anticonvulsants represent a potential improvement for patients whose seizures are incompletely controlled or who experience significant adverse effects with older anticonvulsants. Felbamate, lamotrigine, and topiramate appear to have a broad spectrum of action in seizure control, but felbamate use is limited by the potential for serious adverse effects. Gabapentin, lamotrigine, and topiramate are all well tolerated. Gabapentin has no known drug in0149-2918/97/$3.50
teractions, whereas lamotrigine and topiramate have limited interactions compared with older agents. The sustained-release preparation of carbamazepine may decrease the incidence of adverse effects and increase patient compliance. Fosphenytoin offers a safer method for intravenous administration of phenytoin and the added flexibility of intramuscular administration. Taken together, these recent advances in treatment may bring about improved efficacy and decreased adverse effects for many patients with epilepsy. Key words: epilepsy, pharmacotherapy, seizures, anticonvulsants. INTRODUCTION Epilepsy is one of the most common neurologic disorders, with an annual incidence of up to 70 cases per 100,000’ and affecting about 3% of the US population.* Although many patients are easily controlled with medication, at least 30% do 369
CLINICAL THERAF’EUT1CS@
not achieve satisfactory control.3 Many other patients are completely controlled but experience significant drug-related adverse effects that decrease their overall quality of life. For these reasons, there has been an active search for new antiepileptic drugs. According to the international classification of seizures,4 epilepsy is divided into two main classes-partial seizures and primary generalized seizures. Partial seizures begin in a discrete area of the cerebral cortex and show focal symptoms at onset (eg, sudden fear or repetitive jerking of an arm). Measurement of the electric activity of the brain with electroencephalography similarly shows a discrete area of abnormal activity at onset. These seizures may spread to other areas of the brain. If the entire brain becomes involved, resulting in a generalized tonicclonic convulsion, this is referred to as a secondarily generalized seizure. Conversely, primary generalized seizures do not have a focal onset but demonstrate diffuse electrical discharges on electroencephalography at onset. One example of a primary generalized seizure is an absence (petit mal) seizure, in which the patient has a lapse of consciousness for several seconds, sometimes accompanied by blinking. A more violent example is a primary generalized tonic-clonic seizure, in which the patient has sudden stiffening of all muscles, followed by rhythmic jerking. This may be indistinguishable from the latter part of a secondarily generalized seizure. The seizure classes described above are important in the choice of drug therapy for epilepsy. Traditionally, partial and generalized tonic-clonic seizures have been treated with phenytoin, phenobarbital, or Primary generalized carbamazepine. 370
seizures have been treated with valproic acid (also effective in partial seizures). Absence seizures are treated with ethosuximide or valproic acid. In individual patients, however, the usefulness of these drugs may be affected by adverse drug reactions, interactions with other medications, or lack of efficacy.5 Since 1993, four novel anticonvulsant drugs have been approved by the US Food and Drug Administration (FDA): felbamate,* gabapentint lamotrigine,* and topiramate.l Two other drugs, fosphenytoin,” a pro-drug of phenytoin, and a sustained-release preparation of carbamazepine, have also been approved. The following discussion highlights the properties, advantages, and disadvantages of each of these new agents. NEW ANTIEPILEPTIC AGENTS Felbamate
When felbamate was released in July 1993, it was the first new anticonvulsant drug licensed in the United States since valproic acid in 1978. Because of potentially life-threatening adverse effects, it carries a warning, and its use is limited to refractory cases in which the risks of ad-
‘Trademark Felbatol” (Wallace Laboratories, Cranbury, New Jersey). ‘Trademark: Neurontin@ (Parke-Davis, Division of Warner-Lambert Company, Morris Plains, New Jersey). $Trademark: Lamictal” (Glaxo Wellcome Inc., Research Triangle Park, North Carolina). STrademark Topamax@ (Ortho-McNeil Pharmaceuticals, Raritan, New Jersey). “Trademark: Cerebyx@ (Parke-Davis, Division of Warner-Lambert Company). ITrademark: Tegretol@-XR (Novartis Ph-ceuticals Corporation, Summit, New Jersey).
M.K. BAZJL AND
C.W. BAZIL
verse effects are outweighed by the risks of uncontrolled seizures. Felbamate does, however, have the broadest FDA indications of all the new anticonvulsant drugs. Felbamate is approved by the FDA for use as monotherapy and adjunctive therapy in the treatment of partial seizures (with or without secondarily generalized seizures) in adults, and as adjunctive therapy in the treatment of seizures associated with Lennox-Gastaut syndrome in children. Many well-performed clinical trials support these therapeutic indications, including monotherapy and add-on use in partial seizure@ and in atonic, atypical absence, and total seizures associated with the Lennox-Gastaut syndrome.9*10 Mechanism
of Action
Felbamate was originahy synthesized as a meprobamate derivative but has none of meprobamate’s sedating properties. Although the actual mechanism of its anticonvulsant action is unknown, a number of effects are known, including channel blockage of the IV-methyl-D-aspartic acid (NMDA)-activated glutamate receptor, gamma-aminobutyric acid (GABA) enhancement, reduced neuronal firing, and an
inhibitory effect on the glutamate receptor through the strychnine-insensitive site.” Phurmacokinetics
As indicated in Table 1,‘*,13felbamate has a favorable pharmacokinetic profile. Absorption does not appear to be affected by food (in fact, it is generally recommended that the drug be taken with meals to minimize side effects). Felbamate is not highly protein bound; however, this is dependent on albumin concentration. The half-life ranges from 14 to 23 hours,‘* allowing for once-daily dosing, but multiple daily doses are recommended to decrease adverse effects. As shown in Table 11,6~12*14 felbamate interacts strongly with other drugs, particularly other anticonvulsants, and this can make add-on therapy complicated. In general, felbamate levels are decreased in the presence of enzyme inducers. l2 Adverse Effects
As shown in Table 111,15,16 relatively rare but serious (sometimes fatal) reactions, including aplastic anemia and hepatotoxicity, have been seen with felbamate. As a result, the use of felbamate in recent
Table I. Pharmacokinetic comparison of new antiepileptic drugs. Felbatnate Usual dose (mg/d) Absorption
Half-life (h) protein binding Hepatic metabolism*
2400-3600 >90%
14-23 25% 50%
Gabapentin 1NO-3600 Dose-dependent: Low dose, 57%; high dose, 35% 5-7 Minimal 0%
Lamotrigine
Topiramate
100-500 >99%
200-400 SO%
25 55% 90%
19-25 9%-17% 30%
*The majority of these drugs and their inactive metabolites are excreted in the mine. Data from Walker and Patsalos,‘* Perucca,13 and Dichter and Brodie.15
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Table II. Interactions
of new antiepileptic
drugs.
Effect on the Plasma Levels of Other Drugs
“Ng FBM GPT LTG TPM
PHT FBM.L PHT? GPT NC PI-IT NC LTGL PHT NC TPMJ PHTNCor?
CBZ
VPA
PB
FBMl CBZ.l* GPT NC CBZ NC LTG& CBZ NC TPMJ CBZ NC
FBM? VPAt GPT NC VPA NC LTGt VPA NC TPMJ VPA-l
FBMl PBT GPT NC PB NC LTG-l PB NC Effect on TPM unknown; PB NC
PHT = phenytoin; CBZ = carbamazepine; VPA = valproate; PB = phenobarbital; PBM = felbamate; GPT = gabapentin; LTG = lamotrigine; TPM = topiramate; NC = no change. *The lO,ll-epoxide metabolite increases, so CBZ dose may require reduction. Data from Bourgeois et aL6 Walker and Patsalos,12 and Bourgeois.14
Table III. Comparison Felbamate Gabapentin Lamotrigine Topiramate
of adverse effects of new antiepileptic
drugs.
Anorexia, headache, nausea, insomnia Rare idiosyncratic reactions: hepatic failure, aplastic anemia Somnolence, dizziness, ataxia, headache, gastrointestinal distress Dizziness, headache, diplopia, nausea, ataxia Idiosyncratic reactions: rash, Stevens-Johnson syndrome Fatigue, dizziness, ataxia, paresthesia, diplopia, cognitive disturbances,
renal stones
Data from Dichter and Brodie15 and Shorvon.‘6
years has been limited to only the most refractory epilepsy cases. There have been 32 cases of aplastic anemia attributed to felbamate, 10 of which were fatal. There was a broad range of age (13 to 70 years) and duration of felbamate exposure (72 to 354 days) and most patients were taking other anticonvulsant drugs at the time. There have also been 19 cases of hepatic failure, 5 of which were fatal. l5 All of these patients were taking other anticonvulsant drugs concomitantly. The total number of patients who have been exposed to felbamate is not known; therefore, the overall
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can only be estimated. Most researchers place the risk at between 1 per 2000 patients and 1 per 8000 patients per exposure. For this reason, patients’ blood count and liver function should be carefully monitored for at least the first year of exposure to felbamate. Even though concomitant administration of another anticonvulsant drug was seen in almost all cases of aplastic anemia and in all cases of hepatic failure, this has not been shown to be an independent risk factor. Other adverse effects are dose dependent and usually transient. Most common risk
M.K. BAZIL AND C.W. BAZIL
are anorexia, weight loss, insomnia, and headache.15 Prudent dosing schedules may help minimize these problems. For example, dosing earlier in the day may help patients who complain of insomnia, dosing with meals may decrease nausea, and dosing schedules of three times daily (TID) or four times daily (QID) may increase overall tolerability. Dosing
Felbamate is available in 400- and 600mg tablets and in a 600-mg/5-mL suspension. The usual starting dose is 600 mg once daily (QD). This is increased by 600mg increments every 3 to 7 days, usually on a twice-daily (BID) schedule if tolerated. The minimal effective dose in adults is generally 2400 mg/d. The recommended maximum dose is 3600 mg/d’*; however, in clinical practice, doses of up to 4800 mg/d have been used without significant side effects. Gabapentin
Gabapentin was the second new antiepileptic drug to be released in the 1990s. Gabapentin has been approved only as add-on therapy in the treatment of partial seizures, and its efficacy has been demonstrated in a number of studies.17~18 There are trials of gabapentin monotherapy in progress. In addition, there are anecdotal reports of efficacy in a wide variety of other conditions, including migraine,19 amyotrophic lateral sclerosis,20 and chronic pain.*’ Mechanism
of Action
Gabapentin was originally synthesized as a GABA-mimetic agent. However, the mechanism of action remains unknown. Gabapentin does not act at any known sub-
type of GABA receptor and does not affect GABA release. In addition, there is no interaction with benzodiazepine, glutamate, glycine, or NMDA receptors and no effect on sodium or calcium channels. It has been suggested that gabapentin acts through alteration of the metabolism of brain amino acids, especially glutamate.** Gabapentin is known to bind with high affinity to a unique site in the central nervous system (CNS)23;however, the relationship (if any) of this site to gabapentin’s anticonvulsant properties remains unknown. Pharmacokinetics
Gabapentin has a unique pharmacokinetic profile (Table I). The most interesting and important aspect of gabapentin pharmacokinetics is its dose-dependent absorption. After oral administration of a 300-mg dose, the bioavailability is 57%; however, this falls to 42% with a 600-mg dose and 35% at higher doses.24 This occurs because the drug is absorbed via the large neutral amino acid transporter system in the intestine, which is saturable. As the dose increases, absorption becomes less efficient, and both the rate and extent of absorption are decreased.25 Absorption pharmacokinetics are not altered by food. The half-life of gabapentin is 5 to 7 hours; consequently, TID dosing is usually required. Gabapentin is excreted unchanged in the urine, and renal clearance is linearly related to creatinine clearance.” Doses in patients with renal insufficiency must therefore be reduced, as the drug is removed by dialysis. Gabapentin is an ideal drug to be used in polytherapy or in complicated cases in which patients are receiving many medications (Table II). Because gabapentin has no effect on hepatic enzyme systems, it does not affect the metabolism of other anticonvulsant drugs and 373
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is not itself affected by them.2G2*It also is not protein bound and so will not displace protein-bound drugs such as phenytoin. To date, the only reported drug interactions with gabapentin are the observations of a 20% reduction in bioavailability of gabapentin when administered with an aluminum/magnesium antacid29 and a decrease in clearance of gabapentin when administered with cimetidine.25 Adverse Efects Gabapentin is generally well tolerated. The most common side effects include somnolence, dizziness, ataxia, headache, and gastrointestinal distress, all of which are usually mild and self-limited (Table III).15 No serious or idiosyncratic reactions have been documented to date.15 Dosing Gabapentin is available in lOO-, 300-, and 400-mg capsules. The usual recommended starting dose is 300 mg per day, which is increased daily by 300-mg increments. However, some clinicians begin at higher doses and titrate more rapidly. Mild side effects typically resolve with slower titration. The recommended final daily dose is 900 to 1800 mg, administered TID or QID. In practice, however, most patients require at least 1800 mg/d for treatment of epilepsy, and doses of 3600 to 4800 mg/d are commonplace. Lamotrigine
Lamotrigine is approved as add-on therapy in adult patients with partial seizures.30,31 There has been one large trial32 of lamotrigine monotherapy versus carbamazepine in new-onset seizure patients; this study showed that the drugs have equivalent efficacy and that lamotrigine 374
may be somewhat better tolerated overall. In addition, there is considerable evidence that lamotrigine has a broad spectrum of action (similar to that of valproic acid) and is effective in other seizure types, including absence,33*34atypical absence, myoclonic, atonic, and primary generalized seizures.35 Although it is not yet approved for use in children, there is abundant evidence of its safety and efficacy in this population.34*36T37 However, caution should be used, especially in younger children, as the incidence of severe skin reactions appears to be much higher than in adults. There are also anecdotal reports of lamotrigine use in the treatment of chronic pain. Mechanism of Action Lamotrigine was originally synthesized as an antifolate compound. The drug has been shown to act at voltage-sensitive sodium channels to inhibit release of glutamate, which may explain its anticonvulsant effect.38 Pharmacokinetics Lamotrigine is well absorbed after oral dosing, with peak plasma concentrations occurring in 1.5 to 4 hours. Unlike gabapentin, lamotrigine shows a linear relationship between oral dose and plasma concentration. Lamotrigine is not highly protein bound and does not compete for binding sites with phenytoin, valproic acid, or other highly bound agents. The plasma half-life of lamotrigine in monotherapy is 25 hours.15 However, this is affected dramatically by coadministration of drugs that affect hepatic microsomal enzymes (Table II). In the presence of enzyme inducers, the half-life decreases to about 12 to 14 hours. With an enzymeinhibiting drug such as valproic acid, the half-life of lamotrigine increases to 60
M.K. BAZIL AND C.W. BAZIL
hours. Because lamotrigine does not affect hepatic enzymes and is not highly protein bound, there is no appreciable effect of lamotrigine on other drugs, with the possible exception of increased levels of the lO,ll-epoxide metabolite of carbamazepine.12 Adverse Effects
The adverse-effect profile of lamotrigine is generally favorable (Table III). The most common side effects include dizziness, headache, diplopia, unsteadiness, and double or blurred vision.15 Gastrointestinal side effects such as nausea are also common but are usually mild and self-limiting. Much attention has been given to the incidence of rash, which occurred in up to 10% of patients in the initial trials. In 3 of every 1000 patients, the rash was severe enough to require hospitalization. The occurrence of rash is increased with rapid dose escalation and with concomitant valproic acid administration.15 As a result, the current recommendation is to titrate the drug slowly, particularly in the presence of valproic acid. However, it should also be noted that most patients can be safely rechallenged after an initial mild rash. A trial of lamotrigine versus carbamazepine in monotherapy actually showed a higher incidence of rash with carbamazepine.15 Dosing
Lamotrigine is available in 25-, lOO-, 150-, and 200-mg scored tablets. To minimize the occurrence of rash, therapy is usually begun slowly and titrated over 6 weeks to the minimal effective dose. In patients taking valproic acid, the initial dose is 25 mg every other day, and the target dose is 50 mg BID. With enzymeinducing agents, the initial dose is 50 mg
QD with a target dose of 150 mg BID and, in monotherapy, 25 mg QD initially with a target dose of 100 mg BID. Topiramate
Topiramate is the newest treatment option for epilepsy. It is a structurally unique agent chemically related to the o-enantiomer of fructose. Topiramate has been approved as adjunctive therapy in adults with partial seizures.3941 Clinical trials investigating the use of topiramate as monotherapy in partial seizures and in other seizure types are in progress. Mechanism of Action
Topiramate’s mechanism of action is unknown, although, like felbamate, there are a number of possible relevant effects, including state-dependent blockade of voltage-activated sodium channels, enhanced GABA activity at GABA, receptors, and antagonism of non-NMDA glutamate receptors.42v43 Phrmacokinetics
Topiramate has a favorable pharmacokinetic profile with good bioavailability, a long half-life, and low protein binding (Table I). Because the drug is eliminated primarily via the kidney, dosage reductions are necessary in patients with renal impairment.13 Although the drug has a long half-life, BID dosing is often used to minimize adverse effects. Topiramate has no appreciable effect on other antiepileptic agents, but other antiepileptic agents can affect the clearance of topiramate (Table II). Adverse Effects
Topiramate is generally well tolerated. The major adverse effects appear to be 375
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CNS related and include cognitive impairment (eg, difficulty in word finding) and fatigue or somnolence. Other observed effects include dizziness, diplopia, nervousness, and confusion.16 Renal stones occurred in 1.5% of patients in the initial trial~‘~; this is a higher rate than expected in the general population and is consistent with the drug’s action as a mild carbonic anhydrase inhibitor.
Dosing Topiramate is available as 25-, loo-, and 200-mg tablets. Therapy is initiated at 50 mg daily and titrated to an effective dose of 200 to 400 mg/d, although up to 1000 mgld has been used.15
Fosphenytoin
Mechanism of Action
Fosphenytoin is a water-soluble prodrug of phenytoin. It is rapidly converted into phenytoin in vivo; thereafter, fosphenytoin’s properties are identical to those of phenytoin. A comparison of the properties of the two drugs is shown in Table IV.44*45The difference lies in fospheny-
Table IV. Comparison
toin’s improved flexibility and tolerability in dosing when compared with intravenous (Iv) phenytoin, which is dissolved in a solution of 40% propylene glycol and 10% ethanol at pH 12 because of its poor water solubility. Parenteral phenytoin requires slow lV infusion in glucose-free solutions to prevent precipitation of the phenytoin, with side effects of hypotension, bmdycardia, and thrombophlebitis caused by the vehicle itself. Phenytoin cannot be given intramuscularly (lM) because of poor absorption and the risk of abscess formation. To avoid these problems, the pro-drug fosphenytoin was developed. Fosphenytoin is indicated for the treatment of adults with partial or generalized seizures when parenteral administration is desired.
of fosphenytoin
Because fosphenytoin is rapidly and completely converted into phenytoin, its mechanism of action in the control of seizures-inhibition of voltage-sensitive sodium channels-is identical to that of phenytoin. Fosphenytoin has no known intrinsic activity before conversion.
and phenytoin. Fosphenytoin
Route of administration Maximum IV infusion rate Time to maximum serum level Adverse effects
IV solution compatibility
IVorIM 150 mg PE/min 20 min Paresthesias; pnuitus; dizziness; ataxia; hypotension; somnolence; nystagmus Dextrose or saline
IV = intravenous; IM = intramuscular; PE = phenytoiu equivalents. Data from Bebin and Sk&“ and Marchetti et a1.45
376
Phenytoin Iv
50 mg/min 20 ruin Infusion site pain, burning, and phlebitis; dizziness; ataxia; somnolence; hypotension; nystagmus Saline
M.K. BAZLL AND C.W. BAZIL
Phnnacokinetics
Fosphenytoin is rapidly converted into phenytoin (within 20 minutes) by phosphatases located throughout the body, with a mean half-life of 8.1 minutes.‘@This conversion appears to be independent of age, although children younger than 5 years have not been studied. For this reason, therapeutic serum levels of phenytoin are achieved at about the same time whether the drug is administered quickly, in its prodrug form (fosphenytoin), or slowly, as the drug itself. When compared with equivalent IV phenytoin doses, the bioavailability of fosphenytoin is approximately lOO%, whether administered IV or IM.44 Fosphenytoin, like phenytoin, is highly bound to plasma proteins, particularly albumin. In fact, fosphenytoin is more tightly bound and will displace phenytoin. Therefore, in a patient taking phenytoin, an infusion of fosphenytoin may cause a transient increase in the serumfree phenytoin level as a result of displacement. l2 As the fosphenytoin is converted into phenytoin, the ratio of bound phenytoin to free phenytoin will return to baseline. This is not typically clinically relevant, as the desired effect is increased phenytoin levels. Because the pro-drug is rapidly and completely converted into phenytoin, drug interactions will be identical to those of phenytoin. Adverse Effects The side-effect profile of fosphenytoin
is generally favorable compared with IV phenytoin. Adverse effects unique to fosphenytoin are paresthesias and pruritus, which frequently occur in the perineal region. These are similar to effects seen with IV infusion of other phosphate esters (eg, dexamethasone).46 Nystagmus, dizziness,
ataxia, hypotension, and somnolence occurred at a frequency about equal to that of phenytoin. Other side effects specifically associated with the infusion (eg, local burning, pain, and phlebitis) were seen much less frequently with IV fosphenytoin than with IV phenytoin. Dosing
Because fosphenytoin is supplied in phenytoin equivalents, calculations for equivalent dosing are not required. The molecular weight of fosphenytoin is 50% higher than that of phenytoin; therefore, a 50% increase in the milligram dose is necessary to achieve a dose equivalent to the phenytoin dose. Fosphenytoin may be administered IV or IM. One controversial issue is the decision of the manufacturer of fosphenytoin (Parke-Davis, Division of WarnerLambert Company, Morris Plains, New Jersey) to discontinue production of parenteral phenytoin. However, generic phenytoin is still available. As a result, the potential for confusion and improper administration exists if institutions choose to stock both parenteral phenytoin and fosphenytoin.
Sustained-Release Carbamazepine Carbamazepine is widely used in the treatment of generalized tonic-clonic seizures. One of the limitations of carbamazepine therapy is its relatively short half-life, requiring TID or QID dosing and adversely affecting compliance. Furthermore, plasma drug levels may fluctuate, resulting in the increased frequency of adverse effects and the inability to reach plasma levels adequate for optimal efficacy.47,48The introduction of a sustained311
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Table V. Average wholesale price of new antiepileptic drugs. Dw
Cost of a 30-Day Supply ($)
Felbamate Gabapentin Lamotrigine Topiramate
62.73 88.88 49.68 147.60
Data from Redbook Upuhte.50”’
release formulation is an attempt to improve compliance and decrease adverse effects by decreasing the magnitude of the fluctuations in plasma drug levels. Carbamazepine sustained release decreased fluctuations in serum carbamazepine concentrations by 50% when compared with prompt-release carbamazepine and was associated with fewer adverse effects.12 Historically, a decrease from QlD or TlD to BID dosing has improved patient compliance.49 For conversion to sustained-release carbamazepine, the total daily dosage of immediaterelease carbamazepine is divided in two and given BlD. Sustained-release carbamazepine is supplied as lOO-, 200-, and 400-mg tablets. It is important to note that the sustained-release tablets must be swallowed whole to avoid disruption of the sustained-release mechanism, and patients should be advised that the empty shell will be excreted in the feces. DRUG LEVELS Although therapeutic levels have not been determined for the four new antiepileptic agents, monitoring of these plasma levels can be used to assess compliance. In addition, as doses are titrated up, the degree 378
of absorption of gabapentin can be evaluated by monitoring blood levels. COST Although the cost of the new antiepileptic drugs (Table V) must also be considered, cost-effectiveness and pharmacoeconomic issues-not merely acquisition cost-must be included in any decisions tegarding formulary inclusion, For example, increased compliance with BID sustainedrelease carbamazepine may lead to decreased adverse effects and improved efftcacy, which would greatly offset the difference in acquisition cost compared with generic carbamazepine. Furthermore, if the new antiepileptic agents allow improved clinical management of epilepsy patients, their overall costs may be lower than those of traditional therapies. Detailed pharmacoeconomic evaluations comparing all of the therapeutic options for epileptic patients would help resolve this issue. A 30-day supply of carbamazepine and sustained-release carbamazepine cost the same, whereas generic carbamazepine costs approximately 40% less.50s51A recent pharmacoeconomic comparison of phenytoin and fosphenytoin revealed an 11% cost savings with fosphenytoin. This
M.K. BAZIL AND C.W. BAZIL
cost savings was realized despite an acquisition cost of $6.72 per loading dose for phenytoin versus $90.00 for fosphenytoin. The reduction in cost was associated with fewer adverse effects with fosphenytoin.51 OTHER NEW AGENTS Several other novel anticonvulsant drugs have been submitted for final approval and may be released by late 1998; two of these drugs are vigabatrin* and tiagabine.7 Vigabatrin was synthesized as an inhibitor of GABA transaminase, and, in fact, its anticonvulsant effects result from this mechanism of action. Vigabatrin appears to be most effective in partial seizure disorders, although it is being used extensively for the treatment of infantile spasms. l2 Tiagabine is thought to enhance GABA-ergic neurotransmission via inhibition of uptake of GABA into cells.12 CONCLUSIONS The place each of these new agents will hold in the armamentarium against seizures has yet to be determined. It is important, however, that the novel anticonvulsant drugs represent a potential improvement for patients whose seizures are incompletely controlled by or who experience significant adverse effects from older anticonvulsant drugs. Felbamate, lamotrigine, and topiramate appear to have broad spectrums of action and may be particularly useful in the treat-
*Trademark: Sabril@ (Hoechst Marion Roussel, Kansas City, Missouri). TTrademark:Gabatril@(Abbott Laboratories, Abbott Park, Illinois).
ment of patients with generalized seizures who previously had few alternatives to valproic acid. However, felbamate use is limited by the potential for liver and bone marrow toxicity. Gabapentin has no known drug interactions, making it particularly useful in patients receiving concurrent medications. There is some evidence that lamotrigine may be better tolerated overall than the current firstline anticonvulsant, carbamazepine. However, the introduction of a sustainedrelease preparation of carbamazepine may decrease the incidence of adverse effects and increase patient compliance. Fosphenytoin offers a safer method for IV administration of phenytoin and the added flexibility of IM administration. As more is learned about the use and long-term efficacy of these and other new drugs, the hope is that they can meet the goal of improved quality of life for patients with epilepsy. Address correspondence to: Michelle K. Bazil, RPh, PhD, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 Dekalb Avenue, Brooklyn, NY 11201. REFERENCES Shorvon SD. Epidemiology, classification, natural history, and genetics of epilepsy. Luncet. 1990;336:93-96. Hauser WA, Kurland LY. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia. 1975;16: l-66. Dreifuss FE. New antiepileptic drug development. Epilepsia. 1994;35(Suppl 5): s6-S9.
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1994;35(Suppl5):S54-s57. 10. The Felbamate Study Group in LennoxGastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). NEJM. 1993;328:29-33. 11. Rho JM, Dovevan DS, Rogawski MA. Mechanism of action of the anticonvulsant felbamate: Opposing effects on Nmethyl-o-aspartate and gamma-aminobutyric acid, receptors. Ann Neurol. 1994; 35:229-234.
12. Walker MC, Patsalos PN. Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol The,: 1995;67:351-384.
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18. Bruni J, Saunders M, Anhut H. Efficacy and safety of gabapentin (Neurontin): A multicenter, placebo-controlled, double blind study. Neurology. 1991;41(Suppl 1): 330-331. 19. Mathew NT, Lucker C. Gabapentin in migraine prophylaxis: A preliminary open label study. Neurology. 1996;46:A169. Abstract. 20. Miller RG, Gelinas D, Moore D, et al. A placebo-controlled trial of gabapentin in amyotrophic lateral sclerosis. Neurology. 1996;46:A469. Abstract. 21. Mellick LB, Mellick GA. Successful treatment of reflex sympathetic dystrophy with gabapentin. Am J Emerg Med. 1995;13:96. Letter. 22. Taylor CP. Emerging perspectives on the mechanism of action of gabapentin. Neurology. 1994;44(Suppl S):SlO-S16. 23. Hill DR, Suman-Chauhan N, Woodruff GN. Localization of r3H]-gabapentin to a novel site in rat brain: Autoradiographic
M.K. BAZILAND C.W. BAZIL
studies. Eur J Pharmacol Mol Phannacol Sect. 1993:244:303-309. 24. McLean MI. Clinical pharmacokinetics of
gabapentin. Neurology. 1994;44(Suppl5): S 17-S22. 25. Richens A. Clinical pharmacokinetics of gabapentin. The role of gabapentin. In: Chadwick D, ed. New Trends in Epilepsy Management. London: Royal Society of Medicine Services Limited; 1993:41-46. 26. Hooper WD, Kavanagh MC, Herkes GK, Eadie MJ. Lack of a pharmacokinetic interaction between phenobarbitone and gabapentin. Br J Clin Pharmacol. 1991; 31:171-174. 27. Anhut H, Leppik I, Schmidt B, Thomann
P. Drug interaction study of the new anticonvulsant gabapentin with phenytoin in epileptic patients. Naunyn-Schmiedeberg’s Arch Pharmacol.
33. Panayiotopoulos CP, Ferrie CD, Knott C, Robinson RO. Interaction of lamotrigine with sodium valproate. Lancet. 1993;341: 445. Letter. 34. Besag FMC, Wallace SJ, Dulac 0, et al. Lamotrigine for the treatment of epilepsy in childhood. J Pediatr. 1995;127: 991-996.
35. Timmings PL, Richens A. Lamotrigine for generalized epilepsies. Lancet. 1992;339: 130&1301. 36. Schlumberger E, Chavez F, Palacios L, et al. Lamotrigine in treatment of 120 children with epilepsy. Epilepsia. 1994;35: 359-367.
1988;337:R127.
37. Battino D, Buti D, Croci D, et al. Lamotrigine in resistant childhood epilepsy.
Abstract. 28. Radulovic LL, Wilder BJ, Leppik IE, et
al. Lack of interaction of gabapentin with carbamazepine or valproate. Epilepsia. 1994:35:155-161. 29. Busch JA, Radulovic LL, Bockbrader HN,
et al. Effect of Maalox TC on single-dose pharmacokinetics of gabapentin capsules in healthy subjects. Pharm Res. 1992; 9:S315. Abstract. 30. Messenheimer
J, Ramsay RE, Wilmore LJ, et al. Lamotrigine therapy for partial seizures: A multicenter, placebo-controlled, double-blind, cross-over trial. Epilepsia.
32. Brodie MJ. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet. 1995;345: 476-479.
1994;35:113-121.
31. Matsuo F, Bergen D, Faught E, et al. Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. Neurology. 1993;43: 2284-2291.
Neuropediatrics.
1993;24:332-336.
38. Leach MJ, Marden CM, Miller AA. Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action. Epilepsia. 1986;27:49W97. 39. Shariet M, Viteri C, Ben-Menachem E, et al. Double-blind, placebo-controlled study of topiramate in patients with refractory partial epilepsy. Epilepsy Res. 1996; 251217-224.
40. Tassinari C, Michelucci R, Chauvel P, et al. Double-blind, placebo-controlled trial of topiramate (600 mg/day) for the treatment of refractory partial epilepsy. Epilepsia. 1996;37:763-768.
41. Faught E, Wilder BBJ, Ramsay RE, et al. Topiramate placebo-controlled dose-rang-
381
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ing trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages. Neurology. 1996;46:1684-1690. 42. Coulter DA, Sombati S, DeLorenzo RJ. Selective effects of topiramate on sustained repetitive fling and spontaneous bursting in cultured hippocampal neurons. Epilepsia. 1993;34(Suppl 2):123. Abstract.
46. Czerwinski AW, Czerwinski AR, Whitsett TL, et al. Effects of a single, large, intravenous injection of dexamethazone. Clin Phamacol Thel: 1972;13:638-642. 47. Hoppener RJ, Kuyer A, Meijer JWA, Hulsman J. Correlations between daily fluctuations of carbamazepine serum levels and intermittent side effects. Epilepsiu. 1980;21:341-350.
43. Brown SD, Wolf HH, Swinyard EA, et al.
The novel anticonvulsant topiramate enhances GABA-mediated chloride flux. Epilepsia. 1993;34(Suppl 2):122-123. Abstract. 44. Bebin M, Bleck TI? New anticonvulsant drugs: Focus on flunarizine, fosphenytoin, midazolam and stirpentol. Drugs. 1994; 48:153-171.
48. Riva R, Albani F, Ambrosetto G, et al. Diurnal fluctuations in free and total steadystate plasma levels of carbamazepine and correlation with intermittent side effects. Epilepsia. 1984;25:476-48 1. 49. Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel assessment technique. JAMA. 1989;261:3273-3277.
45. Marchetti A, Magar R, Fischer J, et al. A
pharmacoeconomic evaluation of intravenous fosphenytoin (Cerebyx) versus intravenous phenytoin (Dilantin) in hospital emergency departments. Clin Thel: 1996; 18:953-966.
382
50. Redbook Update. Montvale, NJ: Medical Economics; December 1996. 51. Redbook Update. Montvale, NJ: Medical Economics; January 1997.
Recent Advances in the Pharmacotherapy of Epilepsy Michelle K. Bazil, RPh, PhD,I and Carl W. Bazil, MD, Ph@ ‘Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, and 2The Neurological Institute, Columbia Presbyterian Medical Center, New York, New York
ABSTRACT The therapeutic options for the treatment of epilepsy have expanded during the 1990s. Since 1993, four novel agents (felbamate, gabapentin, lamotrigine, and topiramate) have been approved by the US Food and Drug Administration, primarily for adjunctive treatment of partial seizures. In addition, a water-soluble pro-drug of phenytoin, fosphenytoin, and a sustainedrelease preparation of carbamazepine have been introduced. The novel anticonvulsants represent a potential improvement for patients whose seizures are incompletely controlled or who experience significant adverse effects with older anticonvulsants. Felbamate, lamotrigine, and topiramate appear to have a broad spectrum of action in seizure control, but felbamate use is limited by the potential for serious adverse effects. Gabapentin, lamotrigine, and topiramate are all well tolerated. Gabapentin has no known drug in0149-2918/97/$3.50
teractions, whereas lamotrigine and topiramate have limited interactions compared with older agents. The sustained-release preparation of carbamazepine may decrease the incidence of adverse effects and increase patient compliance. Fosphenytoin offers a safer method for intravenous administration of phenytoin and the added flexibility of intramuscular administration. Taken together, these recent advances in treatment may bring about improved efficacy and decreased adverse effects for many patients with epilepsy. Key words: epilepsy, pharmacotherapy, seizures, anticonvulsants. INTRODUCTION Epilepsy is one of the most common neurologic disorders, with an annual incidence of up to 70 cases per 100,000’ and affecting about 3% of the US population.* Although many patients are easily controlled with medication, at least 30% do 369
CLINICAL THERAF’EUT1CS@
not achieve satisfactory control.3 Many other patients are completely controlled but experience significant drug-related adverse effects that decrease their overall quality of life. For these reasons, there has been an active search for new antiepileptic drugs. According to the international classification of seizures,4 epilepsy is divided into two main classes-partial seizures and primary generalized seizures. Partial seizures begin in a discrete area of the cerebral cortex and show focal symptoms at onset (eg, sudden fear or repetitive jerking of an arm). Measurement of the electric activity of the brain with electroencephalography similarly shows a discrete area of abnormal activity at onset. These seizures may spread to other areas of the brain. If the entire brain becomes involved, resulting in a generalized tonicclonic convulsion, this is referred to as a secondarily generalized seizure. Conversely, primary generalized seizures do not have a focal onset but demonstrate diffuse electrical discharges on electroencephalography at onset. One example of a primary generalized seizure is an absence (petit mal) seizure, in which the patient has a lapse of consciousness for several seconds, sometimes accompanied by blinking. A more violent example is a primary generalized tonic-clonic seizure, in which the patient has sudden stiffening of all muscles, followed by rhythmic jerking. This may be indistinguishable from the latter part of a secondarily generalized seizure. The seizure classes described above are important in the choice of drug therapy for epilepsy. Traditionally, partial and generalized tonic-clonic seizures have been treated with phenytoin, phenobarbital, or Primary generalized carbamazepine. 370
seizures have been treated with valproic acid (also effective in partial seizures). Absence seizures are treated with ethosuximide or valproic acid. In individual patients, however, the usefulness of these drugs may be affected by adverse drug reactions, interactions with other medications, or lack of efficacy.5 Since 1993, four novel anticonvulsant drugs have been approved by the US Food and Drug Administration (FDA): felbamate,* gabapentint lamotrigine,* and topiramate.l Two other drugs, fosphenytoin,” a pro-drug of phenytoin, and a sustained-release preparation of carbamazepine, have also been approved. The following discussion highlights the properties, advantages, and disadvantages of each of these new agents. NEW ANTIEPILEPTIC AGENTS Felbamate
When felbamate was released in July 1993, it was the first new anticonvulsant drug licensed in the United States since valproic acid in 1978. Because of potentially life-threatening adverse effects, it carries a warning, and its use is limited to refractory cases in which the risks of ad-
‘Trademark Felbatol” (Wallace Laboratories, Cranbury, New Jersey). ‘Trademark: Neurontin@ (Parke-Davis, Division of Warner-Lambert Company, Morris Plains, New Jersey). $Trademark: Lamictal” (Glaxo Wellcome Inc., Research Triangle Park, North Carolina). STrademark Topamax@ (Ortho-McNeil Pharmaceuticals, Raritan, New Jersey). “Trademark: Cerebyx@ (Parke-Davis, Division of Warner-Lambert Company). ITrademark: Tegretol@-XR (Novartis Ph-ceuticals Corporation, Summit, New Jersey).
M.K. BAZJL AND
C.W. BAZIL
verse effects are outweighed by the risks of uncontrolled seizures. Felbamate does, however, have the broadest FDA indications of all the new anticonvulsant drugs. Felbamate is approved by the FDA for use as monotherapy and adjunctive therapy in the treatment of partial seizures (with or without secondarily generalized seizures) in adults, and as adjunctive therapy in the treatment of seizures associated with Lennox-Gastaut syndrome in children. Many well-performed clinical trials support these therapeutic indications, including monotherapy and add-on use in partial seizure@ and in atonic, atypical absence, and total seizures associated with the Lennox-Gastaut syndrome.9*10 Mechanism
of Action
Felbamate was originahy synthesized as a meprobamate derivative but has none of meprobamate’s sedating properties. Although the actual mechanism of its anticonvulsant action is unknown, a number of effects are known, including channel blockage of the IV-methyl-D-aspartic acid (NMDA)-activated glutamate receptor, gamma-aminobutyric acid (GABA) enhancement, reduced neuronal firing, and an
inhibitory effect on the glutamate receptor through the strychnine-insensitive site.” Phurmacokinetics
As indicated in Table 1,‘*,13felbamate has a favorable pharmacokinetic profile. Absorption does not appear to be affected by food (in fact, it is generally recommended that the drug be taken with meals to minimize side effects). Felbamate is not highly protein bound; however, this is dependent on albumin concentration. The half-life ranges from 14 to 23 hours,‘* allowing for once-daily dosing, but multiple daily doses are recommended to decrease adverse effects. As shown in Table 11,6~12*14 felbamate interacts strongly with other drugs, particularly other anticonvulsants, and this can make add-on therapy complicated. In general, felbamate levels are decreased in the presence of enzyme inducers. l2 Adverse Effects
As shown in Table 111,15,16 relatively rare but serious (sometimes fatal) reactions, including aplastic anemia and hepatotoxicity, have been seen with felbamate. As a result, the use of felbamate in recent
Table I. Pharmacokinetic comparison of new antiepileptic drugs. Felbatnate Usual dose (mg/d) Absorption
Half-life (h) protein binding Hepatic metabolism*
2400-3600 >90%
14-23 25% 50%
Gabapentin 1NO-3600 Dose-dependent: Low dose, 57%; high dose, 35% 5-7 Minimal 0%
Lamotrigine
Topiramate
100-500 >99%
200-400 SO%
25 55% 90%
19-25 9%-17% 30%
*The majority of these drugs and their inactive metabolites are excreted in the mine. Data from Walker and Patsalos,‘* Perucca,13 and Dichter and Brodie.15
371
CLINICAL THERAPEUTICS”
Table II. Interactions
of new antiepileptic
drugs.
Effect on the Plasma Levels of Other Drugs
“Ng FBM GPT LTG TPM
PHT FBM.L PHT? GPT NC PI-IT NC LTGL PHT NC TPMJ PHTNCor?
CBZ
VPA
PB
FBMl CBZ.l* GPT NC CBZ NC LTG& CBZ NC TPMJ CBZ NC
FBM? VPAt GPT NC VPA NC LTGt VPA NC TPMJ VPA-l
FBMl PBT GPT NC PB NC LTG-l PB NC Effect on TPM unknown; PB NC
PHT = phenytoin; CBZ = carbamazepine; VPA = valproate; PB = phenobarbital; PBM = felbamate; GPT = gabapentin; LTG = lamotrigine; TPM = topiramate; NC = no change. *The lO,ll-epoxide metabolite increases, so CBZ dose may require reduction. Data from Bourgeois et aL6 Walker and Patsalos,12 and Bourgeois.14
Table III. Comparison Felbamate Gabapentin Lamotrigine Topiramate
of adverse effects of new antiepileptic
drugs.
Anorexia, headache, nausea, insomnia Rare idiosyncratic reactions: hepatic failure, aplastic anemia Somnolence, dizziness, ataxia, headache, gastrointestinal distress Dizziness, headache, diplopia, nausea, ataxia Idiosyncratic reactions: rash, Stevens-Johnson syndrome Fatigue, dizziness, ataxia, paresthesia, diplopia, cognitive disturbances,
renal stones
Data from Dichter and Brodie15 and Shorvon.‘6
years has been limited to only the most refractory epilepsy cases. There have been 32 cases of aplastic anemia attributed to felbamate, 10 of which were fatal. There was a broad range of age (13 to 70 years) and duration of felbamate exposure (72 to 354 days) and most patients were taking other anticonvulsant drugs at the time. There have also been 19 cases of hepatic failure, 5 of which were fatal. l5 All of these patients were taking other anticonvulsant drugs concomitantly. The total number of patients who have been exposed to felbamate is not known; therefore, the overall
372
can only be estimated. Most researchers place the risk at between 1 per 2000 patients and 1 per 8000 patients per exposure. For this reason, patients’ blood count and liver function should be carefully monitored for at least the first year of exposure to felbamate. Even though concomitant administration of another anticonvulsant drug was seen in almost all cases of aplastic anemia and in all cases of hepatic failure, this has not been shown to be an independent risk factor. Other adverse effects are dose dependent and usually transient. Most common risk
M.K. BAZIL AND C.W. BAZIL
are anorexia, weight loss, insomnia, and headache.15 Prudent dosing schedules may help minimize these problems. For example, dosing earlier in the day may help patients who complain of insomnia, dosing with meals may decrease nausea, and dosing schedules of three times daily (TID) or four times daily (QID) may increase overall tolerability. Dosing
Felbamate is available in 400- and 600mg tablets and in a 600-mg/5-mL suspension. The usual starting dose is 600 mg once daily (QD). This is increased by 600mg increments every 3 to 7 days, usually on a twice-daily (BID) schedule if tolerated. The minimal effective dose in adults is generally 2400 mg/d. The recommended maximum dose is 3600 mg/d’*; however, in clinical practice, doses of up to 4800 mg/d have been used without significant side effects. Gabapentin
Gabapentin was the second new antiepileptic drug to be released in the 1990s. Gabapentin has been approved only as add-on therapy in the treatment of partial seizures, and its efficacy has been demonstrated in a number of studies.17~18 There are trials of gabapentin monotherapy in progress. In addition, there are anecdotal reports of efficacy in a wide variety of other conditions, including migraine,19 amyotrophic lateral sclerosis,20 and chronic pain.*’ Mechanism
of Action
Gabapentin was originally synthesized as a GABA-mimetic agent. However, the mechanism of action remains unknown. Gabapentin does not act at any known sub-
type of GABA receptor and does not affect GABA release. In addition, there is no interaction with benzodiazepine, glutamate, glycine, or NMDA receptors and no effect on sodium or calcium channels. It has been suggested that gabapentin acts through alteration of the metabolism of brain amino acids, especially glutamate.** Gabapentin is known to bind with high affinity to a unique site in the central nervous system (CNS)23;however, the relationship (if any) of this site to gabapentin’s anticonvulsant properties remains unknown. Pharmacokinetics
Gabapentin has a unique pharmacokinetic profile (Table I). The most interesting and important aspect of gabapentin pharmacokinetics is its dose-dependent absorption. After oral administration of a 300-mg dose, the bioavailability is 57%; however, this falls to 42% with a 600-mg dose and 35% at higher doses.24 This occurs because the drug is absorbed via the large neutral amino acid transporter system in the intestine, which is saturable. As the dose increases, absorption becomes less efficient, and both the rate and extent of absorption are decreased.25 Absorption pharmacokinetics are not altered by food. The half-life of gabapentin is 5 to 7 hours; consequently, TID dosing is usually required. Gabapentin is excreted unchanged in the urine, and renal clearance is linearly related to creatinine clearance.” Doses in patients with renal insufficiency must therefore be reduced, as the drug is removed by dialysis. Gabapentin is an ideal drug to be used in polytherapy or in complicated cases in which patients are receiving many medications (Table II). Because gabapentin has no effect on hepatic enzyme systems, it does not affect the metabolism of other anticonvulsant drugs and 373
CLINICAL THERAPEUTICS”
is not itself affected by them.2G2*It also is not protein bound and so will not displace protein-bound drugs such as phenytoin. To date, the only reported drug interactions with gabapentin are the observations of a 20% reduction in bioavailability of gabapentin when administered with an aluminum/magnesium antacid29 and a decrease in clearance of gabapentin when administered with cimetidine.25 Adverse Efects Gabapentin is generally well tolerated. The most common side effects include somnolence, dizziness, ataxia, headache, and gastrointestinal distress, all of which are usually mild and self-limited (Table III).15 No serious or idiosyncratic reactions have been documented to date.15 Dosing Gabapentin is available in lOO-, 300-, and 400-mg capsules. The usual recommended starting dose is 300 mg per day, which is increased daily by 300-mg increments. However, some clinicians begin at higher doses and titrate more rapidly. Mild side effects typically resolve with slower titration. The recommended final daily dose is 900 to 1800 mg, administered TID or QID. In practice, however, most patients require at least 1800 mg/d for treatment of epilepsy, and doses of 3600 to 4800 mg/d are commonplace. Lamotrigine
Lamotrigine is approved as add-on therapy in adult patients with partial seizures.30,31 There has been one large trial32 of lamotrigine monotherapy versus carbamazepine in new-onset seizure patients; this study showed that the drugs have equivalent efficacy and that lamotrigine 374
may be somewhat better tolerated overall. In addition, there is considerable evidence that lamotrigine has a broad spectrum of action (similar to that of valproic acid) and is effective in other seizure types, including absence,33*34atypical absence, myoclonic, atonic, and primary generalized seizures.35 Although it is not yet approved for use in children, there is abundant evidence of its safety and efficacy in this population.34*36T37 However, caution should be used, especially in younger children, as the incidence of severe skin reactions appears to be much higher than in adults. There are also anecdotal reports of lamotrigine use in the treatment of chronic pain. Mechanism of Action Lamotrigine was originally synthesized as an antifolate compound. The drug has been shown to act at voltage-sensitive sodium channels to inhibit release of glutamate, which may explain its anticonvulsant effect.38 Pharmacokinetics Lamotrigine is well absorbed after oral dosing, with peak plasma concentrations occurring in 1.5 to 4 hours. Unlike gabapentin, lamotrigine shows a linear relationship between oral dose and plasma concentration. Lamotrigine is not highly protein bound and does not compete for binding sites with phenytoin, valproic acid, or other highly bound agents. The plasma half-life of lamotrigine in monotherapy is 25 hours.15 However, this is affected dramatically by coadministration of drugs that affect hepatic microsomal enzymes (Table II). In the presence of enzyme inducers, the half-life decreases to about 12 to 14 hours. With an enzymeinhibiting drug such as valproic acid, the half-life of lamotrigine increases to 60
M.K. BAZIL AND C.W. BAZIL
hours. Because lamotrigine does not affect hepatic enzymes and is not highly protein bound, there is no appreciable effect of lamotrigine on other drugs, with the possible exception of increased levels of the lO,ll-epoxide metabolite of carbamazepine.12 Adverse Effects
The adverse-effect profile of lamotrigine is generally favorable (Table III). The most common side effects include dizziness, headache, diplopia, unsteadiness, and double or blurred vision.15 Gastrointestinal side effects such as nausea are also common but are usually mild and self-limiting. Much attention has been given to the incidence of rash, which occurred in up to 10% of patients in the initial trials. In 3 of every 1000 patients, the rash was severe enough to require hospitalization. The occurrence of rash is increased with rapid dose escalation and with concomitant valproic acid administration.15 As a result, the current recommendation is to titrate the drug slowly, particularly in the presence of valproic acid. However, it should also be noted that most patients can be safely rechallenged after an initial mild rash. A trial of lamotrigine versus carbamazepine in monotherapy actually showed a higher incidence of rash with carbamazepine.15 Dosing
Lamotrigine is available in 25-, lOO-, 150-, and 200-mg scored tablets. To minimize the occurrence of rash, therapy is usually begun slowly and titrated over 6 weeks to the minimal effective dose. In patients taking valproic acid, the initial dose is 25 mg every other day, and the target dose is 50 mg BID. With enzymeinducing agents, the initial dose is 50 mg
QD with a target dose of 150 mg BID and, in monotherapy, 25 mg QD initially with a target dose of 100 mg BID. Topiramate
Topiramate is the newest treatment option for epilepsy. It is a structurally unique agent chemically related to the o-enantiomer of fructose. Topiramate has been approved as adjunctive therapy in adults with partial seizures.3941 Clinical trials investigating the use of topiramate as monotherapy in partial seizures and in other seizure types are in progress. Mechanism of Action
Topiramate’s mechanism of action is unknown, although, like felbamate, there are a number of possible relevant effects, including state-dependent blockade of voltage-activated sodium channels, enhanced GABA activity at GABA, receptors, and antagonism of non-NMDA glutamate receptors.42v43 Phrmacokinetics
Topiramate has a favorable pharmacokinetic profile with good bioavailability, a long half-life, and low protein binding (Table I). Because the drug is eliminated primarily via the kidney, dosage reductions are necessary in patients with renal impairment.13 Although the drug has a long half-life, BID dosing is often used to minimize adverse effects. Topiramate has no appreciable effect on other antiepileptic agents, but other antiepileptic agents can affect the clearance of topiramate (Table II). Adverse Effects
Topiramate is generally well tolerated. The major adverse effects appear to be 375
CLINICALTBERAPEUTICS’
CNS related and include cognitive impairment (eg, difficulty in word finding) and fatigue or somnolence. Other observed effects include dizziness, diplopia, nervousness, and confusion.16 Renal stones occurred in 1.5% of patients in the initial trial~‘~; this is a higher rate than expected in the general population and is consistent with the drug’s action as a mild carbonic anhydrase inhibitor.
Dosing Topiramate is available as 25-, loo-, and 200-mg tablets. Therapy is initiated at 50 mg daily and titrated to an effective dose of 200 to 400 mg/d, although up to 1000 mgld has been used.15
Fosphenytoin
Mechanism of Action
Fosphenytoin is a water-soluble prodrug of phenytoin. It is rapidly converted into phenytoin in vivo; thereafter, fosphenytoin’s properties are identical to those of phenytoin. A comparison of the properties of the two drugs is shown in Table IV.44*45The difference lies in fospheny-
Table IV. Comparison
toin’s improved flexibility and tolerability in dosing when compared with intravenous (Iv) phenytoin, which is dissolved in a solution of 40% propylene glycol and 10% ethanol at pH 12 because of its poor water solubility. Parenteral phenytoin requires slow lV infusion in glucose-free solutions to prevent precipitation of the phenytoin, with side effects of hypotension, bmdycardia, and thrombophlebitis caused by the vehicle itself. Phenytoin cannot be given intramuscularly (lM) because of poor absorption and the risk of abscess formation. To avoid these problems, the pro-drug fosphenytoin was developed. Fosphenytoin is indicated for the treatment of adults with partial or generalized seizures when parenteral administration is desired.
of fosphenytoin
Because fosphenytoin is rapidly and completely converted into phenytoin, its mechanism of action in the control of seizures-inhibition of voltage-sensitive sodium channels-is identical to that of phenytoin. Fosphenytoin has no known intrinsic activity before conversion.
and phenytoin. Fosphenytoin
Route of administration Maximum IV infusion rate Time to maximum serum level Adverse effects
IV solution compatibility
IVorIM 150 mg PE/min 20 min Paresthesias; pnuitus; dizziness; ataxia; hypotension; somnolence; nystagmus Dextrose or saline
IV = intravenous; IM = intramuscular; PE = phenytoiu equivalents. Data from Bebin and Sk&“ and Marchetti et a1.45
376
Phenytoin Iv
50 mg/min 20 ruin Infusion site pain, burning, and phlebitis; dizziness; ataxia; somnolence; hypotension; nystagmus Saline
M.K. BAZLL AND C.W. BAZIL
Phnnacokinetics
Fosphenytoin is rapidly converted into phenytoin (within 20 minutes) by phosphatases located throughout the body, with a mean half-life of 8.1 minutes.‘@This conversion appears to be independent of age, although children younger than 5 years have not been studied. For this reason, therapeutic serum levels of phenytoin are achieved at about the same time whether the drug is administered quickly, in its prodrug form (fosphenytoin), or slowly, as the drug itself. When compared with equivalent IV phenytoin doses, the bioavailability of fosphenytoin is approximately lOO%, whether administered IV or IM.44 Fosphenytoin, like phenytoin, is highly bound to plasma proteins, particularly albumin. In fact, fosphenytoin is more tightly bound and will displace phenytoin. Therefore, in a patient taking phenytoin, an infusion of fosphenytoin may cause a transient increase in the serumfree phenytoin level as a result of displacement. l2 As the fosphenytoin is converted into phenytoin, the ratio of bound phenytoin to free phenytoin will return to baseline. This is not typically clinically relevant, as the desired effect is increased phenytoin levels. Because the pro-drug is rapidly and completely converted into phenytoin, drug interactions will be identical to those of phenytoin. Adverse Effects The side-effect profile of fosphenytoin
is generally favorable compared with IV phenytoin. Adverse effects unique to fosphenytoin are paresthesias and pruritus, which frequently occur in the perineal region. These are similar to effects seen with IV infusion of other phosphate esters (eg, dexamethasone).46 Nystagmus, dizziness,
ataxia, hypotension, and somnolence occurred at a frequency about equal to that of phenytoin. Other side effects specifically associated with the infusion (eg, local burning, pain, and phlebitis) were seen much less frequently with IV fosphenytoin than with IV phenytoin. Dosing
Because fosphenytoin is supplied in phenytoin equivalents, calculations for equivalent dosing are not required. The molecular weight of fosphenytoin is 50% higher than that of phenytoin; therefore, a 50% increase in the milligram dose is necessary to achieve a dose equivalent to the phenytoin dose. Fosphenytoin may be administered IV or IM. One controversial issue is the decision of the manufacturer of fosphenytoin (Parke-Davis, Division of WarnerLambert Company, Morris Plains, New Jersey) to discontinue production of parenteral phenytoin. However, generic phenytoin is still available. As a result, the potential for confusion and improper administration exists if institutions choose to stock both parenteral phenytoin and fosphenytoin.
Sustained-Release Carbamazepine Carbamazepine is widely used in the treatment of generalized tonic-clonic seizures. One of the limitations of carbamazepine therapy is its relatively short half-life, requiring TID or QID dosing and adversely affecting compliance. Furthermore, plasma drug levels may fluctuate, resulting in the increased frequency of adverse effects and the inability to reach plasma levels adequate for optimal efficacy.47,48The introduction of a sustained311
CLINICALTI-IERAF’EUTICS”
Table V. Average wholesale price of new antiepileptic drugs. Dw
Cost of a 30-Day Supply ($)
Felbamate Gabapentin Lamotrigine Topiramate
62.73 88.88 49.68 147.60
Data from Redbook Upuhte.50”’
release formulation is an attempt to improve compliance and decrease adverse effects by decreasing the magnitude of the fluctuations in plasma drug levels. Carbamazepine sustained release decreased fluctuations in serum carbamazepine concentrations by 50% when compared with prompt-release carbamazepine and was associated with fewer adverse effects.12 Historically, a decrease from QlD or TlD to BID dosing has improved patient compliance.49 For conversion to sustained-release carbamazepine, the total daily dosage of immediaterelease carbamazepine is divided in two and given BlD. Sustained-release carbamazepine is supplied as lOO-, 200-, and 400-mg tablets. It is important to note that the sustained-release tablets must be swallowed whole to avoid disruption of the sustained-release mechanism, and patients should be advised that the empty shell will be excreted in the feces. DRUG LEVELS Although therapeutic levels have not been determined for the four new antiepileptic agents, monitoring of these plasma levels can be used to assess compliance. In addition, as doses are titrated up, the degree 378
of absorption of gabapentin can be evaluated by monitoring blood levels. COST Although the cost of the new antiepileptic drugs (Table V) must also be considered, cost-effectiveness and pharmacoeconomic issues-not merely acquisition cost-must be included in any decisions tegarding formulary inclusion, For example, increased compliance with BID sustainedrelease carbamazepine may lead to decreased adverse effects and improved efftcacy, which would greatly offset the difference in acquisition cost compared with generic carbamazepine. Furthermore, if the new antiepileptic agents allow improved clinical management of epilepsy patients, their overall costs may be lower than those of traditional therapies. Detailed pharmacoeconomic evaluations comparing all of the therapeutic options for epileptic patients would help resolve this issue. A 30-day supply of carbamazepine and sustained-release carbamazepine cost the same, whereas generic carbamazepine costs approximately 40% less.50s51A recent pharmacoeconomic comparison of phenytoin and fosphenytoin revealed an 11% cost savings with fosphenytoin. This
M.K. BAZIL AND C.W. BAZIL
cost savings was realized despite an acquisition cost of $6.72 per loading dose for phenytoin versus $90.00 for fosphenytoin. The reduction in cost was associated with fewer adverse effects with fosphenytoin.51 OTHER NEW AGENTS Several other novel anticonvulsant drugs have been submitted for final approval and may be released by late 1998; two of these drugs are vigabatrin* and tiagabine.7 Vigabatrin was synthesized as an inhibitor of GABA transaminase, and, in fact, its anticonvulsant effects result from this mechanism of action. Vigabatrin appears to be most effective in partial seizure disorders, although it is being used extensively for the treatment of infantile spasms. l2 Tiagabine is thought to enhance GABA-ergic neurotransmission via inhibition of uptake of GABA into cells.12 CONCLUSIONS The place each of these new agents will hold in the armamentarium against seizures has yet to be determined. It is important, however, that the novel anticonvulsant drugs represent a potential improvement for patients whose seizures are incompletely controlled by or who experience significant adverse effects from older anticonvulsant drugs. Felbamate, lamotrigine, and topiramate appear to have broad spectrums of action and may be particularly useful in the treat-
*Trademark: Sabril@ (Hoechst Marion Roussel, Kansas City, Missouri). TTrademark:Gabatril@(Abbott Laboratories, Abbott Park, Illinois).
ment of patients with generalized seizures who previously had few alternatives to valproic acid. However, felbamate use is limited by the potential for liver and bone marrow toxicity. Gabapentin has no known drug interactions, making it particularly useful in patients receiving concurrent medications. There is some evidence that lamotrigine may be better tolerated overall than the current firstline anticonvulsant, carbamazepine. However, the introduction of a sustainedrelease preparation of carbamazepine may decrease the incidence of adverse effects and increase patient compliance. Fosphenytoin offers a safer method for IV administration of phenytoin and the added flexibility of IM administration. As more is learned about the use and long-term efficacy of these and other new drugs, the hope is that they can meet the goal of improved quality of life for patients with epilepsy. Address correspondence to: Michelle K. Bazil, RPh, PhD, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 Dekalb Avenue, Brooklyn, NY 11201. REFERENCES Shorvon SD. Epidemiology, classification, natural history, and genetics of epilepsy. Luncet. 1990;336:93-96. Hauser WA, Kurland LY. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia. 1975;16: l-66. Dreifuss FE. New antiepileptic drug development. Epilepsia. 1994;35(Suppl 5): s6-S9.
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